The grouting quality of tendon ducts is very important for post-tensioning technology in order to protect the prestressing reinforcement from environmental corrosion and to make a smooth stress distribution. Unfortunately, various grouting defects occur in practice, and there is no efficient method to evaluate grouting compactness yet. In this study, a method based on wavelet packet transform (WPT) and Bayes classifier was proposed to evaluate grouting conditions using stress waves generated and received by piezoelectric transducers. Six typical grouting conditions with both partial grouting and cavity defects of different dimensions were experimentally investigated. The WPT was applied to explore the energy of received stress waves at multi-scales. After that, the Bayes classifier was employed to identify the grouting conditions, by taking the traditionally used total energy and the proposed energy vector of WPT components as input, respectively. The experimental results demonstrated that the Bayes classifier input with the energy vector could identify different grouting conditions more accurately. The proposed method has the potential to be applied at key spots of post-tensioning tendon ducts in practice. Post-tensioning technology is widely used in bridge construction, which can reinforce concrete beams and increase their bearing capacity. Filling the tendon duct with grouting mortar is an important procedure of this technology in order to protect the prestressing reinforcement from environmental corrosion and to make a smooth stress distribution. Unfortunately, various grouting defects including cavities, partial grouting, and even no grouting may occur inside the tendon ducts. The prestressing reinforcement would seriously corrode due to water, air, and chlorides when defects exist in the duct. The corrosion of the reinforcement could further lead to bridge collapse without forewarning ,2. It isMany non-destructive testing (NDT) techniques, such as ultrasonic echo, impact echo, ultrasonic tomography, and ground penetrating radar, have been applied to detect grouting defects in post-tensioning tendon ducts. Krause et al.  investigIn recent years, piezoelectric materials have been widely applied in ultrasonic-, stress wave-, and electromechanical impedance-based structural defect detection because of their wide bandwidth and low price ,11,12,13There are few researches on the grouting compactness monitoring in post-tensioning tendon ducts using PZT transducers. Jiang et al. applied piezoelectric transducers to monitor grouting compactness in a post-tensioning tendon duct on a cross section . One traThe ultrasonic stress waves received by the PZT sensors are non-stationary signals, whose power spectra change with time. Time-frequency analysis, such as wavelet transform (WT) and wavelet packet transform (WPT), is able to reveal their frequency components more accurately than frequency analysis like fast Fourier transform (FFT) . It alsoIn this study, the detection of various grouting defects in post-tensioning tendon ducts, including partial grouting and cavity defects, was studied using stress waves generated and received by piezoelectric transducers. A method based on WPT and Bayes classifier was proposed to evaluate the grouting quality. Six typical grouting conditions with both partial grouting and cavity defects of different dimensions were experimentally investigated. The energy of received signals attenuated to varying degrees in different grouting conditions. The patterns involved in the energy distribution of received signals at multi-scales were investigated and utilized to identify different grouting conditions. The Bayes classifier was applied to take into account the randomness of practical measurements. Finally, the energy vector of WPT components was proposed as the input of Bayes classifier, and was proved to perform better than the traditionally used total energy in the classification of different grouting conditions.The grouting quality evaluation method proposed in this study was based on WPT and Bayes classifier. As the stress wave propagated in the grouted tendon duct, it would attenuate to different degrees depending on the grouting quality. The WPT was therefore applied to explore the energy distribution of received signals at multi-scales. Considering that the energy of stress wave received in different grouting qualities may overlap and that the grouting conditions could be very complex in practice, a Bayes classifier was further employed to identify the types and dimensions of grouting defects by taking the energy vector of WPT components as the input. The schematic of the proposed method is presented in WPT is a time-frequency analysis method developed based on WT. Compared with WT, its advantage is the complete level-by-level decomposition of nonstationary signals both in high-frequency regions and low-frequency regions . WPT hasThrough The wavelet packet coefficients of the Here, Appropriate selection of the mother wavelet function and the decomposition level plays an important role in the performance of WPT on the analysis of practical signals. Among various mother wavelets, the family of Daubechies wavelets is orthogonal, compactly supported, and has good time-frequency localization property . A Daubefunction . It is tThe signal energy of the The total energy of all the WPT components The total energy of all the WPT components was traditionally used as an index to distinguish structural defects of different types or dimensions. Six grouting conditions of different types or dimensions were experimentally investigated in this study. Theoretically, the total energy of WPT components for signals received in different grouting conditions increased strictly along with the increase of grouting compactness. However, it was found that the total energy of WPT components could have similar values for different grouting conditions and has certain randomness when a specimen with a specific grouting condition was tested multiple times. As a result, the value ranges of the total energy of WPT components for different grouting conditions overlapped with each other to various degrees, although their mean values were different. Misdiagnoses occurred if the total energy of WPT components was used solely as the classification criterion for grouting quality evaluation in practice. More details will be discussed in Among various machine learning methods, Bayes classifier is a probabilistic classification model based on the Bayes theory. It has been proved to be a powerful tool for pattern recognition ,48. The Here, It can be seen that the evaluation of the post possibility of The classification of one certain testing data can be realized by calculating and comparing the possibility values of Equation (7) for all the model classes. The most appropriate class corresponds to the highest possibility. By taking the energy vector of WPT components as the input, the Bayes classifier makes full use of the time-frequency characteristics of received signals and contributes to more accurate classification of grouting conditions in post-tensioning tendon ducts.Piezoelectric ceramic is able to convert electrical and mechanical energy into each other. This property is called piezoelectricity. Piezoelectric material will generate electric charge when subjected to strain, namely the positive (direct) effect. In the converse piezoelectric effect, piezoelectric material will produce strain when it is polarized by electric field. Piezoelectric materials can thus be used as both actuators and sensors because of the positive and converse piezoelectric effect. In this study, PZT transducers were used to generate and receive ultrasonic stress waves. One PZT patch sandwiched with marble protection , namely There are various kinds of tendon duct grouting defects in practice. Bleeding of the grouting mortar introduces cavities in the upper part of the transverse tendon duct. Grouting mortar leakage and no pressure stabilizing step in the end of the grouting process would cause diverse partial grouting conditions. Steel wires used to tie the prestressing steel strands together may accumulate at the deformed or curved sections when the prestressing tendon passed through the duct. There may be other sundries, such as waste concrete, stacked inside the duct because of nonstandard operations in practice. Moreover, the vent pipe may be blocked during the concrete casting. These factors would block the mortar in the grouting process and further result in the 0%-grouting condition. In this context, six specimens were designed, as shown in As shown in The received stress wave signals have certain randomness in practice. Each specimen of a specific grouting condition was tested 60 times in order to obtain enough data with randomness. The stress wave signals received by Sensor 2 were analyzed here. The three-level WPT was therefore applied to analyze the received signals and to decompose them into eight frequency scales. As an example, Then, the respective energies of all the WPT components were calculated for all the signals received in the six grouting conditions. The mean value and variation range of the energy vector of WPT components for each grouting condition are shown in As for comparison, the Bayes classifier method was applied to identify different grouting conditions by, respectively, taking the total energy and the energy vector of WPT components as the input. Since each tendon duct specimen was tested for 60 times, there are in total 360 data samples for all the grouting conditions. Three hundred data samples were used to independently train the two Bayes classifiers with different inputs, and 60 data samples were used to test and compare their performances. The overall classification accuracies of the two Bayes classifiers input with the total energy and the energy vector were, respectively, 75% and 100%. The confusion matrixes of corresponding classification results are respectively displayed in The proposed method based on the Bayes classifier input with the energy vector of WPT components of received stress waves successfully identified the six grouting conditions investigated with 100% classification accuracy. WPT decomposed the analyzed signals both in high-frequency regions and low-frequency regions, and helped to clearly explore the energy distribution of stress waves in multi-frequency scales. The frequency components of stress waves had various sensitivities to different grouting conditions. The energy distribution of WPT components could therefore classify different grouting conditions more precisely than the total energy of WPT components that equaled the total energy of stress waves. It was evident that the energy vector provided more detailed time-frequency characteristics of received signals for classification, and that the Bayes classifier further helped to make an accurate grouting quantity evaluation.Although more grouting conditions have been investigated here than previous studies, it is impossible to cover all the possible grouting scenarios in practice for training this classification method. In fact, it is a problem for most defect diagnosis methods based on data clustering or classification. If an unexpected grouting scenario occurs, the identification result of the proposed method would be the most similar class investigated in this study. For examples, a 50%-grouting condition would be identified to be the 60%-grouting condition, and a 2 cm-cavity condition would be identified to be the 1 cm-cavity condition. In the future, more typical grouting conditions can be involved in the proposed method to improve its applicability and effectiveness in practice.In this study, a method based on WPT and Bayes classifier was proposed to evaluate grouting quality in post-tensioning tendon ducts by using stress waves generated and received by piezoelectric transducers. One PZT transducer bonded on the prestressing reinforcement was used as the actuator, while four PZT transducers mounted on the surface of the duct were utilized as the sensors. Six typical grouting conditions with both partial grouting and cavity defects of different dimensions were experimentally investigated. Due to the randomness of practical measurements, the variation ranges of the energy of stress waves received in different grouting conditions overlapped to various degrees. The WPT was thus applied to explore the energy distribution of received stress wave signals at multi-scales. After that, the Bayes classifier was employed to take into account the randomness of practical measurements in the grouting quality evaluation. As for comparison, the traditionally used total energy and the proposed energy vector of WPT components were, respectively, input to the Bayes classifier. The overall classification accuracy of the Bayes classifier input with the total energy was 75%, while that of the Bayes classifier input with the energy vector achieved 100%. The experimental results demonstrated that the Bayes classifier input with the energy vector overcame the shortcoming of using only the total energy as the classification criterion and could identify grouting conditions more accurately. The proposed grouting quality evaluation method has the potential to be applied at key spots of post-tensioning tendon ducts in practice.For future work, more grouting conditions especially the cavity at different positions will be studied through finite element simulation and experiments. The effects of water existing in grouting defects and post-tensioning tendons on the grouting quality evaluate would be figured out. The propagation path of stress waves in various grouting conditions will be investigated in order to involve more typical grouting conditions in the classification study.


Epilepsy is a chronic neurological disease and patients with epilepsy have an increased risk for cognitive, behavioral, and psychosocial disorders that can adversely impact the quality of life. Various factors like common underlying predisposition, mechanisms underlying epileptogenesis, direct effects of seizures, and adverse effects of anti-seizures drugs or other non-pharmacological therapies may play a causal role in such epilepsy associated comorbidities. New and validated screening approaches as well as novel therapeutic approaches are warranted, that may help with the early detection and treatment of comorbid conditions. Experimental models of epilepsies can play a critical role for improving our understanding of not only of the fundamental mechanism of epileptogenesis but also to generate new insights regarding the relationship between epilepsy and related comorbidities.This Research Topic compiles 12 articles, including 3 reviews, 1 mini-review, and 8 original research contributions from leading scientists in the field. The collection of papers on this topic offers an up-to-date overview of current knowledge and approaches for studying epilepsy and related comorbidities. The articles highlight the pivotal role of numerous experimental and clinical studies that have elucidated novel mechanistic insights about the pathophysiology of these conditions. Translational perspective of research in this domain as well as important methodological issues and some emerging hypotheses in the field are also highlighted. Recent progress in the pharmacotherapy and management of these conditions have also been critically analyzed and discussed. The content of each of these articles is summarized below.Arief et al., describes the role of non-mammalian models  for better understanding the mechanisms of epileptogenesis as well as for screening compounds with potential anti-seizure properties. This review highlights that a more comprehensive evaluation of these currently under-utilized non-mammalian models may help preclinical epilepsy research progress.The systematic review on non-mammalian models of epilepsy research by Muke et al., reports on the anti-convulsive potential of nasally administered coumarin fraction of medicinal plant Eclipta alba using PTZ induced kindling model. Their mechanistic studies showed that the efficacy of coumarin nasal formulation (CNF) was due to its ability to reduce oxidative damage and neuroinflammation. These exciting findings suggest the promising role of CNF as a therapeutic modality for epilepsy and related comorbidities.The article by Kumar et al., focuses on the current status of our understanding of the pathogenesis and therapeutic avenues related to three of the most common type of epilepsy that occur during sleep, namely hypermotor epilepsy (SHE), benign partial epilepsy with centrotemporal spikes (BECTS), and Panayiotopoulous syndrome (PS). The article also discusses the recent advances in the pharmacotherapy of these conditions.Sleep disorders and epilepsy share a complex reciprocal relationship. The review article by Zeng et al., in their original research article elucidate the effects of Ginsenoside compound K (GCK), the key metabolite of Ginsenoside Rb1, Rb2, and Rc, on acute seizure and the potential mechanism underlying its effects. Their study showed that that GCK exerts its effect by enhancing the expression of proteins related to GABAergic inhibition.Moto et al. showed that aqueous extract of C. quadrangularis, a plant belonging to family Vitaceae and traditionally well-known for its anticonvulsive properties, exerts antiepileptic as well as anxiolytic effects in the pilocarpine model of epilepsy. The authors also report that the neuroprotective effect of this herbal extract is mediated by its antioxidant properties as well as through modulation of GABAergic transmission.Currently available anti-seizure drugs (AEDs) raise several concerns related to lack of efficacy in a significant proportion of epilepsy patients and adverse events as well as their limited supply in Countries with poor resources and high costs. Over the years, traditional herbal medicines have occupied a prominent role in the treatment and management of epilepsy. However, robust experimental evidence related to the effectiveness and side effects of such herbal medications are limited. The article by Aguilar et al., tested male and female genetically epilepsy-prone rat (GEPR-3), a GEPR strain that exhibits inherited susceptibility to tonic-clonic seizures, in a battery of behavioral tests and showed that GEPR-3s showed increased anxiogenesis in multiple behavioral tests of anxiety. These interesting new data underscores the importance of genetic influence that may underlie both the seizure disorder and epilepsy associated comorbidities.The genetically epilepsy-prone rat (GEPR) represents an useful animal model for studying mechanisms of epilepsy especially for genetically determined seizure predisposition. The GEPR shows heightened sensitivity to convulsant drugs as well as to kindling, hyperbaric, and hyperthermic seizures. Griffin et al., presents the state-of-the-art on DS preclinical animal models with a focus on seizure phenotypes and behavioral comorbidities. The authors have critically analyzed the use of these models for drug screening with an emphasis on assay protocols and pharmacological profiles. In particular, the article provides a detailed overview of the electrophysiological and behavioral drug screening assays in zebrafish and summarizes the data on 3,000 drugs screened to date. The authors advocate that this preclinical strategy offers a modality for effective drug screening especially for genetic epilepsy.Dravet syndrome (DS) is a severe form of epilepsy formerly known as severe myoclonic epilepsy of infancy (SMEI) that appears in infancy or early childhood as frequent febrile seizures. As the condition progesses, it also leads to other types of seizures like monoclonus and status epilepticus. Ye et al., outline new findings about the neuroprotective effect of L-3-n-butylphthalide (NBP), a compound obtained from the seed extracts of Apium graveolens. Using a mouse model of chronic epilepsy, they demonstrate the effectiveness of this compound in alleviating both seizure severity and the associated behavioral and cognitive alterations. Their studies further show that NBP mediates such protective effects by increasing the transcription of neuroprotective factors like, brain-derived neurotrophic factor (BDNF), and Klotho as well as by restoring the expression of neural synaptic proteins such as postsynaptic density protein 95 and glutamic acid decarboxylase 65/67. These findings suggest that NBP is a potential therapeutic agent to control epileptic seizures and related psychological and cognitive comorbidities.In their original research article, Song et al., developed a new rodent model of extended hippocampal kindling to investigate the effects of three AEDs with different mode of action on spontaneous recurrent seizures. The authors showed that phenytoin and levetiracetam mitigated the spontaneous recurrent seizures whereas lorazepam reduced the severity of motor seizures, but had little effect on duration of hippocampal discharges. Although the model needs to be further characterized, it may prove valuable for assessment of novel drugs in the future.Kasahara et al. provides an overview of the salient features of animal models of neonatal seizures, namely hypoxia-ischemia-induced seizures and febrile seizures. Furthermore, pharmacological strategies to address epileptogenic changes have also been addressed.The mini review by Amini et al. provides interesting insights regarding the link between neuroinflammatory changes and pathophysiology of seizures. The authors studied the effects of lipopolysaccharide (LPS) preconditioning in a rat model of electroconvulsive shock (ECS) induced seizures. Their data indicate LPS preconditioning exerts a protective effect on seizure duration, which was associated with enhanced expression of interferon regulatory factor (IRF3), and other genes associated to Toll like Receptor 4 (TLR4) signaling pathway as well as down-regulation of pro-inflammatory mediators in the hippocampus.The research article by Meng Choo et al., explore the effects of ethanolic leaf extract of Orthosiphon stamineus in seizures using a zebrafish model. The authors report that treatment with the extract reduces Pentylenetetrazol (PTZ) induced seizures and ameliorates seizure-induced elevation of NF-kB, neuropeptide Y and TNF-α in the brain. Although he active constituent of O stamineus was not identified as yet, it is noteworthy that the anti-seizure effect of the extract was comparable to standard AED like Diazepam. This highlights that this herbal product may be a promising candidate for drug development in epilepsy.The studies by We are very grateful to the basic research and clinical investigators who have contributed to this research topic. We hope that these diverse and thoughtful papers will be useful to researchers to inspire their work and stimulate new discussions in this exciting research area. These studies also highlight the avenues for advancing the field for improving treatment and quality of life of patients. Further characterization of neural circuits and signaling mechanisms that contribute to the pathogenesis of these conditions may lead to the development of safer and more effective therapeutic approaches to tackle epilepsy as well as the associated comorbidities.AC took the initiative for the editorial write-up. MS, JA, and AV also contributed in writing, revising, and proofreading. All the authors approved the editorial.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.


A number of studies have found that higher socio-economic position (SEP) appears protective of becoming frail. However, not only can SEP be defined in early, mid or late life, by education, occupational status or income/material disadvantage respectively, but frailty may occur in the young old as well as the very old. Do the same measures of SEP reflect inequalities in frailty in the young old as the very old? Does it matter when in the lifecourse SEP is measured? Have inequalities in frailty between SEP groups changed across the generations of older people? We seek to answer such questions from cohorts across the spectrum of later life. The first presentation, from the 1958 British Birth Cohort Study, examines the association between early-life SEP and frailty at age 50 and whether this association is due to continued disadvantage into mid-life. The second presentation moves to very old age, examining the role of early, mid and late life disadvantage on the progression of frailty between ages 85 and 90 in the Newcastle 85+ cohort. The third presentation, based on the electronic health records of adults aged 75 years and over in England, focuses on whether SEP modifies frailty trajectories in the last year of life. The final presentation examines whether SEP inequalities in frailty have changed over different generations of older people, and utilises data from the Cognitive Function and Ageing Studies. Together these presentations increase understanding of which SEP groups should be targeted for interventions to reduce frailty throughout later life.


Musculoskeletal issues are extraordinarily overwhelming in industrialized nations and reportedly influence between 70%–80% of adults at some point during their lives . Over coApproximately 40% of Discogenic LBP (DLBP) might be associated with degeneration of the nucleus pulposus, tearing of the annulus, and intradiscal changes . The treConsidering the busy schedule of army staff, and side effects of surgery, it seems vital to identify a cost-effective package of exercise training for pain relief and treatment of army staff with DLBP. For this purpose, there will be two important questions: what is the prevalence of DLBP among army staff in Asian countries as most of the previous researches were conducted in Western and American countries. Secondly, what is the optimal package of exercise training for treatment and pain relief among this population?We strongly suggest researchers continue to examine the prevalence of DLBP among army staff. Importantly, it may be necessary to develop a specific package of office/home-based exercise therapy for this population.A package of office-based exercise training with therapeutic aims was recently suggested, in the treatment of neck, shoulder and lower back pain among office workers . This pa


In the middle of March 2019, a group of scientists and clinicians (as well as those who wear both hats) gathered in the green campus of the Weizmann Institute of Science to share recent scientific findings, to establish collaborations, and to discuss future directions for better diagnosis, etiology modeling and treatment of brain malformations. One hundred fifty scientists from twenty-two countries took part in this meeting. Thirty-eight talks were presented and as many as twenty-five posters were displayed. This review is aimed at presenting some of the highlights that the audience was exposed to during the three-day meeting. Our cognitive capacity is housed in the complex and well-organized cerebral cortex. Although the basic principles, cellular mechanisms and a large proportion of the molecules that underlie cortical development are shared by mammalian species, the human brain has exceptional features that have been better understood in recent years, thanks to the ground-breaking work of several distinguished labs. Prof. Arnold Kriegstein and Prof. Wieland Huttner and colleagues have been among the pioneers of a trend of shifting from the classical rodent model systems and focusing on human cortical development. Kriegstein and his colleagues, study the progenitor cell population that shapes the developing human brain, in particular the population of progenitors that is responsible for neurogenesis of the upper layers in the human brain and resides in the outer subventricular zone (OSVZ) see , and wasWork from the lab of Dr. Silvia Cappello sheds lights on the molecular link between ECM, oRG and cortical folding. Dr. Cappello and her team identified a secreted molecule that binds cell membrane bound receptors and is essential for the delamination of oRGs in human derived organoids. Similarly, its expression in the mouse brain shifts the progenitors to a more basal location and induces ectopic folds by remodeling of cytoskeletal elements like F-Actin and β-catenin. The team demonstrated that mutations in this gene are associated with congenital malformations and periventricular heterotopia (PH). The transition between basic science and the clinic is not always a straight forward one, but nonetheless fascinating. Transcriptome profiling of oRGs led to a better understanding of the origin of Glioblastoma multiforme, a primary cancer of the brain and one of the most lethal ones. oRG transcriptional signatures highly correlate with one of the cellular population identified within the tumor and indeed, cells that display MST migratory dynamics were identified in tumors. Moreover, a direct correlation between MST, the stem cell-like properties and tumorigenicity of the tumor cells was demonstrated.in vitro modeling system. The activation of the Hippo-Yap signaling pathway was also correlated with the proliferative capacity of oRGs in human and in the ferret , pachygyria and global developmental delay. Prof. Francis found that the protein is expressed during mouse cortical development in multiple regions including the proliferative zones, the VZ and the SVZ. Its knockdown leads to changes in the spindle orientation of the progenitors, causing premature delamination of the RG and thus to increased abundance of intermediate progenitors. These changes were linked to downregulation of F-Actin at the ventricular surface. Further elucidation of the phenotype came from the identity of scaffolding protein partners that are present at the postsynaptic density as well as in the dividing progenitor.in vivo genetically based tracing and revealed that these rogue cells are in fact glial progenitors that are born during prenatal stages. These observations led to the discovery of yet another migration mode; blood vessel guided migration. Prof. Nakajima and his team found that blood vessel guided erratic migration promoted angiogenesis and vessels branching. They were able to identify the molecules that mediate the attraction of the migrating progenitors to the endothelial cell wall, and validated their findings by loss of function studies using gene editing in both in vivo and in vitro systems. These finding may prove to be of an immense importance since glioma cells that are guided to blood vessels are likely to use an overlapping molecular mechanism.Neuronal migration is a well described phenomenon that is essentially the movement of neurons from their place of birth to their final location in the brain. Decades of study led to the understanding that complex migratory events take place during cortical development which persists into the early postnatal ages not only in rodent but also in human . In the The evolutionary expansion of the human brain was accompanied by acquisition of novel migration dynamics. Using Macaque as a non-human primate model the lab of Prof. Colette Dehay is studying the dynamic diversity of the OSVZ progenitors that produce the super granular layer compartment (SG). Prof Dehay found that the diversity of the molecular profiles of oRGs/bRGs is mirrored by the existence of cells with distinct morphologies . The bRG morphotypes differ in their neurogenic capacity, their progeny size and the directionally of the MST that can be either basally or apically directed. New levels of complexity of radial migration mode can be uncovered when lamina and area specific migration is carefully studied. Comparing SG neurons to deeper Infragranular layer (IG) migratory neurons shows higher radial migratory speed of the SG neurons prior to the appearance of the cortical convolutions. Areal difference in migration modes in area 17 and area 18 in the Macaque visual cortex were detected only for SG and not IG neurons, with a more directed radial movement in area 17 and more spread trajectories in area 18. These behaviors were attributed to cell autonomous changes in the leading-edge protrusions, and vesicular flow directionality that are controlled by differential levels of expression of molecular motor modulators in the different brain regions.Neuronal migration follows either a radial or a tangential migratory pathway, depending on the area of the developing nervous system in which the neurons originate. Inhibitory interneurons follow a tangential migratory route, parallel to the surface of the ventricle. In the rodent brain, a saltatory type of tangentially migrating interneurons was described in which the leading edge bifurcates and the nucleus follows one of the branches while the other retracts. The molecular basis of the saltatory migratory pattern and its contribution to the timed invasion of the IN to the forming cortex, was until recently unknown. A recent manuscript from the lab of Prof. Laurent Nguyen  identifiThe lab of Prof. Mercedes Paredes is studying the developmental basis of brain malformation and operates under the working hypothesis that during the prolonged period of human brain development, cellular abnormal maturation may occur that will lead to aberrant connectivity and cortical dysplasia. Interneurons have an important function as coordinators of cortical activity, and as such are of great interest in studying the etiology of a large number of neuropathologies. Prof. Paredes, described a unique architectural organization of the proliferative niche of human interneurons, the hMGE that can re-form after xenografting. She suggests that one of the mechanisms that contributes to the rapid developing brain of the young infant is a collection of late arriving IN that migrate close the lateral ventricle and invade the frontal lobe . This stExcitatory and inhibitory neurons are not the only cell type that exhibit impressive migratory ability. Cajal-Retzius cells (CRs), the first-born neurons in the developing cerebral cortex exhibit such activities. CRs are a transient population that consists of a collection of three linages that are born in distinct locations in the embryonic brain, all of which produce Reelin, an instructive ECM molecule whose function is critical for cortical lamination, and dendritogenesis . Dr. Alein vitro, as evident by the presence of nodules of MAP2 + cells that were stacked close to the ventricles of the organoids. The migratory defect was in fact a sum of a dual contribution at the levels of the progenitors as well as that of the migrating neurons. Disrupted scaffold of the progenitors, was seen in the patient’s derived organoids as well as after acute, localized reduction of DCHS1 and FAT4 mRNA, due to destabilization of the cytoskeleton. This was accompanied by a shift in the transcriptome of vRG-like cells from patients-derived organoids to an oSVZ/iSVZ-like molecular signature. Mutated neurons exhibited cell autonomous changes in their migratory dynamics, with more resting time points and decreased velocity. This work not only dissected the molecular and cellular events that lead to the brain malformation and highlighted fundamental species-specific differences between mouse and human models. Knockdown of Dchs1 or Fat4 in the mouse led to a fundamentally different observation where within mouse embryonic neuroepithelium resulted in increased progenitor cell numbers and reduced neuronal differentiation  or the more severe Miller-Dieker lissencephaly Syndrome  encodes a chromatin remodeling factor. Haploinsufficiency due to de novo mutations that span the entire CHD8 gene define a genetic subtype of ASD (Modeling Autism spectrum (ASD) disorder is a challenging task. ASD is a heterogeneous disease in multiple aspects; in its phenotypic manifestation and severity, in its genetic roots and in the complexity of contributing environmental factors. Dr. Gaia Novarino, undertook this challenge and is focusing on ASD caused by the loss of function of chromatin modulators. She is asking not only what is the etiology of ASD but also is there a particular developmental time window in which the gene function is critical and whether the deleterious effects may be reversible. Chromodomain helicase DNA binding protein 8 . The malformations that can be detected include periventricular nodular heterotopia, abnormal cortical layering, abnormal sulcation associated with polymicrogyria, corpus callosum agenesis, and microcephaly. Prof. Malinger and Prof. Lerman-Sagie added to the standard ultrasound examination the use of orthogonal planes and preformed meticulous search for detrimental findings. Significant signs that can be detected early include delayed cortical development, premature abnormal sulcation, hemispheric asymmetry, irregular shape or asymmetry of the lateral ventricles, thick or non-continuous cortex, irregular ventricular borders, corpus callosum abnormalities and abnormal interhemispheric fissure. Prof. Tally Lerman-Sagie also described the pathology features of dysgyria in a fetus with a tubulinopathy.in utero imaging  in patients with Periventricular Nodular Heterotopia (PNH) in which the amino acids sequence of the predicted protein is not expected to change and speculates that the mutation may lead to mis-splicing of FLNA.Prof. Ute Hehr, from the University of Regensburg, leads an “open exomes” initiative for the identification of causative genes in a large cohort (approximately 350) of brain malformation patients. About third of the sequence variants that Prof. Hehr and her team identified across different brain abnormalities can be classified as pathogenic variants yet a similar proportion are of unknown significance. Prof. Hehr described two pathological synonymous variants in F-actin-binding cytoplasmic cross-linking phosphoprotein Filamin A  a gene that is implicated in early-onset epileptic encephalopathy, developmental delay and autism. Complete deletion of the lncRNA promoter is embryonic lethal and a single allele removal increases the expression of CHD2 due to a cis inhibitory effect of the lncRNA on CHD2 expression. This observation opens a possibility to augment the normal CHD2 allele expression levels in cases of CHD2 haploinsufficiency (A relatively large variety of Long non-coding RNA (lncRNA) are expressed in the brain but their function in particular in the neurodevelopmental context is poorly understood. Dr. Igor Ulitsky and his team found specific lncRNAs that are required during neurogenesis. Additionally, they identified a conserved lncRNA that is located upstream to a chromatin modifier, ficiency .TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB5, or TUBG1) and Dyneinopathies . Prof. Nadia Bahi-Buission showed that despite being grouped together, each class actually contains a wide and often non-overlapping range of brain malformations. One of the challenges that basic research is facing, therefore, is not only discovering new causative genes but also understanding the often-complex genotype-phenotype correlation.MCD classification schemes are based on causative genes, include for example Tubulinopathies  variants to disease phenotypes, the best-known being Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome, was presented by Prof. Daniela Pilz. BWCFF is associated with cortical malformations, mainly pachygyria, in 60–70% of patients. However, mutations in ACTG1 are also associated with isolated non-syndromic deafness and one has been reported in isolated coloboma. Variants in exons 5 and 6 of ACTB have recently reported with syndromic thrombocytopenia (ACTB-AST), and ACTB haploinsufficiency has been described with an ID syndrome associated with cardiac and renal malformations. A specific ACTB variant  has been reported in Dystonia-Deafness syndrome  for the evaluation and treatment of the patients’ everyday function and quality of life.The concept that deregulation of a signaling cascades is pathogenic and likely responsible for a wide spectrum of brain malformation echoed in the current meeting.TSC1, TSC2, AKT3, DEPDC5) are associated with focal MCD, epilepsy and autistic traits in tuberous sclerosis complex (TSC) patients, hemimegalencephaly (HME), several megalencephaly (ME) subtypes, ganglioglioma (GG), polyhydramnios-megalencephaly-symptomatic-epilepsy (PMSE), familial focal epilepsy with variable foci (FFEVF) and cortical dysplasia)  lesions  is a protein complex that is a member of phosphoinositide 3-kinase (PI3K)-related protein kinase family. The mTOR signaling pathway was highlighted in several talks as key to understanding both normal developmental sequences and pathological brain malformation. The mTOR pathway is an established role in multiple basic cellular events and its activation or inhibition is known to have harmful consequences review . Mountinsplasia) . Prof. Esplasia) . The TSCsplasia) . mTOR hysplasia)  (reviewesplasia) . Single-splasia) . The con lesions .Prof. Stéphanie Baulac provided evidence of a somatic second-hit mutation in the mTORC1 repressor DEPDC5 pointing at a double-allelic hit: a brain somatic mutation identified in the postoperative specimen in addition to a germline mutation that sustain the focal nature of the cortical dysplasia (FCD) . An FCD-Epilepsy is prevalent in cases of brain lesions. It is common to heterogeneous disorders with a diverse and often unknown underlying genetic etiology. Prof. Renzo Guerrini presented the challenges in identifying phenotypic similarities using neurophysiological and imaging diagnostics  review . Prof. Cin utero electroporation. These rats with bilateral SBH show spontaneous epilepsy that start at 2–3 months of age, and seizures become more frequent and last longer as epilepsy progresses , Schizencephaly and FCD I and in a large proportion of FCD II and heterotopia cases . Short rThe last part of the meeting concerned an open discussion on major themes and points raised during the three days and focused on the issues: (1) understanding brain development in humans: what we know and what is still missing; (2) The issue of MCDs classification: what are the optimal future directions to integrate clinical, imaging, neuropathology and molecular data, and (3) the place of MCD animals models, i.e., to identify what is available, eventually through construction of a database and what is the place of alternative models .One of the innovative aspects of this meeting was to gather clinicians and scientists in the field and try to get them to speak the same language and identify common research goals. The clinicians in the audience identify as possible threats to research development the lack of a common registry of MCD cases through European countries, the need to improve brain imaging in clinical setting, to define which types of follow up sequential imaging are needed and how to organize transition care and long term follow up studies. With advent of prenatal genome-wide analysis made available on large scale, areas which need to be further developed and integrated in the routine clinical practice are the prenatal with the postnatal brain MRI imaging or any other imaging technologies enabling accurate prediction of the phenotypes.in vitro systems with human cells seem to progressively replace the role and overcome the limitations of mouse models. In this respect the creation of tissue banking and the way to connect these facilities would greatly facilitate research. Follow-ups on this meeting can be seen in the activities of COST Action CA16118; www.neuro-mig.org.Basic scientists see as a threat to discovery of genes and mechanisms involved in MCD the fact that through NGS too many variants and too many genes are discovered, i.e., the tremendous heterogeneity of the molecular processes leading to brain malformations and the lack of a standardized way to interpret genomic variants. Hence, at the moment it does not seem possible to create a uniform pipeline for functional validation of variants, which requires specific approaches for each type of gene or pathway. Many are strongly in favor of linking basic science to clinic and apply discoveries achieved in animal models to human disorders in a more structured way. However, there is yet no unanimity about which model represents the best choice. The use of the ideal closest model to humans, the primate brain raises too many ethical issues to be considered as valid choice, while As summarized above, during this 3-day meeting a broad variety of talks related to basic and clinical research on MCD were presented. In an inspiring environment, fruitful discussions between clinicians, neuroscientists, geneticists, gynecologists, pathologists and other specialists took place that we feel will be the starting point for many collaborations and will enable further future advancements in the field that ultimately will lead to benefits for affected individuals and their families.The datasets generated for this study will not be made publicly available. This is a meeting report and some of the speakers presented unpublished data. The text is confirmed by the speakers.TS wrote the full outline of the review. TB edited and contributed the figure. MP, TL-S, EA, WK, LN, BZ, NB-B, RL, NR, and OR edited and formatted 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.


Histomonas meleagridis is the causative agent of histomonosis in gallinaceous birds, predominantly in turkeys and chickens. Depending on the host species the outcome of the disease can be very severe with high mortality as observed in turkeys, whereas in chickens the mortality rates are generally lower. The disease is known for more than 100 years when in vitro and in vivo investigations started to understand histomonosis and the causative pathogen. For decades histomonosis could be well-controlled by effective drugs for prevention and therapy until the withdrawal of such chemicals for reasons of consumer protection in Europe, the USA and additional countries worldwide. Consequently, research efforts also focused to find new strategies against the disease, resulting in the development of an efficacious live-attenuated vaccine. In addition to efficacy and safety several studies were performed to obtain a deeper understanding of the immune response of the host against H. meleagridis. It could be demonstrated that antibodies accumulate in different parts of the intestine of chickens following infection with H. meleagridis which was much pronounced in the ceca. Furthermore, expression profiles of various cytokines revealed that chickens mounted an effective cecal innate immune response during histomonosis compared to turkeys. Studying the cellular immune response following infection and/or vaccination of host birds showed a limitation of pronounced changes of B cells and T-cell subsets in vaccinated birds in comparison to non-protected birds. Additionally, numbers of lymphocytes including cytotoxic T cells increased in the ceca of diseased turkeys compared to infected chickens suggesting an immunopathological impact on disease pathogenesis. The identification of type 1 and type 2 T-helper (Th) cells in infected and lymphoid organs by in situ hybridization did not show a clear separation of Th cells during infection but revealed a coherence of an increase of interferon (IFN)-γ mRNA positive cells in ceca and protection. The present review not only summarizes the research performed on the immune response of host birds in the course of histomonosis but also highlights the specific features of H. meleagridis as a model organism to study immunological principles of an extracellular organism in birds.The protozoan parasite  Histomonas meleagridis is an important flagellated parasite of poultry causing the disease histomonosis  (patitis) . Historipatitis) . Howeverpatitis) , updatedpatitis) , a summapatitis) , a recappatitis) , and asspatitis) .H. meleagridis might be a model to unravel peculiar immune mechanisms of extracellular pathogens considering that the avian immune response against these organisms is not as investigated in depth compared to viral or bacterial infections.The purpose of this review is to emphasize on studies investigating mechanisms of the immune response of host birds against the disease. This includes early studies describing inflammatory reactions of birds' up to recent investigations on specific immune cells and signaling proteins involved in host defense. Furthermore, the host reaction due to vaccination and its functional aspects are reviewed. Finally, H. meleagridis can occur directly or via embryonated eggs of the nematode Heterakis gallinarum which was already described by Graybill and Smith  the disease can cause high mortality due to severe necrotic inflammation of the ceca and the liver, while in chickens  clinical signs are milder and pathological manifestations are often restricted to the ceca of infected birds.Histomonosis was firstly described in turkeys by Cushman  more thand Smith . Horizonnd Smith  or orallnd Smith .The firsnd Smith . The patH. meleagridis migrates into the mucosa and deeper layers of the cecal wall leading to inflammation and ulceration, resulting in a thickening of the cecal tissue and formation of fibrin. Occasionally, ulcers erode throughout the cecal wall leading to peritonitis. Following destruction of cecal tissue, the parasite is able to infiltrate into blood vessels and to reach the liver via the portal vein. As a consequence, areas of inflammation and necrosis can occur in the liver. Liver lesions are highly variable in appearance: they may be up to 4 cm in diameter and can involve parts or the entire organ. Liver and cecal lesions together are a strong hint during post mortem investigations. The disease causes generally less severe lesions in chickens. Especially changes in the liver occur less frequently in chickens as compared to turkeys. In the final stage, the disease may become systemic when DNA of histomonads can be found in the blood and in the tissues of many organs, whether lesions are present or not  and CD8+ T-cytotoxic (Tc) cells plays a major role in host-pathogen interaction. CD3+CD4+CD8α− T cells are predominantly of helper phenotype, act as coordinators of the immune response by producing a variety of cytokines and secrete soluble molecules to the extracellular space which affects other cells of the immune system. In contrast, CD3+CD4−CD8α+ T cells are cytotoxic cells, promoting the cytolytic pathway. A protective immune response may rely on the ability of CD4+ T cells to accumulate high numbers of effector cells in order to activate a response against an invading pathogen. They can promote B cell-immunity with antibody production or, on the opposite, directly modulate, respectively control, the activity of different types of T cells. Secreted cytokines can activate macrophages and other cells through cell to cell signal communication. Powell et al. , with possible consequences on modulation of the immune response following vaccination and/or infection, needs to be understood. Furthermore, mechanisms on the function of innate immunity, particularly pro-inflammatory cytokines and antigen-presenting cells, could be useful to link the transition from the innate to the adaptive stage of the immune response. This can unveil essential features such as the quality and persistence of the acquired immune response which is helpful in establishing vaccination schedules. Data collected in experimental studies investigating histomonosis or following vaccination against the disease revealed important changes in the immune response but further identification on pathogen-specific mechanisms would be valuable. Hence, determining specific immunological correlates of protection e.g., the role and function of pathogen-specific T cells would contribute in pin-pointing features that mediate protection. Consequently, unraveling selective mechanisms that induce protection would be useful to promote such effector functions for facilitating new prospects in research on vaccination against histomonosis. Finally, along with studies on screening virulence factors of the protozoa, further explorations on the molecular plethora for potential immunogenic components are necessary to explain pathogen-directed immune reactions of the host.Further studies on the immune response of poultry against TM, FK, MH, and DL conceived and designed the review. All authors read 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.


Topesthesia, the recognition of tactile stimulation location on the skin, can be severely affected by neurological injuries, such as stroke. Despite topesthesia being crucial for manipulating objects and interacting with the environment during activities of daily living, deficits cannot be quantitatively captured with current clinical assessments and are, as a consequence, not well-understood. The present work describes a novel automated assessment tool for tactile mislocalization in neurological patients with somatosensory deficits. We present two cases of ischemic stroke patients, describe their tactile localization deficits with the automated assessment, and compare the results to a standard manual clinical assessment. Using the automated assessment tool, it was possible to identify, locate, precisely quantify, and depict the patients' deficits in topesthesia. In comparison, the clinical assessment was not sensitive enough and some deficits would remain undetected due to ceiling effects. In addition, an MRI structural analysis of the lesion supported the existence of somatosensory deficits. This novel and quantitative assessment may not only help to raise awareness of the implications of deficits in topesthesia, but would also allow monitoring recovery throughout the rehabilitation process, informing treatment design, and objectively evaluating treatment efficacy. Tactile sensory function is essential for recognition and manipulation of objects –3. This One difficulty of assessing localization, besides reproducibility of stimuli and test locations, is the visualization and quantification of localization errors. There have been few approaches resulting in hand-drawn schematics with arrows originating from the stimulus location  and terminating at the perceived location , 13, or Recently, we presented an novel automated approach to quantify and visualize tactile mislocalization on the hand . This syThe ReHaptic Glove system was designed as a novel automated assessment tool for tactile mislocalization in neurological patients with somatosensory deficits. We studied two chronic stroke patients that suffer from impaired tactile localization using the automated assessment tool. The magnetic resonance imaging (MRI) of the head analyzed here was performed as part of the standard stroke protocol of the Department of Neurology at the University Hospital Zurich. The scans included T1, T2, and fluid attenuated inversion recovery imaging, all with standard parameters on a 3.0 T Siemens  scanner.Patient 1, a 67-years-old  right handed man, was hospitalized in 05/2013 with multiple cerebral infarctions in the right posterior cerebral artery territory. Stroke MRI showed ischemic lesions in the right thalamus, parts of the internal capsule, and the medial occipitotemporal gyrus . In addiPatient 2, a 68-years-old  right handed woman, was hospitalized in 12/2016 following an acute right middle cerebral artery infarction. Ischemic lesions were detected in the right inferior frontal gyrus (pars opercularis), insula, lateral parts of the pre- and post-central gyrus, superior temporal gyrus, supramaginal gyrus, and corona radiata . On admiPrior to the assessments, both patients received information about the investigations. Written informed consent was obtained from the patients for performing the investigations and the publication of this case report. This case study was conducted in accordance with the Declaration of Helsinki and was approved by the Cantonal Ethics Commission of the Canton of Zurich (Req-2016-00285). The investigations of patient 1 and patient 2 were performed approximately 47 and 12 months after the insult, respectively.The localization deficits were first manually assessed, based on the instructions of the localization subscale of the Nottingham Sensory Assessment (NSA)  and the The automated assessment was conducted with the ReHaptic Glove, a research prototype system based on two gloves with haptic feedback and a touchscreen computer . Each glAdditionally, we conducted an MRI-based structural analysis of the lesions for both patients. The analysis of the lesions was based on T2-weighted images with the greatest extent of damage noticeable. The lesion borders were drawn in native space, using MRIcron software . The anaClinical assessment scores are listed in the first part of Patient 1 obtained maximum scores for both hands and all locations in the clinical assessment  hand and partial deficits for the right  hand based on the clinical assessment. Our automated assessment showed severe localization deficits for the left  hand. The outcome measures for the right  hand of patient 2 provided by the automated assessment were in a similar range as the outcome measures of patient 1. The scores of the clinical assessment as well as the automated assessment are summarized in The aim of this case study was to test an automated tool to assess mislocalization in stroke patients and to illustrate its utility and potential as a sensitive assessment tool for clinical applications. The two case reports illustrate that using the present instrumented approach allowed detecting, quantifying, and visualizing deficits in topesthesia, beyond of what is possible with the clinical assessment for localization. Furthermore, the presence of somatosensory deficits can be explained with the MRI-based lesion location analysis.In the case of patient 1, the clinical assessment could not detect any somatosensory deficits, and the subjective discomfort with tactile localization could not be captured. In addition, it was observed that the patient had problems when holding objects when not paying attention, which is a strong indication for lasting somatosensory deficits . In contFor patient 2 the clinical localization assessment revealed severe deficits in the left  hand and minor deficits in the right . While the clinical assessment resulted in a very low score for the left  hand showing only the ratio of correctly localized stimuli and providing very limited information on the type of distortion, the automated assessment uncovered the detailed morphology and severity of the somatotopic distortions. The perception of tactile stimuli on the left hand was completely reduced to the palmar area, as visible in One minor limitation of the comparison between the clinical assessment and the automated assessment arises from the stimulation type. While in the clinical assessment the tactile stimulation consists in touching or poking the patient's hand with a thin tool (activating more slowly adapting mechanoreceptors), the stimulation of the automated assessment consists in tactile vibration. This tactile vibration is mainly perceived superficially and is applied on locations with more subcutaneous tissue (fat) unlike the vibration stimuli applied with a tuning fork placed upon a bony prominence. Nevertheless, both touch and vibrotactile sensation are conveyed via the dorsal column–medial lemniscus pathway. Furthermore, the task is to locate suprathreshold stimuli on the skin requiring cortical analysis to provide more complex interpretation of primary somatosensory information instead of just assessing the absence of touch appreciation or the precise nature of the stimuli. Thus, whether suprathreshold tactile stimulation is in the form of touch or tactile vibration should not be crucial for the interpretation of the assessment outcomes.The voxel-based structural lesion analysis based on MRI scans did not allow to identify individual finger areas in the brain within the ROIs for these two case reports. This is due to two limitations: low spatial resolution of the 3.0 T scanner and the fact that the Anatomy toolbox does not yet include templates with individual finger areas. More studies using scanners with higher spacial resolution e.g., , 30, 37], 3730, 3In order to better understand the consequences of post-stroke distorted somatotopic representations leading to deficits in tactile localization and its importance to functional recovery, it is necessary to be able to quantitatively assess and monitor these deficits. While current clinical assessments can detect the existence of major deficits in topesthesia, they still fail to sensitively quantify them. The two case reports on stroke patients presented in this work demonstrate the utility and advantages of using a new, more sophisticated assessment tool to quantify mislocalization. This automated, technology-assisted assessment allows to assess topesthesia on the volar side of the hand in a standardized way with well-controlled stimulation for higher repeatability and provides continuous outcome measures on ratio scales. The computed visual representations allow clinicians to get a very detailed overview of the distorted perception for the entire hand at a glance. Thus, the automated assessment is expected to accelerate clinical routine examinations, while providing richer information and facilitating the interpretation compared to current clinical scales. In the two case reports, the proposed automated assessment was able to uncover deficits where clinical assessments could not due to ceiling effects and low sensitivity, and further suggested the presence of deficits in the ipsilesional hand, which is often referred to as the “non-affected” side in stroke patients. Furthermore, the existence of the revealed deficits in both patients could be related to the lesion location based on a voxel-based structural MRI analysis. These two cases show that strokes affecting the dorsal column—medial lemniscus pathway at different levels  can result in vibrotactile localization deficits. In cross-sectional studies such an assessment tool combined with MRI could allow a more detailed analysis to improve knowledge about somatotopy in different brain areas, as for example systematic distortions on neighboring fingers could be an indicator for co-located finger representations in the brain regions.Different studies have shown that mislocalization can persist many years after stroke , 14, 39 All datasets generated for this study are included in the manuscript and/or the supplementary files.Prior to the assessments, both patients received information about the investigations and gave their written consent. This case study was conducted in accordance with the Declaration of Helsinki and was approved by the Cantonal Ethics Commission of the Canton of Zurich (Req-2016-00285).MR, JH, OL, and RG designed the study. MR developed the methodology and conducted the instrumented assessment, performed the analysis, and drafted the manuscript. JD performed the MRI voxel-based lesion analysis. MR, JD, M-CH-R, and FC interpreted the results. JH recruited the patients and conducted the clinical assessment. LZ documented the medical histories of the two patients. All authors revised the manuscript and approved the final version.AL is scientific advisor for Hocoma AG , which develops rehabilitation technology. The ReHaptic Glove research prototype was developed at the Rehabilitation Engineering Laboratory at ETH Zurich and is not commercially available. The remaining 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.


Antibiotics, a variety of articles are presented that cover the breadth of human research in this field from in vitro work on novel therapies to commentary on public health strategies.Treating infection is a key part of the work of most clinicians. Whilst new drug technologies like biologics have begun a revolution in the treatment of cancer and autoimmune disease, there has been a conspicuous absence of new classes of antibiotic over the last 30 years. This, coupled with the mass use of antibiotics in farming and the continued emergence of resistant pathogens has created a perfect storm, and antimicrobial resistance is now viewed as a global public health emergency ,2. CombaStaphylococcus aureus. Infection caused by carbapenem-resistant Enterobacteriaceae (CRE) provide a particular challenge to clinicians worldwide. Suay-Garcia and Pérez-Gracia [The emerging crisis of antibiotic resistance and paucity of novel therapies, has led to a resurrection of historic drug development pipelines. Robertson and Musiol-Kroll  provide z-Gracia  provide Antimicrobial stewardship, including the prevention of inappropriate antibiotic prescribing is key to preventing the continued rise and spread of resistant pathogens. However, there is currently no international consensus on the definition or accurate quantification of the global burden of inappropriate prescribing. Hood and colleagues  provide For many clinicians, the threat or challenge of managing infection due to antimicrobial resistant organisms is often focused on a single patient, ward or practice. In this issue, Holmes and Hughes discuss the wider health economic implications of failing to act to combat resistant pathogens . The heaAntibiotics.Articles on in vitro work by Vianna et al.  on antim


The etiopathologies behind autoimmune thyroid diseases (AITDs) unravel misbehavior of immune components leading to the corruption of immune homeostasis where thyroid autoantigens turn foe to the self. In AITDs lymphocytic infiltration in the thyroid shows up a deranged immune system charging the follicular cells of the thyroid gland (thyrocytes) leading to the condition of either hyperthyroidism or hypothyroidism. The inflammation in AITDs consistently associate with ER function due to which disturbances in the ER protein homeostasis leads to unfolded protein response (UPR) that promotes pathogenesis of autoimmunity. The roles of ER stress in the instantaneous downregulation of MHC class I molecules on thyrocytes and the relevance of IFN γ in the pathogenesis of AITD has been well-documented. Thyroglobulin being the major target of autoantibodies in most of the AITDs is because of its unusual processing in the ER. Autoimmune disorders display a conglomeration of ER stress-induced UPR activated molecules. Several epidemiological data highlight the preponderance of AITDs in women as well as its concurrence with breast cancer. Both being an active glandular system displaying endocrine activity, thyroid as well as breast tissue show various commonalities in the expression pattern of heterogenous molecules that not only participate in the normal functioning but at the same time share the blame during disease establishment. Studies on the development and progression of breast carcinoma display a deranged and uncontrolled immune response, which is meticulously exploited during tumor metastasis. The molecular crosstalks between AITDs and breast tumor microenvironment rely on active participation of immune cells. The induction of ER stress by Tunicamycin advocates to provide a model for cancer therapy by intervening glycosylation. Therefore, this review attempts to showcase the molecules that are involved in feeding up the relationship between breast carcinoma and AITDs. The eminent Nobel Laureate Paul Ehrlich predicted the concept of autoimmunity, calling it “horror autotoxicus” involving a perplexing situation wherein the immune system starts assaulting self-cells leading to the development of autoimmune diseases. Today autoimmune diseases pose notable clinical issues owing to their chronic nature and higher rate of prevalence in relatively younger populations who are at the peak of their reproductive years . ImmunolHence, the fulcrum of the present review is an attempt to delineate the molecules, which are involved in crosstalks between two major AITDs (GD and HT) and breast cancer pathology.Metabolic homeostasis is much under the control of a properly functioning thyroid gland. The two major thyroid hormones are L-thyroxine  and L-triiodothyronine (T3), release under the influence of thyroid stimulating hormone (TSH). TSH acts on TSH receptors (TSH-R)  and stimulates the expression of membrane protein called sodium/iodide symporter (NIS), which mediate the inward translocation of iodine into the thyrocytes.  Fig.The spectrum of autoantigens reacting with the patient sera in cases of AITDs mainly involves three thyroid autoantigens: thyroglobulin (Tg), thyroid peroxidase (TPO), and TSH-R. These complex glycosylated proteins are post-translationally modified that affect their stimulatory role on the immune system.The most abundant glycosylated iodoprotein in the thyrocyte lumen is Tg (200–300 g/l), which is 670 kDa in size. Tg, accumulated in the colloid, provides the matrix for the sequestration of iodine and synthesis of thyroid hormones [Reviewed in ]. Tg iod2O2 and synthesis of thyroid hormones. Owing to its intracellular localization, it is also known as “microsomal antigen”  directed against TSH-R has been categorically described into three types: (i) thyroid stimulating antibody (TSAb) or thyroid stimulating immunoglobulin (TSI): binds to an epitope on TSH-R leading to the activation of the receptor (the effect is same as that of TSH), (ii) thyrotropin binding inhibitory immunoglobulins (TBII) or thyroid stimulation blocking antibody (TSBAb): bind to same or different epitope where they obstruct binding of radiolabelled TSH (shown in assays), and (iii) neutral TRAb. The physio-pathological development of GD observes unregulated and incessantly functional thyroid cells that are stimulated by TSAb . It has sting GD . The binsting GD . The higsting GD . In 95% sting GD . In a resting GD . Furthersting GD . In moststing GD .+T cell differentiation  and inflammation .Albeit GD patients show tremendous immunomodulatory assault of the thyroid gland, the extrathyroidal embodiment of the disease holds its enigmatic effect. There are reports of orbital infiltration leading to inflammation and connective tissue remodeling in the orbit that is the manifestation of thyroid-associated ophthalmopathy (TAO) . The inv+ phenotype on B cells in patients with GD, dispenses high expansion of B cells and anti TSH-R antibody production  engage the CD8+ cytotoxic T cells that kill thyrocytes through the secretions of perforin and granzyme  association initiates the destruction of thyrocytes, a remarkable study by Giorgio et al. showed the active role of infiltrating T lymphocytes in Fas-mediated cytotoxicity, where T cells actively expressed Fas and CD69. They showed that the T cells only expressed Fas but unlike thyrocytes, they did not show significant concentrations of FasL . The uprThe destruction of thyrocytes aided by all the above-mentioned plethora of molecular participants in the thyroid gland results in hypothyroidism.Endoplasmic reticulum (ER), being the cellular repertoire of calcium, forms the pivot on which various cellular metabolic processes depend, aiming at the maintenance of homeostasis. The immune system as well as target tissue of AITDs, the thyrocytes, shares the characteristic of secretory cells with an extended ER.Under the conditions of imposed stress instigating AITDs, the function of ER in sustaining proteostasis gets disturbed that leads to ER stress. This initiates a cascade of signaling events called unfolded protein response (UPR) . The mamAutoimmune inflammation has been studied to be induced by stress triggers and ER stress finds an important role in the pathogenesis of such autoimmune disorders , 122. ThThe break-down of self-tolerance in autoimmunity is majorly accounted for the accurate processing and presentation of peptides on MHC class I molecules. UPR plays an inevitable role in the processing of MHC class I peptide presentation during ER stress impinged by conditions of autoimmunity. It has been studied that induction of UPR impairs expression of MHC class I . UlianicThe very specialized function of thyrocytes is essential in the secretion of thyroid hormones Tg, T4, and T4, which relies substantially on the proper functioning of the ER. Hence, stimuli causing ER stress paves the way to UPR in thyrocytes . Adminisautoimmune regulator (AIRE) gene finds its expression in thymus, lymph nodes and fetal liver, which are the workshops for T cell maturation , which The discussion on NIS would be incomplete here without mentioning about the anti-NIS autoantibodies. As reviewed, reports have endorsed anti-NIS autoantibodies in AITDs but we are in dearth of successful data that can prove the role of these autoantibodies in the autoimmune thyroid pathogenesis .The malignancy in breast is dependent on the hormonal activity . Being wThe breast carcinoma shows unusual quantities of stroma with fibroblasts, vascular tissues and lymphocytic infiltration that are implicated in the development of cancer . The tum+ T cells in patients with autoimmune diseases is in congruence with the similar pattern observed in malignancy  through IL-6 , 185. ThThe adhesion molecules have been studied to act as the potential markers of the autoimmune manifest, which play crucial role in the immunomodulation of the patient . These mThe expression pattern of adhesion molecules in the vasculature depends on the cytokines of pro-inflammatory and pro-angiogenic stimulus that we have seen from the above discussed data on the thyroid autoimmunity. The activated endothelial cells secrete adhesion molecules like VCAM-1 and E-selectins . These aThe pictorial representation of this molecular crosstalk has been illustrated in Under the conditions of imposed ER stress, the cells and their environing extracellular surroundings are under constant pressure to discern life or death decision. Breast cancer is one good example of this situation. We have learnt from various studies that ER stress and hence the ensuing UPR plays major role in the pathophysiology of breast carcinogenesis . Young eThese are the key signatures which are common to the pathophysiology of both AITDs and breast cancer. Therefore, a radical approach to develop molecules against the aforementioned UPR signatures can be a potential therapeutic intervention to tackle both the diseases.The development of cancer is not only pronounced by the intrinsic autonomous biochemistry operating in the tumor but also the changes in the neighborhood of the primary tumor niche, which involves alterations in the concentrations of various molecules beyond their homeostatic levels. The pathophysiology of AITDs strongly hints that there is a significant upsurge in the concentration of various molecules that cross the boundary of one endocrine organ (thyroid) to another (breast). We have witnessed a distinctive collaboration among molecules showing heterotypic association amid the AITD manifest and the incipient breast tumor, which is remarkable. Despite the developments in the treatment of autoimmune disorders using immunomodulatory molecules, the results are not always satisfactory. Hence the knowledge about key molecules involved in the development of autoimmunity with special emphasis on stress-induced signaling molecules like the UPR markers is a mandate. Targeting the molecules involved in ER stress can help alleviate the destruction caused by the possible crosstalks between AITDs and breast cancer. For instance, in some models of autoimmune disorders, the IRE1 inhibitor has come out as a potential therapeutic candidate , 207, thThe glycosylation status of autoantibodies, especially IgG is important in the pathophysiology of autoimmune diseases . ER beinThe role of Galectin-9 , which is a glycan-binding protein, in the innate as well as adaptive immune response is very pertinent. Gal-9, being one of the prime regulatory molecules acting against inflammation, works by downregulating the Th1 and Th17 response . LeskelaThe significance of concomitant occurrence of polymorphism in the CTLA-4 gene, reported in both AITDs and breast cancer, need further explorations on its functional front. Studies have proven that the blockage of CTLA-4 not only recovers the T cell activity but also mitigates breast cancer pursuit, whereby therapeutic targeting of CTLA-4 would add up a step in the therapy of breast cancer . AccordiThe past two decades has witnessed tremendous research on the underlying mechanism of AITDs. Accumulating data have exhibited insights into the dynamism of immune cells in development and progression of cancer. Experiments involving the pharmacological activation of ER stress in cancer cells reported about the secretion of some soluble factors that led to the induction of not only UPR markers but also pro-inflammatory cytokines in the macrophages . This phSR and RM conceived the idea. SR, ATJ, AJ, DD, AS, JK, and RM contributed to the writing of manuscript. SR, ATJ, AS, JK, and RM contribute to the proof reading, editing and figure preparation for 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.


In mammals and birds, the reproductive system is very sensitive to states of energy deficit. For example, chronic food restriction in prepubertal female rats prevents the normal onset of puberty . In chicThe hypothalamic pituitary gonadal (HPG) axis is central to the reproductive system. Pulsatile gonadotropin-releasing hormone (GnRH) released from the hypothalamus stimulates the secretion of luteinising hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary. In females, FSH promotes follicle maturation and LH regulates ovulation whereas in males, FSH is mainly involved in spermatogenesis and LH stimulates the synthesis and the secretion of testosterone by the testis.Compelling evidence indicates that common regulatory signals involving energy sensors are implicated in the integrated control of energy balance and reproduction. At the whole animal level, energy sensors play a crucial role to indicate whether energy reserves are abundant (obesity) or poor (in case of food restriction and sports training). These energy sensors can be hormones, kinases, or nutrients.Some fertility disorders related to abnormal metabolism have highlighted the importance of the role of hormones produced by white adipose tissue (adipokines) in the regulation of mechanisms involved in human and animal reproductive functions . It is wGiven the tight link between energy metabolism and reproduction, in this special issue, we propose to discuss the role of some energy sensors such as adipokines on the fertility in different species including mammals and birds. Birds have some metabolic and reproductive peculiarities interesting to study the relationship between adipokines, metabolism, and reproduction.This special issue includes one novel research article and 4 reviews summarized as follows:In this review article, P. Kurowska et al. described the structure, expression, and function of apelin and its receptor, APJ. They also reported data concerning ELABELA, an endogenous ligand for APJ recently discovered. The authors summarized the physiological and pathological role of apelin in the hypothalamus-pituitary-gonadal axis. For example, this article summarizes the results of a series of recent studies on the effect of apelin on reproduction pathologies, like polycystic ovary syndrome, endometriosis, and ovarian cancer. Many of these pathologies are still in critical need of therapeutic intervention, and the authors report data showing that apelin could be a target in various reproductive pathologies.K. Dobrzyn et al. focused their attention on adiponectin that is the most abundant adipokine in plasma. After a brief description of the structure of the hormone and its main receptors, AdipoR1 and AdipoR2, the authors described the role of adiponectin in the hypothalamus-pituitary-ovary axis. Furthermore, they reported new data about the involvement of adiponectin in the embryo development and in the physiology of the placenta in different species including humans.n = 25) and two groups of GDM—GDM1  and GDM2 . In HUVECs, they showed that ANGPTL4 expression was decreased in GDM patients (with no difference between GDM1 and GDM2) whereas adiponectin gene expression was similar between control and GDM patients and leptin expression was undetectable. In cord blood, the leptin/adiponectin ratio (LAR) was increased in GDM2 compared to controls and GDM1 and did not differ between GDM1 and controls.P. Popova et al. investigated the gene expression of adipokines ) in human umbilical vein endothelial cells (HUVECs) and adipokine concentration in cord blood from women with gestational diabetes mellitus (GDM) depending on glycaemic targets. Three groups of patients were studied: control . Several human polymorphisms of these adipokines are also reported. A list of transgenic animals for different adipokines or adipokine receptors is presented with a description of phenotypes.Y. Elfassy et al. summarized the current data on the localization in the male genital tract and the role of seven adipokines  and other cytokines in male reproductive fertility. This review is interesting because most of the published reviews about the link between adipokines and fertility are focused on females but not on males. More precisely, the authors described the regulation of these adipokines in blood and seminal plasmas in different conditions (infertilities associated or not with obesity) based mainly on N. Mellouk et al. provided an overview of the structure and function related to metabolic and reproductive mechanisms of four adipokines  in avian species as compared to mammals. They emphasize and discuss why avian species are an interesting model to study the adipokines.In animal and human species, the optimum body condition level is necessary for normal physiological activities including reproductive efficiency. Inadequate nutrition impairs human fertility and reproductive potential in livestock. This special issue reports how the adipokines convey the body metabolic status to the hypothalamic-pituitary-gonadal axis to regulate fertility. It shows that the molecular mechanisms of these adipokines in reproductive tissues are still unclear. Thus, further research investigations need to be undertaken to unveil the exact mechanism of actions and signalling pathway of adipokines in gonadal dynamics and functions which might improve reproductive efficiency.