Bronchiectasis in pediatric age is a heterogeneous disease associated with significant morbidity.The most common medical conditions leading to bronchial damage are previous pneumonia and recurrent lower airway infections followed by underlying diseases such as immune-deficiencies, congenital airway defects, recurrent aspirations and mucociliary clearance disorders.The most frequent symptom is chronic wet cough. The introduction of high-resolution computed tomography (HRCT) has improved the time of diagnosis allowing earlier treatment.However, the term “bronchiectasis” in pediatric age should be used with caution, since some lesions highlighted with HRCT may improve or regress. The use of chest magnetic resonance imaging (MRI) as a radiation-free technique for the assessment and follow-up of lung abnormalities in non-Cystic Fibrosis chronic lung disease is promising.Non-Cystic Fibrosis Bronchiectasis management needs a multi-disciplinary team. Antibiotics and airway clearance techniques (ACT) represent the pillars of treatment even though guidelines in children are lacking. The Azithromycin thanks to its antinflammatory and direct antimicrobial effect could be a new strategy to prevent exacerbations. Non-cystic fibrosis bronchiectasis (NCFB) is a chronic pulmonary disease characterized by a progressive and often irreversible bronchial dilatation, caused by structural changes in the bronchial wall and chronic airway inflammation.The actual incidence is unknown but the prevalence has increased in developing countries and among lowest socioeconomic classes where the disease often shows an infectious etiology.The highest NCFB prevalence is among children of indigenous populations, such as Australian aborigines, New Zealand Maoris, Alaskan natives and Pacific Islander children .In this respect, two New Zealand studies over the period 1998–2002, one reporting national cases of chronic suppurative lung disease (CSLD) and other CSLD hospital admissions in Auckland, showed a considerable disproportion between the average annual incidence among Maori and Pacific Islander children  compared to European children . This difference seems to be directly related to the poor condition in which these populations live. The incidence among European populations is estimated to be around 0.2 / 100,000 in UK and 2,3/100,000 in Ireland .Tabl.Tabl6].TChildren with Protracted Bacterial Bronchitis (PBB) exhibit a condition of persistent endobronchial infection and neutrophilic inflammation, known risk factors for the onset of NCFB. These factors have led to the hypothesis according to which the PBB and NCFB represent different stages of a single disorder .Patients with PCD have a congenital abnormality of ciliary function that causes impairment of mucociliary clearance and chronic respiratory tract infections often beginning in the first years of life. A history of neonatal respiratory distress without prematurity and recurrent middle ear problems are both very evocative of diagnosis; chronic rhino-sinusitis and bronchiectasis may be observed among older children .Bronchiectasis can also complicate primary and secondary immune-deficiencies. Defective immune function is associated with repeated, chronic and severe lung infections leading to recurrent episodes of airways inflammation, repair and ultimately structural damage.Most frequent immune disorders include defective production or function of all immunoglobulin classes, individual classes or subclasses and defects of specific antibody production such as bacterial capsular polysaccharide .Aspiration of gastrointestinal contents has been proved as a cause of bronchiectasis in both children and adults even though there are no case control studies of gastro-esophageal reflux as a risk factor for bronchiectasis in children . ConversNCFB in children usually exhibits chronic respiratory symptoms.Chronic wet cough is the commonest finding and may be present for many years before reaching a diagnosis. The likelihood of bronchiectasis increases if these symptoms are accompanied by exertional dyspnea, recurrent infections of the lower airways, hemoptysis and chest wall deformities . RecurreRepeated episodes of pulmonary exacerbations are also associated with progressive decline in lung function and reduced quality of life.At present, there is no validated definitions of “exacerbation” in children with NCFB. Exacerbation criteria used in adults  are less useful in children who are often unable to expectorate .In a recent retrospective study involving 115 children with NCFB, Kapur et al. highlighted that an increase in cough frequency and modifications in its features, an increase of auscultation findings of crepitations and wheezing were useful clinical indicators of exacerbation .Infections are common cause of exacerbations whose triggers can be either respiratory viruses or bacteria, hence an accurate etiological diagnosis might reduce the use of antibiotic therapy and the risk of resistance .No standardized method for classifying bronchiectasis has been defined in pediatric age, even though clinical, radiological and microbiological findings are usually used to quantify the disease severity .A radiological diagnosis of bronchiectasis in the child should be done with caution since a radiological regression of lesions has been observed after treatment , 17. CheHigh-resolution computerized tomography (HRCT) is the gold standard for the diagnosis of NCFB. The commonest HRCT findings include bronchial dilatation, bronchial wall thickening, lack of normal bronchial tapering, any bronchi with an internal diameter greater than the diameter of the accompanying pulmonary artery (signet ring sign) and bronchi visible closer than two centimeters to the pleural surface Table . In chilMosaic perfusion defects and air trapping on expiration can also be observed.Although a tendency to certain distributions has been described in groups of patients with specific conditions, the localization and pattern of abnormalities on HRCT is not necessarily linked to the etiology , 20.Several radiographic scores such as Bhalla, Nathanson, Reiff, and Webb’s scores, use combination of CT findings as markers of disease extension and severity –24.Bhalla score is a commonly accepted score for children. It includes several items such as:a) severity of bronchiectasis; b) peribronchial thickening; c) extent of bronchiectasis (number of lung segments); d) extent of mucus plugs; e) abscesses or sacculations; f) generalities of the bronchial division involved (bronchiectasis/plug); g) number of bubbles; h) emphysema (number of lung segments); i) collapse/consolidation , 25.According to Goyal and colleagues, HRCT should be considered in every child with a chronic wet cough persisting after 4 week of oral antibiotics . NeverthIn recent years, chest magnetic resonance imaging (MRI) has been proposed as a radiation-free technique for the assessment and follow-up of several chest disorders.Montella et coll. in a recent prospective study have shown that high-field 3.0-T MRI had a good correlation with HRCT in identifying bronchiectasis and the commonest alterations related to non-CF lung disease  , 27.Similarly, Maglione et al. in their recent comparative study of PCD and FC highlighted an excellent agreement between MRI and CT for most abnormality parameters in both diseases .Moreover, for some findings such as mucus plugging, MRI may be more helpful and informative than HRCT, thanks to the high protonic density of mucous, which is more easily distinguished from bronchial wall thickening. Consequently, MRI may be more sensitive in detecting early airway wall changes and mucus retention that may precede more serious structural damage in the larger airways.In addition, MRI may identify some functional aspects of lung tissue such as lung perfusion or ventilation and since it does not expose the patient to ionizing radiation, it may be particularly useful in the long-term monitoring of lung diseases . NeverthSpirometry can be useful to give additional and functional information on disease severity in older children and can reveal either an obstructive or mixed obstructive/restrictive airflow pattern.Several evidences indicate that reduced FEV1 is associated with more severe disease and severity of structural abnormality highlighted with HRCT, but it does not always correlate with the clinical course and it has a poor sensitivity in detecting exacerbations .Furthermore, spirometry performed during radiological examinations (chest CT and MRI) can improve image quality and the detection of bronchiectasis so it is useful in order to standardize lung volumes .Other tests such as measurement of static lung volumes and the 6-min walk test may be used to assess functional impairment. Exercise testing may be more informative than static spirometry in assessment of lung function, especially in patients whose performance or symptoms do not correlate with spirometric findings .In the last years, there has been a growing interest in the multiple breath inert gas washout (MBW), a technique used to quantify ventilation heterogeneity, which is considered an early sign of chronic obstructive lung diseases such as asthma and cystic fibrosis. Airway narrowing due to mucus retention, inflammation and airway wall structural damage causes inhomogeneity of lung ventilation. This inhomogeneity compromises the gas mixing efficiency of the lung and can be measured by following the washout of an inert gas during tidal breathing. In particular, lung clearance index (LCI) is a measure of lung physiology derived from multiple breath washout tests and is defined as the cumulative expired volume (CEV) at the point where end-tidal inert gas concentration has fallen to 1/40th of the starting concentration, divided by the functional residual capacity (FRC).Moreover, since only tidal breathing is required, LCI is simple and reproducible hence it is ideal for use in children .Recently, some study have showed that in non-CF bronchiectasis LCI correlates with CT severity score and with spirometric markers of airway obstruction. In addition, these parameters are abnormally increased in a significant percentage of non-CF bronchiectasis patients with a normal FEV1. These findings suggest that LCI may be a potential marker of disease severity and a useful index of airflow obstruction, although further studies are required to validate this hypothesis .Bronchoscopy is helpful to identify underlying structural anomalies and to obtain lower airway secretions in children unable to expectorate . A retroFinally, bronchiectasis may be considered as the result of an altered balance between degradation and deposition of the extracellular matrix resulting from a modification of the relationship between metalloproteases and their tissue inhibitors. For these reason, the detection of metalloproteases (MMP-9) in exhaled breath condensate could be a useful marker of airway injury in patients with NCFB .Table 2MNCFB requires multidisciplinary management in order to control symptoms, reduce exacerbations and preserve lung function.Although only one organ is concerned, the disease can be complicated by a reduction in statural weight gain and poor overall quality of life.Redding and coll. in a prospective study monitoring 93 children with NCFB for 3 years, reported that more than two exacerbations occurred in the majority of cases (74%) and a complete medical care was associated with a reduction of exacerbation rate .Antibiotics and airway clearance techniques (ACTs) represent the milestones of NCFB management although the guidelines in children are only a few Fig. .Fig. 2MaHaemophilus influenzae, Streptococcus pneumonia, Moraxella catarrhalis and Staphylococcus aureus. Pseudomonas aeruginosa is rarely found in the childhood and it is more often detected in older children or associated with underlying diseases with increased lung damage [Antibiotics should be used in the treatment of acute exacerbation or as prophylaxis treatment to reduce the frequency of acute events. The use and choice of antibiotics should be guided by exacerbations severity, airway microbiology results (sputum culture) and whenever possible by BAL culture. The most commonly isolated bacteria in children are non-encapsulate g damage , 40. Nong damage .In our opinion, bacteria involved in exacerbations should always be identified in order to use a targeted antibiotic therapy that minimizes the future risk of resistance.Sputum sample culture or nasopharyngeal aspirates (in children who are unable to expectorate) should be obtained before starting antibiotics. A pharyngeal swab after coughing may be a surrogate of the lower respiratory tract pathogens in very young children and it is sometimes preferred in some older children .To date, despite the advances in the management of many pediatric diseases antibiotic therapy remains one of the most effective tool for the treatment of pediatric NCFB.Prolonged cycles of antibiotics (very often more than 4 weeks) are often necessary to eradicate some respiratory pathogens responsible for exacerbation .A recent review involving 15 studies (925 participants), showed a significantly reduction in the rate of exacerbations and hospitalization in children and adults with NCFB who had been treated with prolonged antibiotics (four or more weeks). However, the risk of emerging drug resistance was increased more than threefold, therefore an accurate patient selection is essential .Unfortunately, there are currently no randomized controlled trials (RCTs) evaluating the efficacy of inhaled antibiotics in children with NCFB, even though this option in adult patients has been largely used and showed several benefits. The rationale for using inhaled antibiotics in lung diseases lies in the possibility to administer a relatively high dose of drugs directly to the site of disease reducing systemic absorption and related toxicity.A systematic review conducted by Brodt et al. comprising 12 trials with 1264 adults with clinically stable NCFB and chronic bronchial infection, showed that inhaled antibiotics were more effective than placebo in reducing sputum bacterial load and the risk of acute exacerbations .According to current BTS guidelines, nebulized antibiotics should be considered in children who experience recurrent exacerbations (or deteriorating lesions) unaffected by prolonged oral antibiotic or if colonized with Pseudomonas Aeruginosa .Nebulized gentamicin in children with NCFB seems to be well tolerated and produce satisfactory drug level in the sputum. Nebulized tobramycin was mainly used in children with CF and demonstrated good efficacy in reducing the concentration of Pseudomonas and improving the FEV1 . HoweverIn the recent years, there is an increased interest in the use of macrolides for the treatment of NCFB, mainly due to their antinflammatory effects and their well-established direct antimicrobial effect on Gram-positive cocci and atypical pathogens but also for the properties to decrease mucus production.Two meta-analyses that included seven studies evaluating various macrolides  reported a significant reduction in the frequency of exacerbations compared with placebo , 43.Similarly, the EMBRACE trial (Effectiveness of Macrolides in patients with Bronchiectasis using Azithromycin to Control Exacerbations) involving three centers in New Zealand, showed that the use of Azithromycin three times a week for 6 months in adult patients with NCFB has resulted in a significant reduction in event-based exacerbations and increase of the time of the first event-based exacerbation compared with placebo .P. aeruginosa. These evidences suggest that chronic macrolide therapy should be used with caution in subjects with NCFB but without P. aeruginosa infection [Despite these encouraging evidences, the risk of drug resistances should not be underestimated. In that regard, in BLESS study (Bronchiectasis and Low-dose Erythromycin Study) Rogers and colleagues reported changes in microbiota composition of patients with NCFB (determined by 16S rRNA gene sequencing of sputum samples from 86 participants) after 48 weeks of low-dose erythromycin. Moreover, long-term erythromycin treatment seems to induce replacement of H. influenzae with more macrolide-tolerant pathogens such as Airway clearance techniques (ACTs) are usually recommended in children with bronchiectasis even though evidences supporting this practice are lacking and mainly derives from study on Cystic Fibrosis.In the childhood, the family compliance may significantly influence the adherence to ACT and the non-adherence is the primary cause of treatment failure in chronic pediatric lung conditions. Other factors to consider when choosing ACT are child’s age, level of collaboration and maturity.Lee et colleagues showed that ACTs seemed to be safe for adults and children with stable bronchiectasis leading to improvements in sputum expectoration, selected measures of lung function, patient symptoms and HRQoL  .Different types of ACTs include: active cycle of breathing techniques, autogenic drainage, forced expiration techniques, postural drainage, oscillating positive expiratory pressure, high-frequency chest wall oscillation, and physical exercise. This latter is highly recommended for all ages in the management of bronchiectasis and chronic suppurative lung disease.Furthermore, the application of positive expiratory devices and high-frequency chest wall oscillation showed an improvement of FEV1 as indices of lung function. However, all the studies were conducted in individuals in a stable clinical state, so the effects of these techniques during an acute exacerbation remain unclear and further studies are necessary, especially in children , 51.Finally, the use of both beta2 agonists and hypertonic solutions before performing airway clearance techniques are all considered useful strategies for improving clearance of bronchial secretions in NCFB.The mucolytic agents could theoretically be useful in the management of bronchiectasis due to their ability to reduce the viscosity of the mucus and thus make it easier to expectorate. Among these drugs, recombinant human DNase, acts in degrading DNA released by neutrophils in the infection site.A recent Cochrane review involved four trials with 528 adult participants, concluded that little evidence is available to recommend the routine use of mucolytic agents in bronchiectasis [In 2015 Welsh et al. in an “overview of Cochrane systematic reviews” regarding the various treatments currently available for non-cystic fibrosis bronchiectasis, reported that RhDNase seems to be associated with an increase in exacerbations, although three reviews only involved pediatric population.Current BTS guidelines conclude that due to a potential worsening of pulmonary function, RhDNase should not be used in management of bronchiectasis in pediatric patients .Two reviews reported beneficial effects for other agents such as hypertonic saline (exacerbations), erdosteine (FEV1) and mannitol (QoL) .About this last one, a recent RCT showed that the use of mannitol 400 mg inhaled twice daily for 12 months in adult patients with bronchiectasis seems to improve the quality of life and increase the time to the first exacerbation even though it did not reduce exacerbation rates , 55.The role of hypertonic saline in the management of NCFB is still debated. Although the recent Cochrane systematic reviews of Welsh et al. concluded that there is inconclusive evidence on the use of nebulized hypertonic for reducing exacerbation, several studies suggested that in concentrations of 3–14%, hypertonic saline could improve tracheobronchial clearance.A probable mechanism of action consists in the reduction of sputum viscosity by inducing liquid flux from the epithelium into the mucus so that the mucus is cleared more easily by the cilia.Kellet and coll. Demonstrated that nebulized hypertonic saline significantly reduced sputum viscosity and can be used safely and effectively as an adjunct to physiotherapy in patients with stable bronchiectasis , 57.Several studies have reported the presence of a certain degree of bronchial hyper-responsiveness and chronic airflow bronchial obstruction in subjects with bronchiectasis. For this reason, inhaled corticosteroids (ICS) therapy may potentially improve several bronchial inflammatory parameters and clinical symptoms, even though high doses with increased risk of side effects are often required .The use of combined therapy with long-acting beta2-agonist (LABA) and ICS administered together in a single device showed a synergistic effect in decreasing bronchial inflammation.A Cochrane’s systematic reviews of all randomized controlled trials on the use of combined ICS and LABA compared to a control  in children and adults with bronchiectasis, concluded that in adults combined therapy was partially more effective than high-dose ICS in improving some clinical symptoms like cough free-day and dyspnea. However, no significant improvement in the rate of hospitalization and no change in lung function indices have emerged. Moreover, no data are provided in children with bronchiectasis in a stable or acute state .A single-center observational study performed by Wei et al. involving 120 adult patients with NCFB, reported that subjects who received salmeterol-fluticasone combined therapy versus routine therapy showed significant improvement in HRQoL and rates of exacerbations, without risk of severe adverse events .Previously, Martinez-Garcia also reported in a 12-month randomized and double-blind trial including 40 patients with NCFB, that inhaled medium-dose of formoterol-budesonide combined therapy was more effective and safe compared with high-dose of budesonide in improving clinical symptoms such as dyspnea, cough and wheeze .Despite these encouraging findings, there is a lack of safety data about the combined ICS/LABA therapy in children, therefore more robust evidence is needed to recommend its routinely use in NCFB.Finally, surgical treatment such as segmentectomy and lobectomy may be reserved for patients with localized bronchiectasis with persistent symptoms, recurrent infections despite maximal therapy and hemoptysis. Nevertheless, further studies are needed before surgery can be recommended as a safe treatment for NCFB. Factors that seem to be relative contraindications for surgical resection of bronchiectasis include non-cylindrical disease, persistent infection of Pseudomonas documented by sputum culture, residual disease after resection and non-localized disease –65.NCFB is an emerging pediatric disease whose prevalence is probably underestimated worldwide.The most common causes include infections, immunodeficiency, recurrent aspiration and primary ciliary dyskinesia. An early diagnosis is essential to prevent a progressive decline in lung function and recurring exacerbations that are inevitably associated to a poorer quality of life.An etiological diagnosis is also essential in order to improve the course of the disease by using specific therapy  Fig. .The use of HRCT represents the gold standard to confirm the diagnosis although magnetic resonance imaging (MRI) could be a promising radiation-free technique to identify NCFB and to follow its evolution over time.Actually, the pillars of treatment are represented by targeted antibiotic therapy in combination with airway clearance techniques. Prolonged antibiotics are often necessary to decrease the bacterial load, therefore the risk of emerging drug resistances should not be overlooked. Inhaled antibiotics, inhaled hypertonic and inhaled mannitol can be useful instruments in improving the quality of life.Finally, Azithromycin and other macrolides seem to reduce the frequency of event-based exacerbations compared with placebo, therefore it may be a precious option in NCFB management.


Precision medicine attempts to device novel individual cancer therapy strategies. Using bioinformatics, relevant knowledge is extracted from huge data amounts. However, tumor heterogeneity challenges chemotherapy due to genetically and phenotypically different cell subpopulations, which may lead to refractory tumors. Natural products always served as vital resources for cancer therapy  and are also sources for novel drugs. Targeted drugs developed to specifically address tumor-related proteins represent the basis of precision medicine. Natural products from plants represent excellent resource for targeted therapies. Phytochemicals and herbal mixtures act multi-specifically, i.e. they attack multiple targets at the same time. Network pharmacology facilitates the identification of the complexity of pharmacogenomic networks and new signaling networks that are distorted in tumors. In the present review, we give a conceptual overview, how the problem of drug resistance may be approached by integrating phytochemicals and phytotherapy into academic western medicine. Modern technology platforms  can be applied for diverse treatment modalities such as cytotoxic and targeted chemotherapy as well as phytochemicals and phytotherapy. Thereby, these technologies represent an integrative momentum to merge the best of two worlds: clinical oncology and traditional medicine. In conclusion, the integration of phytochemicals and phytotherapy into cancer precision medicine represents a valuable asset to chemically synthesized chemicals and therapeutic antibodies.Concepts of individualized therapy in the 1970s and 1980s attempted to develop predictive  Resistance to anticancer drugs already appeared in the very early days of cancer chemotherapy more than half a century ago –6, and ia priori, whether or not an individual tumor would respond to drug therapy and to adapt treatment according to the individual drug sensitivity profile of tumors [e.g., HER2- or estrogen-receptor-targeting small molecules or therapeutic antibodies) may be straightforward, the reliable prediction of treatment efficacy for the clinically long established cytotoxic drugs is much more complicated, since their cellular targets frequently less well-defined and these kinds of cytostatic drugs reveal broader modes of action against malignant and even normal proliferating cells.Current chemotherapy protocols are based on the result of prospective, randomized, double-blind phase III studies, which results in similar clinical standard treatment guidelines. However, each tumor may behave in a different manner and the treatment success of individual patients still cannot be reliably predicted, although the statistical probability of treatment response for larger groups of patients can be estimated from the results of clinical trials. The reason is that even tumors of the same origin and histology may differ from patient to patient in their biological behaviour. Even more, cells of the same tumor may be different from each there, and there is a substantial heterogeneity which greatly influences the response of tumor cell subpopulations to chemotherapy. While some subpopulations respond well to treatment, others resist and give rise to treatment failure. The appearance of drug resistance is a major, still unresolved obstacle in cancer therapy even after many decades of enormous efforts in cancer research. It has therefore been attempted to understand the molecular mechanisms of drug resistance and to predict f tumors . Wherease.g. “-omics” technologies, DNA/RNA sequencing, and network pharmacology) can be applied for diverse treatment modalities such as cytotoxic and targeted chemotherapy as well as phytochemicals and phytotherapy  comprising meta-analyses on DNA sequencing results and related implications for drug development, and (2) the availability of individual targeted agents and biomarkers for therapy monitoring [A crucial decision in individualized therapy is not only the choice of the right drug for the right patient, but also the right combination of drugs and the duration and dose of treatment. Because of the complexity of tumor genomes, this may be difficult to dissect with the classical methodology of clinical trials. As a direct consequence of the deciphering of the human genome at the verge from the second to the third millennium, techniques have been developed that allow to determine (1) genomic variations such as single nucleotide polymorphisms (SNPs) , copy nunitoring . A multinitoring .The challenge of this new concept of precision medicine will be to delineate individual and efficient cancer therapy strategies, which are superior to traditional concepts of standardized tumor treatment. Enormous amounts of “-omics” data together with drug combination studies and biological network data analyses are required, since tumors consist of heterogeneous subpopulations with distinct biological features , 22. A pAdvancements in molecular diagnostics is only one side of the coin, and the development of novel drugs has to keep pace, which may be an even more difficult task to master. Drug development and marketing is a time- and cost-intensive process and the number of newly approved drugs declined for decades, mainly because of their failure in clinical phase 2 trials, despite the fact that time and expenditure on drug research and development (R&D) consistently increased during recent years , 25. TheIn this context, a surprising concept emerged . Existine.g. by laser-capture microdissection or fluorescence-activated cell sorting), (2) whole genome amplification (e.g. with the help of Phi29 DNA polymerase), and (3) transcriptome-wide next generation sequencing technologies. The problem of tumor heterogeneity especially applies to drug resistance. Single cell sequencing will facilitate the detection of even the smallest populations of drug-resistant cells. Thereby, single-cell sequencing and may form the basis for novel and improved treatment options to eradicate drug-resistant tumor cells with specific genetic alterations [Cancers of the same histological type do not only differ from patient to patient, but also consist of heterogeneous subpopulations of cells within one and the same tumor. Heterogeneity represents a considerable challenge to cancer chemotherapy, since it aggravates the effective eradication of all cells of genetically and phenotypically different subpopulations. Even few surviving tumor cells may lead to repopulation and refractory tumors. Single-cell sequencing allows novel insights into the diversified and complex molecular architecture of heterogeneous tumors. The isolation and sequencing of single tumor cells are technically very challenging and consists of three major steps: (1) single cell isolation  experience a thriving revival [Although medicinal herbs belonged to the standard repertoire to combat diseases since ages, they gradually lost relevance with increasing successes of synthetic pharmaceuticals in western countries during the 20 revival –36.Secondary metabolites are synthesized by plants as a defense against competitors, herbivores and pathogens and as signal compounds that attract insects for reproduction. Repelling predators is crucial for plants since they do not have elaborated immunological defense mechanisms nor can they flew, because they are sessile. Secondary metabolites maintain crucial functions for survival and reproductive fitness of plants , 38. In Artemisia annua L. for malaria therapy represents and appreciation for the entire scientific community working on phytotherapy and natural products [The conferment of the Nobel Award for Physiology or Medicine 2015 was Youyou Tu and her life-time achievements on artemisinin from the Chinese medicinal plant, products . TherefoResearch and development on artemisinin as malaria medication followed the rules and strategies of classical pharmacological drug, but not those of the development of a typical phytotherapeutic drug. The process ended with a chemical substance rather than with a standardized herbal product. The same applies for many other drugs which became established parts of modern pharmacopoeias. A majority of modern drugs, which are derived in one or the other way from natural sources were only inspired by nature , but notAs a matter of fact, traditional medicine is being applied million times on this globe, and therefore the general conditions are basically different from those of synthetic chemical drugs. This may be an advantage, but represents a disadvantage at the same time, because there is less burning economic pressure to fulfil the strict regulations of the drug-approval authorities. If a herbal preparation is not marketed as drug by a pharmaceutical company, it can be either sold over the counter as dietary supplement without fulfilling any quality control measures, or it can be used as therapeutic drug for individual compassionate uses. These practices demonstrate that herbal medicines are popular among patients, but they frequently do not provide sufficient evidence that they are safe and efficient.As popular herbal medicines are among physicians, practitioners and patients all over Asia, as critical they are considered among the medical community in the West. Several reasons can be discussed to explain this contradiction. One problem is certainly that herbal medicine does not belong to the standard repertoire of knowledge that is taught in our medical schools to the students. This is a fatal situation to our point of view. Another critical issue is, however, that the safety and quality of herbal products has still not been proven to the same extent, as it is routinely done for synthetic drugs.The medical use of plants by traditional healers is frequently accompanied by spiritual and magical rituals. While these practices are doubtless of interest to cultural anthropology, rationale phytotherapy should focus solely on seeking scientific evidence for the pharmacological activity of medicinal plants. On the other hand, the demystification and “secularization” of medicinal plants also applies to industrialized countries, where “green medicine” is sometimes associated with esoteric elements.- ethnobotany: documentation of traditional knowledge;- botanical verification of medicinal herbs ;- standardization of herbal products and mixtures;- avoidance of contaminations and adulterations;- elucidation of molecular and cellular modes of action;- placebo-controlled, double-blind and randomized clinical trials.If we consider phytotherapy as a regular discipline of life science, which rules and methods should be applied to do so? Crucial elements of quality control include - ethnobe.g. the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA), both of which enforce regulatory sets of specifications including the quality, purity standards, dosage, production, precautions, storage, and labeling of these medicines [To guarantee the marketing of safe and efficacious herbal products, national and international authorities regulate the approval of these medicines, edicines . Monograi.e. bioprospecting). Since the use of medicinal plants is mainly based on the traditional knowledge of indigenous communities, commercialization of herbal products by pharmaceutical industries should, follow fair rules of benefit-sharing with those, where the knowledge comes from. Biopiracy practices by multinational companies in the past should be banned [th 2014. It entered into force on October 12th 2014. Main principles are (1) informed consent of the country of origin of the resource and (2) mutually agreed terms between indigenous peoples and collaborative commercial partners.A main goal of the utilization of these diverse genetic resources is to market herbal products . Other genetic aberrations occur in the course of tumor progression as a consequence of genomic instability of tumors. They do not have a major impact on the malignancy of cancer (passenger genes). Targeted drugs developed to specifically address proteins encoded by driver genes represent the basis for individualized or precision medicine. Instead of standardized therapy regimens for all patients suffering from the same tumor type, targeted drugs can be individually used depending on the specific expression of aberrant targets in each single patient. Two main categories of targeted drugs have been developed: (1) monoclonal antibodies that address cell-surface proteins. Examples are cetuximab and panitumumab against the epidermal growth factor receptor (EGFR), bevacizumab against vascular endothelial growth factor (VEGF) and rituximab against CD20. (2) Small chemical molecules that easily can enter tumor cells to attack intracellular targets (e.g. cancer-related kinases). Imatinib mesylate is a showcase example of historical relevance for the proof-of-principle of the entire concept of targeted therapy. This drug binds and inhibits the oncogenic BCR/ABL fusion protein. Other small molecules are erlotinib and gefitinib against EGFR, vemurafenib against BRAF and bortezomib against the proteasome.The problem with classical standard chemotherapy is that drugs do not sufficiently distinguish between normal and malignant growing cells. As long as cells are dividing, they are attacked by the drugs. A new concept is to seek for molecular differences between normal and cancerous cells and specifically attack cancer-related targets by drugs. Targeted drugs are designed to kill cancer cells by their binding to the target. Since this target is not present in normal cells, targeted cells are expected not to exert side effects on normal organs. Sophisticated techniques are used to identify targets for cancer therapy such as “-omics” technologies, cytogenetic methods, etc. Frequently, tumor cells bear amplified genes leading to protein overexpression are not present in normal cells. Also, chromosomal translocations may generate fusion genes coding for novel fusion proteins that are not existing in healthy cells. Some of these aberrantly expressed genes drive the development of cancer if they contain oncogenic sequences , single nucleotide polymorphisms, cell cycle arrest, use of alternative signalling pathways or antigen shedding may cause ineffectiveness of treatment [(1) Tumors frequently develop resistance against targeted drugs. Alterations in the target structure  Unexpectedly, targeted drugs also reveal side effects in normal organs. Although the targets that are addressed by these drugs are not present in normal cells, there are nevertheless other non-specific off-target effects. Known side effects of targeted therapies include hepatotoxicity, dermatotoxicity , hypertension Natural products from plants and other natural origin provide an excellent resource for targeted therapies –51.(1) The number of targets for therapeutic intervention is still increasing and novel drugs for novel targets need to be developed. Natural products may serve as lead compounds that can be chemically modified to generate derivatives with improved pharmacological properties.(2) Natural products that overcome drug resistance. An example is the multidrug resistance (MDR) phenotype. Drug efflux pumps of the ATP-binding cassette (ABC) transporter family confer resistance to a broad spectrum of anticancer drugs including man targeted small molecules . The lige.g. PHY906) [(3) The severe side effects of classical cytotoxic (non-targeted) as well as of targeted therapy may be alleviated or abolished by natural products and medicinal plants ( PHY906) –57.To illustrate the potential of natural products for targeted therapy, we have chosen STAT3. An important molecule in signal transduction processes of tumors represents signal transducer and activator of transcription 3 (STAT3). Upon binding of specific ligands  to their receptors, receptor-associated Janus kinases (JAK) are activated, which in turn activate STAT3. After phosphorylation of STAT3 at tyrosine at position 705, STAT3 dimerizes and translocates to the nucleus, where it binds to the DNA Figure . As tranConstitutively activated STAT3 promotes carcinogenesis and STAT3 overexpression has been reported in many tumor types , 59. Recetc.) inhibit downstream signalling including the STAT3 pathway. The same is true for JAK 1/2, which are upstream of STAT3.(1) Inhibitors acting upstream of STAT3: Tyrosine-kinase inhibitors of cell surface receptors  STAT3 inhibitors that disrupt dimerization at the SH2 domain. The SH2 domain of STAT3 consists of the tyrosine-phosphorylation site at Tyr705 and two closely neighbored binding sub-pockets. Most STAT3 inhibitors bind to the SH2 domain .(3) Inhibitors of the STAT3 DNA binding domain. The sterical hindrance by small molecules to bind to DNA inhibits the transcription factor activity of STAT3.2 domain of the protein , microadrug target disease’ network models using high-throughput screening and bioinformatics. Such approaches help to investigate underlying mechanisms of drug actions on biological networks by comparing the action of a drug with its target [As a consequence of the complexity of drug actions, another new concept is emerging called polypharmacology, which focuses on drugs attacking multiple instead of single targets to perturb disease-associated networks , 66. To s target .Cancer is a complex disease arising from changes in multiple biological networks , which iTo be highly effective, interventions within biological networks should be multiple on the one hand, but extremely selective on the other hand to spare normal organs from detrimental side effects . HolistiThere are various sophisticated signaling networks driving tumorigenesis and tumor progression that can be therapeutically targeted. Instead of initial time-consuming laboratory experiments, network biology approaches for well-known pathways with various drugs might be more suitable for timely cancer drug discovery .Network pharmacology facilitates the identification of new signaling networks that are distorted in various cancer types. Recently, Jaeger et al. discovered several known but unexpected as well as unknown pathways in triple negative breast cancer  and in oIn the past few years, numerous novel signaling networks have been unraveled that contribute to carcinogenesis and tumor progression. It becomes more and more clear that the complex nature of alterations in cancer cells can hardly be attacked by drugs addressing single targets or pathways. Comprising, novel therapeutic strategies have to be devised that are able to inhibit entire malignancy-regulating networks. It is hoped that network pharmacology provides a platform for the development of a novel generation of drugs fulfilling this requirement.Network pharmacology became a powerful tool to systematically reveal complex biological relationships. In cancer and other diseases, network pharmacology relies on “-omics” approaches to detect the variables at fundamental cellular and molecular units in response to the specific pathophysiology and/or drug treatment. The generated dataset of variables helps to generate networks from the genomic up to the metabolomic level to classify molecular processes in disease conditions. The high availability of multi-omics cancer databases opens new opportunities for data integration that promises an in-depth understanding of cancer and clinically and biologically meaningful tumor stratification .The “-omics” technologies allow to measure not only well-known signaling pathways and biological networks in its entirety, but also to detect novel pathways and mechanisms that have not been described before in a given experimental context. Another considerable advantage is that cellular alterations caused by even highly complex herbal mixtures can be measured. Frequently, the holistic approach of herbal medicine cannot be satisfactorily investigated by the reductionistic methods of western science. Novel methods of network pharmacology may offer new solutions for holistic approaches.e.g. transcriptomics or proteomics) do not allow to draw conclusions about the functional state of proteins (e.g. their phosphorylation state). This emphasizes the necessity to validate pathways identified by expression analyses by additional experiments.On the other hand, some disadvantages have to be considered. With huge amounts of generated data, it may be difficult to distinguish causative mechanisms from irrelevant “background noise”. Additional verification experiments are indispensable to substantiate the results obtained from “-omics” technologies. In the past, time and concentration kinetic experiments have rarely been performed in network pharmacology, because of the high costs. This bears the danger that optimal time points and drug concentrations to measure a pharmacological effect may be missed. With decreasing prices and further technology developments, this disadvantage might be overcome. Another general disadvantage is that expression analyses  Plants or herbal mixtures can be considered, if their bioactive chemical constituents are known. This approach is based on their use in traditional medicines and is largely experience-based. In a way, herbal mixtures are comparable to multidrug combination therapy with synthetic drugs and polypharmacology .(2) Multi-target specific therapy may also be reached with single phytochemicals with selective polypharmacological approaches , 94. The(3) Recent concepts in network pharmacology emphasize the potential of synthetic lethality . ProteinQi-enriching and blood-tonifying herbs in TCM [A network pharmacology approach for green tea polyphenolics revealed their multiple bioactivities towards various diseases including cancer. A total of 200 human targets were identified. This study illustrated the mechanisms of pleiotropic activity of green tea polyphenolics towards cancer, diabetes, neurodegenerative disease, cardiovascular disease, muscular disease, and inflammation . Recentls in TCM .Network pharmacology may also help to better understand the reasons for failure of drugs in clinical trials regarding clinical efficacy, side effects and toxicity. The world populations are heterogeneous and genetic polymorphisms in pharmacologically relevant genes varying across geographical region are significant . In addiThe fact that chemosensitivity testing was not established as routine laboratory method may have historical reasons. In times as combination therapy protocols were established as being superior to monotherapy, data showing that tumors can reveal resistance towards many drugs at the same time was compromising the utility of drug combination regimens.e.g. ABC-transporter-mediated multidrug resistance, apoptosis resistance etc.). A re-thinking may lead to a revival of predictive testing. Rather than prediction of drug sensitivity (which is not sufficiently reliable), drug resistance can be predicted with high precision. With multi-modal treatment options at hand, the knowledge about high probability that a specific drug would fail in a specific patient is valuable, because it allows early to switch to other more effective drugs or therapy strategies.On the one hand, clinical experiences showed combination therapy protocols were able to improve treatment results, but sustainable use of patients from cancer is far from reality in many cases. On the other hand, molecular mechanisms were discovered in basic sciences that explained the appearance of broad spectrum resistance phenomena (The development of resistance and the severe side effects of classical cytotoxic cancer therapy lead to a paradigm shift from the poorly specific cytotoxic anticancer drugs to targeted drugs, which were expected to be more tumor-specific. Indeed, this turned out to be a thriving concept with numerous new drugs on the market, which of course did not replace the classical cytotoxic drugs, but did supplement the armory to fight cancer. Although treatment outcomes could be further improved by targeted drugs they unfortunately also reveal side effects and are subject to resistance development. In this context, the therapeutic potential of phytochemicals cannot be overseen. They were already valuable in the era of cytotoxic drugs. Paclitaxel, vincristine, camptothecin, etoposide are just a few examples for established plant-drived anticancer drugs. There is a plethora of literature demonstrating that phytochemicals are also valuable for targeted cancer therapy.Cancer stem-like cells are rare self-renewing omnipotent cells, which proliferate upon appropriate stimulation and differentiate into heterogeneous lineages in tumors. They are frequently resistant to conventional chemo- and radiotherapy. Interestingly, natural products have been described to inhibit cancer stem-like cells –107. ThiWith the recent developments in bioinformatics, network pharmacology emerges as novel concept in therapy research. Phytotherapy with mixtures of several herbs as well as isolated single compounds exert their bioactivity by targeting multiple sites in diseased cells. A challenge for research in network pharmacology will certainly be to extract meaningful information from thousands of data points. What is a mechanistically relevant signal and what is background noise? Finding the needle in the haystack will be a task for the future and smart computer algorithms are required. Network pharmacology has to cope with multiple dimensions of problems. The multi-targeted nature of drug action, resistance development, side effects on normal organs and tissues, inter-individual biological variations, as well as inter- and intra-tumoral differences have to be considered. Especially the problem of tumor heterogeneity and possibilities to tackle with genetically diverse tumor subpopulations deserve attention from our point of view. Heterogeneous tumor populations represent a main reason for the development of resistant refractory tumors. Resistance also prevents to apply doses high enough to kill all cells, because of the severe side effects of anticancer drugs. Therefore, novel strategies to eradicate heterogeneous tumor subpopulations might not only fight the development of drug resistance but also facilitate to reduce side effects.Integrating precision medicine into routine cancer therapy is certainly one of the predominant tasks of the next years to come Figure . To real


The goal of this review is to describe in what ways feedback or adaptive stimulation may be delivered and adjusted based on relevant biomarkers. Specific treatment mechanisms underlying therapeutic brain stimulation remain unclear, in spite of the demonstrated efficacy in a number of nervous system diseases. Brain stimulation appears to exert widespread influence over specific neural networks that are relevant to specific disease entities. In awake patients, activation or suppression of these neural networks can be assessed by either symptom alleviation  or physiological criteria, which may be predictive of expected symptomatic treatment. Secondary verification of network activation through specific biomarkers that are linked to symptomatic disease improvement may be useful for several reasons. For example, these biomarkers could aid optimal intraoperative localization, possibly improve efficacy or efficiency , and provide long-term adaptive automatic adjustment of stimulation parameters. Possible biomarkers for use in portable or implanted devices span from ongoing physiological brain activity, evoked local field potentials (LFPs), and intermittent pathological activity, to wearable devices, biochemical, blood flow, optical, or magnetic resonance imaging (MRI) changes, temperature changes, or optogenetic signals. First, however, potential biomarkers must be correlated directly with symptom or disease treatment and network activation. Although numerous biomarkers are under consideration for a variety of stimulation indications the feasibility of these approaches has yet to be fully determined. Particularly, there are critical questions whether the use of adaptive systems can improve efficacy over continuous stimulation, facilitate adjustment of stimulation interventions and improve our understanding of the role of abnormal network function in disease mechanisms. Current evidence points to various forms of invasive brain stimulation, including stimulation for epilepsy and deep brain stimulation (DBS) for movement disorders, as exerting widespread influence over multiple brain areas through modulation of disease- and patient-specific neural networks  and can potentially reduce the number of pulses per second needed for effective stimulation  that analyze a symptom and may communicate with a common controller , but mostly which remain experimental or conceptual. As with any new field, the translation of biomarkers into portable or implanted devices will require more critical analysis of the clinical utility in a particular condition, stability over time, the ability to record the signal, and the correlation of the proposed biomarker with clinical symptoms relevant to the disease  has just reached clinical usefulness  reduces the amount of unnecessary stimulation by intermittently modulating the network to a less excitable state. However, the parameters of stimulation when “on” are fixed and stimulation occurs in response to detection of a potentially ictal or hyperexcitable state , adaptive stimulation was envisioned for maintenance of “consciousness” in traumatic brain injury patients .Little et al. investigated short term  adaptive DBS of the STN for Parkinson's disease based on processing of local LFPs and using an on/off system dependent on beta frequency amplitude, but with dynamic, variable widths of stimulation, hence fitting within the definition of adaptive  interfaces (BCI/BMI) using constant brain sensing  and direct, nearly continuous contingent output for motor control  , customized electrodes using the responsive Neuropace system, and anterior thalamic DBS  is a chronic, progressive movement disorder that affects ~0.9 million people in the United States  PAC between beta oscillations and higher frequency superimposed oscillations characteristic of PD  can provide neural circuit-specific insight into functional activation of the basal ganglia through STN–GP synaptic interactions, particularly through a comparison of responses to stimulation at effective  and ineffective (~10–40 Hz) stimulation frequencies  is a progressive disease with varying presentations, including motor and non-motor symptoms. Conventional DBS targets  focus on symptomatic relief of motor symptoms, although STN DBS does show also consistent improvement of midline and non-motor symptoms, particularly FOG. There is also the possibility of multifocal targeting with two or more DBS electrodes within known nodes , but this configuration will have the added complication of how to adjust cooperatively parameters from the additional recording/stimulation contacts. It also further highlights the need for brain modeling to understand circuitry and biomarkers to assist in automatic adjustment  is an idiopathic neuropsychiatric disorder defined by motor and phonic tics and often associated with psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) Leckman, . For theRecordings from the thalamic nuclei of anesthetized TS patient undergoing DBS revealed low frequency firing in bursts   for treatment resistant depression (TRD) has developed over the past 10 years  appear to correlate reproducibly in the OR with appropriate lead placement via tractography as described above  characterized by abnormal, repetitive muscle contractions and postures  may theoretically respond to brain stimulation (Hardenacke et al., Although fornix stimulation in clinical trials has shown limited clinical efficacy (Ponce et al., Identifying and verifying the usefulness of biomarkers for accurate electrode placement and creating more effective adaptive brain stimulation systems will require considerable additional development, and is clearly subject to significant research and initial clinical trials. Methods for optimal electrode localization and verification of both symptom suppression and physiological efficacy are clearly needed, likely through modulation of appropriate neural networks. Placing stimulating electrodes into defined anatomical targets in the operating room without symptom suppression or intraoperative clinical testing will require better imaging with emphasis on pre-operative tractography and functional MRI as well as use of biomarkers during surgery, as they are developed and validated. Understanding pathophysiology and structural connectivity in individual disease processes will elucidate key pathways and, subsequently, the hubs of electrical activity for optimal sites of stimulation. Spontaneous and evoked potentials, phase-amplitude coupling, and other electrophysiological measures can provide intraoperative data beyond imaging to place leads in locations correlated with more reliable outcomes. Possible neurochemical or other markers may also act as biomarkers to join imaging and electrophysiological measures as suitable signals for stimulation optimization. As external, wearable devices become more widespread and available, further data on motion and tremor may also eventually be included in adaptive control on a long-term basis if these data can be communicated effectively to an internal device (Roy et al., KH, IC, WG, and DT wrote this manuscript collectively, with KH contributing the initial draft and subsequent significant editing by all of the authors. All contributed to the ideas contained within the manuscript and all contributed at least one major section. All authors have reviewed and edited this final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Exercise training which meets the recommendations set by the National Physical Activity Guidelines ensues a multitude of health benefits towards the prevention and treatment of various chronic diseases. However, not all individuals respond well to exercise training. That is, some individuals have no response, while others respond poorly. Genetic background is known to contribute to the inter-individual (human) and -strain  variation with acute exercise and exercise training, though to date, no specific genetic factors have been identified that explain the differential responses to exercise. In this review, we provide an overview of studies in human and animal models that have shown a significant contribution of genetics in acute exercise and exercise training-induced adaptations with standardized endurance and resistance training regimens, and further describe the genetic approaches which have been used to demonstrate such responses. Finally, our current understanding of the role of genetics and exercise is limited primarily to the nuclear genome, while only a limited focus has been given to a potential role of the mitochondrial genome and its interactions with the nuclear genome to predict the exercise training-induced phenotype(s) responses. We therefore discuss the mitochondrial genome and literature that suggests it may play a significant role, particularly through interactions with the nuclear genome, in the inherent ability to respond to exercise. Furthermore, it is becoming increasingly understood that phenotypes which define exercise training-induced adaptations are complex with numerous structural, functional, physiological, and molecular changes that occur in multiple organs  and systems  in response to exercise training. Thus, the complexity of physiological and molecular changes occurring with endurance and resistance training stresses the importance of establishing collaborative efforts among investigators which have expertise in the known phenotypic adaptations with endurance and resistance training.Another limitation is identification of an appropriate animal modeling system that mimics heterogeneity in humans. Given the need to access specific tissues and organs  and the need to control confounding variables , animal models remain necessary. The National Institutes of Health recognized this form of “bidirectional translation”  provide cohorts of animals that are genetically homozygous, and thus provide the ability to interrogate specific genomes. Further, when multiple inbred strains are tested  for any phenotype, investigators then interrogate the amount of between-strain variation in characteristics and importantly, initial indications of the genomic location associated with that phenotype/trait . Inbred mouse models have been used extensively to investigate inherent physical activity  followed by a cross of their offspring (F1) and then 20 generations of brother–sister mating to develop new inbred lines  are developed from an initial cross of two inbred strains (Fhttp://www.informatics.jax.org/mgihome/nomen/strains.shtml). An obvious advantage of consomic strains is that they can be utilized as an additional confirmatory measure of strain screen analyses that indicated significant QTLs for a specific trait. However, as with other inbred models, the minimal heterogeneous background is a limitation. Conplastic inbred mice were developed with the intention to analyze interactions between mitochondrial and nuclear genomes (http://www.informatics.jax.org/mgihome/nomen/strains.shtml). Conplastic strains are created by backcrossing the nuclear genome from one inbred strain into the cytoplasm of another (http://www.informatics.jax.org/mgihome/nomen/strains.shtml). Currently, the conplastic approach is the only breeding model that provides an opportunity to analyze interactions between the two genomes. Likewise, the heterogeneity that is needed to develop a bidirectional translation approach between animals and humans is limited. Congenic and consomic inbred strains are two additional rodent models (rats and mice) that have been utilized to determine specific gene regions (congenic) and chromosomal (consomic) contribution to specific phenotypes , providing reference to the genetic composition of each mouse. Additionally, CC mice, as opposed to the available inbred mouse and rat strains, were developed using controlled randomization of genetic factors that allows expression of hidden phenotypes ; and (5) a unique platform upon which to determine novel gene functions  that capture approximately 90% of the known genetic variation in laboratory mice with the captured variation being randomly distributed across the genome  mouse breeding system. DO mice are derived from the same eight founder strains of the CC mice; however, the generation of DO mice begins with a randomized and strict breeding scheme of the CC mice so that each DO mouse is genetically unique Schmidt . The DO We therefore propose that CC and/or DO mouse models be considered in future studies investigating the heritability of exercise training-induced adaptations. While relatively new, the CC model has been successfully used to mimic several human diseases  with exercise training-induced responses, such findings are not translatable between animals and humans given the inconsistencies in training designs and phenotypic measures. Thus, a phenotype must be defined for exercise training-induced adaptations that translate between animal models and humans.2max) and extensive changes in metabolic enzymes such as succinate dehydrogenase (SDH), phosphofructokinase (PFK), and hexokinase, along with several other biomarkers, are often used as direct indices of successful adaptation to repeated endurance exercise exposures. Furthermore, numerous structural adaptations in various tissues and organs , in addition to functional changes at the cellular and molecular level in systems, respond and adapt to endurance exercise training.A wide variety of general systemic and organ responses to endurance training in humans have been well documented over the past 70–80 years. In particular, changes in aerobic capacity  study has been the primary source of our current understanding of the inter-individual variation in response to endurance exercise training. The hallmark investigation of the HERITAGE study was a twin study of otherwise healthy untrained male identical brothers  and sprint interval training , the individual response to training was dependent on the training protocol utilized. While there was inter-individual variation within each training protocol, all individuals responded to at least one training protocol to suggest that the “non-response” may be decreased by changing the training stimulus. In totality, these studies suggest that the “non-response” to endurance exercise is abolished through increasing the training stimulus. These findings are interesting, but considerably larger sample sizes are needed to confirm this argument given that there were only 21 and 78 subjects in each study, respectively , the length of training time , and the frequency, duration, and intensity of training programs. Exercise training in rodents has generally consisted of methods to induce continuous aerobic exercise. Treadmills, swimming, and running wheels have been used in training studies in rats and mice  over the past several hundred years, mutations targeted in livestock  have not been found to support any of the suggested QTL from the FAMuSS study , and 22 ribosomal RNAs (rRNA) (Chinnery and Hudson 2max)—the primary indicator of how well individuals respond to endurance training—is partly dependent upon how well the mitochondria respond to exercise-induced reactive oxygen species production, and their adaptability to increase efficiency of ATP production . Functions and adaptations of the mitochondria are heavily dependent upon the mitochondrial genome. Because mitochondrial DNA regulates overall mitochondrial function, and mitochondrial function significantly contributes to an individual’s aerobic capacity, investigators have hypothesized that the mitochondrial DNA sequence is associated with the inherent ability to respond to exercise training , and also respond to production of reactive oxygen species  and TP53 (humans) gene has a necessary role in regulating responses to exercise training through its association with mitochondrial biogenesis and respiration, the precise mechanism through which this occurs is not fully understood  has a role in mitochondrial function and may determine an individual’s response to exercise training. p53 is encoded by the Another important role of p53 in response to endurance exercise-induced training is to regulate mitochondrial polymerase gamma (POLG1). POLG1 is an enzyme considered to be the only mtDNA repair enzyme, and has been demonstrated to initiate mtDNA mutation repair and mitochondrial biogenesis in response to endurance exercise training . Another animal, known as the mitochondrial–nuclear eXchange Mice, is a model that allows the combination of the nuclear genome from one mouse strain, via oocyte enucleation, with mtDNA from a different mouse strain, a method similar to the well-known ‘3-parent babies’ . However, attention is yet to be directed on how the mitochondrial genome influences such adaptations. Furthermore, given that genetic background strongly contributes to exercise training-induced responses, and that other lines of work hint towards a significant contribution of the mitochondrial genome (e.g., mediation by p53; Safdar et al. The preponderance of evidence that demonstrates an existing association between genetics and physical activity is drawn primarily from considering the nuclear genome while few efforts have considered the mitochondrial genome. From the human and mouse studies by Bouchard et al.  and MassIn conclusion, we suggest that future work investigating the relationship between exercise and genetics consider employing animal models such as the CC or DO mice that are designed to control for the genetic diversity inherent in human models (Roberts et al.


Critical to development of new therapies for Alzheimer’s disease (AD) is the ability to detect clinical or pathological change over time. Clinical outcome measures typically used in therapeutic trials have unfortunately proven to be relatively variable and somewhat insensitive to change in this slowly progressive disease. For this reason, development of surrogate biomarkers that identify significant disease-associated brain changes are necessary to expedite treatment development in AD. Since AD pathology is present in the brain many years prior to clinical manifestation, ideally we want to develop biomarkers of disease that identify abnormal brain structure or function even prior to cognitive decline. Magnetic resonance imaging, fluorodeoxyglucose positron emission tomography, new amyloid imaging techniques, and spinal fluid markers of AD all have great potential to provide surrogate endpoint measures for AD pathology. The Alzheimer’s disease neuroimaging initiative (ADNI) was developed for the distinct purpose of evaluating surrogate biomarkers for drug development in AD. Recent evidence from ADNI demonstrates that imaging may provide more sensitive, and earlier, measures of disease progression than traditional clinical measures for powering clinical drug trials in Alzheimer's disease. This review discusses recently presented data from the ADNI dataset, and the importance of imaging in the future of drug development in AD.


Here we introduce a MIxS extension to facilitate the recording and cataloguing of metadata from samples related to hydrocarbon resources. The proposed MIxS-HCR package incorporates the core features of the MIxS standard for marker gene (MIMARKS) and metagenomic (MIMS) sequences along with a hydrocarbon resources customized environmental package. Adoption of the MIxS-HCR standard will enable the comparison and better contextualization of investigations related to hydrocarbon rich environments. The insights from such standardized way of reporting could be highly beneficial for the successful development and optimization of hydrocarbon recovery processes and management of microbiological issues in petroleum production systems.The online version of this article (doi:10.1186/s40793-016-0203-5) contains supplementary material, which is available to authorized users. Hydrocarbon Occurrences are defined as the natural and artificial environmental features that are rich in hydrocarbons Fig. . Hydroca2S production, an undesirable process better known as reservoir “souring”. Moreover, in terms of microbial monitoring, such methodologies will help us determine to what extent the indigenous microbial community of an HCR is represented by the analysis of readily recoverable produced fluids, and if analysis of produced fluids can reduce the need to analyze material directly recovered from the hydrocarbon rich formation, such as reservoir cores which are much more difficult to obtain. It will also be practically important if the analysis of planktonic populations from produced fluids can provide an alert to potential MIC phenomena caused by sessile populations. A growing inventory of HCR systems will also allow us to determine if specific beneficial or detrimental microbially catalyzed processes in HCRs are the result of the same microbial populations in most instances, or whether a particular process is driven by different organisms in different HCR environments.Restraining or harnessing the potential of these microbes requires a considerable understanding of their metabolisms and role in these environments. Tools and methodologies that allow the enumeration, taxonomic identification, and metabolic prediction of these microbes are therefore essential towards this goal. Such methodologies will enable us to address questions relating to microbial spatiotemporal variability and what drives them within an HCR. This will also help us determine whether particular microorganisms were present in the HCR at the time of deposition or whether they were introduced at a later stage through fluid migration (e.g. during the formation or recovery of the hydrocarbon resource). Other interesting questions pertain to hydrocarbon recovery processes, and especially the effect of water injection (aka “water flooding”) on the indigenous and introduced microbial communities associated with HCRs. One particular operational issue related to this is stimulation of biogenic HIn addition to environmental parameters, the outcome from microbiological surveys of HCRs can be strongly impacted by logistical and technical constraints. These include sample acquisition, transport and preservation; the choice of DNA amplification primers ; enumeration methods ; sequencing platform  and related downstream bioinformatics pipelines.There is a growing list of studies on HCRs, but their collective retrieval (or their corresponding sequences from public repositories) is currently impossible even with complex keyword searches. Moreover, the majority of available datasets lack sufficient contextual data, which would facilitate more comprehensive comparative analysis –6.In order to maximize the knowledge gained from these largely unexplored microbial ecosystems it is important to formalize and standardize environment descriptors for studies of these habitats. It is equally important to define a minimum set of contextual parameters, which should accompany the submission of sequence information from HCR studies to the International Nucleotide Sequence Database Collaboration . The adoThe need for standardization is not novel or unique to HCR studies. Since 2005, the Genomic Standards Consortium , 4 has mbiome only the subclasses aquatic biome, polar biome, and terrestrial biome are currently present. The term subterranean biome , which would include biomes related to certain HCR (e.g. hydrocarbon reservoir) as well as other subterranean biomes [environmental feature branch, additional HCR terms such as gas reservoir, oil sand, and coalbed will need to be included in addition to the existing oil reservoir term. Finally, in the environmental material section of ENVO, HCR terms like formation water, injection water, drilling fluid, tailing pond and many more would supplement the existing oil field production water term. It is therefore apparent that expansion of ENVO to include HCR-related terms will greatly benefit the standardization of a growing number of studies on these environments. An initiative to introduce such HCR-related terms in ENVO is currently underway.Around the same time a separate effort aimed at the development of ENVO, a standardized and semantically controlled representation of environment descriptors was undertaken . ENVO qun biomes –16 is cuIn an effort to assist with the standardization of data acquisition and observations derived from HCR-related environments we introduce the MIxS-HCR minimum information standard. This standard is tailored for HCR-related studies and aims at capturing key environmental parameters influencing microbial activity in these environments and standardizing their method of reporting. This is accomplished by the adoption of terms  from previously reported environmental packages  as well as the introduction of new checklist items specific to these environments. A checklist consisting of 93 fields from several disciplines including geology, geochemistry, petrophysics, reservoir engineering, and production chemistry has been compiled Table . Some ofAmongst the different minimal information standards mentioned above, the MIMS and MIMARKS survey sequence specifications are probably the most relevant ones for HCR-related studies as the majority of these studies involve single gene  or whole metagenome surveys. As such, in addition to the HCR environmental package, the MIxS-HCR extension also includes a subset of the MIxS checklist containing MIMS and/or MIMARKS survey fields (depending on the study)  describing hydrocarbon-rich environments which are not covered under the HCR term. These include anthropogenic hydrocarbon occurrences (e.g. oil and gas production systems) as well as surface and seabed hydrocarbon occurrences  Fig. . Many ofThe newly proposed MIxS-HCR minimum information standard provides the foundation for consistent capture and reporting of valuable contextual information derived from studies pertained to hydrocarbon resources. Its first release has already gained approval by the GSC board and will be incorporated in INSDC’s sequence submission process. A web forum has also been set up to promote MIxS-HCR future improvements and extension to cover a wider range of hydrocarbon occurrences. Active involvement of the research community and adoption of the MIxS-HCR standard are key elements to the success of this initiative.


Alzheimer’s disease (AD) represents the most common neurodegenerative disease leading to dementia, and its prevalence is increasing every year, thus representing a major health and socioeconomic issue. AD pathology affects the brain several years before any of the clinical symptoms appears; therefore, early diagnosis is highly recommended in order to start the treatment as soon as possible, especially in view of the upcoming disease-modifying drugs . To this


There is emerging evidence that there are shared genetic, environmental and developmental risk factors in psychiatry, that cut across traditional diagnostic boundaries. With this background, the Discovery biology of neuropsychiatric syndromes (DBNS) proposes to recruit patients from five different syndromes , identify those with multiple affected relatives, and invite these families to participate in this study. The families will be assessed: 1) To compare neuro-endophenotype measures between patients, first degree relatives (FDR) and healthy controls., 2) To identify cellular phenotypes which differentiate the groups., 3) To examine the longitudinal course of neuro-endophenotype measures., 4) To identify measures which correlate with outcome, and 5) To create a unified digital database and biorepository.N = 4500) will undergo brief clinical assessments and a blood sample will be drawn for isolation of DNA and peripheral blood mononuclear cells (PBMCs). From among this set, a subset of 1500 individuals (300 families and 300 controls) will be assessed on several additional assessments , with the intention of conducting repeated measurements every alternate year. PBMCs from this set will be used to generate lymphoblastoid cell lines, and a subset of these would be converted to induced pluripotent stem cell lines and also undergo whole exome sequencing.The identification of the index participants will occur at well-established specialty clinics. The selected individuals will have a strong family history (with at least another affected FDR) of mental illness. We will also recruit healthy controls without family history of such illness. All recruited individuals (We hope to identify unique and overlapping brain endophenotypes for major psychiatric syndromes. In a proportion of subjects, we expect these neuro-endophenotypes to progress over time and to predict treatment outcome. Similarly, cellular assays could differentiate cell lines derived from such groups. The repository of biomaterials as well as digital datasets of clinical parameters, will serve as a valuable resource for the broader scientific community who wish to address research questions in the area. Severe mental illnesses are a major source of morbidity and disability, with about 2–3% of the population at risk for developing these disorders . These iTraditional clinical classification systems conceptualize the psychiatric disorders as a group of discrete syndromes that are independent of each other. For example, schizophrenia, bipolar disorders and other psychotic disorders are considered to differ from each other, based on their unique clinical characteristics, course, family history and treatment response . HoweverGiven these observations, it is necessary that attempts to understand the biology of these disorders considers their genetic basis, differences in neurodevelopment, as well as the overlapping nature of the individual psychiatric syndromes. One way to account for these factors would be to prospectively follow-up affected and unaffected individuals, whose family history suggests an elevated risk of developing disease  from a stage when they are asymptomatic, so that clinical investigations can capture the evolution of alterations in brain function. Such a strategy combined with modern human genetics and analysis of cellular function in brain cells using ‘disease in dish’ models should help us understand the cellular and molecular underpinnings psychiatric illness.The Discovery biology of neuropsychiatric syndromes [DBNS] is one such research initiative in Bangalore, India, built on a collaboration between clinicians and scientists at the National Institute of Mental Health and Neuro Sciences (NIMHANS), the National Center for Biological Sciences (NCBS), and the Institute for Stem Cell Biology and Regenerative Medicine (InStem). It aims to understand the developmental trajectories and basic biology of these major psychiatric disorders. The study will use multiple techniques , and in-depth clinical assessments of participants in a cohort of multiple affected families with a strong family history of mental illness. The facilities created, and the data sets, will provide a resource for future research to help answer questions with implications for basic neuroscience as well as drive translational research with positive impact for clinical psychiatry.The basic premise of this research initiative is that there exist shared genetic, environmental and developmental factors across the major psychiatric disorders. We aim to identify such overlaps by examining clinical, brain imaging, neurophysiological and neuropsychological measures, as well as clinical histories, across disorders. In addition, we would examine the longitudinal trajectory of these neurobiological measures. We will recruit multiple affected families with patients having one or more of 5 syndromes  so that they broadly represent the major and common psychopathologies. The identification of the index participants will occur at well-established specialty clinics at NIMHANS. Importantly, the index patients chosen will have a strong family history of mental illness. The families will then become part of a single sample, who will be subjected to a uniform set of clinical analyses; and a bio-repository will be set up using cellular material from these individuals. Several endophenotype assessments , will be also be performed, as these empirical measures will provide robust and consistent measures of brain function. Familial stress, and psycho-social factors will also be evaluated using structured assessments. It is expected that such deep interrogation of brain networks and sub-cellular networks using molecular and cellular analysis; as well as social and psychological measurements, would lead to better mechanistic understanding of these disorders.Specific objectives of the program are as follows:Short-term objectivesTo identify 300 families in whom multiple members (more than 2 affected first degree relatives in a nuclear family) are diagnosed to have a major psychiatric disorder  with structured assessments.To study brain structural [grey (magnetic resonance imaging-MRI) and white matter (diffusion tensor MRI)] abnormalities, resting and task-related functional MRI activity, neuropsychological performance, brain electrical activity and eye movement abnormalities in probands with major psychiatric disorders and their unaffected first-degree relatives (FDR); in comparison with matched healthy controlsTo identify cellular phenotypes that differentiate between the groups using experiments on cell lines Create a unified digital database of all the above information.Long-term objectives (5 years and beyond)e.To examine the time course and progression of structural/functional brain abnormalities, neuropsychological performance, brain electrical functions and eye movement abnormalities in probands and unaffected FDRs and study their relationship to course of illness and disease conversion.f.To examine cell lines from good and poor outcome patients to try and identify cellular mechanisms that might underpin or correlate with specific clinical outcomes.In comparison with healthy controls, patients could have significant specific grey matter volume deficits and white matter hypo-connectivity; aberrant neuro-hemodynamic response involving frontal, striatal & limbic brain regions during fMRI; abnormal brain electrical activity and antisaccade/ smooth pursuit eye movements; prominent and specific patterns of impairments in verbal memory, verbal fluency, sustained attention and executive functions.Unaffected relatives could also have brain abnormalities; and a proportion of these individuals may develop a clinical syndrome. A composite endophenotype comprising of neuroimaging and neurocognitive parameters could differentiate three groups . Subjects could show the deficits even in periods of clinical remission; and in a proportion of severely ill subjects these deficits may progress over a period.Cellular assays could similarly differentiate cell lines derived from the three groups. Greater brain abnormalities/composite endophenotype measures/cellular abnormalities at baseline may predict poorer course and outcome/ treatment response. The relation between these, and the genetic variations, would be amenable for further analysis, to understand the genotype-phenotype conversion.The affected probands will be recruited from the adult psychiatry services and specialty clinics  of the NIMHANS, Bangalore. Unaffected FDRs will also be recruited from the families. An attempt will be made to recruit as many individuals as possible from each family. All clinics will together recruit age and gender matched control subjects, who will neither have an axis I psychiatric disorder, nor have a family history of such disorders in two previous generations.N = 4500) will undergo brief clinical assessments and a blood sample will be drawn for isolation of DNA and peripheral blood mononuclear cells (PBMCs). From among this set, a subset of 1500 individuals (300 families and 300 controls) will be assessed at baseline on several additional assessments , with the intention of conducting repeated measurements every alternate year. These individuals will form the neurodevelopmental endophenotype cohort (NEC). PBMCs from the NEC will be used to generate lymphoblastoid cell lines and a subset of this would be converted to IPS lines and also undego whole exome sequencing.All recruited individuals  measures and cortical hemodynamic changes as robust endophenotypes , 28–42 HHeritability estimates for severe mental illnesses range from 60% - 90%, suggesting that a large proportion of etiological variance is attributable to genetic factors –45. DespCritical to understanding the evolution of neuropsychiatric syndromes is the unravelling of cellular and sub-cellular processes that are altered in a given syndrome. This poses a unique challenge in the study of the brain related diseases, as the tissue is inaccessible. The availability of living brain cells is critical to study ongoing cellular processes in neurons and glial cells. Recent developments in stem cell technology allow the use of somatic tissues to be reprogrammed into IPS lines. These can then be differentiated into neural cells including neurons and glia. We propose to use this approach to derived cellular models of disease in the context of neuropsychiatric illness. Methods have been developed, that allow the establishment of stable cell lines from lymphocytes isolated from a sample of peripheral blood . These LThe functional unit of the brain is the synapse and it is likely that alterations in synapse formation, structure and function underlie neuropsychiatric illness. Synapse development and function is underpinned by complex sub-cellular processes and the “disease in a dish” model offers a unique opportunity to understand these events and their role in mental illness. To functionally characterize the IPS derived neural cell models we will test for neuronal activity. This will be done using whole cell patch-clamp recordings to test for the ability of neurons to generate action potentials. In addition, we will also measure function through the measurement and analysis of calcium transients using fluorescent calcium indicator dyes. More detailed analysis of response to neurotransmitters can also be performed using these approaches. In addition, neural networks will be examined in cultures using multi-electrode arrays.Given the neurodevelopmental nature of mental illness, it is likely that altered synapse formation and pruning plays a role in disease development. To understand this process, we propose to characterize synapse development in our cellular models. This can be done by differentiating IPS into neurons in cell culture and characterizing neurite outgrowth during this process using well-established quantitative assays.Metabolic alterations in neural cells are strongly implicated in mental illness and multiple roles for mitochondrial dysfunction in the development of several mental disorders is widely discussed. To map these potential defects, we will perform basic characterization of mitochondrial structure and function using well-established fluorescence based assays. Metabolic alterations arising from altered mitochondrial function or additional genetic factors will be captured by metabolic profiling using small molecule mass-spectrometry. Such analyses may also include changes in the levels of neurotransmitters.The sample size was calculated for each trait and number of times of assessment separately for each trait  for repe2 is the assumed common variance in the two groups, (μ1 − μ2) is the difference in means of the two groups, k is the number of time points and ρ is the assumed correlation of the repeated measures; then the number of subjects/ families (assuming independence) in each of two groups is,Let σThe power and type I error were kept at 80% and 5% respectively.If the affected group and high-risk group (FDRs) have an average family size of ‘m’, thereby the total number of observations = ‘nm’, then the effective sample would be N = nm/[1 + (m-1) λ]; where ‘λ’ is the intra-familial correlation (intra-class correlation) on the quantitative trait.We have used this N in the standard power computation formula for unbalanced ANOVA for the number of observations in the affected group and FDRs along with the control group.Corpus callosal volume: This white matter tract has been implicated in all major psychiatric disorders and has also been examined in large scale studies. Using published literature on corpus callosal volume , sample Eye movement parameters: Eye movement abnormalities have been identified as putative endophenotypes in recent large studies . Sample Using this formula, we have calculated sample size using brain imaging and brain physiology measures. These are as follows:These power calculations described above will adequately address our capacity to detect group differences. Moreover, as we detect genetic differences (rare variants/ accumulation of damaging variants), and also submit the genetic data generated to pathway based modelling, these emerging data will be used to analyse MRI and EEG data in a specific manner.The human brain is a complex organ and its output, i.e. manifest behavior, arises from processes operating at multiple scales ranging from individual molecules within cells and integrating into increasingly higher levels of complexity including cell- cell interactions and circuit formation leading to emerging structure and function. These multi-scale events are underpinned not only by genetic factors that determine the functional biochemistry of brain cells, but also by epigenetic factors that modulate the expression of genes in an individual genome. Given the inherent variability between the genome of individuals as well as the range of environmental factors that can influence gene expression, it is not surprising that uncovering the etiology and pathogenesis of mental illness remains one of the greatest challenges in modern biology. To meet this challenge, our proposal to assemble a cohort of clinically dense families and prospectively follow the development of disease in them, would be useful. The use of clinically dense families coupled with next generation sequencing offers an opportunity to uncover rare and de novo variants and study their segregation pattern within a family. These observations could offer insights into the inherited basis of mental illness, as also be extrapolated to the whole population. Simultaneously, the detailed clinical history and demographics collected for members of the cohort will offer an insight into environmental factors that may mediate epigenetic regulation of the genome in an individual and therefore explain the development of mental illness .Numerous case-control studies have identified changes in brain structure and function at multiple levels. However, we are unaware of any study which has mapped the development of such changes from at-risk state to disease onset, using multiple measures. Most of our knowledge of brain perturbations that lead to psychopathology has been derived from cross-sectional “snap-shots”, or explorations which commence after the development of a recognizable syndromal state. The specific roles that genes, environment and their interaction play in typical and atypical development are unclear, especially across the course of mental illness. Existing knowledge of brain and behavioral development is insufficient to permit identification of specific time points at which normal and psychopathological trajectories diverge and the processes that underlie such deviations. We propose to set up a prospective longitudinal cohort of individuals who are at-risk of developing psychiatric disorders and follow them with periodic endophenotype assessment over time. This approach offers the opportunity to map structural and functional changes in brain function as they develop, along with behavioral changes that lead to disease development. This is likely to be vastly more informative than previous cross-sectional case-control studies. We will use advanced imaging methods to accurately track, changes in brain structure and connectivity , the neurodevelopmental processes related to the normal developmental sequence and deviations from it. In contrast to conventional genetic association studies where disease status is based on clinical observations, neuroimaging phenotypes can capture aspects of disease phenotypes at the physiological level. Neuroimaging genetic studies thus offer the prospect of gains in statistical power, since genes code not for mental or behavioural traits, but for the neural phenotypes that underpin them . NeuroimThe validity of the discrete disease constructs  and classificatory models of mental disorders, which have hitherto been adequate for clinical purposes, have been strongly challenged by recent findings of wide overlaps between these discrete entities in terms of genetic underpinnings, neurodevelopmental substrates, responses to pharmacological agents and behavioural treatments –15. In fBy recruiting individuals from different disorders and mapping endophenotypes across different domains, we hope that we will be able to achieve increased power to identify the common neurobiological factors underlying severe mental illness. Such attempts have been made by recent research consortia like the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) and Consortium on the Genetics of Schizophrenia (COGS) , 11, 63.Of the neuropsychiatric disorders that we have included in this study, the outlier is dementia, which usually manifests at a later age than the others. However, dementia is also increasingly recognized to have its beginnings in adolescence, as early studies point to recognizable brain changes in persons at high risk, starting many years before the recognizable symptoms of the disease are palpable –67. MoreIt is now possible to assemble and manipulate so-called neural spheroids, generated from human induced pluripotent stem cells, to study the normal development of the human brain and deviations from the developmental sequence. Since many neuropsychiatric disorders are possibly influenced by individual genetic influences, it is difficult to study these diseases in standard animal models. Instead, these types of diseases can be modeled using the cells from the patient. One can use the information from longitudinal tracking of the basic processes underlying brains fundamental neurodevelopmental sequence in normal development and in disease, to a] investigate the internal cellular processes, underlying the processes involved in neurodevelopment, b] Model, deviations in cellular processes, which lead to deviations in neurodevelopmental processes, and c] test, the processes and outcomes of physical and drug treatments.The unified digital database of clinical-endophenotype measures and the bio-repository generated in DBNS will provide a wealth of quantitative detail, which can then be interrogated both within and across phenotype  as well as genetic data . Other than the specified objectives, some of the other expected off-shoots of the project are as follows:n = 1250) have been recently published from the B-SNIP cohort [The program seeks to identify valid endophenotypes in psychiatry using a large sample; and have next generation sequencing data for the same set of individuals. Using appropriate statistical techniques for data reduction  and endophenotype-genetics relationships , we hope to identify the genetic basis of these endophenotypes. Similar endophenotype-genetics analyses  will prove useful. Additional use of peripheral cells will also advance bench to bedside translation.The unique feature of this program is the combination of a clinical longitudinal approach with prospective assessment of biological measures. A proportion of the FDRs will convert to clinical illness during the follow-up period. The program should be able to identify measurable predictors of disease conversion in FDRs at various biological levels – brain imaging, psycho-physics, epigenetics etc. In addition, examination of cellular endophenotypes across FDRs who have converted to clinical disease and who have not, in the same family, may point towards disease conversion related functional output at the cellular level.The DBNS is thus an ambitious, and optimistic, attempt to create a database that combines a wealth of clinical data with a comprehensive psychological and biological assessment, over time. The resources generated will hopefully serve as a platform to answer several questions related to the neurobiology of psychiatric disorders; as well as address fundamental questions about neuro-development and degeneration, as relevant to common psychiatric disease syndromes. This would improve our understanding of these illnesses, and perhaps develop strategies for amelioration, of these conditions which are a significant public health concern.