Acute kidney injury (AKI) is common in children admitted to hospital. Whilst some recover normal kidney function following an acute kidney insult, a significant proportion experience long-term sequelae. The aim of this review is to summarize current understanding of the processes that can lead to sequelae following AKI. Kidney injury, repair, recovery and progression are described. Risk factors for progression are outlined, and potential strategies to stratify the risk of progression in children with AKI are discussed. Clinical management priorities to minimize sequelae are suggested. Looking ahead, novel therapeutic targets are discussed with the potential to accelerate adaptive repair and ameliorate the progression and sequelae of AKI in the future. The incidence of acute kidney injury (AKI) in children is rising. One in three children worldwide experience AKI during an episode of hospital care . Most chTraditionally, AKI in children had been understood to be an entirely reversible phenomenon. In recent years, this customary view has been challenged by emerging evidence that supports a strong link between AKI and chronic kidney disease (CKD) in adult patients . In thisChildren have the potential to recover ostensibly normal kidney function following an episode of AKI, however a growing body of evidence suggests that chronic sequelae may be under-recognized. Over one-third of 176 children treated for AKI at a U.S. tertiary center had reduced kidney function, or remained dialysis dependent, at the time of discharge from hospital . In the 2 presents challenges in defining baseline kidney function for infants. Thirdly, children have substantial renal reserve, so significant kidney damage resulting from an AKI episode can be compensated by hyperfiltration and may therefore not be reflected in the plasma creatinine level until adolescence or adulthood [Some children do recover their baseline kidney function following AKI, however understanding functional renal recovery in children is challenging for a number of reasons. Firstly, pediatric follow-up studies to date have not applied a standard definition of renal recovery, with definitions varying from dialysis independence during a hospital stay through to normalization of plasma creatinine, blood pressure and proteinuria. Secondly, the natural history of increasing glomerular filtration rate (GFR) in the first year of life from 15 to 90 ml/min/1.73 mUntil recently, progress in characterizing the events that follow an acute kidney insult was hampered by the lack of a consensus definition of progression and its associated events. Following recognition of this issue, a working group of the 13th Acute Dialysis Quality Initiative (ADQI) Conference sought to clarify these concepts. This group outlined a paradigm for understanding the clinical course of AKI and proposed definitions for terms related to events mediating resolution or progression . They coConcepts relating to progression following AKI are best understood in the context of the sequence of events described above. In the development phase, a kidney insult leads to injury. In the extension phase, repair processes are initiated in response to injury. Adaptive repair is a coordinated process, resulting in the resolution of renal structure without long-term sequelae. In contrast, maladaptive repair results in durable reduction in kidney function usually associated with a change in renal structure. The extension phase represents the net result of renal injury and repair processes. Renal recovery is a consequence of adaptive repair that leads to durable improvement in kidney function or structure. Conversely, progression is defined as a durable change in kidney structure or function detected by biomarkers, imaging studies or histopathology .2 or evidence of structural kidney damage for less than 3 months. This concept bridges the gap between the “Loss” and “End Stage” categories of the pediatric RIFLE criteria [Recent progress has been made in operationalizing a definition of renal recovery; the Kidney Disease: Improving Global Outcomes (KDIGO) AKI work group developed the entity “acute kidney disease” to characterize partial functional recovery following AKI . This wacriteria . In clinThere is a growing understanding of the pathophysiologic mechanisms that underlie progression following AKI. Acute kidney insults disrupt tubules, capillaries and glomeruli, with the proximal tubule being particularly vulnerable . Repair Animal models of AKI have led to the identification of a number of mechanistic pathways that contribute to progression following an acute kidney insult. These include oxidative stress, the DNA damage response pathway, epigenetic changes, mitochondrial dysfunction and the complement pathway, as illustrated in Fig. Oxidative stress plays a key role in both the development of kidney injury following an acute insult and maladaptive repair and progression following the injury itself , 24. NotThe DNA damage response is a network of signaling pathways that can trigger cell cycle arrest, or cell death, in response to injury. DNA damage response pathways are activated by AKI . AberranEmerging evidence suggests a role for complement pathways in progression following an acute kidney insult. Knock-out of cell surface complement regulatory proteins from proximal tubular epithelial cells increases susceptibility to progressive injury in ischemia–reperfusion models of AKI , 36. ComIt is anticipated that growing knowledge of the mechanisms that underlie progression following AKI will ultimately lead to therapies that may ameliorate long-term sequelae, as discussed further in the section The identification of children who are most at risk of progression following AKI is necessary in order to target interventions to minimize progression. Risk factors for long-term sequelae following AKI and techniques to stratify the risk of progression in children are outlined in this section.The severity of a kidney insult is a well-established risk factor for progression following AKI. Insults that are severe and/or prolonged can disrupt the balance of inflammatory and anti-inflammatory factors required to facilitate adaptive repair processes, and thus compromise renal recovery , 38. MulPre-existing CKD confers an increased risk of progression following AKI. Animal studies have demonstrated a propensity for maladaptive repair in the context of reduced renal mass . ClinicaMany of the risk factors for progression outlined above are challenging to quantify. Strategies with greater discriminative power to identify children at risk of progression are needed. Large data techniques in which electronic health information, such as laboratory values, vital signs and patient characteristics, are used to build prediction models for events have been successfully used to stratify adult patients at risk of developing AKI . FurtherThe use of urinary biomarkers to inform the risk of progression following AKI has shown some potential. In adult patients, three biomarkers have been found to predict progression of AKI among patients with acute cardiorenal syndrome, namely urinary angiotensinogen, urinary neutrophil gelatinase-associated lipocalin and urinary interleukin-18 . Whilst Imaging applications have shown promise in identifying features that may predict progression following AKI. Two magnetic resonance imaging (MRI) techniques, namely diffusion-weighted-MRI and blood oxygen level-dependent-MRI, have been used to evaluate tubulointerstitial alterations and parenchymal hypoxia in patients with both AKI and CKD with some success . UltrasoThere is a clinical need to develop reliable strategies to stratify the risk of progression following AKI in the pediatric population in order to tailor appropriate therapy and follow up with the aim of minimizing long-term sequelae.Strategies to minimize progression following AKI in children have not been systematically studied to date. Interventions should target removal of kidney insults and optimization of conditions that facilitate adaptive repair. Clinical priorities include optimization of kidney perfusion, removal of iatrogenic insults, attention to urinary drainage and correction of acid–base and electrolyte disturbances.Several factors underlie the kidneys’ vulnerability to malperfusion after an acute insult. Autoregulation of renal blood flow can be disrupted, compounded by falling oxygen tension in the renal medulla which is already relatively hypoxic under normal physiologic conditions. Repair processes are particularly vulnerable to hypoxia in the context of tubulointerstitial edema, vasoconstriction, endothelial injury and capillary compression in AKI . ImpaireClinical observations in adult critical care patients support the key role of optimal renal perfusion in promoting adaptive repair following AKI. Both higher systemic oxygen delivery and higher mean arterial blood pressure are independently associated with a lower risk of sequelae following AKI . HoweverNovel therapies to reduce the impact of renal hypoperfusion on progression following AKI are on the horizon. These will be discussed further in the section Persistent or repeated kidney insults hamper adaptive repair. In children with AKI, urgent evaluation of all factors that may compromise adaptive repair, as well as their removal, is therefore paramount.A common iatrogenic kidney insult in the hospital setting is medication with nephrotoxic potential—in one study 86% of non-critically ill children were exposed to this risk . FrequenRelieving the urinary tract obstruction is a well-established management priority in AKI in both adults and children . This isAcid–base homeostasis can be severely disrupted following AKI. Processes such as proximal tubular bicarbonate reabsorption, distal tubular proton excretion and medullary urea recycling are compromised. Severe acidosis can compromise the coordination of adaptive repair by disrupting protein charge, conformation and function. In the clinical setting, controlling acid–base disturbance is likely to facilitate adaptive repair.Electrolyte dysregulation is a further feature of AKI that can disrupt cellular function and thus hamper adaptive repair. Careful attention to plasma electrolyte levels and correction of gross abnormalities may therefore ameliorate progression.Renal replacement therapy (RRT) may be necessary to control electrolyte and acid–base disturbance in children with oligo-anuric AKI. The optimal timing and modality of RRT to reduce the risk of progression have not yet been determined. In critically ill children, earlier initiation of continuous RRT may improve survival . A key pWhilst current clinical strategies to minimize progression focus on optimization of the microenvironment in order to facilitate adaptive repair, treatments to accelerate recovery are on the horizon. Potential targets for future therapies and their associated biochemical pathways are discussed in this section and summarized in Table A key pathway with future therapeutic potential is that of hypoxia and oxidative stress, both factors which can mediate progression , 24. A nMitochondrial dysfunction, which can result from AKI, presents an additional pathway relevant to progression. Suppression of mitochondrial biogenesis has been demonstrated in animal models of AKI  and is lEpigenetic changes can influence repair and progression following an acute kidney insult. Epigenetic alterations are activated after AKI and include histone modifications, DNA methylation and chromosomal conformational changes . Novel tThe response of renal tubular epithelial cells to DNA damage is implicated in fibrosis of the kidney. Modifying the cell cycle of renal tubular epithelial cells via inhibition of tumor suppressor p53 and inhibiting downstream signaling from tubular cells in cell cycle arrest can prevent progression and fibrosis . FurtherWhilst the avenues discussed above hold promise for future accelerated adaptive repair in children at risk of AKI progression, they are all several steps away from being evaluated in the clinical setting. For now, the mainstays of clinical management to minimize progression remain optimization of renal perfusion, urinary drainage and the extracellular environment, and minimization of ongoing kidney insults.Acute kidney injury is common in children treated in hospital, and a significant proportion experience long-term sequelae. Following AKI, adaptive repair processes can result in the recovery of kidney function; conversely, maladaptive repair can lead to progression, defined as a durable change in kidney structure or function detected by biomarkers, imaging studies or histopathology.Established risk factors for progression include severity of the kidney insult, the cumulative impact of multiple AKI episodes and pre-existing CKD. Further risk stratification using electronic health record data, biomarker panels and imaging modalities are being evaluated.Clinical strategies aimed at minimizing progression include optimization of kidney perfusion, urinary drainage and electrolyte and acid–base balance, as well as prompt removal of ongoing kidney insults. Future therapies that may accelerate adaptive repair following AKI and ameliorate progression are on the horizon.Increasing severity of acute kidney injuryRecovery of plasma creatinine to baselineA durable change in kidney structure or function detected by biomarkers, imaging or histopathologyExtra-renal complications following AKI.Progression following AKI is defined as:Plasma creatinine may not changeinjury initiates repair mechanismsadaptive repair results in progressionprogression can lead to chronic sequelae.Following an acute kidney insult, which of the following are true?Chronic kidney diseaseRepeated episodes of AKISeverity of the kidney insultInterstitial fluid overload.Risk factors for progression following AKI in children include:Early angiotension-converting enzyme inhibitionDiuretic therapyOptimizing kidney perfusionAll of the above.Clinical management priorities to reduce progression following AKI include:Oxidative stressCell cycle modificationHistone deacetylase inhibitionAll of the above.Mechanistic pathways for future therapies include:


During the transition period, fatty liver syndrome may be caused in cows undergo negative energy balance, ketosis or hypocalcemia, retained placenta or mastitis problems. During the transition stage, movement of non-esterified fatty acids (NEFA) increases into blood which declines the hepatic metabolism or reproduction and consequently, lactation performance of dairy cows deteriorates. Most of studies documented that, choline is an essential nutrient which plays a key role to decrease fatty liver, NEFA proportion, improve synthesis of phosphatidylcholine, maintain lactation or physiological function and work as anti-oxidant in the transition period of dairy cows. Also, it has a role in the regulation of homocysteine absorption through betaine metabolite which significantly improves plasma α-tocopherol and interaction among choline, methionine and vitamin E. Many studies reported that, supplementation of rumen protected form of choline during transition time is a sustainable method as rumen protected choline (RPC) perform diverse functions like, increase glucose level or energy balance, fertility or milk production, methyl group metabolism, or signaling of cell methionine expansion or methylation reactions, neurotransmitter synthesis or betaine methylation, increase transport of lipids or lipoproteins efficiency and reduce NEFA or triacylglycerol, clinical or sub clinical mastitis and general morbidity in the transition dairy cows. The purpose of this review is that to elucidate the choline importance and functions in the transition period of dairy cows and deal all morbidity during transition or lactation period. Furthermore, further work is needed to conduct more studies on RPC requirements in dairy cows ration under different feeding conditions and also to elucidate the genetic and molecular mechanisms of choline in ruminants industry. For methylation reaction, SAM contributes three molecules that changed phosphatidylethanolamine into phosphatidylcholine by phosphatidylethanolamine N methyl transferase enzyme, then further phosphatidylcholine generates choline by the action of phospholipases through cytidine diphospho choline pathway  is considered as a top limiting amino acid (AA) for milk production and it is a good opportunity to supplement rumen undegraded form of methionine in the ration of dairy cows typically in order to improve milk or milk protein production, sustain contribution of SAM molecules for choline synthesis and enhance VLDL production to reduce ketones body during the early lactation period in dairy ruminants  concentration in the blood shows liver lipidosis conditions or liver dysfunction, during postpartum period, the concentration of TBIL of cows were found significantly high  is well understood and documented but in the transition period of dairy cows is still under investigation. The reviewed studies suggested that, considering RPC supplementation levels for best responses were noted to be 12–20 g/d of RPC in cows’ ration, but the recommended doses during transition period is still unclear. Therefore, the next step is to determine how much RPC should be given at transition period to overcome its related problems and maintain performance of dairy cows. Further epigenetic mechanism and omics technology might be an effective strategy to further understand choline, folate and methionine interaction and their significant functions during transition period.


We review a recent shift in conceptions of interoception and its relationship to hierarchical inference in the brain. The notion of interoceptive inference means that bodily states are regulated by autonomic reflexes that are enslaved by descending predictions from deep generative models of our internal and external milieu. This re-conceptualization illuminates several issues in cognitive and clinical neuroscience with implications for experiences of selfhood and emotion. We first contextualize interoception in terms of active (Bayesian) inference in the brain, highlighting its enactivist (embodied) aspects. We then consider the key role of uncertainty or precision and how this might translate into neuromodulation. We next examine the implications for understanding the functional anatomy of the emotional brain, surveying recent observations on agranular cortex. Finally, we turn to theoretical issues, namely, the role of interoception in shaping a sense of embodied self and feelings. We will draw links between physiological homoeostasis and allostasis, early cybernetic ideas of predictive control and hierarchical generative models in predictive processing. The explanatory scope of interoceptive inference ranges from explanations for autism and depression, through to consciousness. We offer a brief survey of these exciting developments.This article is part of the themed issue ‘Interoception beyond homeostasis: affect, cognition and mental health’. On this view, the brain is not an elaborate stimulus-response link but a statistical organ that actively generates explanations for the stimuli it encounters—in terms of hypotheses that are tested against sensory evidence. This perspective can be traced back to Helmholtzian formulations of unconscious inference . Over thinteroception  and emphasize the key role of uncertainty or precision in shaping the interplay between prior beliefs and sensory evidence. Precision-weighting of recurrent signalling in cortical hierarchies is closely associated with neuromodulation, providing important clues about developmental origins of conditions like autism; it is also associated with attention, suggesting novel accounts for symptom expression due to aberrant attention to interoceptive signals.Turning to functional neuroanatomy, we outline the functional architecture of interoceptive inference and review recent suggestions that perceptual predictions originate preferentially in agranular cortices ,17, whil2.Current formulations of Helmholtz's notion are now the most popular metaphors for neuronal processing and are usually considered under the Bayesian brain hypothesis as predictive coding ,19–21. Pface—see figures expectation. These causes are referred to as hidden because they have to be inferred from their sensory consequences. In other words, they can never be directly observed and are forever hidden behind a sensory veil.In these schemes, neuronal representations in higher or deeper levels of neuronal hierarchies generate predictions of representations in lower levels. These descending predictions are compared with lower-level representations to form a prediction error . This mismatch or difference signal is passed back up the hierarchy, to update higher representations . The recurrent exchange of signals between adjacent hierarchical levels resolves prediction error at each and every level, resulting in a hierarchically deep explanation for sensory inputs. In computational terms, the activity of neuronal populations is assumed to encode Bayesian beliefs or probability distributions over states in the world that cause sensations active inference )Extending active inference to include autonomic reflexes and interoceptive predictions raises many further interesting questions . For exaThe practical implications of these ideas are highlighted by their application to a variety of clinical conditions in which atypical interoceptive inference may play important roles in aetiology and/or in symptom expression. Emotional disorders like alexithymia are relatively straightforward to explain in terms of atypical interoception, while more complex and heterogeneous constructs like anxiety have been considered in terms of interoceptive prediction error for more than a decade ,83,101. res cogitans and res extensa, also achieved a certain notoriety for introducing the doctrine of the ‘beast machine’ (ca 1694). He argued that while humans had minds directing their behaviour, non-human animals (‘brutes’) were nothing more than unthinking, unfeeling machines that breathe, digest, perceive and move ‘like clockwork’. Now that we can see how human minds are deeply grounded in embodied physiology, and that similar functional principles may unite physiological regulation with perception of the external world and the guidance of actions and behaviour, an inversion of Descartes’ doctrine seems plausible: that our subjective experiences of selfhood may arise because of, and not in spite of, the fact that we too are ‘beast machines’.Altogether, considering embodied selfhood through the lens of prediction error minimization brings a new way to think about an old doctrine. Rene Descartes, besides dividing the world into


While transplant recipients are susceptible to develop non-melanoma skin cancer and these cutaneous lesions are the significant source of morbidity; therefore, a routine screening of these patients for skin malignancies should be performed. Phenotypic, clinical and environmental factors associated with the skin tumors following renal transplantation are different particularly due to geographic area as well as due to the study sample size, genetic variations, infectious diseases and also history of immunosuppression regimens. An important and also vital issue that has been raised recently in Nephrology science is the risk factors for non-melanoma skin cancer in kidney transplant patients in different populations in various geographic regions.et al  have been completely observed by authors.The authors declared no competing interests.No funding from any source.


Here, we are releasing the interactome figure in which all the nodes (schizophrenia-associated genes and their interactors) and edges (PPIs) are all labeled by their gene symbols, and are color coded by whether they are known or novel PPIs/interactors (We recently published the schizophrenia interactomeeractors . An elec


Electrical brain stimulation (EBS) is an appealing method to treat neurological disorders. To achieve optimal stimulation effects and a better understanding of the underlying brain mechanisms, neuroscientists have proposed computational modeling studies for a decade. Recently, multi-scale models that combine a volume conductor head model and multi-compartmental models of cortical neurons have been developed to predict stimulation effects on the macroscopic and microscopic levels more precisely. As the need for better computational models continues to increase, we overview here recent multi-scale modeling studies; we focused on approaches that coupled a simplified or high-resolution volume conductor head model and multi-compartmental models of cortical neurons, and constructed realistic fiber models using diffusion tensor imaging (DTI). Further implications for achieving better precision in estimating cellular responses are discussed. Electrical brain stimulation (EBS) is an intriguing electrotherapy designed to regulate cortical excitability through a regulated current, and is used increasingly to treat various neurological disorders and as an adjunct to medical therapy for depression  is the most cost-effective way to demonstrate the stimulus-induced electrical current flow in the brain with a myriad of possible combinations of stimulus parameters .The simplified head model is a concentric sphere composed of three or four layers based on the assumption that the head is a perfect sphere, and is a model used widely for noninvasive brain stimulation  to each compartment of the neuronal models. Then, the external current was multiplied by waveforms that are time-derivatives of TMS coil current waveforms and this product stimulated neurons  was constructed using MRI data  along the tractography-based fibers (axons) was estimated for noninvasive stimulation (Opitz et al., While considerable literature has investigated brain stimulation effects using the magnitude of the stimulus-induced electric field, multi-scale models demonstrated that the spatial extent of excitation thresholds was not consistent with the distributions of the electric field. For example, an electric field with a higher magnitude induced by magnetic stimulation was focused on the top of the gyrus, while neural activations were observed in the sulcal walls (Janssen et al., There are challenges in the technical features of multi-scale modeling, which entails a two-step process:First, the electric field distribution produced by brain stimulation is computed using the head models.Second, multi-compartmental models of cortical neurons are constructed virtually in the head models, and then external electric fields are applied to the neuronal models.Two types of head models, simplified and anatomically realistic, are used in the multi-scale models. The simplified head model is highly efficient with respect to computational time and it is easy to couple neuronal models with the head model directly. Because of the speed of the simplified head model, spherical models comprising concentric spheres are used widely in present navigators for TMS. However, they may provide inaccurate patterns of the stimulus-induced electric field that result in falsely guided stimulation (Nummenmaa et al., A further challenge arises in coupling the neuronal and the head model, which has a complex and diverse geometry. Although the anatomically realistic head model requires intricate procedures to combine neuronal models because of this geometry, recent analyses have focused on it because it may provide more precise predictions at the macroscopic and microscopic levels. For typical PN, it is intuitive to couple layer 2/3 neurons with the head model by aligning them perpendicular to the cortex in the same way that layer 2/3 neurons are positioned within the gray matter. In contrast, modeling layer 5 PN is quite complicated because their axons extend into the white matter. When layer 5 neurons are combined with the simplified head model, the axons extend straight because of their simple geometry. In the anatomically realistic head model, the direction of the axons might be fixed in a specific direction by restricting neuronal distributions to a small area (for example, a block of the precentral gyrus; see Figure Patton and Amassian  were theHern et al.  reportedThese modeling studies presented lack explicit validation, and modeling results are confirmed commonly by established experimental observations. In electrical stimulation, neurons located perpendicular to the electrode showed depolarization in the axon and hyperpolarization in apical dendrites during anodal stimulation, and concomitantly, the opposite polarization patterns were observed in cathodal stimulation (Hern et al., Computational studies using volume conductor head models have demonstrated a stimulus-induced electric field that interpolates the target area activated, and thus cannot deduce detailed neuronal responses. Numerical studies using a multi-compartmental model of neurons have shown computed neural responses, but they cannot provide extensive target sites and have little control over external stimulation parameters. To guide cellular targets induced by brain stimulation with myriad combinations of stimulus parameters, recent literature has introduced multi-scale models that combine volume conductor head models and multi-compartmental neuron models. In addition, because it is necessary to estimate realistic electric fields using the anatomically realistic head model, constructing multi-scale models with this model is an undisputed method that provides accurate activated cellular targets. Thus, it may be important to increase the realism of multi-scale models further. Therefore, future studies may illustrate the cellular responses in a more detailed manner and further our understanding of the underlying mechanisms during brain stimulation.HS performed the literature survey, and wrote the article. SCJ oversaw all survey procedures and approved the final manuscript.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.


The regulation of endurance training is usually based on the prescription of exercise intensity. Exercise duration, another important variable of training load, is rarely prescribed by individual measures and mostly set from experience. As the specific exercise duration for any intensity plays a substantial role regarding the different kind of cellular stressors, degree, and kind of fatigue as well as training effects, concepts integrating the prescription of both intensity and duration within one model are needed. An according recent approach was the critical power concept which seems to have a physiological basis; however, the mathematical approach of this concept does not allow applying the three zones/two threshold model of metabolism and its different physiological consequences. Here we show the combination of exercise intensity and duration prescription on an individual basis applying the power/speed to distance/time relationship. The concept is based on both the differentiation of intensities by two lactate or gas exchange variables derived turn points, and on the relationship between power (or velocity) and duration (or distance). The turn points define three zones of intensities with distinct acute metabolic, hormonal, and cardio-respiratory responses for endurance exercise. A maximal duration exists for any single power or velocity such as described in the power-duration relationship. Using percentages of the maximal duration allows regulating fatigue, recovery time, and adaptation for any single endurance training session. Four domains of duration with respect to induced fatigue can be derived from maximal duration obtained by the power-duration curve. For any micro-cycle, target intensities and durations may be chosen on an individual basis. The model described here is the first conceptual framework of integrating physiologically defined intensities and fatigue related durations to optimize high-performance exercise training. However, including high intensity speed endurance exercise provided a stimulus for muscle mitochondrial biogenesis, substrate regulation, and angiogenesis.The regulation of endurance training is usually based on the prescription of individual exercise intensity zones/domains, , maximal heart rate (HRmax), or maximal power output (Pmax) for setting exercise intensity  or ventilatory (VT1) and a second lactate (LT2/LTP2) or ventilatory (VT2) threshold or turn point which has been successfully integrated into the practice  is defined as the first increase in blood lactate concentration (La) accompanied by a first change of increase in ventilation (VT1) and distinct changes in other ventilatory variables. The second lactate turn point (LTP2) is defined as the second abrupt increase in La accompanied by a sharp increase in ventilation (VT2) and distinct changes in other ventilatory variables , of maximal oxygen uptake (%VO2max), or % HR reserve (%HRR) as well as % oxygen uptake reserve (VO2R) are not able to discriminate these phases correctly on an individual basis  are applied to prescribe exercise intensity limits for prolonged endurance exercise training , the total duration  , the duration of the single workloads (tpeak) as well as recovery intensity (Prec) and duration (trec) and the corresponding mean load (Pmean) have to be considered  are suggested to be set in relation to sub-maximal  and maximal markers (Pmax) from an incremental exercise test: Ppeak = Pmax, Prec = %PLTP1, Pmean = %PLTP2  with short workload durations and PSimilar to constant load exercise , we may chose four different duration domains with clearly distinct adaptation effects on various physiological processes and exercise performance. To prescribe these duration domains one needs the maximal duration for at least 2–3 different intensities to draw the power-duration relationship as can be seen in Figure From this concept  but to apply a certain percentage of tmax  zone from a moderate zone without fatigue, a zone with compensated fatigue and finally zone 4 with clear fatigue needs to be taken with caution. Carefully conducted studies and retrospective analysis of distances covered at defined intensities are needed to identify the stability or variability of these percentages for athletes with different age, training status and sex, and individual physiological markers are needed to guide the training. As could be shown in a pilot test Figure , heart rA second important limit is the method to derive the power-duration or velocity—distance relationship. To obtain a valid regression line, data points must be obtained from highly motivated athletes from competitions. However, maximal performance changes during the training year due to periodization will make it a bit more difficult to obtain optimal distances throughout the year. Additionally, not all sports allow obtaining these markers under comparable and possibly standardized conditions such as in cycling or on-snow cross-country skiing. Semi-specific tests such as ergometer or ski-roller tests may help to overcome this problem.1/VT1. Although athletes may withstand such volumes from an acute metabolic state of view, some long-term problems such as orthopedic complaints  as well as disturbances in energy or fluid supply may arise from such as concept (Noakes, A third limit may be the idea to maximize volumes by reducing intensity below LTP Noakes, .Despite those limits, this concept gives a solid theoretical framework that allows optimizing both intensity and duration of the whole spectrum of endurance training load for the first time. It may help to improve exercise training for top level performance even though it is already close to the limits of tolerance for the human body.This methodological consideration included a single pilot tests which were not part of a formal study but a proof of principle determination of markers from standard performance diagnostic tests which was performed in accordance with the recommendations of Declaration of Helsinki. The subject gave written informed consent in accordance with the Declaration of Helsinki.PH: Author wrote the manuscript, draw the figures, and graphs. GT: Author contributed equally in writing the manuscript.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.


Triticeae members, particularly wheat and barley, make an important contribution to world food reserves by providing rich sources of carbohydrate and protein. These crops are grown over diverse production environments that are characterized by a range of environmental or abiotic stresses. Abiotic stresses such as drought, heat, salinity, or nutrient deficiencies and toxicities cause large yield losses resulting in economic and environmental damage. The negative effects of abiotic stresses have increased at an alarming rate in recent years and are predicted to further deteriorate due to climate change, land degradation, and declining water supply. New technologies have provided an important tool with great potential for improving crop tolerance to the abiotic stresses: microRNAs (miRNAs). miRNAs are small regulators of gene expression that act on many different molecular and biochemical processes such as development, environmental adaptation, and stress tolerance. miRNAs can act at both the transcriptional and post-transcriptional levels, although post-transcriptional regulation is the most common in plants where miRNAs can inhibit the translation of their mRNA targets via complementary binding and cleavage. To date, expression of several miRNA families such as miR156, miR159, and miR398 has been detected as responsive to environmental conditions to regulate stress-associated molecular mechanisms individually and/or together with their various miRNA partners. Manipulation of these miRNAs and their targets may pave the way to improve crop performance under several abiotic stresses. Here, we summarize the current status of our knowledge on abiotic stress-associated miRNAs in members of the Triticeae tribe, specifically in wheat and barley, and the miRNA-based regulatory mechanisms triggered by stress conditions. Exploration of further miRNA families together with their functions under stress will improve our knowledge and provide opportunities to enhance plant performance to help us meet global food demand.The continued growth in world population necessitates increases in both the quantity and quality of agricultural production.  Triticeae is an important tribe of the Pooideae grasses which comprises many nutritionally and economically valuable crops, such as wheat, barley, and rye (Mochida and Shinozaki http://faostat.fao.org/). By supplying many crucial minerals, vitamins, and essential amino acids, and owing to its relatively low fatty acid content, wheat is a widely preferred staple food for human and animal consumption , hua enhancer-1 (hen1), and dcl1 are detected as hypersensitive to abiotic stress-associated hormones such as abscisic acid (ABA)  are small non-coding RNA molecules that act as gene expression regulators at the post-transcriptional level  where the processed miRNAs are called “transposable element-related miRNAs (TE-miRs)”  prior to nuclear export is essential for protection against the possible action of exonucleases; thus, almost all plant miRNAs undergo methylation , they characterized tandemly duplicated miRNA family members that are physically linked (approximately by 1.9 kb) and resulted from large duplication events. They succeeded in showing that intra/inter-chromosomal duplications, along with subsequent inversion and rearrangement events, resulted in spawning of miR159a and miR159b in chromosome 1. They estimated that this event extends back to 30 mya based on an analysis of synonymous substitution and duplication events. miR159c, which is located in chromosome 2, was also believed to have originated from similar events. However, the evolutionary timescale could not be measured since sequence similarity in the flanking regions was lacking , miR1435, and miR5024   in several plants, such as maize and + and Cl− ions on plant metabolism and physiology is a serious factor limiting crop growth and production in many regions of the world . Phosphate is found in a higher concentration in the soil compared to other nutrients; however, P uptake can be a problem since the orthophosphate form (Pi) is only readily used by plants  of the United Nations  family members is required in many important molecular activities such as enzyme activation, gene expression, protein synthesis, and carbohydrate metabolism , mercury (Hg), lead (Pb), and arsenic (As) together with some transition metals like copper (Cu) are potentially toxic for living organisms. Plants have evolved several mechanisms to survive under conditions where such metals are present. The first response of plants to toxic metal stress is avoiding the uptake. If the metal has already been absorbed, plants will try to halt the uptake process and prohibit the spread Manara .In orderon Table . Correspon Table . Based oTriticeae are grasses and face frequent mechanical stress  and miRNA in response to abiotic stress will be explained since siRNAs are highly similar to miRNAs. Additionally, an emerging topic from the small RNA world, miRNA inheritance, will be described with respect to its potential use for crop improvement.Triticeae. Among these studies, the miR164 family was reported to target six NAC family members, of which four had negative effects on drought tolerance in rice seedlings   family of TFs. SPL is a conserved family of transcription factors and has been detected in all green plants including single-celled algae  family members  are members of the RNAi mechanism and resemble miRNAs in many aspects despite differences in their biogenesis and target preferences Axtell . Plant mTAS loci. These siRNAs, called trans-acting siRNAs or ta-siRNAs, are produced by DCL4 from dsDNA that is generated by the action of Suppressor of Gene Silencing 3 (SGS3) on the miRNA-cleaved TAS transcript following its transcription by RNA-dependent RNA polymerase 6 (RDR6)  genes , were responsive to heat stress and downregulation of these targets reduced heat tolerance in Arabidopsis  or by being transferred to the zygote through uptake by the germ line cells    which lack the heterochromatin remodeler DDM1 protein (DECREASE IN DNA METHYLATION 1), have been detected in sRNA libraries of sperm cells. These siRNAs were proposed to silence TE activity in the sperm , and AT5G21030 (AGO8), indicating sRNA-mediated epigenetic regulation is an ongoing process in the female gametes  DNA glycosylase expression was upregulated while Met1 methyltransferase was downregulated in diploid central cells. DME DNA glycosylase-mediated demethylation in the companion cells results in elevated sRNA levels which subsequently percolate into gametes to control TE activity by CG methylation  RRF-1 defective C. elegans mutants. Though RdRP-mediated siRNA amplification does not continue this silencing indefinitely, Alcazar et al. suggested that either the siRNA levels fail to meet a threshold after each generation or another signal which controls the amplification is diluted over generations  and its ancestors are still present in nature (Pont et al. Triticeae relatives that have adapted to adverse environments should therefore provide targets for editing the miRNA coding sequences in wheat and barley.Domestication of the Although miRNAs have great potential for crop improvement, other small RNA species may also be used to enhance abiotic stress tolerance. The association of small RNAs such as siRNAs, snoRNAs, or snRNAs with stress tolerance opens additional opportunities for modifying regulatory pathways. The interaction between miRNAs with other small RNA species may confer new approaches to improving abiotic stress tolerance. However, our knowledge of these mechanisms and processes is still in its infancy and more work is needed.Triticeae and is particularly tolerant to environmental extremes. The high diversity and stress tolerance of this crop are likely due to its outbreeding nature compared to the strong inbreeding system in wheat and barley (Martis et al. Rye is an important member of the Abiotic stresses are major limitations to crop production and represent significant obstacles to maintenance of adequate food supplies. To meet the demands of an increasing world population, we need varieties that show high, stable yield across diverse environments. Over the two last decades, there has been considerable advance in the identification of stress-responsive genes and their associated proteins. Modification of the expression of these genes has shown promising results for improving the stress tolerance of wheat and barley. However, bringing these lines to farmers’ fields has been a problem since no transgenic wheat or barley lines have been commercially released and consumer resistance to the application of this technology has not diminished. Emphasis has shifted to the use of variation within the cultivated, land race and wild germplasm pools for these crops and in exploring the modification of regulatory pathways (Tester and Langridge


College freshmen are highly vulnerable to experiencing weight gain, and this phenomenon is associated with an increased risk of chronic diseases and mortality in older adulthood. Technology offers an attractive and scalable way to deliver behavioral weight gain prevention interventions for this population. Weight gain prevention programs that harness the appeal and widespread reach of Web-based technologies  are increasingly being evaluated in college students. Yet, few of these interventions are informed by college students’ perspectives on weight gain prevention and related lifestyle behaviors.The objective of this study was to assess college freshmen students’ concern about weight gain and associated topics, as well as their interest in and delivery medium preferences for eHealth programs focused on these topics.Web-based surveys that addressed college freshmen students’ (convenience sample of N=50) perspectives on weight gain prevention were administered at the beginning and end of the fall 2015 semester as part of a longitudinal investigation of health-related issues and experiences in first semester college freshmen. Data on weight gain prevention-related concerns and corresponding interest in eHealth programs targeting topics of potential concern, as well as preferred program delivery medium and current technology use were gathered and analyzed using descriptive statistics.A considerable proportion of the freshmen sample expressed concern about weight gain  and both traditional  and less frequently addressed  associated topics within the context of behavioral weight gain prevention. The proportion of students who reported interest in eHealth promotion programs targeting these topics was also generally high . Email was the most frequently used electronic platform, with 96% (48/50) of students reporting current use of it. Email was also the most frequently cited preferred eHealth delivery platform, with 86% (43/50) of students selecting it. Facebook was preferred by the second greatest proportion of students .Most college freshmen have concerns about an array of weight gain prevention topics and are generally open to the possibility of receiving eHealth interventions designed to address their concerns, preferably via email compared with popular social media platforms. These preliminary findings offer a foundation to build upon when it comes to future descriptive investigations focused on behavioral weight gain prevention among college freshmen in the digital age. It is well established that weight gain and the onset of obesity are common in college students . Over onTechnology represents a particularly attractive and scalable platform for behavioral weight gain prevention interventions in college students. Nearly all (99%) college students regularly use the Internet  to accesConcerns regarding physical inactivity and poor dietary habits among college freshmen have been described previously -26, but Thus, the primary purpose of this study was to collectively gauge college freshmen students’ level of concern about weight gain prevention topics, level of interest in and preferred delivery platforms for eHealth programs focused on these topics, and technology use in general and for the purposes of maintaining current weight.Survey data concerning college freshmen students’ perspectives on weight gain prevention were collected as part of a longitudinal investigation focused on health issues and first semester experiences of college freshmen. Specifically, two separate Web-based surveys were administered to a sample of male and female college freshmen at the beginning (baseline) and end (follow-up) of the fall semester.A convenience sample of incoming college freshmen was recruited from a large public university in the Southeastern United States during the first 2 weeks of the fall semester via fliers distributed around campus, as well as the direct distribution of fliers in conjunction with verbal invitations in large freshmen classes and at the student union. Individuals had to be self-identified first-year college freshmen with Internet access to participate in the study.The recruitment fliers provided the directions and link (URL) needed to access the baseline Web-based survey. Before the completion of this survey, participants gave informed consent via a secure website. The survey was available to complete beginning the first day of class  and ending on September 2, 2015. Participants received an email 11 weeks later, at the end of the fall semester, asking them to complete the follow-up Web-based survey. The opportunity to complete this follow-up assessment occurred over a 1-month time period . Participants who completed the Web-based surveys were eligible for a gift card drawing (US $50 drawing at baseline and US $100 drawing at follow-up). The study was approved by the University of South Carolina’s institutional review board.The baseline and follow-up surveys were developed and administered via a secure website . Variables of present interest measured as part of either the baseline survey or follow-up survey are described below.As part of the follow-up survey, students reported their level of concern about six specific health topics  on a 4-point Likert scale .As part of the follow-up survey, students were asked to respond to the following item: “Please rate how interested you might be in an eHealth promotion program  tailored to college freshmen on these different topics.” Students specifically rated their level of interest on different health topics relevant to weight gain prevention  on a 4-point Likert scale . Students also responded to the following item on the baseline survey: “If you were to receive health information delivered by social media, which would be your preferred platforms from which to get the health promotion information? Please select up to 3 to indicate your top 3 choices.” Response options to this item included the following: email, Twitter, Facebook, Instagram, Vine, private discussion board or bulletin board or forum, Snapchat, other (specify), and would prefer not to receive health information via social media.Students indicated which popular electronic platforms they used regularly via the baseline survey  ,31.Students reported their frequency of self-weighing on the baseline survey .Students also responded to items about whether or not they used a smartphone app to track diet, used a smartphone app to track physical activity, and used a wearable physical activity monitoring device on the follow-up survey.Demographic data, specifically age, sex, race, and ethnicity, were obtained as part of the baseline survey.2).Students reported their height and body weight via the baseline Web-based survey. Body mass index was calculated as weight (kg)/height  version 22.0 for Windows (IBM Corp). Descriptive statistics were calculated for all variables. Means and standard deviations (SDs) are presented for continuous variables. Frequencies and percentages are presented for categorical variables. For the items addressing level of concern about specific health topics, very concerned and somewhat concerned response categories were aggregated to highlight the collective proportion for which there was at least some level of concern. Similarly, for the items indicating degree of interest in eHealth promotion programs focused on different topics, very interested and somewhat interested responses were coalesced to highlight the collective proportion who expressed at least some interest. Independent Fifty-five college freshmen enrolled in the study and completed the baseline survey. Fifty  also completed the follow-up survey. Those who completed both surveys averaged 18.3 years of age (SD 0.6) and were predominantly white and normal weight. Two-thirds were women . There wThis formative study preliminarily suggests that a considerable proportion of college freshmen have concerns about weight gain and associated lifestyle behaviors during their first semester and are interested in receiving eHealth programs focused on different weight gain prevention topics. The findings also indicate that the technology platforms most frequently preferred for receiving eHealth programs are email and Facebook.To our knowledge, this study is the first to provide an assessment of freshmen college students’ level of concern about a range of weight gain prevention topics. The first semester of freshman year has been identified as the period of highest risk for weight gain during the college experience , and theOur findings are congruent with previous studies that have gauged freshmen college students’ level of concern about weight gain prevention topics -26. For Nevertheless, in this study, the students’ level of concern for weight gain prevention and associated topics generally paralleled their level of interest in eHealth promotion programs centered on these topics, pointing to their openness to receive guidance and support about maintaining their current weight through popular technology mediums ,30,31. HGiven that email was used and preferred as an eHealth delivery method by the highest proportion of students relative to other platforms, researchers and practitioners may want to consider employing this medium when designing electronic-based weight gain prevention programs for first-year college students . These fA high proportion of students in this study reported using Snapchat , which is consistent with a recent market study of 9381 college students . This maThis study was characterized by several limitations that must be considered when interpreting the findings. The sample size was small and homogeneous . Thus, it is unknown whether different response patterns may have emerged for different subgroups of college freshmen. Similarly, it is unknown how a different target outcome  may have affected responses in certain subgroups. The sample also comprised self-selected students who may have had more interest in weight gain prevention, other health issues, and technology than those who did not volunteer. Given these factors, it may be premature to generalize the findings broadly. However, these results point to the need for further exploration into these important research questions in a larger, more diverse sample in the different contexts of weight gain prevention, weight loss, and prevention of weight regain after weight loss. Additionally, this study did not inquire about all potential preferred eHealth delivery platforms, which represents another study limitation. Assessing students’ preferences for an even broader array of widely accessible technology delivery mediums  , as it rDespite these limitations, this study was the first to simultaneously assess concern about and interest in receiving eHealth programs via different delivery platforms focused on a range of lifestyle topics relevant to weight gain prevention among college freshmen, expanding the focus from diet and physical activity to other areas associated with weight gain prevention, which might be pertinent to the target population. Unlike previous studies ,29, thisOverall, this descriptive, formative study preliminary demonstrated that college freshmen have concerns about a range of weight gain prevention-related topics and are generally interested in receiving eHealth promotion programs focused on these topics. The greatest majority of students selected a traditional medium  as their preferred method for receiving an eHealth program, although a substantial proportion also preferred Facebook. This study fully opens the conversation on an impactful and under-researched area, yielding findings that provide a foundation to build upon when it comes to future descriptive investigations focused on behavioral weight gain prevention among college freshmen in the digital age. Ultimately, such studies may help inform the design of future, far-reaching technology-based weight gain prevention interventions that have the potential to enhance program receptiveness, exposure, engagement, and effectiveness for college freshmen.


Atypical sensory function is included in the diagnostic criteria for ASD and is likely an important contributor to anxiety. Difficulties in understanding and labeling emotions , although a co-morbidity, may arise in part from atypical sensory function and can lead to confusion and uncertainty about how to respond to social and emotional situations. Intolerance of uncertainty(IU) describes people who have a particularly hard time with ambiguity and is known to be a key mechanism underlying some anxiety disorders. While evidence for linking these ideas is to date incomplete, we put forward a model including each concept as a framework for future studies. Specifically, we propose that IU is a critical mediator for anxiety in ASD, and explore the relationships between sensory function, alexithymia and IU. We further explore the role of the medial prefrontal cortex (mPFC) in regulating emotional response, in connection with limbic and insula-based networks, and suggest that disrupted integration in these networks underlies difficulties with habituation to strong emotional stimuli, which results in an enhanced perception of threat in many people with ASD. Behavioral and biologically-based treatments for anxiety in ASD will benefit from attending to these specific mechanisms as adjunct to traditional interventions.Severe symptoms of anxiety add substantial additional burden to many individuals diagnosed with Autism Spectrum Disorder (ASD). Improved understanding of specific factors that contribute to anxiety in ASD can aid research regarding the causes of autism and also provide targets for more effective intervention. This mini-review article focuses on emerging evidence for three concepts that appear to be related to each other and which also strongly predict anxiety in ASD samples.  Severe symptoms of anxiety co-occur frequently in autism spectrum disorder  atypical sensory function, which is included in the diagnostic criteria for ASD; (2) difficulty identifying/labeling emotions , which has been shown to be frequently severe in ASD; and (3) intolerance of uncertainty (IU), which has been suggested as a critical pathway to anxiety in ASD. While these ideas come from very different backgrounds, existing research shows that they are closely related, at least as measured with current instruments. A critical challenge is to define how these ideas diverge biologically and behaviorally.Sensory function in ASD samples may be marked by both over-responsivity  and under-responsivity . Both extremes may occur in the same children  and neurotypical controls (n = 75), showing strong correlations between dimensional measures of autism symptoms and several measures of anxiety. Structural equation modeling demonstrated that this relationship was almost completely accounted for by a combination factor of alexithymia, emotional acceptance and IU. High alexithymia levels are also seen in young children diagnosed with ASD  protocol had significantly reduced parent-reported anxiety symptoms. Importantly, pre-treatment IU scores significantly mediated the change in anxiety scores such that children with higher pre-treatment IU showed less improvement of their anxiety symptoms.Hodgson et al.  conducteWe have presented evidence for associations between anxiety in ASD with atypical sensory function, emotion recognition and regulation , and cognitive (IU) difficulties. While these represent just a few among many possible pathways to emotion dysregulation in autism  make it difficult to tease them apart using only survey data. It is likewise difficult to understand relationships between behavioral data and psychophysiological data , with key connections to amygdala, hippocampus and insula regions among others (Giustino and Maren, Several studies of mPFC dysfunction in ASD samples have focused on social disabilities such as face processing (Kleinhans et al., One key question is how much these difficulties with adaptation/flexibility arise from bottom-up or top-down integration Shalom, . For exaInsula cortex is critical for integration of interoceptive and sensory information and regulating emotional response (Gasquoine, Traditional CBT approaches may focus on mechanisms of anxiety that are less relevant for ASD youth and adults (Kerns et al., Individual differences provide essential context for any treatment implications. For instance, we propose here that difficulties with habituation contribute to atypical sensory function in ASD. However, Schoen et al.  identifiThere is an urgent need to investigate the relevance of many possible underlying mechanisms related to emotion dysregulation in ASD. This mini-review article has focused on three such mechanisms—atypical sensory function, alexithymia and IU–that appear to be closely related to each other and that strongly predict anxiety in ASD. Although support for each of these concepts is emerging, evidence linking the three constructs together remains incomplete. Thus, this model is speculative, but we believe it builds a helpful framework for future studies. Such difficulty integrating cognitive and emotional information putatively arises at least in part from disruptions in neural systems involving mPFC and limbic structures, in conjunction with insula cortex. Improved understanding of the contribution of these and other mechanisms should lead to better, more specific interventions for anxiety in ASD.Both authors conceived the project. MS wrote the preliminary draft and both authors edited and approved the final manuscript.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.


Sense of agency (SoAg) is the feeling of control over one's actions and their effects. It can be augmented or attenuated by internal signals and by external cues. Research has shown a reduction in the SoAg in older adulthood, but the reasons behind this change remain unclear. We investigated agency processing differences that may underpin age-related changes in SoAg. Using a modified version of a vicarious agency paradigm, we tested the modulation of SoAg by manipulating external situational agency cues in younger and older adults. Our results show that the illusion of vicarious agency was less pronounced in older adults. These results were replicated in a second experiment which also showed that older adults performed significantly better in interoception and proprioception tasks. We suggest that increased reliance on internal cues may explain differences in agency processing in older adulthood. It is inextricably linked to everyday notions of freedom and responsibility  and therneurocognitive factors underpinning age-related changes in the SoAg.Research suggests a general reduction in feeling of control over life events in older adulthood e.g. –5). Rece. Rece5])internal processes serving motor control )deficit, which in turn may be responsible for age-related changes in SoAg. More specifically, this cue integration approach emphasizes the contribution of various sources of information to SoAg. Moreover, it is thought that these different sources of information are optimally integrated; the dominance of internal or external cues to agency will depend on their relative reliability [different sources of information older adults may be less likely to recognize their own causal efficacy.Although more work is needed to fully understand the mechanisms underpinning age-related changes in SoAg, our results offer some preliminary insights. Both of our experiments show that older adults were less sensitive to illusory agency experiences (both in terms of agency and ownership). At first glance, this may seem advantageous as it suggests a more robust and less malleable experience of agency in older adults. However, in the context of a more recent optimal cue integration model of SoAg ,13, thisiability ,13. In tExperiment 2 aimed to investigate possible mechanisms underpinning this effect. We measured the performance on two internal monitoring tasks: interoceptive and proprioceptive accuracy. We found that older adults performed significantly better on measures of proprioceptive and interoceptive accuracy. This may explain why the older adults were less susceptible to the illusion: an increase in the relative weighting of internal cues diminished the effect of external cues on agency processing in older adults.et al.'s [In summary, our study aimed to investigate agency processing differences underpinning age-related changes in SoAg. Using Wegner et al.'s  vicariou


The treatment of psychiatric diseases with Deep Brain Stimulation (DBS) is becoming more of a reality as studies proliferate the indications and targets for therapies. Opinions on the initial failures of DBS trials for some psychiatric diseases point to a certain lack of finesse in using an Open Loop DBS (OLDBS) system in these dynamic, cyclical pathologies. OLDBS delivers monomorphic input into dysfunctional brain circuits with modulation of that input via human interface at discrete time points with no interim modulation or adaptation to the changing circuit dynamics. Closed Loop DBS (CLDBS) promises dynamic, intrinsic circuit modulation based on individual physiologic biomarkers of dysfunction. Discussed here are several psychiatric diseases which may be amenable to CLDBS paradigms as the neurophysiologic dysfunction is stochastic and not static. Post-Traumatic Stress Disorder (PTSD) has several peripheral and central physiologic and neurologic changes preceding stereotyped hyper-activation behavioral responses. Biomarkers for CLDBS potentially include skin conductance changes indicating changes in the sympathetic nervous system, changes in serum and central neurotransmitter concentrations, and limbic circuit activation. Chemical dependency and addiction have been demonstrated to be improved with both ablation and DBS of the Nucleus Accumbens and as a serendipitous side effect of movement disorder treatment. Potential peripheral biomarkers are similar to those proposed for PTSD with possible use of environmental and geolocation based cues, peripheral signs of physiologic arousal, and individual changes in central circuit patterns. Non-substance addiction disorders have also been serendipitously treated in patients with OLDBS for movement disorders. As more is learned about these behavioral addictions, DBS targets and effectors will be identified. Finally, discussed is the use of facial recognition software to modulate activation of inappropriate responses for psychiatric diseases in which misinterpretation of social cues feature prominently. These include Autism Spectrum Disorder, PTSD, and Schizophrenia—all of which have a common feature of dysfunctional interpretation of facial affective clues. Technological advances and improvements in circuit-based, individual-specific, real-time adaptable modulation, forecast functional neurosurgery treatments for heretofore treatment-resistant behavioral diseases. Closed loop deep brain stimulation (CLDBS) paradigms are heralded as the future of DBS systems. In our experience using open loop DBS (OLDBS) to treat psychiatric conditions, we encountered several limitations: (1) Relying on short-term clinical outcomes to identify optimal stimulation parameters is inadequate; (2) The continuous stimulation paradigm commonly used with DBS interferes with the normal function of the target structure impeding clinical improvement; (3) Monitoring the progression of the illness using clinical outcomes scores is insufficient to determine true network engagement and disease modification in the context of invasive neuromodulation. The closed loop systems can address those limitations. CLDBS systems promise circuit based learning and adaptation, improved system efficacy, increased safety, and reduced risk of tissue damage from prolonged stimulation. OLDBS, however, requires input through a human interface, unadaptable monomorphic stimulation between programming, habituation to stimuli, attenuation of response, and diminished efficacy over time  of Mental Disorders V  which could necessitate leads placed in the brain. In addition to allowing for input in a CLDBS system, using peripheral biomarkers correlated to disease symptoms could help the clinician follow the progression of the disease, therefore providing critical information even when the CLDBS stimulation may not provide significant clinical benefit.Responsive neurostimulation for epilepsy  is a proprietary system used not only to treat medically refractory epilepsy  location cues or visual drug/drinking cues  could be interpreted by a peripheral sensor and an abortive stimulus could be delivered into a CLDBS circuit, attenuating the initial reward response pathway activation. Also, peripheral physiologic signals of autonomic activation, similar to those discussed above in PTSD, could trigger an abortive stimulus.The environmental, emotional, and psychological triggers for the phenomenon of craving in substance abuse in humans are varied, individualized, and difficult to interpret. What may trigger one person to compulsively seek their substance of choice may attenuate that compulsion in another. What is known is that the dopaminergic mesolimbic circuitry is intimately involved with the ritualized behavior leading up to actual substance use , or other places associated with substance use. Facial recognition software could also be used to identify particular persons who are associated with substance use for a patient; certain faces could be recognized via specialized contact lenses with facial recognition software capabilities .The higher cortical functions that trigger the dopaminergic surge ultimately end in the NAc but the hub of activity of the mesolimbic system is the VTA Figures . The dopTM epilepsy system. As we mentioned in previous sections, the signals can be exported from the device to allow further analysis in Matlab. It is even conceivable that a sensor would be able to interpret visual cues and patterns specific to the individual.Once CLDBS leads are placed, as part of the system learning, a given patient's specific triggers could be examined for neural firing patterns preceding behaviors associated with addictive chemical use. These exposures can be performed in a controlled environment such as the clinic or a laboratory where the patient is presented cues of addiction while LFPs are recorded for evoked potentials. An alternate method is to use the on-demand recording feature of the device in real-life situations. In this paradigm, the patient activates the recording in the presence of specific relevant symptoms to the condition while in their regular environment. Device-based neural pattern recognition could then be programmed and stimulation modulation would follow, delivering appropriate stimuli in situations when the patient is more likely to use or drink. The methodology of obtaining, encoding, and interpreting these signals, both the environmental and physiologic, are conceivable and, at least in part, already available in commercially available devices such as the RNSNon-substance addictive behaviors, are becoming increasingly recognized as legitimate disorders Potenza,  and the It has been long known that patients with movement disorders can infrequently develop hypersexual  (Uljarevic and Hamilton, Recognition and interpretation of non-verbal communication is a complex developmental process that takes years to fully develop, starting in infancy and progressing through adulthood (Black et al., Interpretation of facial affect has been demonstrated to be disordered in adults and adolescents with PTSD (Masten et al., CLDBS systems could interpret visual cues and facial features and monitor or modulate inappropriate responses. Facial recognition programming could, with physiologic and neurotransmitter sensors, function to interpret social cues more accurately and system output could deliver an abortive response to inappropriate activation of particular nodes in the circuit Figures .The facial recognition software would interpret facial patterns according to typical responses. Inappropriate activation of the sympathetic system due to misinterpretation as threat of social cues by the patient could be then aborted as the sensing arm of the CLDBS system identifies mismatch of the response initiation and the facial recognition interpretation. These aberrations, interpreted by the device, could then signal for stimulus delivery to the effector node—the amgydala seems the likely target (Langevin, Facial expression analysis software exists and is being increasingly refined (Chu et al., Additionally, cortical EEG implants placed over the parietal and temporal lobes monitoring the P1 and N170 patterns could detect aberrations which are consistent with scalp EEG aberrations noted in trials of ASD patients misinterpreting facial cues (Black et al., As technology advances in conjunction with our understanding of brain circuitry and neurotransmitter disorders, the opportunities to treat patients with heretofore treatment-resistant “behavioral” diseases are pregnant with promise. These patients with limited medical options may 1 day be able to break free from their behavioral and interpretive constraints. As history has shown, the treatment of these disorders is a challenging ethical field fraught with paternalism and loss of individual autonomy. Dissidents and proponents abound on each side of any argument—the resultant din can color or stall discussions that arise with every new advancement. CLDBS systems are on the horizon and the vanishing point may not be so distant; cautious progress should be our guide.RB this author is the primary author for the paper. J-PL senior author, editing, intellectual guidance, final approval.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.


Vibrio cholerae and to result in misidentification of genes involved in growth in vitro. Fortunately, the bulk of this bacterium’s genome was unaffected by this bias, and recognizing the H-NS effect allows filtering to improve the accuracy of the results.The property of transposons to randomly insert into target DNA has long been exploited for generalized mutagenesis and forward genetic screens. Newer applications that monitor the relative abundance of each transposon insertion in large libraries of mutants can be used to evaluate the roles in cellular fitness of all genes of an organism, provided that transposition is in fact random across all genes. In a recent article, Kimura and colleagues identified an important exception to the latter assumption . They provide evidence that the Mariner transposon exhibits locus-specific site preferences in the presence of the histone-like nucleoid structuring protein H-NS. This effect was shown to bias results for important virulence loci in  In the second, by sequencing transposon junctions in the transposon bank during or after its initial expansion on media designed for optimal propagation, investigators can infer the identities of so-called “essential genes” or “growth-promoting” genes involved in cellular survival or viability in vitro, based on the absence or significantly reduced density of insertions present within these genes. In the latter case, the underlying assumption that transposition is primarily random is more critical, such that a role in fitness can be ascribed to loci sustaining fewer insertions than expected.Since their discovery as mobile elements of “selfish DNA” responsible for horizontal gene transfer and genetic variability among organisms, transposons have been recognized as powerful tools to query gene function. Their defining feature, random gene insertion, generates libraries of mutants in which the disrupted loci can be readily identified, allowing phenotypes to be correlated with mutant genotypes. The development of high-throughput DNA sequencing has allowed identification of such correlations at the whole-genome scale in large libraries of transposon mutants. A variety of related techniques to identify the sequences at the junctions of transposon insertions and the genome, methods that can generally be termed transposon insertion sequencing, or TIS  experiment , was shown to exhibit an H-NS-mediated decrease in insertion density and yet is strongly expressed. Readthrough transcription into the transposon from the rfb genes is expected to increase rather than decrease antibiotic resistance gene expression; therefore, transcriptional repression does not appear to be sufficient to explain the low insertion density at this site in the presence of H-NS.The authors noted a potential caveat in that similar results might be obtained if H-NS inhibits expression of the transposon-encoded antibiotic resistance gene used for selection of mutants. While difficult to fully exclude, this possibility seems unlikely because transposon insertion density throughout the genome does not correlate with gene expression levels at the insertion sites, consistent with independent expression of the antibiotic resistance gene in the transposon. Moreover, at least one locus, in vivo transposon mutagenesis presents several issues in interpretation of TIS experiments. The most apparent problems are that genes without insertions would not be evaluated for selective loss of insertions after exposure of the mutants to experimental conditions and that the dynamic range of mutant phenotypes would be reduced for genes with unusually low initial insertion densities. The bias imparted by H-NS is particularly troublesome in this regard as it preferentially affects AT-rich DNA, often a characteristic of horizontally transmitted virulence factors. Also, a major application of TIS has been the identification of essential or growth-promoting genes. These genes are inferred to encode cellular factors essential for life and may represent previously uncharacterized components of cellular pathways. The members of this class also represent potential antibiotic targets in microbial pathogens. As shown by Kimura and colleagues, if interference with transposition, rather than fitness defects, were to cause a lack of insertions at certain locations, then some genes would be falsely identified as essential. In addition to H-NS, several other conserved bacterial proteins participate in nucleoid structure, and there may be more genes whose roles in fitness are incorrectly identified by TIS. Understanding these factors that affect transposition will aid in filtering out such false positives.Inhibition of transposition at selective sites during in vitro transposition in which cellular factors are absent during the reaction and mutagenized DNA is then introduced into bacterial cells. This approach is practical only in naturally transformable organisms such as Haemophilus influenzae and Streptococcus pneumoniae   , 7. V. cformable , so it mectivity .Aside from aiding in interpretation of TIS experiments, these results may have important biological implications. Prior to their modification in the laboratory for use as genetic tools, transposons adapted for their optimized spread in nature by balancing propagation, transmission, and maintenance of their genomes within those of their hosts. Regulation of transposition, often involving host regulatory factors , can aidCTX and tcp in V. cholerae. H-NS is postulated to protect cells from ectopic expression of newly acquired genes (tcp and CTX genes. Transposition into newly acquired DNA could also lead to aberrant gene expression by introduction of ectopic promoters or disruption of negative-control elements, leading to inappropriate expression of horizontally acquired genes. Therefore, inhibition of transposition may allow V. cholerae to retain the potential benefits of gene transfer and to avoid deleterious mutations or inappropriate expression levels that may be caused by mutagenesis. Likewise, Mariner transposons may have evolved to steer clear of insertion locations that would otherwise markedly interfere with survival of their carrier organisms. How this eukaryotic transposon might recognize bacterial H-NS to discern these disadvantageous sites is unclear. Mariner transposons are influenced by chromatin structure, and it is possible that they can recognize conserved features of genomic DNA structure generated by bacterial nucleoid proteins. Further study will be required to evaluate the potential adaptive role of inhibition of transposition by H-NS binding and whether it is generalizable to other classes of transposons.The discovery of pronounced genome-scale effects of H-NS on transposition may relate to the proposed role of H-NS in tolerance of recipient cells with respect to horizontal gene transfer events. DNA with AT composition higher than that of the rest of the genome is a hallmark of recently acquired genomic islands, including virulence loci such as ed genes , which m


Clostridium difficile, without any impact on mortality, in real-world settings. So, although using PCT-guided antibiotic stewardship is promising, after more than a decade of randomized controlled trials on this topic the evidence in its favor is still less than compelling due to limitations in trial design, not taking into consideration fundamental aspects of PCT biology, and the absence of evidence-based antimicrobial duration in intervention and control groups. In this commentary we highlight some questions and limitations of primary PCT study data that might impact interpretation and clinical use of PCT at the bedside.Using biomarkers as a guide to tailor the duration of antibiotic treatment in respiratory infections is an attractive hypothesis assessed in several studies. Recent work aiming to summarize the evidence assessed the effect of a procalcitonin (PCT)-guided antibiotic treatment on outcomes in acute lower respiratory tract infections (LRTI), suggesting that significant reductions in antibiotic duration occur when using a PCT-guided algorithm. However, controversial evidence also suggested PCT-guided algorithms were associated with increased antibiotic duration and increased incidence of  Clostridium difficile, without any impact on mortality, in real-world settings in the US. In this commentary, we highlight some questions and limitations of primary PCT study data that might impact interpretation and clinical use of PCT at the bedside.Using biomarkers as a guide to tailor the duration of antibiotic treatment in respiratory infections is an attractive hypothesis assessed in several studies. A recent meta-analysis aiming to summarize the evidence assessed the effect of a procalcitonin (PCT)-guided antibiotic treatment on outcomes in acute lower respiratory tract infections (LRTI) suggested significant reductions in antibiotic duration occur when using a PCT-guided algorithm . HoweverA major concern in PCT-guided trials is antibiotic use in the control group. According to the World Medical Association’s Helsinki declaration, “the benefits, risks, burdens, and effectiveness of a new intervention must be tested against those of the best current proven intervention,” but defining “best current proven intervention” is difficult . HeterogFor instance, usual care is sometimes far from the best available care or what should be standard of care. Trials using a protocolized rather than an unrestricted standard care control group will likely have enhanced validity as long as the protocolized care control group is representative of standard care practices . In PCT Also, PCT algorithms consider that a PCT < 0.1 μg/L bacterial infection is very unlikely and antibiotics should not be prescribed or should be withheld. It is well known that in several bacterial infections, for example, VAP , 9, PCT In addition, another important limitation of PCT use is related to the lack of information on specific conditions and populations where its value is inadequate because of intrinsic constraints. In critically ill patients the presence of acute kidney injury or the use of renal replacement therapies has a profound effect on PCT concentrations –14. AddiClinical use of biomarker-guided antibiotic stewardship such as PCT is promising, but after more than a decade of RCTs on the topic the evidence in its favor is still less than compelling due to limitations in trial design. These limitations include not taking into consideration fundamental aspects of PCT biology and the absence of evidence-based antimicrobial duration in intervention and control groups, namely in VAP. A double-trigger criteria, in which antibiotics are stopped according to the clinical course and either decreases in biomarker levels, according to an algorithm, or the completion of 5–7 days of treatment, whichever comes first , might b


The search is limited to English-language articles published between January 1980 and September 2016. Results show that existing robot-assisted ankle rehabilitation techniques can be classified into wearable exoskeleton and platform-based devices. Platform-based devices are mostly developed for the treatment of a variety of ankle musculoskeletal and neurological injuries, while wearable ones focus more on ankle-related gait training. In terms of robot design, comparative analysis indicates that an ideal ankle rehabilitation robot should have aligned rotation center as the ankle joint, appropriate workspace, and actuation torque, no matter how many degrees of freedom (DOFs) it has. Single-DOF ankle robots are mostly developed for specific applications, while multi-DOF devices are more suitable for comprehensive ankle rehabilitation exercises. Other factors including posture adjustability and sensing functions should also be considered to promote related clinical applications. An ankle rehabilitation robot with reconfigurability to maximize its functions will be a new research point towards optimal design, especially on parallel mechanisms.This review aims to compare existing robot-assisted ankle rehabilitation techniques in terms of robot design. Included studies mainly consist of selected papers in two published reviews involving a variety of robot-assisted ankle rehabilitation techniques. A free search was also made in Google Scholar and Scopus by using keywords “ankle Conventional rehabilitation programs for musculoskeletal and neurological disabilities require cooperative and intensive efforts from both therapists and patients , 2. ThisSaglia et al.  have sumA systematic review by Zhang et al.  has demoZhang et al.  also con∗,” “robot∗,” “rehabilitat∗,” or “treat∗.” The search is limited to English-language articles published between January 1980 and September 2016. Valuable references listed in relevant publications were further screened. Since this review focuses on comparative analysis of existing ankle rehabilitation devices in terms of robot design, only one of the studies with the same robot-assisted ankle rehabilitation technique will be included and discussed. The inclusion criterion is that if the study clearly presented the robot design, and the most recent one will be selected when there are multiple studies meeting the inclusion criterion. Included prototypes are either intelligently controlled or have multiple DOFs and have also been experimentally validated. Ankle devices specially designed for assessment [Included studies mainly come from the selected papers in a systematic review  that focsessment , 11 willsessment –14. It sWearable ankle rehabilitation robotic systems usually have one to three DOFs , 6, 15. A variety of platform-based robotic systems have been proposed and developed based on the consideration of ankle anatomy. The simplest representation of ankle motion is a hinge joint in the sagittal plane. A platform following this model is the ankle stretching device developed by Zhang et al. . This isSaglia et al.  have devFor an ankle rehabilitation robotic system with three rotational DOFs, the parallel mechanism is more often employed than serial mechanisms due to some features (safe workspace and large torque generation capacity). The multi-DOF ankle robot with AaEE has been considered to be suitable for comprehensive ankle therapy. Two typical examples of such robot platforms were developed by the rehabilitation robotics group at the University of Auckland , 16. TheWhile the robot developed by Jamwal et al.  and ZhanTo ensure comprehensive ankle exercises in a three-dimensional space, the requirement of three rotational DOFs can be a prerequisite of an optimal ankle rehabilitation robot. However, an ankle device with two DOFs for ankle (dorsiflexion/plantarflexion and inversion/eversion) is also acceptable since ankle adduction/abduction is limited and primarily controlled by rotation of the leg . TherefoWith regard to the torque capacity of different ankle robots, many factors affect their performance, including the device structure and the selection of actuators. We focus on comparing and discussing these ankle devices with consistent rotation centers in terms of actuation capacity. The torque capacity of the motor-driven devices directly depends on the driving ability of the motor and the friction of the robot joint. A typical motor-driven ankle training device is the one developed by Zhang et al. . Its outIn terms of robot functionality, the installation of a variety of sensing components also affects the robot design. Wearable devices are more difficult to be integrated with a sensing system due to the operation in a gait pattern . If goinIn addition to the selection of robot structure, optimization techniques should be also applied to the robot to have a suitable workspace and improve its torque generation capacity. Dimensional synthesis is one of the most difficult issues in the field of parallel robots with or without actuation redundancy. To deal with the optimal design of a redundantly actuated parallel robot used for ankle rehabilitation, Wang et al.  presenteRobot-assisted ankle rehabilitation exercises can be delivered in a variety of ways to reduce motor impairment and enhance functional motor outcomes. While existing robot-assisted ankle rehabilitation techniques have shown great potential for treating ankle disabilities , few canBy comparing a variety of ankle rehabilitation robots, it was found that an optimal robotic design for comprehensive ankle rehabilitation should be characterized with appropriate workspace and actuation torque, aligned rotation center between the robot and the ankle joint, and adjustable robot posture. However, this will definitely increase the cost due to complex robotic design. The authors also believe that no “one-size-fits-all” design exists for optimal robot-assisted ankle rehabilitation techniques, and therapy should be essentially tailored to each patient's needs and disabilities. Some examples of optimal ankle rehabilitation robots for certain applications are summarized in Additionally, Siegler et al.  have demHowever, two more design issues should be considered towards optimal ankle rehabilitation robots. One is the fixation issue of the human foot and shank, and a commonly used method is using straps attaching the foot on a footplate and the shank on a fixed leg holder. Again, since the anatomical ankle joint is not an ideal hinge joint , the rigAn attempt was made to ensure that a variety of robotic designs proposed for ankle rehabilitation were reviewed. In this review, we assumed that the same robotic prototype reported in different studies and dates by the same group had the same design, although some minor improvements  could have been made. However, other research may exist in which the ankle was not identified as a key term within the article; instead, some studies described the ankle complex as lower extremity or lower limb. Only articles after 1980 were included in this study as robot-assisted ankle rehabilitation techniques were quite limited before then. We included published journal and conference papers with a clear description of the robot design but did not include those written in languages other than English. Some studies may therefore have been excluded on this basis, leading to a potentially incomplete search.An optimal ankle rehabilitation robot design must be characterized with aligned rotation center as the ankle joint, appropriate workspace, and actuation torque.The number of robot DOFs depends on specific applications. The single-DOF robot is mostly developed for a special application such as ankle stretching along dorsiflexion and plantarflexion, while multi-DOF devices are more suitable for comprehensive ankle rehabilitation exercises.Other factors, including the adjustability of robot posture, sensing functions, the fixation of the human foot and shank on the robot, and mechanical stops, also affect their clinical applications. Adjustable robot posture can enable its use on a large population of patients with varying ankle disabilities. Robots with all required sensing functions allow for the implementation of advanced interactive training. The leg holder should be designed with some flexibilities to accommodate the difference between the robot structure and the human anatomy. Mechanical stops must be set for training safety especially on robotic systems whose workspace is larger than the actual ankle motions.Ankle rehabilitation robots with reconfigurability will be a new research area towards optimal design with appropriate workspace and actuation torque, especially on parallel mechanisms. Multiobjective optimization techniques can be involved to make robots in optimal kinematic and dynamic performance.This review focuses on the design analysis of existing ankle rehabilitation robots. Although most robot-assisted ankle rehabilitation techniques have been demonstrated to be effective for ankle physical therapy, they have drawbacks in the design that have impeded their applications in a wide range. Comparative analysis indicates the following: