Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune cell activation and fibrosis of the skin and internal organs, occurring mainly in females. Although a lot of progress has been made in the discovery of genetic risk factors for SSc, environmental factors triggering onset of SSc have not been identified. This provides a foundation for the involvement of processes related to biological ageing to trigger SSc onset and perpetuation in the genetically susceptible host. Consequently, we have investigated key determinants of biological ageing, namely telomere attrition and the role of telosome proteins in the pathology of systemic sclerosis and how it impacts on individual leukocyte cell subsets.Epigenetic processes, such as telomere attrition have been implicated in SSc . The lenThis study aimed to evaluate telosome biologyin an independent, clinically well-defined SSc cohorts. Moreover, we aimed to investigate whether there are differences in telomere attrition between different immune cell subsets and if these differences are accompanied by changes in expression of genes involved in telomere functioning.Telomere lengths were determine by Q-PCR  and teloWe observed significant telomere attrition with increasing chronological age in a control population  but not in dcSSc samples from independent Dutch (n=143) and UK cohorts (n=160). Despite this, dcSSc telomere lengths were on average shorter than controls at any given chronological age, reflecting more miles on the clock with the disease state. We also observed dcSSc specific telomere shortening in pDCs (p=0.001) compared to controls. This shortening was not further accelerated with increasing chronological age.Analysis of the telosome, indicated significant expression changes in six key proteins relating to DNA repair and telosome stability and regulation (p<0.01).We have demonstrated that dcSSc exhibits features consistent with accelerated biological ageing. This process appears to be independent of increasing chronological age, indicative of aberrant telosome biology with disease preempting the development of clinical symptoms at a later chronological date. Our data have provided novel insight into the pathogenesis of dcSSC and identified new targets for therapeutic intervention. They have also confirmed pDCs as an important cell type in dcSSc pathogenesis.


Children born very preterm  without major intellectual or neurological impairments often express selective deficits in visual-perceptual abilities. The alterations in neurophysiological development underlying these problems, however, remain poorly understood. Recent research has indicated that spontaneous alpha oscillations are slowed in children born very preterm, and that atypical alpha-mediated functional network connectivity may underlie selective developmental difficulties in visual-perceptual ability in this group. The present study provides the first source-resolved analysis of slowing of spontaneous alpha oscillations in very preterm children, indicating alterations in a distributed set of brain regions concentrated in areas of posterior parietal and inferior temporal regions associated with visual perception, as well as prefrontal cortical regions and thalamus. We also uniquely demonstrate that slowing of alpha oscillations is associated with selective difficulties in visual-perceptual ability in very preterm children. These results indicate that region-specific slowing of alpha oscillations contribute to selective developmental difficulties prevalent in this population. Children born very prematurely, even in the absence of brain injury and when intelligence is broadly normal, often experience selective developmental difficulties including problems with visual-perceptual abilities  in school-age children born very preterm are slowed  children and 27 full-term controls were tested as part of a longitudinal study investigating the long-term impact of neonatal procedural pain on the neurocognitive development of very preterm children . Subjects were supine during recording and were instructed to maintain visual fixation on a “happy face” stimulus which was presented 40 cm above their eyes. A research assistant accompanied each subject within the magnetically shielded room to monitor the subjects. Data were digitized continuously at 1200 Hz, stored offline for analysis, and subsequently downsampled to 600 Hz. Fiducial coils were attached at the nasion as well as the right and left preauricular points, and each was energized at a distinct high narrow-band frequency. T1 weighted volumetric MRI images were also collected (1.5 T). Due to practical limitations imposed by multimodal neuroimaging in special child populations, MRI images were not available for all subjects. For those subjects without usable MRIs, a substitute matching MRI was found using the NIH database. MRIs for 4 very preterm children and 22 typically developing controls were taken from the NIH pediatric database. To obtain matching MRIs for individual subjects several candidate volumetric MRIs were selected from the database based on small differences between MEG and candidate MRI fiducial points. A best-matching structural MRI was then fitted to the subject’s digitized head surface manually.Head motion was corrected for by obtaining a dipole source solution for each fiducial coil 30 times/s throughout the recording of spontaneous activity. The MEG data were then transformed to a common position by performing an inverse solution, data rotation, and forward solution 30 times/s , using the eegfilt function from the EEGLAB toolbox, a two-way least-squares FIR filter . Regional analysis of oscillatory slowing revealed that this pattern was widespread and encompassed prefrontal, temporal, and parietal areas, as well as aspects of thalamus and cingulate cortex. Complete results of the analysis of regional oscillatory slowing in very preterm children are presented in Figure Analysis of global peak oscillatory frequency  revealed statistically significant slowing in school-age children born very prematurely p = 0.02. RegionaVisual-perceptual ability, indexed by the visual perception subscale of the Beery VMI, was associated with oscillatory slowing in multiple regions, including several known to be involved in the processing of visual information including inferior parietal cortex, ventral temporal cortex, and thalamus. Regional slowing was not significantly associated with FSIQ or the Motor or Visual-Motor scores on the Beery VMI for the very preterm children. Peak oscillatory frequency was not associated with any of the psychometric tests for full-term children for any region. Complete results of the analysis of associations between regional oscillatory slowing and visual-perceptual ability in preterm children are provided in Table We provide the first source-resolved analysis of slowing of alpha oscillations in children born very preterm. Identification of the specific brain regions across thalamocortical systems involved in slowed alpha oscillations in very preterm children represents an important step, as altered alpha oscillations may mediate relations between neonatal procedural pain and cognitive outcome in children born at extremely low gestational age , congruent with earlier reports of slowed alpha oscillations over frontal MEG sensors (Doesburg et al., The perspective that oscillatory slowing is associated with impairment of normal brain function is consistent with observations of MEG slowing in association with neurological insults in other contexts. For example, regional analysis of excessive low-frequency oscillations has been introduced as a method for mapping abnormal functional brain activity following mild traumatic brain injury (Huang et al., Slowing of alpha oscillations, together with the purported association of this phenomenon with the loss of integrity in structural brain connectivity, raises questions regarding relations between alpha oscillatory slowing and communication in brain networks. In particular, evidence increasingly indicates that coherence of alpha-band oscillations plays a critical role in communication among brain regions supporting cognition and perception (see Palva and Palva, The observation that slowing of alpha-band oscillations in very preterm children occurred in thalamus is also significant as animal research has demonstrated that thalamocortical mechanisms underlie the generation of alpha oscillations, as well as their slowing under pathological conditions (see Hughes and Crunelli, Our results showing significant slowing in deep brain structures such as the thalamus should be interpreted with caution. Reconstructing MEG signals from deep structures is not only difficult, but in many cases impossible because the SNR is too small (see Quraan et al., We demonstrate that slowing of spontaneous alpha oscillations is evident in widespread brain regions in very preterm children. These alterations of alpha oscillations were concentrated in regions involved in visual processing including thalamus, posterior parietal cortex, and interior temporal cortex, as well as in prefrontal regions relevant for executive functions. We provide the first evidence that slowing of spontaneous alpha oscillations is associated with functional outcome in preterm children. This association between slowing of alpha oscillations in particular brain regions and function was specific for visual-perceptual abilities, and was typically found in posterior parietal and inferior temporal brain regions implicated in visual processing. These results indicate that area-specific atypicalities in alpha oscillatory brain activity are associated with selective difficulties in children born very prematurely.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.


Evolutionary theory predicts that once an individual reaches an age of sufficiently low Darwinian fitness, (s)he will have reduced chances of keeping cancerous lesions in check. While we clearly need to better understand the emergence of precursor states and early malignancies as well as their mitigation by the microenvironment and tissue architecture, we argue that lifestyle changes and preventive therapies based in an evolutionary framework, applied to identified high-risk populations before incipient neoplasms become clinically detectable and chemoresistant lineages emerge, are currently the most reliable way to control or eliminate early tumours. Specifically, the relatively low levels of (epi)genetic heterogeneity characteristic of many if not most incipient lesions will mean a relatively limited set of possible adaptive traits and associated costs compared to more advanced cancers, and thus a more complete and predictable understanding of treatment options and outcomes. We propose a conceptual model for preventive treatments and discuss the many associated challenges. The preventive measures include changes in lifestyle, pressure to abandon dangerous habits like cigarette smoking or excessive alcohol consumption and efficient campaigns aimed at eradication of infections strongly associated with many common cancers . The benefits of widespread screening for breast and prostate tumours are more controversial. Indeed, it is not clear how much of the observed decrease in mortality caused by these common cancers is due to early detection as opposed to improved treatment options . Given the high rate at which mutant cells are produced in at least some tumours  are manifested has a firm ecological and evolutionary basis as an alternative to classical therapies, at least for certain risk groups and for certain cancer types. We present a conceptual model for such evolutionary prevention of cancer, and argue why this should constitute a major effort in health programmes and medicine.Here, we propose that ecological and evolutionary insights can be used to design more efficient interventions for cancer prevention and management. The central tenet of this framework is that protecting and bolstering natural defences through lifestyle changes and/or active medical treatments implemented Evolution provides a framework for understanding the interrelations among the environment, (epi)genotypes and phenotypes and how they influence tumour phenology. The evolutionary process in cancer occurs at two characteristic scales: emergence at the population level and progression within individual hosts.in situ tumours, but do not develop cancer  (epi)genetic changes are very likely to be composed of both advantages (higher population growth) and disadvantages (costs), and (ii) the net fitness effect and thus potential to survive and spread will depend on (changing) environments. Because cancer growth is usually associated with increased genotypic and phenotypic heterogeneities  most advanced cancers, medicine will rarely, if ever, predictably manage late-stage disease. We suggest that knowledge about these same evolutionary factors promoting the emergence of chemoresistant lineages – i.e. cell population turnover and tumour heterogeneity – can be used to develop approaches to Two characteristics of cancer give encouragement for investigating preventive strategies. First, cancers are thought to proceed through a number of premalignant states before they are diagnosed genetic variants compatible with resistance are less likely to have already emerged. Thus, while the risk of cancer developing years or tens of years following the treatment is expected to be reduced, if low-dose preventative therapeutic intervention was to fail, then the unverified prediction is that those malignancies that do eventually emerge will be no more resistant to chemotherapies than would have been the case had the preventive treatment not been administered. This crucial hypothesis will need to be carefully tested in animal models before large-scale preventive intervention is envisaged. However, some supportive evidence already exists. For example, although the preventive efficacy of tamoxifen for women who are BRCA 1 or 2 carriers is controversial, to the best of our knowledge no increase in drug-resistant tumours has been reported for this chemopreventive strategy genetically changed clone that has a high probability of leading its descendants down the path of tumourigenesis , then it is unlikely that resistant cells will be present. Certain cancers, however, have well-characterized defects in the DNA repair processes and are known for their genetic variability at relatively small cell population sizes, for example, BRCA breast and ovarian tumours, Fanconi anaemia-associated cancers or HNPCC-associated colorectal tumours  and changes in human behaviours (to reduce voluntary or inadvertent exposures), cancer prevention could take two main routes: reinforcing existing disease check mechanisms through, for example, prophylactic vaccination Finn , and attWhat kinds of conditions are particularly amenable for preventive evolutionary medicine? It is estimated that 5–10% of cancers arise in the context of genetic predisposition, with variation between different tumour types ranging from less than 0.5% for connective tissue or testicular tumours to about 15% for prostate carcinoma  the number of treatments, doses and products employed for preventative therapy versus analogous interventions once a cancer is detected (including costs associated with possible cancer relapse), (ii) over treatment, that is the percentage of people treated preventatively who would not have developed cancer at a later time and (iii) costs related to decreased capacity of work of cancer patients. These costs do not include other important considerations that are difficult to quantify monetarily, in particular (i) the psychological  effects of preventative treatments versus cancer diagnosis and associated therapy and (ii) lifestyle benefits of successful prevention.Before such an in-depth economic analysis is performed, we note that about 10% of all cancers arise in genetically ‘high risk’ groups, which represent less than 1% of the total population. The current cost of treatment of these patients in the USA is a staggering $15 billion per year . We need to better understand how lifestyles and their changes influence evolutionary cell biology, and in so doing, change cancer dynamics. To the extent that actual medical intervention is possible for certain cancers, we need to evaluate how molecules, either with specific actions on cells  or presumably with a systemic effect on the microenvironment (e.g. aspirin) affect the ecology and evolutionary dynamics of the transition from benign to malignant neoplasms. However, it is necessary to keep in mind that there are many valid critiques for the development of specific molecules to prevent cancers. As we have argued above, these include health programme costs, side effects and whether such drugs risk inducing new cancers or other diseases. Similarly, because different anticancer strategies (tolerance/avoidance versus resistance/eradication) that our bodies naturally employ are ostensibly a product of our evolutionary history , artificMoreover, potential side effects will mean that the notion of disease ‘risk’ must be integrated into decision making if the idea of preventive evolutionary medicine for cancer is to gain any traction. Such disease ‘risks’ include genealogical factors or genetic predispositions to the disease, elevated exposure to carcinogens including cancer-causing pathogens and previous bouts with cancer. Preventive therapies directed at cells (as opposed to tumour microenvironments) would need to be cancer cell specific, targeting either known genetic defects, such as PARP inhibitors for patients at high cancer risk due to mutations in BRCA1/2, ATM or PTEN genes (Chalmers et al. We have a scientific understanding of why current approaches to cancer eradication generally fail: chemotherapies select resistant cells and these are likely to grow unfettered during and possibly post therapy. Although we obviously must continue to investigate declared cancers with new and innovative methods, we argue here that we also need to carefully consider active, interventionist strategies that prevent cancers in the first place or eradicate them prior to detection, especially given the likelihood that we are all continuously, naturally controlling precancerous lesions. For some types of cancer and for those individuals at heightened risk of contracting the disease, we propose that this natural control could be supplemented with preventive measures, based on insights from evolutionary biology.


The number of medical center–based farmers markets has increased in the past decade, but little is known about how such organizations contribute to the preventive health goals of the patient-centered medical home.In 2010, we started a seasonal farmers market at Penn State Hershey Medical Center to help support the institution’s commitment to the medical home.We obtained descriptive data on the farmers market from hospital and market records and tracking information on the market’s Facebook and Twitter sites. We computed summary measures to characterize how the market has begun to meet the 6 standards of the 2011 National Committee for Quality Assurance’s report on the medical home.During the 2010 and 2011 seasons, 146 medical center volunteers from 40 departments formed 23 interprofessional teams that spent an average of 551 volunteer hours per season at the market, providing health screenings (n = 695) and speaking to customers (n = 636) about preventive health. Fifty-five nonmedical community health partners provided 208 hours of service at the market alongside medical center staff. Market programming contributed to 5 regional preventive health partnerships and created opportunities for interprofessional mentoring, student leadership, data management, development of social media skills, and grant-writing experience. The market contributed to all 6 medical home standards outlined by the National Committee for Quality Assurance.Medical center markets can support medical home standards. With systematic tracking of the health effects and integration with electronic medical health records, markets hold potential to contribute to comprehensive patient-centered care. Patient-centered medical homes (PCMHs) are increasingly prevalent in the United States; more than 7,600 clinicians and 1,500 practices have earned PCMH recognition as of 2011 . The ultFarmers markets at medical centers represent one such unique partnership that can contribute to the preventive health goals and NCQA standards for a PCMH. Medical center–based markets have increased exponentially over the past decade –14. Of tIn addition to increasing access to healthful products, medical center farmers markets can contribute to the PCMH by providing services to help alter dietary and lifestyle choices, including health screenings, cooking demonstrations, physician “prescriptions” to purchase healthy produce, and information on lifestyle-change programs. Furthermore, medical center–based markets can furnish a sustainable supply of interprofessional staff to provide such services — including medical center volunteer staff, student interns, and health professionals interested in continuing education opportunities. Because such markets typically operate at least 6 months per year (and could operate year-round in milder climates and indoors), they can contribute to building long-term links with health care providers to promote comprehensive patient-centered care. Furthermore, public health services and programs provided by medical center markets can contribute to core values of the PCMH model, including sensitivity to context and cultural differences, interdisciplinary collaboration, information management, community engagement, and access to care. Forging service-learning experiences outside of the clinical setting and in community venues such as markets is crucial to educating medical personnel and trainees about local needs and systems-based factors necessary to address both acute patient care and larger public health issues . AlthougAt Penn State Hershey Medical Center (PSHMC), we have used our farmers market, which has operated on campus for 2 years, to advance PCMH preventive health goals while developing continuing education opportunities for health professionals and trainees within an organization that has recently transitioned to the PCMH. In response to local needs assessments indicating high rates of obesity and sedentary lifestyles , market In 2010, we launched a weekly farmers market open seasonally on Thursdays from May through October on 10,000 square feet of farmland surrounding the PSHMC campus. The vision for the market was to combine agricultural, medical, and community resources to contribute to the long-term health of the region by providing more comprehensive care and services for patients and families. The market provides 25 vendors offering locally produced fruits and vegetables . It is rHealthy People 2010  to forge strategic partnerships between the market and health professionals in areas such as medicine, public health, and nutrition. A permanent “preventive health” booth within the market was established for addressing community health needs.Healthy People 2010 priority areas . Professionals and students from more than 40 disciplinary backgrounds signed up to volunteer for initial market sessions and submitted programming ideas.To capitalize on the expertise and knowledge within the academic medical center and to address the PCMH focus on interdisciplinary teamwork, the nursing community outreach team invited multiple Penn State health professionals and trainees to volunteer at the market. Managers of 60 departments were contacted, and managers whose resources and expertise matched the needs assessment were given priority. Invitations requested that volunteers join with nursing volunteers to provide health screenings and to develop educational topics that addressed We aimed to combine healthy lifestyle programming with nutritious market offerings in a way that would add greater value than traditional health fairs could. Although health fairs are the most recognized form of community-based health promotion in the United States, the lack of continuity and appropriate follow-up may limit their effectiveness. We believed the recurrent presence of interprofessional teams involved in one-on-one teaching with interactive tools at a weekly market could enhance PSHMC’s mission to serve as a community venue for preventive health promotion and whole-person care . By operThe nursing department began developing a plan with the market director to provide weekly preventive health-screenings  , interdiTo measure the impact of the market in meeting education and PCMH goals, we obtained descriptive data from hospital and market records and tracking information on the market’s e-mail listserv and its Facebook and Twitter sites. We computed summary measures to characterize how the market met the 6 standards outlined in the 2011 NCQA report on the PCMH  and bundled it with the produce. Funding for the 6-month program was established through a community organization with ties to the market. Through the collaboration, unsold market produce was used effectively, and students provided free labor while also taking advantage of opportunities in leadership, education, and professional development centered on local needs. Ultimately, market customers helped subsidize the project by purchasing produce at full price, which in turn enabled farmers to sell produce for the program at reduced cost. This partnership with low-income workers continued after the market season, enabling students and staff to engage an additional 142 adults and 14 children from the partner populations in immunization and dental-care programs. Many of the at-risk clients benefiting from medical outreach services had underlying respiratory disease and had never been immunized for influenza. The sites at which low-income workers were served have become partner sites for a first-year medical school course, “Social Influences in Health,” which requires students to make service-learning visits to underserved areas.Partnership with local food banks: Medical students delivered produce to local food banks and were invited to partner with the US Department of Agriculture’s National School Lunch Program  for high-risk patients. Medical center administration has recognized these students by granting them institutional community service awards.Market leadership has identified multiple areas for refinement of its operations to better meet PCMH standards, including establishing more comprehensive computer databases and capitalizing on automated technology to track processes and outcomes related to PCMH priorities. Such priorities include the following:Enhanced health care accessInterdisciplinary partnerships among hospital employees, students, communities, and regional health systemsIncreased cultural sensitivityImprovements in clinical skillsImprovements in social media skills for advancing preventive healthIncreased understanding of community health needsLeadership and civic activism related to community healthReduced health care costsImproved quality of care, as measured by patient health outcomes, and patient/family satisfactionAlthough our experiences suggest positive effects related to these PCMH goals, more inquiry will be necessary. We developed a logic model  based onWe have found that medical center markets can uniquely and cost-effectively support a medical center in achieving NCQA standards of the PCMH. The whole-person focus of the PCMH model demands not only competent clinical care but also commitment to such concepts as sensitivity to context and cultural differences, interdisciplinary collaboration, community engagement, and access to care — all of which can be addressed in the community space of a market. Markets that are developed around local needs and operate recurrently for extended periods may be especially valuable in areas that have a high prevalence of chronic disease. Collaborative partnerships between medical centers and markets could promote PCMH goals in multiple geographic regions and help train current and future health professionals to provide comprehensive, patient-centered care.


Germ cell protein expression in melanoma has been shown to correlate with malignancy, severity of disease and to serve as an immunologic target for therapy. However, very little is known about the role that germ cell proteins play in cancer development. Unique germ cell pathways include those involved in immortalization, genetic evolution, and energy metabolism. There is an ever increasing recognition that within tumors there is a subpopulation of cells with stem-cell-like characteristics that play a role in driving tumorgenesis. Stem cell and germ cell biology is intertwined. Given the enormous potential and known expression of germ cell proteins in melanoma, it is possible that they represent a largely untapped resource that may play a fundamental role in tumor development and progression. The purpose of this paper is to provide an update on the current value of germ cell protein expression in melanoma diagnosis, prognosis, and therapy, as well as to review critical germ cell pathways and discuss the potential roles these pathways may play in malignant transformation. The primary objective of melanoma treatment is to specifically eradicate the tumor while minimizing damage to normal tissue. In order to accomplish this goal, it is necessary to identify tumor-specific targetable pathways. One group of proteins that exhibit selective expression in cancer includes a group of proteins whose expression is otherwise normally limited to germ cells. Most of the research into germ cell proteins in cancer has focused on expression differences and immunogenic potential for vaccines. However there is an increasing effort to decipher the potential role germ cell proteins may play in oncogenesis.cancer testis antigen (CTA) was coined to refer to those proteins that are expressed primarily in the testis or placenta and cancers but not generally in normal adult tissues [The first germ cell-specific antigen discovered was the Melanoma Antigen 1 (MAGE-A1) in a patient with prolonged survival despite bulky lymph node disease [ tissues . Neverth tissues . The ter tissues . HoweverThere are now over 100 families and 255 cancer testis entries compiled in a database by Ludwig Institute for Cancer Research . The larThe developmental pathways leading to cancer are still being elucidated. However, it is now clear that melanoma tumors are heterogeneous, and subpopulations of cells with stem-cell-like features are present . Germ ceDespite recent advances in melanoma care, patients continue to die from this disease. Germ cell proteins may hold the key to new therapeutic approaches to prevent the development and evolution of cancer. This review will focus on differences in germ cell protein expression, role in diagnosis, prognosis, and therapy. Further we will discuss critical germ cell pathways and consider the potential roles these pathways may play in malignant transformation.Among malignancies, melanoma is one of the tumors with the highest frequency of CTA expression . Also inGerm cell protein expression has a potential diagnostic role. This is critically important in melanoma as the diagnosis of early melanoma versus an unusual benign mole can be quite challenging. Melanoma diagnosis is dependent on dermatopathologist's visual review of tissue sections. A study by Farmer et al. on the discordance of the histopathologic diagnosis of melanoma found that 38% of the samples reviewed had two or more discordant diagnoses . RecurreThe high expression of CTAs in melanoma and lack of expression in normal skin make the presence of these germ cell proteins a potential diagnostic tool . PrimaryExperiments have also been performed evaluating the germ cell protein SPANX. The expression pattern revealed a statistically significant difference between normal skin, benign nevi, and melanoma . The preThus germ cell protein/CTA expression patterns may serve as a diagnostic tool to differentiate between malignant and benign skin lesions. In addition to potential diagnostic value, germ cell proteins may also have prognostic value. After melanoma diagnosis, clinicians determine the relative prognosis in order to anticipate further care needs. Currently, prognostic information from the primary tumor is largely based on histopathologic criteria including Breslow's depth, ulceration, and mitotic rate. Nevertheless, some lesions that should have had a good prognosis by these variables ultimately prove to be lethal and some with a poor prognosis never recur. Thus there is need to better segregate the lethal and nonlethal lesions. A summary of CTAs and their associated prognostic features is presented . AccordiFurther a study found a specific prognostic relationship between the stage of melanoma and antigen present. According to Vourc'H-Jourdain et al., MAGE-A3 was significantly related to an increase in disease-free survival when expressed in stage III melanoma patients .There is also potential prognostic value in determining the type of CTA present in the tumor. According to Velazquez et al. primary tumors that are NY-ESO1 positive are thicker than those tumors negative for this antigen , while BThus CTA expression may have prognostic value in helping predict the potential aggressiveness of a tumor, potentially allowing clinicians to tailor therapeutic approaches accordingly.Even without a complete understanding of germ cell protein function in cancers, there have been advances in germ cell protein-based therapies. However, until more is known about their function, the related therapies primarily revolve around germ cell protein immunogenicity. Tumor cells are generally considered antigenic but not immunogenic, allowing them to evade host immune defenses . Recent Melanoma-specific vaccines have been created to specific germ cell proteins in an effort to drive the patient's own immune system to attack the cancer cells. There are several current trials to test the efficacy of such vaccines in melanoma patients, particularly MAGE and NY-ESO1 antigens . In addiIn addition to the role of CTAs as direct immunologic targets, germ cell protein expression may also provide clinicians with insight into tumor sensitivity to certain drugs. Cell lines which express at least one of three MAGE genes are more susceptible to tumor necrosis factor-mediated cytotoxicity , while tThus germ cell proteins may not only serve as direct immunologic targets but they may also direct the pharmacologic therapeutic approach.While the presence of germ cell proteins in malignancies is well documented, the reason why they are expressed is not clearly understood. Theories on germ cell protein expression can be grouped into three general categories including (1) accidental/nonfunctional, (2) accidental/functional, and (3) programmed/functional.The first is an accidental activation of germ cell-specific genes, which do not provide any functional benefit to the cancer cell. This scenario would include processes like widespread epigenetic regulation that would turn on germ cell genes secondarily but without any benefit to the cell. The most noted epigenetic controls in germ cell gene expression appear to be DNA methylation and posttranslational histone modifications .The second category consists of the accidental activation of germ cell genes, but with a functional benefit to the cancer cells. By providing a benefit, the cancer cells that express these germ cell genes may survive and thrive better than those without expression thereby expanding the population expressing beneficial germ cell proteins.Lastly, the expression of germ cell proteins may be programmed into the cell to be activated under certain conditions. These conditions could include hypoxia, lack of nutrients, and oxidative stress. Primitive organisms, like yeast, tend to increase genetic recombination when they experience such stresses in order to create new phenotypes that may be better suited for the environment . A recenIn all three scenarios it would be expected that there would be differential expression of germ cell proteins in the tumor mass as the cancer progresses. Indeed, germ cell proteins are often heterogeneously expressed. Specifically, heterogeneity has been noted in the expression of SSX, GAGE, and NY-ESO1 –47. ThisDrosophila has recently been identified [There is increasing evidence that germ cell pathways can be activated and may play a role in tumorigenesis. Hypoxic stress has been noted to induce germ cell protein expression in rat kidney fibroblasts, suggesting that hypoxia by itself may be enough to turn on some of these pathways . The gerentified . Knock-dentified . TogetheAlthough it is possible that germ cell protein expression is accidental/nonfunctional in cancer, given the association of upregulation with hypoxia and role in brain tumor development, it is more likely that expression of these pathways is programmed and functional in tumor development.Although there have been significant advances in unraveling the pathways involved in tumorigenesis, the role of germ cell proteins in this process remains to be fully understood. A recent review by Fratta et al.  covered Genes of the class I MAGE family have been found to be associated with the p53 corepressor, Kap1. This complex between MAGE and Kap1 may suppress apoptosis in tumors . The supMAGE-A1 was found to inhibit transcription by interacting with the transcriptional regulator, SKIP, and recruiting histone deactlyase 1 (HDAC1) . SKIP inHk), phosphoglycerate kinase-2 (Pgk2), and glyceraldehyde 3-phosphate dehydrogenase (Gapd) [Germ cells express a unique set of metabolic enzymes that allow them to utilize certain substrates more effectively. Spermatocytes are able to utilize lactate, pyruvate, and glucose while spermatids are only able to use lactate . There ae (Gapd) . Increase (Gapd) . Even ine (Gapd) . Diagnose (Gapd) . ExpressThe ability of germ cells to utilize lactate is also dependent on a testis-specific enzyme, Lactate Dehydrogenase C or LDHC . ExpressThe change in metabolism seen in cancer cells is potentially attributable to this expression of alternate enzymes that are normally expressed in germ cells. Tumors may exploit these proteins to adapt to changes in substrate concentrations that accompany abnormal cell proliferation. This display of metabolic adaptations supports the theory of programmed expression of germ cell proteins because by expanding a cell's useable substrates for energy, the cell has an increased chance of survival.Cell division requires cell cycling through mitosis; however germ cells also have the capacity to undergo meiosis. Unlike mitosis, in the first meiotic division the sister chromatids remain attached to each other and recombination occurs across homologous chromosome arms. The expression of meiosis proteins in cells attempting to undergo mitosis (termed meiomitosis) could cause genomic instability . MeiosisThus meiosis proteins have been noted to be expressed in melanoma and could function to cause genomic instability.Since telomeres shorten with every round of division, cancer cells must express a mechanism to maintain telomere length in order to protect the genetic material . In ordeIn summary, the expression of germ cell proteins in melanoma has the capacity to prevent cell death, alter transcription, improve energy options, promote evolution of the genome, and provide infinite growth potential.Germ cell proteins are expressed in melanoma and numerous other malignancies. The expression of these proteins in melanoma has been demonstrated to have both diagnostic and prognostic value. Therapeutically research is advancing based on CTA vaccines. However, the role of germ cell proteins during oncogenesis is still largely unknown. It is likely that they contribute to altered metabolism, immortalization, and genomic instability in melanoma and other cancers. The high level of expression of germ cell proteins within melanoma makes the disease an ideal model for dissecting their role in tumorgenesis. These efforts may provide insights into microenvironmental processes that differentially regulate the germ cell genes which in turn likely serve to drive tumorgenesis. Ultimately research unraveling these pathways may allow for the development of new therapeutic targets to control or potentially eradicate tumor cell growth.


Andropadus virens), a widely distributed African passerine, found across secondary and mature rainforest habitats and the rainforest-savanna ecotone. Satellite data that captured ecosystem structure and function explained up to 66% of the variation in song characteristics. Song differences observed across habitats, including those between human-altered and mature rainforest, have the potential to lead to reproductive divergence, and highlight the impacts that both natural and anthropogenic change may have on natural populations. Our approach offers a novel means to examine the ecological correlates of animal behavior across large geographic areas with potential applications to both evolutionary and conservation biology.Environmentally imposed selection pressures are well known to shape animal signals. Changes in these signals can result in recognition mismatches between individuals living in different habitats, leading to reproductive divergence and speciation. For example, numerous studies have shown that differences in avian song may be a potent prezygotic isolating mechanism. Typically, however, detailed studies of environmental pressures on variation in animal behavior have been conducted only at small spatial scales. Here, we use remote-sensing data to predict animal behavior, in this case, bird song, across vast spatial scales. We use remotely sensed data to predict the song characteristics of the little greenbul ( Acoustic characteristics of bird song, such as the temporal and spectral structure, may vary among habitats as a result of environmental pressures imposed by natural selection Morton . NumerouAndropadus virens), a common African rainforest passerine. We recorded vocalizations during field surveys across habitats, including those modified by humans. Because little greenbuls are found across much of equatorial Africa in a diversity of forest habitats, they provide an excellent test case for integrating quantitative data on acoustic behavior with detailed remote-sensing data on habitat characteristics.Distinguishing between habitats has now been made possible using spaceborne sensors that capture ecosystem characteristics that assist in explaining their biological function, health, and diversity Calder . HoweverLittle greenbuls have a repertoire of four songtypes. Songtype I and II are characterized by simple chatter with limited frequency ranges, whereas songtypes III and IV are more complex. In a previous analysis, the two complex songtypes (III and IV) were found to differ significantly between rainforest and ecotone habitats in Cameroon and were used as indicators of differences in habitat structure and/or cultural similarities (Slabbekoorn and Smith The objectives of this study were to: (i) evaluate the extent to which remote-sensing data alone can predict song characteristics of the little greenbul, (ii) determine whether distinct habitat types, such as primary rainforest, human-altered secondary forest, and ecotone, may harbor greenbul populations with unique song characteristics, and (iii) discuss some of the practical advantages and disadvantages of using remotely sensed data to examine the ecological correlates of avian song and predict evolutionary processes across large spatial scales.2 area) including undisturbed mature rainforest, anthropogenically degraded rainforests (or secondary forest), and ecotone forest  in Cameroon . Each song file was then visually inspected for background noise showing any spectral and temporal overlap with little greenbul song. If any overlap was found, the file was excluded from further analysis. Background noise that did not show overlap with little greenbul song was filtered using Avisoft-SASLAB Pro software  to ensure that the little greenbul song was the sound with the highest amplitude in the song file. This was a prerequisite for using the Automatic Parameter Measurement (APM) command in Avisoft-SASlab. APM was then applied to detect little greenbul song notes  using an amplitude threshold of −18 dB SPL relative to the maximum SPL in the sound file. This procedure ensured that measurements were standardized across all sound files. Within each detected song note, the following parameters were measured: start time, end time, entropy – measured as the mean of all spectra, maximum frequency – measured as the highest frequency exceeding threshold, minimum frequency – measured as the lowest frequency exceeding threshold, and peak frequency – measured at the sampling point with the highest amplitude. Song rate was calculated by dividing the song duration  by the number of notes in the song. We strove to include five individuals per site and up to five of each of the songtypes per individual. Statistical analyses were conducted on the mean value per songtype and per individual. Spectrogram settings for all analyses were: Fast Fourier Transform size = 512, Hamming window, bandwidth = 41 Hz, resolution = 31 Hz, temporal overlap = 87.5%. All measurements were then entered into Microsoft Excel (2007) from which we derived the following variables: song duration, song rate, average entropy of all song elements, and minimum, maximum and peak frequency of the song.Individual songs with a sufficiently good signal-to-noise ratio were clipped from the larger field recordings using Syrinx software  MODIS (Moderate Resolution Imaging Spectroradiometer), high resolution ∼100 m) ALOS PALSAR (Advanced Land Observing Satellite Synthetic Aperture Radar), and coarse resolution (∼2.25 km) QuikSCAT scatterometer (QSCAT), and derived products   best explained observed variation in acoustic features (responses), we used regression trees in ‘tree’  and externally (by using independent test sites). The internal verification used subsets of records iteratively to construct model, test the accuracy, and improve the predictive model Breiman . QuantitRegression trees and random forests were applied in the following manner: regression trees were performed on each song characteristic for each songtype , and witResults revealed that combinations of remotely sensed variables describing habitat characteristics explained large percentages of the variation in songtypes III and IV of the little greenbul. For example, remote-sensing variables explained 66% of the variation in maximum frequency of songtype III and 45% of the variation in minimum frequency of songtype IV.For songtype III, the best predictor of variation in maximum frequency was a remote-sensing layer capturing reflectance characteristics  was found to have a positive association with songtype IV maximum frequency, with higher max frequencies recorded in regions with higher reflectance values . However, a test of our model at new sites not used in model construction also resulted in accurate predictions (St. Estimate of Error = 19.4 Hz). Spatial predictions of songtype III maximum frequency suggest major breaks between habitat types within Cameroon, and suggest that this song characteristic is tightly linked to ecological conditions Fig. . SongtypTheobroma cacao) and coffee (Coffea spp.) plantations adjacent to human settlements, with significant disturbance associated with burning, firewood harvesting, and various forms of subsistence agriculture (Smith et al. In addition to habitat correlates with song across undisturbed rainforest and ecotone habitats, we also found songtype III maximum frequency to vary between mature rainforest and anthropogenically altered secondary forest, with birds exhibiting lower frequency song in secondary forest Fig. . Mature Spatial variables derived from remote-sensing data alone explained up to 66% of the variation in maximum song frequency in songtype III and 45% in songtype IV minimum frequency in the little greenbul. In the case of maximum song frequency in songtype III, we were able to use this high percentage of variation explained to make predictions of the song characteristics of little greenbul songs across a large unsampled region, including Southern Cameroon and parts of the neighboring countries of Equatorial Guinea, Gabon, Republic of Congo, and the Central African Republic. The ability to model and predict a complex trait such as vocal behavior, from remotely sensed data related to key structural differences in habitat, suggests the utility of satellite-based layers for identifying variation in other complex behavioral and phenotypic characteristics of species.Song characteristics were found to be differentially associated with rainforest, ecotone and secondary forest habitats. Previously, it has been shown that populations of little greenbuls occupying different habitats diverged in acoustic measures of song, with songs of populations in the rainforest having significantly different spectral and temporal characteristics compared to populations in ecotone habitats (Slabbekoorn and Smith Within forested sites themselves, the greatest observed differences in song characteristics occur between mature and secondary forest types. Song characteristics from secondary forests were intermediate between the values of rainforest and ecotone forest and may reflect noise produced with intermediate frequency values by the surrounding animal community (Lawton et al. in situ, it is also possible that individuals from the ecotone might be colonizing secondary forest. Future work seeks to distinguish between these two possibilities.The differences in song characteristics between disturbed and undisturbed forests suggest that human-altered habitats have induced behavioral changes in this species that have been rapid, consistent with findings from studies of some urban bird species (Slabbekoorn and den Boer-Visser We have shown it is possible to accurately predict geographic variation in a behavioral trait, in this case, bird song, using remote-sensing data. These types of spatially continuous predictions for a complex behavior such as song allow for predictions to be made in either inaccessible or infeasible regions, and greatly add in determining how behavioral variation is distributed across a landscape. This approach also affords the opportunity to identify geographic areas of variance in behavioral traits, corresponding to either physical barriers to dispersal, or in the case of little greenbuls, less obvious anthropogenic habitat changes that are associated with distinct behavioral differences within species. While our approach was able to use ground-truthed locations sampled during a subsequent trip to the region, it should be noted that models attempting to relate ecological variation to complex traits can be expected to perform only as well as the original data used as input. Particular importance should be placed on assuring that sampled locations cover as broad an ecological context as possible; niche models often lose their ability to predict in regions that are ecologically speaking represent extremes as compared to locations used as input in training . AdditioBecause behavioral traits are typically studied at relatively small spatial scales, we believe our approach, and extensions of it, has the potential of opening a new frontier for the use of remote-sensing data to investigate animal behavior in both natural and human-altered habitats at very large spatial scales. The observed and predicted variation in song documented in this study could ultimately be driven by a number of environmental factors, including forest structure (Wiley and Richards In conclusion, our approach provides a link between large-scale remotely sensed environmental variables and on-the-ground measurements of behavior that can have both evolutionarily important impacts and conservation implications. Further investigations and experiments are required to test the mechanistic hypotheses about correlations between greenbul song frequencies and habitat-dependent ambient noise profiles. However, the significant acoustic variation across habitats, including those between human-degraded secondary and mature rainforest, has the potential to lead to localized adaptation that may affect reproductive divergence and gene flow. Our approach also has the potential to help identify areas of dynamic biotic change, important for investigating a wide range of biotic processes. Identifying biodiversity hotspots for conservation prioritization and contact zones between evolutionary distinct populations can be difficult and costly. Therefore, we hope to stimulate future studies that will yield fundamental insights into evolutionary processes as well as valuable contributions to conservation.


Plant clonality, the ability of a plant species to reproduce itself vegetatively through ramets (shoot-root units), occurs in many plant species and is considered to be more frequent in cold or wet environments. However, a deeper understanding on the clonality-climate relationships along large geographic gradients is still scarce. In this study we revealed the clonality-climate relationships along latitudinal gradient of entire China spanning from tropics to temperate zones using clonality data for 4015 vascular plant species in 545 terrestrial communities. Structural equation modeling (SEM) showed that, in general, the preponderance of clonality increased along the latitudinal gradient towards cold, dry or very wet environments. However, the distribution of clonality in China was significantly but only weakly correlated with latitude and four climatic factors . Clonality of woody and herbaceous species had opposite responses to climatic variables. More precisely, woody clonality showed higher frequency in wet or climatically stable environments, while herbaceous clonality preferred cold, dry or climatically instable environments. Unexplained variation in clonality may be owed to the influences of other environmental conditions and to different clonal strategies and underlying traits adopted by different growth forms and phylogenetic lineages. Therefore, in-depth research in terms of more detailed clonal growth form, phylogeny and additional environmental variables are encouraged to further understand plant clonality response to climatic and/or edaphic conditions. Plant clonality is characterized by the ability of a plant species to reproduce itself vegetatively through ramets (shoot-root units) that are connected by spacers Distribution patterns of clonal species strongly depend on environmental conditions. Clonality is often considered to be important for the persistence of plants and the maintenance of plant communities in unfavorable environments, especially in cold or wet habitats Since clonal plants are considered to be more adapted to stressful  environments than non-clonal plants, here we tested the hypothesis that clonal plants are more frequent in cold or wet habitats. In China, climate varies strikingly and shows clear latitudinal patterns. At the same time vegetation regions in China are very diverse and are broadly distributed from the cold temperate zones to the tropics. We thus expected that: (1) there were significant relationships between plant clonality and annual temperature and/or precipitation, or the seasonality of each of these, across China. However, as these single climatic variables may covary and interact along latitudinal gradients We collected plant species data based on personal communications (see Acknowledgements) and carried out field investigations in the arid and semi-arid areas of China, authorized by the Chinese Academy of Sciences (CAS). A total of 545 communities across the whole of China, ranging from 18°50'24'' to 50°7'48'' N, and from 80°26'24'' to 128°4'12'' E, were sampled . FloristExamining the bivariate relationships between variables is an important precursor before using structural equation modeling (SEM) because it allows potentially nonlinear relationships to be identified We used structural equation modeling (SEM) to quantify the networks of interactions among latitude, climatic variables and clonality. SEM is a modern version of path analysis that allows for both the direct and indirect theoretical causal relationships between networks of intercorrelated variables to be tested Logistic regressions exhibited an increasing trend of the proportion of clonality in plant communities with temperature seasonality (TS) and precipitation seasonality (PS) while it decreased with MAT and MAP , in whicThere was a positive linear relationship between clonality as a proportion of all species in a community and latitude, since the quadratic model was not significantly better than the linear model . Climate factors and latitude together explained 1, 4 and 4% of the variation in all species Click here for additional data file.


Sc) within individual strains or isolates are intrinsically heterogeneous; the heterogeneity presumably arises due to spontaneous variation in PrPSc structure Sc variants quite quickly, presumably due to ongoing processes of spontaneous “mutations” of PrPSc structure The last several years have marked a noticeable shift in our perception of the prion replication mechanism. According to the “cloud” hypothesis, pools of infectious isoform of prion protein  was shown to result in a stable change in PrPSc properties including PK resistance, conformational stability, and amplification rate Sc variants (referred to as 263KR+ or HyperR+) was 104-fold higher than that of brain-derived 263K. Further experiments revealed that 263KR+ was absent in 263K brain material and emerged de novo as a result of reversible changes in replication environment It is difficult to prove experimentally whether new PrPin vitro using recombinant prion protein (rPrP) Sc are fundamentally different Sc and transmissible disease. An exhaustive search for miniscule amounts of PrPSc in the preparations of rPrP fibrils using PMCA that detects single PrPSc particles yielded negative results Sc-like conformations that might have been present in rPrP fibril preparations. An alternative hypothesis postulates that PrPSc evolved from rPrP fibrils via a series of deformed templating events C misfolding triggered by rPrP fibrils in hamsters was a self-replicating PrP state  characterized by an abnormally short, C-terminal PK-resistant core similar to that of rPrP fibrils Sc, atypical PrPres preferred monoglycosylated PrPC as a substrate and its amplification was RNA-independent. Over the course of several serial passages, atypical PrPres gave rise to PrPSc.The studies on synthetic prions provided intimate insight into the role of deformed templating in the evolution of transmissible protein states. In the last decade, a number of synthetic strains were generated in animals by inoculating amyloid fibrils produced ScSc emerged from a minor subpopulation.According to deformed templating, the parent template and the altered daughter state share common structural motifs. Consistent with this prediction, the study on synthetic strains produced by rPrP fibrils with a range of conformational stabilities revealed a strong correlation between stability of rPrP fibrils and end-product PrPSc variants that replicate better than others in a new host Sc physical properties and neuropathological features Sc in rPrP fibril preparations, such a long adaptation period was attributed to structural transformation of self-replicating states and evolution of authentic PrPSc via deformed templating Cross-species prion transmission often causes diseases with a diminished frequency and is accompanied by a prolonged silent stage, a phenomenon known as species barrier. When followed by serial passaging, the incubation time to disease decreases and strain properties change, reflecting adaptation of prions to a new environment. The “cloud” hypothesis attributes prion adaptation to selection of minor PrPin vitro, because PrPSc often undergoes gradual transformation in cultured cells or under different PMCA formats Sc proteinase resistance profiles were observed in PMCA with partially deglycosylated substrates Sc transformations in diverse cellular or biochemical environments are indicative of its dynamic nature, they should not be confused with actual strain mutation.Deformed templating is one of the mechanisms that account for prion strain mutation and evolution. Defining strain mutation could be difficult when prions are replicated Sc plasticity due to replication in diverse cellular or PMCA environments, it is worthwhile to compare this phenomenon to a norm of reaction, a concept that describes phenotypic variations of a single genotype across a range of environments. The concepts of norm of reaction and phenotypic plasticity were introduced into population genetics to describe variations in phenotype and the ability of an organism to change its phenotype, respectively, in response to changes in the environment. For instance, plants can acquire multiple morphologically distinct phenotypes within a single genotype to fit into a diverse range of environments. Noteworthily, phenotypic plasticity is not attributed to mutations but to an intrinsic norm of reaction. A concept analogous to norm of reaction could be useful for describing variations in PrPSc features observed across diverse replication environments, such as different cultured cells and PMCA formats that do not lead to stable changes in disease phenotype. In other words, norm of reaction is defined as variation of those strain features across diverse replication environments that are not essential for defining strain-ness.With the finding of PrP


Thioredoxin-interacting protein (TXNIP) has been linked to cell apoptosis and inflammation in a number of diseases, including type 2 diabetes  directly activates the NLRP3 inflammasome (Shimada et al., ROS within mitochondria must initiate the mitochondrial cascade upstream, causing inflammasome activation. Several studies show that mitochondrial ROS are present prior to NLRP3 activation (Zhou et al., Based on the mechanisms described, early apoptotic signals play a crucial role in inflammation. The earliest signal found is the shuttling of TXNIP from the nucleus to the mitochondria. A key therapeutic approach to limit inflammasome activation could be to inhibit mitochondrial shuttling of TXNIP. It was previously discussed that TXNIP inhibits reductive properties of TRX. In the mitochondria, this inhibition allows ROS to accumulate until TXNIP is shuttled to the cytoplasm where it interacts with NLRP3 (Davis and Ting, The role of TXNIP in inflammasome activation has proven invaluable in efforts to limit damage to cells and surrounding tissue. Once TXNIP reaches the mitochondria, it triggers a rapid cascade of apoptotic signals that end with TXNIP-NLRP3 binding and inflammasome activation. Early warning signals may be present prior to TXNIP translocation to mitochondria; however, such signals need to be identified. Further investigations into TXNIP localization and mitochondrial shuttling should be undertaken to completely map the signaling pathway, find factors that block TXNIP, and ultimately limit undesirable inflammasome activation.In recent years, there is continued evidence of the central role of inflammasomes in sensing danger signals and orchestrating a subsequent inflammatory program (Kolliputi et al.,


Identification of specific molecular alterations in cancer has revolutionized the diagnosis and treatment of the disease. Study of these alterations has not only greatly expanded our understanding of the biology of carcinogenesis – perhaps more importantly, these molecular alterations have been developed for clinically relevant applications, such as diagnostic tests, prognostic markers, and targets for rational therapeutic approaches. With the recent explosion of genomic, transcriptomic, and proteomic data from a wide variety of human cancers, the use of these molecular alterations as clinical tools will continue to rapidly expand. However, despite these rapid advances, each alteration must still be carefully validated to ensure that its clinical development is justified and will lead to an advance that improves the diagnosis and treatment of cancer.Oncotarget, O'Shannessy et al described important steps in the development of folate receptor alpha (FRA) expression as one such clinical tool [Oncotarget study, the authors characterized an immunohistochemical assay with a specific monoclonal antibody for the FRA protein, confirming its efficacy in both formalin-fixed paraffin-embedded tissue sections as well as fine needle aspiration specimens. In addition to analyzing its expression in a variety of normal tissues, the authors focused on its expression in lung cancers – they reported that immunohistochemical labeling for FRA was positive in a large proportion of lung adenocarcinomas, while it was negative in most squamous cell carcinomas. Thus, FRA expression is an additional characteristic that distinguishes adenocarcinoma from squamous cell carcinoma, and further investigation of the molecular basis of this difference may provide additional insights into the distinct behavior of these two cancer types. In addition, immunohistochemical labeling for FRA may also possess clinical utility in that it could add discriminatory power to the current routine panel for the work-up of lung cancer. However, further studies will be necessary to assess the diagnostic benefit of the addition of FRA to currently employed immunohistochemical stains in this differential diagnosis.In a recent issue of cal tool . This cecal tool . FRA is cal tool ,4. In thThe authors also took a further step to expand the clinical applicability of their findings – they showed that patients with lung adenocarcinomas with high FRA expression  had improved survival compared to those with low FRA expression. Although the association of FRA expression and survival in lung cancer has been previously reported using mRNA-based RT-PCR assays , this stin vitro as well as in mouse xenografts, and the antibody  is currently in clinical trials in human cancer patients [Folate receptors are promising targets for novel therapeutics, and several therapies directed against FRA have been developed. A monoclonal antibody targeting FRA inhibits the growth of cancer cells overexpressing FRA patients ,6. The det al employed rigorous validation of a potentially useful clinical tool – using an immunohistochemical assay with a specific monoclonal antibody, they show that FRA expression is relatively specific for lung adenocarcinoma and that high FRA expression is associated with improved survival. Though further work will be necessary to translate this assay (and the related targeted therapy) into human cancer patients, their study confirmed the potential of FRA as a prognostic marker in lung adenocarcinoma.In their study of FRA in lung adenocarcinoma, O'Shannessy


Disease is a major concern for the conservation of great apes, and one that is likely to become increasingly relevant as deforestation and the rise of ecotourism bring humans and apes into ever closer proximity. Consequently, it is imperative that preventative measures are explored to ensure that future epidemics do not wipe out the remaining populations of these animals. In this paper, social network analysis was used to investigate vulnerability to disease in a population of wild orang-utans and a community of wild chimpanzees. Potential ‘superspreaders’ of disease - individuals with disproportionately central positions in the community or population - were identified, and the efficacy of vaccinating these individuals assessed using simulations. Three resident female orang-utans were identified as potential superspreaders, and females and unflanged males were predicted to be more influential in disease spread than flanged males. By contrast, no superspreaders were identified in the chimpanzee network, although males were significantly more central than females. In both species, simulating the vaccination of the most central individuals in the network caused a greater reduction in potential disease pathways than removing random individuals, but this effect was considerably more pronounced for orang-utans. This suggests that targeted vaccinations would have a greater impact on reducing disease spread among orang-utans than chimpanzees. Overall, these results have important implications for orang-utan and chimpanzee conservation and highlight the role that certain individuals may play in the spread of disease and its prevention by vaccination. Pan troglodytes) and gorilla (Gorilla gorilla) populations in western Africa has provided a clear warning of the susceptibility of great ape populations to disease Disease is a major threat to the survival of the great apes. The emergence of Ebola and its impact on chimpanzee , raccoon (Procyon lotor) and coyote (Canis latrans) rabies vaccination programmes have been relatively successful so far in North America and Europe G. g. beringei) were successfully vaccinated against measles Canis simensis) that ranged within or near a corridor connecting two subpopulations reduced the overall extent of a rabies epidemic in this species Identifying potential superspreaders is important for conservation measures aimed at limiting the spread of epidemics, as these individuals could be targeted in vaccination programmes The identification of superspreaders in great ape societies would provide information for conservation actions aiming to prevent large-scale disease outbreaks in these iconic species. However, it is important not only to identify such individuals but also to assess the efficacy of vaccinating these animals in comparison to simple  random vaccinations. This assessment can be achieved by simulating the removal of individuals from their social network and measuring subsequent network fragmentation. Removal simulations can be interpreted as simulating vaccinations; removing an individual from the network removes all of the disease pathways on which it lies and effectively removes it from the disease transmission network Pongo pygmaeus wurmbii) and chimpanzees (P. t. schweinfurthii), and (ii) to model how vaccinating highly central individuals affects predicted susceptibility to the spread of disease in these two species. This study focussed on 46 independent orang-utans from a population in the Sabangau peat-swamp forest in Central Kalimantan, Indonesia, and 55 members of the Sonso chimpanzee community of Budongo Forest, Uganda. Orang-utans are characterised by an individual-based fission-fusion social organisation The aims of this study were (i) to determine if potential superspreaders exist in two great ape species, Bornean orang-utans . Data collection took place in a 9 kmChimpanzee data were collected between August 2007 and July 2010. 55 independent members of the Sonso community of Budongo forest were observed during focal follows: 12 adolescent females, 24 adult females, eight adolescent males and 11 adult males. Chimpanzee infants were defined as independent after the end of their fourth year The orang-utan data consisted of a total of 165,717 focal scans, recorded over a nine-year period. Nine of the 46 orang-utans  were never observed to associate with another identifiable orang-utan. As the analyses here focus on association patterns, these individuals were excluded from further analysis. Furthermore, these individuals will evidently have negligible or no impact on the spread of contagious disease between individuals, and would not be targeted for vaccination. For completeness, however, we ran all analyses with and without these nine individuals included, and the results were essentially the same. For brevity, therefore, we present only the results where they were not included. The chimpanzee data consisted of 34,143 focal scans recorded over a three-year period. Data were compiled over this long time period to ensure that the overall structure of the community or population was meaningfully represented.The association data for both species were then used to construct weighted association networks, using Dyadic Association Indices (DAIs) as edge weights. These indices standardise the time observed in association in relation to observation effort Central individuals were defined as those with high network strength, high weighted betweenness centrality or high weighted eigenvector centrality. Strength is the total weight of the edges attached to a node, so individuals with high strength are likely to have many strong relationships The importance of central individuals to network structure was then investigated by performing targeted and random removal simulations. To simulate the effect of vaccination or death of the most connected animals in each network, the 10 individuals with the highest strength were removed in a stepwise fashion by removing the individual with the highest strength first The results of the targeted removals were then compared with those produced following random removals in which 10 individuals were selected at random and removed sequentially from the network. The random removal of 10 individuals was repeated 10,000 times. Targeted and random removals were performed on both the orang-utan and the chimpanzee association networks. All of the analyses were performed using igraph The 37 orang-utans were connected by 141 edges out of a possible 666 (21%), thus the network was relatively sparse, in that most of the possible connections between individuals did not exist . IndividThe orang-utan network was more vulnerable to the targeted removal of individuals with high strength, weighted betweenness and weighted eigenvector centrality than to the removal of random individuals . The weiThe chimpanzee network was very dense , with 13After the removal of the individuals with the highest strength and weighted eigenvector centrality, the weighted mean shortest path length increased slightly more than under random removals . The weiThis study used a social network approach to investigate potential vulnerability to disease and to identify the presence of superspreaders in two species of great apes. Comparisons between these species were limited by the differences in network size and, in particular, the differences in the length of time over which data were collected . Although this prevented us from making detailed quantitative comparisons, the markedly different overall patterns that emerged highlight differences in how disease is likely to spread in the two species. The orang-utan network was characterised by sparse and weak connections compared to the density of strong connections in the chimpanzee community, suggesting that disease transmission between individual orang-utans is likely to be limited, in contrast to chimpanzees that are all inter-connected through a range of pathways, allowing for potentially very rapid disease spread. Contagious diseases may thus represent a lesser threat to orang-utans than chimpanzees, which may be a cause of the generally lower mortality seen in this species compared to chimpanzees It is important to note that this study only focused on within-species disease transmission, while in reality disease often spreads between species Although most orang-utans had few social relationships, three resident females possessed greater strength and weighted eigenvector centrality than average and two of these females also had considerably greater weighted betweenness centrality than average. These three females thus occupied disproportionately central positions in the network and could potentially therefore become superspreaders in a future disease outbreak, due to the ability to transmit a disease more widely than other individuals. More generally, females and unflanged males had higher centrality than flanged males, suggesting that these two age-sex classes may be more influential in disease spread than the flanged males of this population. At Tanjung Puting, Galdikas In stark contrast, superspreaders could not be identified in the chimpanzee study community. Although weighted betweenness centrality was positively skewed, strength and weighted eigenvector centrality scores were relatively evenly distributed, with many individuals having high scores. Similarly, at Kibale Forest, Uganda, Rushmore et al. Orang-utan and chimpanzee networks differed in their susceptibility to fragmentation following removals. Random removals had little impact on the structure of the orang-utan network while targeted removals caused considerable fragmentation. In contrast, the chimpanzee network was only more susceptible to targeted than random removals in one measure, weighted mean shortest path length; however, even this effect was much weaker than that found for the orangutan network. Even after randomly removing 10 individuals , the remaining chimpanzees were connected in one cohesive component.Orcinus orca) Apis mellifera) Tursiops truncatus) Greater susceptibility to targeted (but not random) removals has been found in a range of species, such as ground squirrels The chimpanzee network, by contrast, was relatively robust against member loss, suggesting that targeting a small number of key individuals for vaccination would not be a very effective method of preventing disease transmission in this species. This is because the high number of links between individuals ensures that disease can spread rapidly. In addition to devastating Ebola outbreaks, a number of chimpanzee communities have been recorded to suffer from respiratory epidemics, many of which were fatal The results presented here have implications for great ape conservation strategies. First, they suggest that targeted vaccinations are a potentially valuable preventative measure for orang-utans. Second, although chimpanzees are predicted to be far more susceptible to disease spread than orang-utans, vaccinations of targeted individuals may not provide a useful preventative measure. As there is a severe risk of human diseases spreading to chimpanzees alternative preventive measures need to be prioritised; once disease has penetrated a chimpanzee community, it will be difficult to stop.


Bacterial responses to antibiotics are concentration-dependent. At high concentrations, antibiotics exhibit antimicrobial activities on susceptible cells, while subinhibitory concentrations induce diverse biological responses in bacteria. At non-lethal concentrations, bacteria may sense antibiotics as extracellular chemicals to trigger different cellular responses, which may include an altered antibiotic resistance/tolerance profile. In natural settings, microbes are typically in polymicrobial communities and antibiotic-mediated interactions between species may play a significant role in bacterial community structure and function. However, these aspects have not yet fully been explored at the community level. Here we discuss the different types of interactions mediated by antibiotics and non-antibiotic metabolites as a function of their concentrations and speculate on how these may amplify the overall antibiotic resistance/tolerance and the spread of antibiotic resistance determinants in a context of polymicrobial community. Their dAntibiotic resistance in microbes is widespread and it has been demonstrated that soil bacteria are rich in resistance determinants to both natural and synthetic antibiotics commonly used in clinics . The colDespite a better understanding of the different mechanisms leading to resistance, exposure to antibiotics is still considered the major driver in the selection for antibiotic-resistant bacteria  and the The focus on the medical use of antibiotics has limited fundamental research regarding the other potential activities of these compounds in their natural settings, including the environment  and hosts such as humans, animals, and plants. In complex communities containing antibiotic-producing microorganisms, bacteria are naturally exposed to lethal and non-lethal antibiotics making them trained at responding to these compounds. Non-lethal levels of antibiotics can alter the expression of genes involved in a variety of bacterial functions like metabolism, regulation, virulence, DNA repair, and stress response . SubinhiAntibiotics are, like other bioactive small molecules, low molecular weight metabolites produced by secondary metabolism of microorganisms, i.e., are not considered essential for growth and viability. Microorganisms such as bacteria and fungi produce a wealth of small molecules that has been called the parvome . SecondaThe explosion of research in cell–cell interactions mediated by bioactive small molecules in microbiology has led to the general assumption that most interspecies cell–cell interactions could be labeled as “communication” or “signaling.” However, it is important to note that the demonstration of a biological response upon exposure to a chemical does not necessarily imply communication. The improper use of terms like signal, signaling, or communication in microbiology has created confusion since most interspecies metabolite-mediated interactions labeled as “signaling/communication” are often in conflict with evolutionary theories. A detailed analysis of the appropriate terminology is beyond the scope of this review; therefore we refer the reader to recent reviews that have thoroughly discussed the topic . A chemiTable 1, a signal is defined when both partners take advantage of the interaction , while cues or coercions have unidirectional benefits for receivers or emitters, respectively. In true signaling interactions, the production and detection of the signal have co-evolved specifically for that purpose and from an evolutionary perspective these events will only be maintained when both partners benefit from the information conveyed by the signal for which they evolved  from the oropharyngeal microbiota  or inhibit bacterial growth (bacteriostatic). Their concentrations are highly variable in natural communities and bacteria have evolved mechanisms to respond accordingly. Although their antimicrobial properties have been demonstrated in both Figure 2). From high to low concentrations, antibiotics act as either toxins, stress inducers, or as cues/coercions, respectively. Among interactions mediated by subinhibitory antibiotics, receiver bacteria can interestingly induce mechanisms leading to antibiotic resistance or tolerance . How antibiotics become stress inducers or cues/coercions will further be discussed in the following sections, but before we will briefly describe the toxin-like behavior of antibiotics and the impact of antibiotic resistance on the biological response exhibited by bacteria upon antibiotic exposure.To first differentiate the biological responses induced by antibiotics, here we represent their bioactivities from a receiver bacterium’s perspective on a large concentration spectrum , antibiotics behave like toxins on susceptible bacterial cells. However, although the understanding of resistance mechanisms is well-characterized, molecular mechanism(s) induced by lethal concentrations of antibiotics is an area of research where our fundamental understanding is still very limited . Recent Figure 2), antibiotic resistance would also impact receiver bacteria in an antibiotic dose-dependent manner. The presence of an antibiotic resistance mechanism would shift the spectrum of responses to an antibiotic to higher concentrations. The resistance would lower the effective concentration of antibiotics at the target site . Exceptions to this would occur if there were secondary target sites for the antibiotics that mediate other responses. At toxic concentrations, resistance would function in the conventional protective role and allow receiver bacteria to avoid the antibiotic toxicity by blocking death or growth arrest. At subinhibitory concentrations, antibiotic resistance genes would shift the effective antibiotic concentration required for inducing the biological responses  of receiver bacteria  could therefore establish a chemical “arms race” between producer and receiver bacteria independent of lethal effect. In the context of bacterial communities, the displacement of the response curve for a single strain will modify its own behavior, which may in return shift the community composition or activity. Stress induction, coercion, and detection of cues are selectable phenotypes that can be tuned to meet the conditions of natural environments. Selections that reduce stress induction and coercion could be contributing factors in the evolution of the “cryptic resistome” . In the context of chemical interactions within natural communities, antibiotics released by emitter bacteria at lethal concentrations for the receiver cells would not be considered as a signaling event, but rather coercion at the extreme. Coercion can occur at subinhibitory concentrations and one bacterial cell may use chemicals to manipulate another. If the receiver cell possesses the corresponding antibiotic resistance determinant, receiver bacteria will be less susceptible to chemical manipulation and the overall benefit or harm of the interaction will therefore be reduced.In natural environments, antibiotics are likely present in a gradient of concentrations while receiver organisms may also be heterogeneous. Even in a homogeneous clonal population, cells may be present in different physiological states and the presence of antibiotic tolerance and resistance mechanisms will shift the response curves for individual cells within the population  and the active concentration for a particular response will be shifted higher by resistance mechanisms . In natural environments, a population will be expected to exhibit a heterogeneous response because of gradients of antibiotic concentration and heterogeneity in the responsiveness of different cells in the population . These differences in cellular responsiveness may be due to genetic heterogeneity and/or through differences in physiological states of different cells in the population.Outside of the well-mixed homogeneous environments of laboratory cultures, antibiotic effects on bacterial populations will be heterogeneous. For any bacteria, the response to a specific antibiotic will be concentration-dependent . When behaving as stress inducers, antibiotics often induce the SOS stress response, which is also associated with various antibiotic resistance mechanisms. The following section will mainly highlight some of the main resistance mechanisms impacted by the induction of the SOS response in bacteria upon antibiotic exposure.Antibiotics at subinhibitory concentrations can act as stress inducers or cues/coercion on receiver bacteria , and chemical inactivation TetX; . The regEnterococcus species  is the primary mechanism of resistance . Six typ species . Interes species . VancomyStaphylococcus aureus. This affects biofilm formation and autoaggregation (P. aeruginosa biofilms induces tolerance against aminoglycosides by chelating cations (P. aeruginosa virulence-associated genes leading to increased secretion of phenazines and rhamnolipids (P. aeruginosa phenazines (P. aeruginosa biofilms through hydrogen peroxide (H2O2) mediating cell lysis .Although subinhibitory concentrations of antibiotics like tetracycline and vancomycin can induce their own resistance mechanisms, other biological responses have the potential to indirectly impact antibiotic tolerance as well. It was recently demonstrated that subinhibitory concentrations of β-lactam antibiotics induce the autolysin-dependent release of extracellular DNA (eDNA) by regation , two gro cations . Additionolipids . Pyocyanenazines  was recell lysis . These eThese are a few examples demonstrating that sensing of subinhibitory concentrations of antibiotics as cues can trigger direct or indirect mechanisms, for which receiver bacteria will subsequently have the ability to resist or tolerate lethal concentrations of antibiotics. In microbial communities, the response of one organism may lead to induction of antibiotic resistance/tolerance in other bacteria.A significant portion of the antibiotic resistome is made of mobile resistance genes that are horizontally transferable between bacterial cells . Mobile E. coli were demonstrated to display some level of protein translation  or more general mechanisms like biofilms induction. However, the induction of antibiotic resistance/tolerance via cues is not limited to antibiotics. Within natural communities, bacteria are continuously exposed to a variety of small molecules other than antibiotics. Among these bioactive metabolites, some have been shown to induce biological responses in bacteria leading to a change in the overall antibiotic tolerance profile.2S), and volatile ammonia were recently shown to impact the antibiotic tolerance profile of receiver bacteria  patients .For this exercise, we chose a simple polymicrobial community including the pathogens patients , 2011 anirulence . In the S. aureus in an autolysin-dependent manner and triggering biofilm formation as a growth protective mechanism  restored their sensitivity to aminoglycosides to a level comparable to non-persister cells (in vivo and in vitro suggesting that synergistic drug combinations have therapeutic potentials (The nature of the effect of volatile ammonia on antibiotic resistance is dependent on the class of antibiotic. While bacterial exposure to volatile ammonia induces tolerance against β-lactam and tetracycline antibiotics it increases the efficacy of aminoglycosides . Intereser cells . These ttentials .in vitro susceptibilities to isolated organisms has many limitations clinically and in polymicrobial infections, many community interactions can reduce antibiotic efficacy in addition to traditional resistance mechanisms. Understanding chemical interactions within microbial communities should include the role of antibiotics in these communities and mechanisms of resistance. This will provide new opportunities and strategies to accelerate the discovery of bioactive molecules. Finally, we have to continue our efforts toward our global understanding of these non-classical views of antibiotic-mediated resistance mechanisms as complementary and potential strategies to new drug development programs in order to control and adequately manage the spread of antibiotic resistance in the future.Furthering our understanding of bacterial interactions mediated by antibiotics and non-antibiotic molecules will be valuable in the development of new strategies to combat antibiotic resistance. Although significant findings have been made in this emerging area of research, we need to further expand our views of these dynamic interactions in microbial communities. The conventional approach of determining 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.