Christopher et al. (see pages 5159–5172) used multi-temporal, Normalised Difference Vegetative Index (NDVI) measurements with crop simulation modelling to demonstrate the value of various stay-green phenotype parameters for improving grain yield across different environment types.Improved genotypic performance in water-limited environments relies on traits, like ‘stay-green’, that are robust and repeatable, correlate well across a broader range of target environments and are genetically more tractable than assessment of yield Plant breeding is a slow and costly process. The potential release of a new, improved crop variety is limited by many factors, including the extent of genetic variation in key traits that contribute to yield, the confidence a breeder has in the selected phenotype and its association with underlying genotype, and the genotypic association of selected traits with extrapolation to performance across environments. Yield is phenotypically complex, reflecting an underlying genetic complexity and often unpredictable gene–environment interactions, and hence selection for less complex surrogates is desirable.per se.Selection for greater yield in water-limited and hot environments is particularly challenging owing to reduced heritability that reduces the breeders’ ability to identify elite families or lines. Frameworks reflecting underlying biological understanding of adaptation have been hypothesized and numerous traits suggested specifically targeting adaptation to target environments  cover and NDVI scores are also given for each assessment date.LiDAR incorporating a red laser captured the bi-weekly change in vertical distribution of the green vegetation profile . The useAssembling all bi-weekly LiDAR images together generates a temporal point-cloud detailing changes in canopy development for any genotype in a population. Box 3 compares canopy development throughout the season for two wheat NILs contrasting in leaf erectness. Differences in plant stature and canopy erectness are clearly demonstrated with maintained spacing between rows of plants for the erect NIL C676–, whereas canopy closure occurred early for the planophile leaf NIL C676+.® thermo-imaging sensors .Cooler canopies infer greater stomatal conductance and potentially photosynthetic rates (The work of


Background: Antipsychotic-induced weight gain (AIWG) and other adverse metabolic effects represent serious side effects faced by many patients with psychosis that can lead to numerous comorbidities and which reduce the lifespan. While the pathophysiology of AIWG remains poorly understood, numerous studies have reported a positive association between AIWG and the therapeutic benefit of antipsychotic medications.Objectives: To review the literature to (1) determine if AIWG is consistently associated with therapeutic benefit and (2) investigate which variables may mediate such an association.Data Sources: MEDLINE, Google Scholar, Cochrane Database and PsycINFO databases were searched for articles containing all the following exploded MESH terms: schizophrenia [AND] antipsychotic agents/neuroleptics [AND] (weight gain [OR] lipids [OR] insulin [OR] leptin) [AND] treatment outcome. Results were limited to full-text, English journal articles.Results: Our literature search uncovered 31 independent studies which investigated an AIWG-therapeutic benefit association with a total of 6063 enrolled individuals diagnosed with schizophrenia or another serious mental illness receiving antipsychotic medications. Twenty-two studies found a positive association while, 10 studies found no association and one study reported a negative association. Study variables including medication compliance, sex, ethnicity, or prior antipsychotic exposure did not appear to consistently affect the AIWG-therapeutic benefit relationship. In contrast, there was some evidence that controlling for baseline BMI/psychopathology, duration of treatment and specific agent studied  strengthened the relationship between AIWG and therapeutic benefit.Limitations: There were limitations of the reviewed studies in that many had small sample sizes, and/or were retrospective. The heterogeneity of the studies also made comparisons difficult and publication bias was not controlled for.Conclusions: An AIWG-therapeutic benefit association may exist and is most likely to be observed in OLZ and CLZ-treated patients. The clinical meaningfulness of this association remains unclear and weight gain and other metabolic comorbidities should be identified and treated to the same targets as the general population. Further research should continue to explore the links between therapeutic benefit and metabolic health with emphasis on both pre-clinical work and well-designed prospective clinical trials examining metabolic parameters associated, but also occurring independently to AIWG. Second generation antipsychotics  are the cornerstone of schizophrenia treatment. They effectively reduce psychotic symptoms while demonstrating a reduction in extrapyramidal side effects as compared to their typical, or first generation counterparts. However, SGAs are not without their own set of common side effects. Numerous studies have linked SGAs to metabolic changes which place patients at risk for cardiovascular complications, including antipsychotic-induced weight gain (AIWG), dyslipidemia, insulin resistance and type-2 diabetes , and olanzapine (OLZ), representing the two SGAs with the most adverse metabolic profile. Despite differences among agents, even the SGAs considered to be most metabolically neutral, , are associated with significant weight gain in antipsychotic antipsychotic-naïve individuals Correll, . MoreoveDespite the associated cardio-metabolic morbidity, the underlying causes of AIWG and other metabolic changes remain largely elusive. Increased food intake appears to be a component  and 5-HT2c receptor (HTR2C) genes have been substantially investigated. Although DRD2 variants have been associated with improvement of psychopathology  and glucagon-like peptide-1 (GLP-1) were reported to be associated with AIWG. Leptin plays a role in regulating circulating insulin  is a gastric hormone which stimulates the secretion of insulin. Previous associations have been reported between AIWG and GCG rs13429709 in OLZ- or CLZ- treated patients, as well as, the SULT4A1-1 haplotype in OLZ-treated patients from the CATIE trial for which patients had greater clinical response but gained significantly less weight        include MC4R). MC4R has been implicated in appetitive behavior, as well as, metabolic and weight regulation  has been associated with SGA-related AIWG in at least three independent samples  might be associated with AIWG, with each of them contributing limited risk, as expected in complex phenotypes. While there might be genetic variants which contribute to AIWG and therapeutic benefit simultaneously, there is a paucity of studies addressing this relationship and questions remain if AIWG and therapeutic benefit operate independently, i.e., where AWIG would be a pure side effect without therapeutic benefit.In this review, we set out to evaluate whether an association between AIWG and/or other antipsychotic-related metabolic effects  exists in relation to the therapeutic benefit of antipsychotics, across illness stage , ethnicities and study designs. We also discuss evidence whether such an association could be spurious vs. a true phenomenon with clinical implications. If indeed a true association exists between antipsychotic-induced metabolic dysregulation and treatment response, this would carry important clinical implications, such as the ability to safely target metabolic side-effects without compromise of treatment response, and the development of metabolically neutral yet effective drugs.To answer our research questions, we conducted a systematic review of studies investigating the association between therapeutic benefit and AIWG. We searched for relevant systematic review databases, including PROSPERO and the Cochrane Database, and found no similar reviews on this topic. We also followed the PRISMA guidelines and completed a PRISMA checklist (see Supplementary Table schizophrenia [AND] antipsychotic agents/neuroleptics [AND] (weight gain [OR] lipids [OR] insulin [OR] leptin) [AND] treatment outcome. Results were limited to full-text, English journal articles that studied humans up to a publication date of November 2016. The resulting abstracts were reviewed by ATR and MKH and those articles of relevance were assembled. Each of these articles was then hand-searched by ATR and MKH and only those that investigated the association between AIWG or antipsychotic-induced metabolic changes  and therapeutic benefit either by correlation or comparison were included in further analysis. The bibliographies of the remaining articles were then hand-searched by ATR for further relevant articles and any of these additional articles which investigated for an AIWG/metabolic changes and therapeutic benefit link were included in our analysis. Finally, articles that did not perform a statistical analysis were excluded from our analysis.We searched MEDLINE, Google Scholar and PsycINFO databases for articles containing all the following exploded MESH terms combine in the following way: p < 0.05) correlation between AIWG and therapeutic benefit or a statistically significant (p < 0.05) difference in measures of therapeutic benefit relative to weight gain/metabolic changes. In addition, we performed an exploratory analysis to investigate clinical and demographic factors which might impact the association between AIWG and therapeutic benefit to identify potential mechanisms and mitigating factors.Our primary outcome of interest was the examination of a correlation between AIWG metabolic changes and therapeutic benefit. A study population was considered to provide evidence for an AIWG/metabolic changes and therapeutic benefit association when patients treated with an antipsychotic showed a statistically significant   . Study length ranged from 4 to 384 weeks. Weight change was the most commonly reported metabolic effect; 22 of the 31 studies examining AIWG demonstrated evidence for an association between weight gain and symptom improvement. Eight studies found no significant association and only 1 study showed evidence for the reverse relationship . Examining the studies according to study design, DBRCTs and prospective trials demonstrated roughly the same proportion of studies which found an association (67%), while post-hoc analysis of the CATIE trial, Hermes et al. , OLZ (19 studies), risperidone (14 studies) and haloperidol (8 studies) were the most commonly used antipsychotics in our examined studies . Several studies examined specific domains of psychopathology in relation to metabolically-related changes during treatment. Improvement in both positive and negative symptoms appeared to be similarly correlated with AIWG  as compared to those with clinical deterioration  which have rapid weight gain trajectories showed an AIWG-therapeutic benefit association more consistently earlier-on in treatment than lower metabolic liability antipsychotics which have a slower weight gain trajectory. Finally, and notably, the individual antipsychotic examined appeared to influence the AIWG-therapeutic benefit association: those published studies looking at highest metabolic liability antipsychotics, specifically OLZ and CLZ, appeared more likely to show an association between weight gain and improvements in psychopathology, whereas those employing risperidone or haloperidol reported an association less frequently.If indeed there is a correlation between AIWG and therapeutic efficacy, an important question becomes: what is the causal nature of this relationship? There are three potentially overlapping explanations for this association: (1) weight gain directly causes clinical improvement; 2) clinical improvement directly causes weight gain; (3) antipsychotic activity of the drugs causes both AIWG and therapeutic benefit by a) common/interdependent or b) independent/mutually exclusive pathways  and therapeutic response in schizophrenia would have important clinical implications. If a degree of metabolic dysregulation is necessary for therapeutic effects in a subset of patients, this may mean that as clinicians we may have to accept that a certain trade-off between cardiovascular health and mental health is inevitable. By the same token, an early and rapid onset of metabolic changes could potentially be used as a marker of good clinical response. Identification of specific metabolic pathways with overlap to treatment response may be exploited to develop more efficacious treatments.Despite these potential implications, the available literature examining the association between antipsychotic-induced metabolic dysregulation and therapeutic benefit does not allow us to draw firm conclusions as to the clinical significance of what appears to suggest a “statistical,” and somewhat variable association noted mainly between AIWG and treatment response. Thus, given our current state of knowledge, the following observations should be emphasized: (1) AIWG, insulin resistance, and dyslipidemia are considered modifiable, and treatable cardiovascular risk factors; (2) these should be screened for and treated at minimum according to current guidelines , we chose not to undertake a meta-analytical approach. We also did not control for a publication bias in our sample of studies which may have skewed our results in favor of a positive result .In conclusion, this review supports an association between AIWG and therapeutic benefit in patients with schizophrenia, but evidence in terms of clinical significance remains sparse. Additionally, this link was weighted toward patients treated with OLZ and CLZ suggesting these medications possess a shared unique mechanism of action that may relate to their metabolic liability. In this regard, we speculate that the unique effects of CLZ and OLZ on insulin dysregulation could possibly indirectly explain the link between AIWG and therapeutic benefit in a subset of patients. Further research should continue to explore the links between therapeutic benefit and metabolic health with emphasis on both pre-clinical work , and well-designed prospective clinical trials examining metabolic parameters associated, but also occurring independently to AIWG. Evidence from genetic studies examining genes implicated in energy homoeostasis or appetite/satiety regulation and also overlapping with clinical improvement may also provide clues as to shared pathways. More recent results have also pointed to a role of the gut microbiome in the etiology of schizophrenia and in antipsychotic treatment outcomes, which warrants further investigation (Kanji et al., AR and VM summarized studies and drafted the manuscript. AC and IG contributed to drafting and revising the manuscript and enhanced succinctness and clarity. DM and MH contributed clinical and basic expertise in AIWG and therapeutic benefit, overseeing the synthesis of extracted information and manuscript drafting and editing.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 ideal balance between viral oncolysis and immune stimulation is unknown yet very consequential. Cytolysis from virus replication exposes previously unexposed cancer antigens to immune effector cells which are attracted to the area by the virus in the context of a danger response and can attack the tumor; however the immune cells can also remove the virus, and thereby limit viral oncolysis.Oncolytic herpes simplex virus (oHSV) therapy offers great promise at targeting difficult-to-treat solid tumors as evidenced by the first FDA approval of an oncolytic virus, modified HSV-1 talimogene laherparepvec  to treat advanced melanoma [Researchers have explored combination approaches with oHSVs including various chemotherapeutics and low-dose radiation to maximize both viral oncolysis and the effect of the added therapy. In most combination studies with chemotherapy drugs, apoptosis was increased but viral replication was not enhanced -4. Interin vivo thereby prolonging oncolysis possibly by preventing the influx of virus-mediated NK cells that may limit virus replication. 3) Alisertib prevented the increase of monocyte myeloid derived suppressor cells (MDSCs) induced by HSV1716. MDSCs have been shown to be pro-tumorigenic. Taken together, these exciting results demonstrate how a combination strategy may be used to not only improve the effectiveness of oncolytic virotherapy but also increase the efficacy of the combined drug. Further studies are needed to determine if there is one principal mechanism resulting in the increased antitumor effect or if each of these findings (and perhaps others not yet described) combined are responsible for the outcomes. Additionally, the generalizability of these findings to other models will be interesting to investigate.In a recent issue of Oncotarget, Currier et al. describe the synergistic effects of combining Aurora A Kinase inhibitor alisertib (MLB8237) with HSV1716, a first-generation oHSV currently in phase I clinical trial in children with non-central nervous system solid tumors (NCT00931931), in neuroblastoma and malignant peripheral nerve sheath cell lines [In addition to maximizing virus replication and the effect of an added agent, a critical challenge remains exploiting the immune system to create a sustained anti-tumor response. The combination of HSV1716 and alisertib removed unfavorable MDSCs which are known to promote pro-tumorigenic M2 macrophages. Additional opportunities exist with adjuvant immunotherapies such as natural killer (NK) cell therapy and checkpoint molecule inhibitors. Recently, researchers demonstrated synergy between bortezomib, a proteasome inhibitor, and oHSV in causing inflammatory necroptotic tumor cell death [


Despite an increasing research and clinical focus on trans-diagnostic approaches to mental health, it remains unclear whether different diagnostic categories share a common neuronatomical basis. The current investigation sought to investigate whether a shared (trans-diagnostic) set of structural alterations characterized schizophrenia, depression, post-traumatic stress disorder and obsessive-compulsive disorder, and determine whether any such alterations reflected markers of psychiatric illness or pre-existing familial vulnerability.A total of 404 patients with a psychiatric diagnosis were recruited  alongside 201 healthy controls and 20 unaffected first-degree relatives. We collected structural Magnetic Resonance Imaging scans from each participant using the same 3.0 Tesla scanner and acquisition sequence, and tested for trans-diagnostic alterations using Voxel-Based Morphometry.We report that the four psychiatric groups were all characterized by significantly greater gray matter volume in the bilateral putamen relative to healthy controls . Furthermore, the volume of this region was positively correlated with severity of symptoms across groups, so that a higher gray matter volume in the putamen was associated with higher severity of symptoms . Bilateral putamen enlargement was also evident in unaffected relatives compared to healthy controls .These findings indicate that increased putamen volume may reflect a trans-diagnostic marker of underlying familial vulnerability to psychopathology. This raises the prospect that this region could be used to assess degree of familiar vulnerability to psychopathology above and beyond traditional diagnostic boundaries. Our investigation provides support to emerging conceptualisations of psychiatric illness, in which each disorder is best understood as a combination of diagnosis-specific features and a trans-diagnostic factor reflecting general psychopathology.


Therefore, whether mossy fiber sprouting is a potential therapeutic target for epilepsy remains under debate. Moreover, the axon guidance mechanisms of mossy fiber sprouting have attracted the interest of neuroscientists. Sprouting of mossy fibers exhibits several uncommon axonal growth features in the basically non-plastic adult brain. For example, robust branching of axonal collaterals arises from pre-existing primary mossy fiber axons. Understanding the branching mechanisms in adulthood may contribute to axonal regeneration therapies in neuroregenerative medicine in which robust axonal re-growth is essential. Additionally, because granule cells are produced throughout life in the neurogenic dentate gyrus, it is interesting to examine whether the mossy fibers of newly generated granule cells follow the pre-existing trajectories of sprouted mossy fibers in the epileptic brain. Understanding these axon guidance mechanisms may contribute to neuron transplantation therapies, for which the incorporation of transplanted neurons into pre-existing neural circuits is essential. Thus, clarifying the axon guidance mechanisms of mossy fiber sprouting could lead to an understanding of central nervous system (CNS) network reorganization and plasticity. Here, we review the molecular and cellular mechanisms of axon guidance in mossy fiber sprouting by discussing mainly  These mThe basically unidirectional projection of mossy fibers is ensured by several axon guidance cues Figure . Studiesin vivo and epileptiform seizures in vitro have replicated this mossy fiber sprouting  has received the most attention . The expd slices , and intd slices . Additiod slices . Taken td slices  nor BDNFd slices  resultedThe BDNF-induced signaling pathway that is involved in mossy fiber sprouting has not been fully identified. The axonal branching induced by neurotrophins, including BDNF, is partly mediated by 3′,5′-cyclic adenosine monophosphate (cAMP) . An optoO-acetylated gangliosides, whose expression has been shown to correlate with axonal growth in several brain regions, did not contribute to mossy fiber sprouting in adult epileptic rats , whose expression was high in the granule cell layer, blocked activity-dependent mossy fiber sprouting in hippocampal slice cultures by preventing the sprouted collaterals from invading the inner molecular layer . Shetty pocampus –68 in a After the reverse-traveling mossy fibers enter the molecular layer, they are tightly confined in the inner molecular layer and usually do not invade the middle or outer molecular layers [but see the study from Babb and colleagues , which sWhen the pioneer mossy fibers complete their extension to the molecular layer, it is possible that the following mossy fibers fasciculate with them in a manner guided by contact-dependent axon guidance cues, such as PSA-NCAM, which is expressed on mossy fibers. Based on an organotypic coculture system, it has been suggested that PSA-NCAM serves as a contact cue for the following mossy fibers when diffusible chemoattractants from CA3 are no longer available in the late developmental stage .Adult neurogenesis in the dentate gyrus could also account for additional fasciculation to the sprouted mossy fibers, as it has been suggested that adult-born granule cells are the main source of sprouted mossy fibers after status epilepticus (SE) . DentateThe misguidance of mossy fibers to the inner molecular layer has been demonstrated to be regulated by several molecules Figure . It shouRK and YI discussed and wrote 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.


Within each sensory modality, age-related deficits in temporal perception contribute to the difficulties older adults experience when performing everyday tasks. Since perceptual experience is inherently multisensory, older adults also face the added challenge of appropriately integrating or segregating the auditory and visual cues present in our dynamic environment into coherent representations of distinct objects. As such, many studies have investigated how older adults perform when integrating temporal information across audition and vision. This review covers both direct judgments about temporal information  and judgments regarding stimuli containing temporal information . Although an age-related increase in integration has been demonstrated on a variety of tasks, research specifically investigating the ability of older adults to integrate temporal auditory and visual cues has produced disparate results. In this short review, we explore what factors could underlie these divergent findings. We conclude that both task-specific differences and age-related sensory loss play a role in the reported disparity in age-related effects on the integration of auditory and visual temporal information. The normal aging process degrades both auditory and visual temporal perception, contributing to the difficulties older adults encounter with everyday tasks. For example, age-related impairments in speech comprehension and driving performance are associated with temporal processing deficits within audition  and visiIntegration binds auditory and visual stimuli into a unified percept, altering their perception relative to how they are perceived in isolation . CorrectPhysiological aging affects the auditory and visual pathways from the sensory periphery to the cortex, resulting in a decline in many aspects of temporal perception. Within audition, older age reduces sensitivity to temporal fine structure , amplituWithin vision, many age-related temporal processing deficits have been documented, including reduced flicker sensitivity , reducedFurthermore, sensory decline is typically uneven across vision and audition, though the more adversely affected sensory modality varies between tasks . For exaStudies have investigated age-related changes to various measures of audiovisual temporal perception presumed to reflect multisensory integration, with disparate results for transient stimuli like flashes and beeps. Older adults are more susceptible to the sound-induced flash illusion . In thisAge-related effects on the integration of temporally modulated stimuli depend on audiovisual congruency. Partial integration of non-identical auditory and visual temporal rates distorts perceived rate such that the auditory or visual rate subjectively equivalent to a reference is non-veridical . This efResearch on audiovisual speech perception in aging is also relevant to this review, since the temporal relationships between auditory and visual speech cues facilitatIn the McGurk effect, integration of incongruent auditory and visual speech results in a fused percept that matches neither cue . Most stAltogether, research indicates an age-related increase in the integration of temporally offset auditory and visual events. Older adults perceive the sound-induced flash illusion at larger temporal offsets between auditory and visual stimuli than younger adults . When juTables 1, 2). This suggests that age-related effects on integration may be task-specific, as discussed in the next section.In summary, integration of temporal auditory and visual information may be increased, decreased or unchanged by physiological aging  also influences audiovisual interactions . In contUnfortunately, studies of audiovisual integration in older adults have not employed a consistent definition of what constitutes normal hearing and vision, and may not screen both sensory modalities for age-abnormal changes. Even so, screening measures commonly used in older adults such as audiometric thresholds and visual acuity are poor indicators of other aspects of auditory e.g.,  or visuaAudiovisual integration may not necessarily provide older adults with an effective compensatory mechanism for age-related unisensory decline in temporal information. While older adults often benefit from the provision of complimentary auditory and visual cues, it can be to a reduced extent compared to younger adults. Older adults sometimes demonstrate an increased tendency to synthesize conflicting temporal auditory and visual cues into a unified percept but this is not a universal finding. Further research elucidating how closely integration is linked across different audiovisual tasks is needed to clarify this pattern of results. Currently, it remains unclear to what extent age-related changes in audiovisual temporal perception reflect true changes in integration rather than sequential effects of age-related sensory loss. Future research should account for individual differences in unisensory reliability to distinguish age-related sensory loss from age-related effects on integration.CB: conception and planning of review and wrote the manuscript. YC: planning of review and contributed to the writing of Section “Age-Related Changes in Audiovisual Temporal Perception.” AM and AA: conception of review and revision of the manuscript. All authors approved 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.


Psammoma bodies (PBs) are observed most commonly in papillary thyroid carcinoma, meningioma, and papillary serous cystadenocarcinoma of the ovary. We report one case of peritoneal malignant mesothelioma (PMM) with massive deposition of PBs. A 72-years-old man presented with abdominal swelling and marked weight loss. Contrast enhanced computed tomography showed fluid diffuse in peritoneal recesses, thick septa with micronodules in the greater omentum and adjacent enhancement of the thickened peritoneum. The explorative laparoscopy showed diffuse minute parietal peritoneal nodules. The peritoneal biopsy revealed a superficial papillary growth of malignant epithelial-like cells with diffuse involvement of submesothelial tissues. Massive deposition of PBs was observed. Nuclear and cytoplasmic calretinin immunoreactivity was present in neoplastic cells along with membranous D2-40 and membranous/cytoplasmic cytokeratin 5 staining. The patient was treated with chemotherapy . PBs may represent an active biologic process ultimately leading to degeneration/death of tumor cells and retardation of growth of the neoplasm. It may also serve as a barrier against the spread of tumor. Psammomatous malignant mesothelioma may simulate serous psammocarcinoma of the peritoneum. The behavior of serous psammocarcinoma is more closely similar to borderline serous tumor than to serous carcinoma. Further studies are necessary to establish if massive deposition of PBs may define a new variant of psammomatous malignant mesothelioma with a favorable impact to the prognosis of usual psammomatous malignant mesothelioma, as well as in serous psammocarcinoma of the peritoneum. Psammoma bodies (PBs) are concentrically laminated calcific spherules that occasionally appear cracked (psammos [“sand”] + oma [“tumor”]). PBs are observed most commonly in papillary thyroid carcinoma, meningioma, and papillary serous cystadenocarcinoma of the ovary . PBs havA 72-year-old man presented with abdominal swelling and marked weight loss. No history of exposure to asbestos was found. Abdominal ultrasound revealed abundant perihepatic, perisplenic and pelvic fluid. Contrast enhanced computed tomography showed fluid diffuse in peritoneal recesses, thick septa with micronodules in the greater omentum and adjacent enhancement of the thickened peritoneum . MalignaPMM is universally regarded as a fatal disease (median survival 6-12 months; mean symptoms-to survival time 345 days [Attanoos and Gibbs reported that PBs may be seen in approximately 5% to 10% cases of PMMs . But the


Sparus aurata). Cultured sea breams were fed three isonitrogenous diets. The organically produced feed contained sustainable certified fish meal (45%), fish oil (14%), and organic certified wheat; the laboratory feed contained fish meal (45%), fish oil (14%), wheat meal, and soya meal; and the commercial feed included fish meal (46%), fish oil (17%), soya meal, wheat meal, and corn gluten meal. The organic diet had higher amounts of vitamins A, C, and E; specific amino acids; and minerals that enhanced the biosynthesis of collagen. This study shows that fish fed the organic feed had significantly bigger collagen fibril diameters than the fish fed the conventional feed. Furthermore, the organically fed fish had similarly sized collagen fibril diameters as wild fish. More research is needed to understand the long-term effects and the mechanism and function of fish collagen peptide intake on lipid absorption and metabolism; and to identify dietary regimes that are able to improve whole body lipid profiles and suppress the transient increase of plasma triglycerides.This study aims to measure liver collagen fibril diameter in cultured and wild sea breams (


A 52-year-old man with prostatic hyperplasia presented to the emergency department with complaints of lower abdominal pain worsening over three days and inability to urinate. Abdominal examination revealed a protuberant, distended bladder . A FoleyUrinary outlet obstruction is commonly treated by insertion of a Foley catheter, allowing drainage of the distended bladder. Previous recommendations have suggested gradual drainage of an obstructed bladder, for instance by intermittent catheter clamping, to avoid complications of hematuria, hypotension, and post-obstructive diuresis, although the value of this practice is debatable.A systematic literature review of related studies published from 1920 to 1997 found no cases of hematuria severe enough to necessitate further invasive therapy, such as bladder irrigation or blood transfusion.2What do we already know about this clinical entity?Traditional warnings against rapid bladder decompression may prolong definitive care in the ED and result in use of additional resources.What is the major impact of the image(s)?Hematuria is demonstrated after bladder decompression, although the patient suffered no adverse complications.How might this improve emergency medicine practice?Despite the possibility of hematuria, ED patients with bladder outlet obstruction can be rapidly decompressed with low risk of serious sequelae.


Bladder cancer treatment remains a challenge despite significant improvements in preventing disease progression and improving survival. Intravesical therapy has been used in the management of superficial transitional cell carcinoma (TCC) of the urinary bladder  with specific objectives which include treating existing or residual tumor, preventing recurrence of tumor, preventing disease progression, and prolonging survival. The initial clinical stage and grade remain the main determinant factors in survival regardless of the treatment. Prostatic urethral mucosal involvement with bladder cancer can be effectively treated with Bacillus Calmette-Guerin (BCG) intravesical immunotherapy. Intravesical chemotherapy reduces short-term tumor recurrence by about 20%, and long-term recurrence by about 7%, but has not reduced progression or mortality. Presently, BCG immunotherapy remains the most effective treatment and prophylaxis for TCC  and reduces tumor recurrence, disease progression, and mortality. Interferons, Keyhole-limpet hemocyanin (KLH), bropirimine and Photofrin-Photodynamic Therapy (PDT) are under investigation in the management of TCC and early results are encouraging. This review highlights and summarizes the recent advances in therapy for superficial TCC.


We report on a 69-year-old male who presented with an indwelling urinary catheter due to obstructive prostatic disease. The patient also complained of impotence. With repetitive prostatic massage combined with antimicrobial therapy the urinary obstruction was released, the patient's urinary symptoms resolved, and sexual function improved.


Optical coherence tomography angiography (OCTA) is a new, noninvasive technology that enables detailed evaluation of flow in the retinal and choroidal vasculature. The authors believe this to be the first report to describe the optical coherence tomography angiography findings associated with combined central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO). Combined central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) is a rare vasoocclusive entity that has been associated with multiple etiologies that can cause devastating vision loss –8. In thOptical coherence tomography angiography (OCTA) is a new, fast, noninvasive imaging modality that allows detection of blood flow through the retinal and choroidal plexuses without intravenous dye injection . The depThe authors believe this report to be the first to describe the optical coherence tomography angiography findings associated with combined central retinal artery occlusion and central retinal vein occlusion. The commercially available Cirrus 5000 with AngioPlex  was used, without any subsequent image modification or processing.A healthy 69-year-old female presented to the Emergency Department with sudden, painless, visual loss that started immediately following cataract surgery with retrobulbar anesthesia in the left eye (OS) nine days prior to presentation. The patient denied jaw claudication, temporal headache, scalp tenderness, or visual loss in the right eye (OD). Immediately following the event, the patient underwent a work-up which included a transthoracic echocardiogram (TTE), electrocardiogram (EKG), carotid ultrasound, erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP), computed tomography (CT), and magnetic resonance imaging (MRI) of head. All tests were within normal limits.A complete ophthalmologic exam was performed. Best corrected visual acuity was 20/40 OD and hand motion OS. Intraocular pressure measured by Tono-Pen XL (Reichert Technologies) was 18 mmHg OD and 19 mmHg OS. Full ductions were present without pain. Pupils were equally round with an afferent pupillary defect OS. Anterior segment examination in the right eye was significant for a nuclear sclerotic cataract and examination of the left eye revealed corneal edema, trace cell, +1 flare, and a well-centered intraocular lens.Fundus examination by indirect ophthalmoscopy was unremarkable OD. Funduscopic exam OS demonstrated mild disc edema, macular edema, whitening of the macula, subtle tortuosity of vessels, and flame-shaped hemorrhages and cotton wool spots in all quadrants .Spectral domain optical coherence tomography (SD-OCT) was performed on OS and showed increased hyperreflectivity and edema of the inner retina with disruption of the ellipsoid zone (EZ) .OCTA revealed an absence of flow in the foveal and perifoveal area in the superficial and deep retinal capillary plexuses Figures . In contA combined CRAO and CRVO is a rare entity, and the etiology is incompletely understood. Although cardiovascular diseases, hypercoagulopathy, and inflammatory diseases are potential risk factors, our patient presented with a combined occlusion without any history of systemic diseases following cataract surgery with retrobulbar anesthesia –4. SeverThe exact mechanism of combined CRAO and CRVO has not been elucidated, but there are multiple mechanisms proposed to explain the association with retrobulbar injection. Combined occlusion could result from optic nerve sheath hematoma secondary to needle penetration or direct injection into the optic nerve sheath , 21. AnoCombined CRAO and CRVO is an ophthalmological emergency that should be recognized as a serious postsurgical complication due to its poor outcome. Without timely intervention, combined occlusion can lead to rubeosis iridis, neovascular glaucoma, retinal necrosis, periphlebitis of the central vein, and eventually permanent vision loss , 22. VarIn the current report, OCTA showed that the vascular flow of the superficial and deep retinal plexuses were both interrupted OS Figures . In contThis case demonstrates clinical features of combined CRAO and CRVO imaged with OCTA following retrobulbar anesthesia associated with cataract surgery. OCTA technology can facilitate diagnosis and extent of combined CRAO and CRVO as it enables discrimination between superficial and deep retinal vasculature. Additional advantages of OCTA compared to FA include faster image acquisition and no potential allergic systemic effects , 23, 24.In conclusion, OCTA is a new, fast, noninvasive imaging technology that has enabled improved understanding of the pathophysiology of many retinal vascular diseases including combined CRAO and CRVO. To the best of our knowledge, this is the first reported case that describes the OCTA findings associated with combined CRAO and CRVO. Future studies with OCTA will hopefully illuminate additional features of combined CRAO and CRVO and provide a better understanding of this complex disease.


Erectile dysfunction (ED) following treatment for clinically localized prostate cancer, particularly radical prostatectomy (RP), is a major quality of life issue that remains unsatisfactorily addressed. With the introduction and use of cavernous nerve–sparing procedures over the past 25 years, many men recover erections postoperatively that enable sexual intercourse unlike in the prior surgical era, when permanent ED postoperatively was certain. Despite this advance, 26–100% of these patients may never recover normal erectile function (EF). Recent advances in the understanding of ED after RP have stimulated great attention to develop penile rehabilitation programs and neuromodulation. The purpose of penile rehabilitation is to prevent adverse corpus cavernosal tissue structural alterations and thereby maximize the chances of recovering functional erections. Rehabilitation programs are common in clinical practice, but there is no definitive evidence to support their efficacy. Neuromodulation represents another strategy for promoting erection recovery postoperatively. This therapy involves the application of neuroprotective interventions, conceivably targeting biological elements involved in the erection response that are affected by neuropathic injury. Well-conducted, controlled trials with adequate follow-up are required in order to determine the erection preservative benefits of these therapeutic strategies. The purpose of this essay is to describe the mechanisms related to post-RP ED, assess the need for penile rehabilitation and neuromodulation following surgery, and analyze the basic science and clinical trial evidence associated with these applications for preserving EF following prostate cancer treatment.


The human brain possesses a superior capacity to reorganize and profound plasticity after focal lesions following brain injury such as trauma, ischemia, and degenerative disorders. The concept of plasticity describes the mechanisms that rearrange cerebral organization following a brain injury. The development of sophisticated noninvasive neuroimaging techniques over the past decade provides a unique opportunity to examine brain plasticity in humans and invaluable insights into the mechanisms underlying neuroplasticity. Unifying pathogenesis of brain injury by neuroimaging techniques can be beneficial to develop therapeutic strategies with broad applicability for disease prevention and an opportunity to decrease morbidity and mortality from these disorders in human beings.In this special issue on imaging neural plasticity following brain injury, we compiled a series of articles that represent novel primary research and explore brain plasticity following brain injury. T. Wang et al.  investigate the brain impairments following asymptomatic carotid stenosis by utilizing an integrated MRI including pulsed Arterial Spin Labeling (pASL) 22 MRI, Proton MR Spectroscopy (MRS) and resting-state functional MRI (R-fMRI). They found that hypoperfusion in the left frontal lobe, lower NAA/Cr ratio in the left hippocampus, and decreased connectivity to the posterior cingulate cortex in the anterior part of the default mode network might partly contribute to the cognition impairment in these patients.X. Fan et al.  explore the distinctive brain structural and effective connectivity changes within the semantic cognition network by comparing left and right mesial temporal lobe epilepsy (mTLE) patients and these patients to matched healthy controls. Since seizure attacks were rather targeted than random for patients with hippocampal sclerosis (HS), gray matter atrophy of left mTLE was more serve than that of right mTLE across the whole brain and especially within the contralateral semantic cognition network. This study suggested that left HS patients had a higher vulnerability to seizure attacks, reflecting the compensation strategy. The altered effective connectivity between subregions of the ATL may be the possible reason to explain the more severe name-finding impairment but good comprehension ability.H. Yan et al. (“Altered Effective Connectivity of Hippocampus-Dependent Episodic Memory Network in mTBI Survivors”) examined the altered effective interaction in mild traumatic brain injury (TBI) survivors' episodic memory network. Results presented that mild TBI induced increased bilateral and decreased ipsilateral effective connectivity in the episodic memory network compared with normal controls. This study provided some evidence to note the overrecruitment of the right anterior PFC caused dysfunction of the strategic component of episodic memory, which caused deteriorating episodic memory in mTBI survivors.Z. Guo et al.  aimed to evaluate the effects of high frequency repetitive transcranial magnetic stimulation (HF-rTMS) on stroke patients with motor dysfunction and to investigate the underlying neural mechanism. Fifteen stroke patients were assigned to the rTMS treatment (RT) group and conventional treatment (CT) group. RT group showed better improvement in motor scale and enhanced diffusion metrics in the posterior limb internal capsule, which was associated with motor functions.S. Zhang et al.  explored the cortical thickness and white matter integrity following mild-to-moderate hydrocephalic in children. They found that decreased cortical thickness in the left middle temporal and left rostral middle frontal gyrus in these children compared with normal controls, and diffusion metrics were also decreased in the right body part of the corpus callosum. This study provides the evidence that structural brain changes can be used to monitor long-term outcomes and follow-up in the mild-to-moderate hydrocephalic of children.Finally, N. Ilves et al.  investigate the dysfunctions in the large-scale resting-state functional networks following perinatal stroke in children and its association with congenital hemiparesis and neurocognitive deficits. Results indicated that there were no differences in severity of hemiparesis between the periventricular venous infarction (PVI) and arterial ischemic stroke (AIS) groups. A significant increase in default mode network connectivity (FDR 0.1) and lower cognitive functions were found in children with AIS compared to the controls and the PVI group. The children with PVI had no significant differences in the resting-state networks compared to the controls and their cognitive functions were normal. They further inferred that changes in the resting-state networks found in children with AIS could possibly serve as the underlying derangements of cognitive brain functions in these children.Great progress has been made and demonstrated the role of functional connectivity and structural abnormalities underlying brain injury , while there is also unclarity about whether these brain changes can provide a clue (as a biomarker) to establish prognostic models, develop focused treatments, and stratify patients for interventional trials. U. Horn et al. (“MRI-Biomarkers for Hand-Motor Outcome Prediction and Therapy-Monitoring following Stroke”) conducted a comprehensive review about MRI-biomarkers on the evaluation of corticospinal integrity and functional recruitment of motor resources. Compared with the functional connectivity parameters, corticospinal integrity evaluation using structural imaging showed robust and high predictive power for patients with different levels of impairment. They further suggested a combination of different measures in an algorithm to classify fine-graded subgroups of patients, because the best therapy approaches will become feasible as the subgroup become more specified.This special issue provides promising evidence to elucidating neural plasticity associated with a wide range of brain injuries. These articles may enhance further research into examining whether the neuroprognosis of imaging biomarker is beneficial to treatment selection and effectiveness evaluation following brain injury.Lijun BaiLin AiKevin K. W. Wang


Dissociative experiences, including depersonalization and derealisation, represent perturbations of consciousness and selfhood, and are commonly reported by patients during early stages of a psychotic illness. The continuity and integrity of a conscious sense of self is proposed to be grounded upon the control of internal physiological state and its predictive representation through interoception, i.e. the sensing of internal bodily changes. We tested the hypothesized relationship between dissociation and interoceptive deficits in patients with first episode psychosis (FEP), combining behavioural testing with functional neuroimaging.Individuals with first episode psychosis (N=41) and matched community control participants (N=21) performed an interoceptive task (heart-tone synchrony judgments) during functional magnetic resonance imaging (fMRI). Trial-by-trial confidence ratings indexed subjective performance, and measures of metacognitive interoceptive awareness (insight) were derived from confidence-accuracy correspondence. We tested for regional brain activity relating to dissociative symptom scores and objective, subjective and metacognitive aspects of interoception.In patients with FEP, metacognitive impairments in interoception predicted magnitude of dissociative symptoms, accompanied by hypoactivation of right insula cortex. Other dimensions of interoception, and accuracy, confidence and metacognitive insight on an exteroceptive task were unrelated to dissociative symptoms and there were no group differences between FEP patient and control groups.Our findings suggest that symptoms of disturbed conscious integrity and selfhood in early psychosis arise through selective disruption of higher-order metacognitive representations of interoceptive signals. Brain systems supporting the conscious integration of bodily feelings may represent a target for interventions to enhance functioning and, speculatively, mitigate illness progression in psychosis.


Lung cancer is the most common cause of cancer-related death worldwide, less than 7% of patients survive 10 years following diagnosis across all stages of lung cancer. Late stage of diagnosis and lack of effective and personalized medicine reflect the need for a better understanding of the mechanisms that underlie lung cancer progression. Quantitative proteomics provides the relative different protein abundance in normal and cancer patients which offers the information for molecular interactions, signaling pathways, and biomarker identification. Here we introduce both theoretical and practical applications in the use of quantitative proteomics approaches, with principles of current technologies and methodologies including gel-based, label free, stable isotope labeling as well as targeted proteomics. Predictive markers of drug resistance, candidate biomarkers for diagnosis, and prognostic markers in lung cancer have also been discovered and analyzed by quantitative proteomic analysis. Moreover, construction of protein networks enables to provide an opportunity to interpret disease pathway and improve our understanding in cancer therapeutic strategies, allowing the discovery of molecular markers and new therapeutic targets for lung cancer. Lung cancer is the most common cancer-related mortality worldwide, with approximately 27% of all cancer deaths per year . Lung caProteins are involved in all biological processes which can be regarded as the final stage of biological information from genome. Proteomics is extremely dynamic and complex due to the continuous response to the change of environment, drug treatment, and post-translational modification . Large-sProteomics is an analysis of dynamic systems in biology which consists a range of diversity that are insufficient to analyze with any single method. Quantitative proteomics not only provides a list of identified proteins, it also quantifies the changes between normal and disease sample profiles in order to generate classification models. Here, we review quantitative proteomics into four major approaches: gel-based, stable isotope labeling, label free, and targeted proteomics for lung cancer studies Fig. .Fig. 1ThMr) and isoelectric point (pI)-based separation. DIGE has been developed as a multicolor detection for comparing protein abundance of samples within a single gel, where each protein sample is prelabeled with spectrally distinct fluorescent dye [The first and most important step in quantitative proteomic analysis is the separation of a complex protein mixture . Gel-bascent dye . To reducent dye . Gel-frecent dye . Both gecent dye .15N spirulina with a protein-free chow to overcome the limitation of SILAC to cell culture [For quantitative analysis, stable isotope labeling coupled with mass spectrometry (MS)-based techniques is often performed in cancer research . Mass sp culture .Table 1CTo characterize the post-transcriptional modifications in proteomics, several isobaric reagents were developed for selective labeling such as carbonylated residues and cysteine residues which might expand our knowledge of dynamic system in cancer progression –26. MoreLabel-free quantification is an alternative method for samples that cannot directly label, and enables the comparison of protein expression across different samples or treatment regardless the number of samples . Label-fSelected reaction monitoring (SRM), multiple reaction monitoring (MRM), and data-independent acquisition (DIA) are widely used MS-based proteomics which have been considered as true quantification techniques for targeted quantification of protein , 33, 34.Quantitative proteomics allows the discovery of molecular markers and new therapeutic targets for lung cancer. Predictive markers of drug resistance, lung cancer diagnosis, and prognostic markers in lung cancer have also been discovered by quantitative proteomics analysis .Biomarker is a measurable biological indicator found in tissue, cells, blood or other body fluids that may be used for detection, diagnosis treatment and monitoring in cancer research . The chaThe survival rate of lung cancer patients is highly correlated to the stage of lung cancer; therefore, improve the diagnostic strategies for early lung cancer detection may increase patient survival. Hsu et al. identified 133 protein candidates from paired adenocarcinoma (ADC) tissues with different extents of lymph node involvement by iTRAQ-labeling technology coupled with 2D-LC-MS/MS . They fuLabel-free quantitative proteomic analysis was performed and a significant higher protein levels of hepatocyte growth factor (MET), dipeptidyl peptidase IV (DDP4) and Receptor-type tyrosine-protein phosphatase F (PTPRF) in malignant pleural effusion (PE) samples were found comparing to benign and paramalignant PE samples . ProteomA recent study applied highly multiplexed liquid chromatography-selected reaction monitoring (LC-SRM) assay to verify the biomarker candidates in plasma samples for lung cancer. A total of 17 proteins were verified as potent tumor markers, especially, a novel plasma-based biomarker, zyxin (ZYX) was identified as a potential early diagnostic marker for NSCLC . OverallThe major challenge for lung cancer therapy is chemoradioresistance, where protein markers might serve as the potential molecular predictors of drug resistance and overcome this shortage. Recent study of a SILAC-based quantitative proteomic approach has been utilized to evaluate the cellular protein abundance changes upon paclitaxel (PTX) treatment. Tumor suppressor programmed cell death 4 (PDCD4) in lung cancer tissues were positively correlated with the longer overall survival of lung cancer patients with PTX treatment, suggesting that PDCD4 may be used as a predictive marker of resistance to PTX in lung cancer patients . FurtherDuring the stages of drug development, proteomics can also take place in a high-throughput analysis for the identification and optimization of suitable lead compounds. Several tyrosine kinase inhibitors (TKIs) have been approved from the US Food and Drug Administration (FDA) for use in advanced lung cancer. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the two common biological targets for lung cancer drug development , 50. AppEGFR has become an important biological target for lung cancer. Inhibitors that target EGFR and block the signaling pathway have been developed and are clinically active . Three EChromosomal rearrangements of ALK have been found to be associated with lung cancer and its inhibitors ceritinib are superior for patients with chemotherapy . CeritinOur recent study demonstrated ectopic ATP synthase that presents on the plasma membrane of lung cancer cells is a potential biological target for drug development , 63. CitModern high-throughput technologies generate a huge amount of data, however, proper data mining tools is the key for discovery of cancer-related proteins and networks. Fully understanding of the biological significance of differential protein networks from normal to disease cells depends on the information generated from proteomic datasets. Exploration of proteomic datasets using bioinformatic analysis enables us to elucidate new molecular interactions, protein functional annotation, protein motif and complex interaction and disease pathway.With the advent of high-throughput omics data, bioinformatics has become a viable tool to improve our knowledge of health and disease individuals and it also provides a systems-level approach to interpret organisms and functional activities of their components by studying underneath interactions. Bioinformatics can be defined as a combination of mathematical and computational strategies for interpreting biological processes from the existing raw data. Data curation, tool development, and practical applications are the three major aims for bioinformatics . To dateMathematical and statistical approaches have become essential components for bioinformatics tool development. For example, developing a tool for protein structure requires serious consideration of the primary protein sequence, differential geometry and topology of the protein folding regardless of its biological functions. It is painstaking task for experimental biologists to interpret their dataset without bioinformatics tools, therefore, bioinformatics tool development takes an important part of proteomic and biological researches.Protein-protein interaction (PPI) networks provide an overall picture for the understanding of biological processes in cancer research. Proteins are not functioning solely, they have interactions with other proteins or molecules that mediate signaling pathways and biological processes. Hub proteins are highly connected to other proteins in a network, whereas some others have few interactions . The dysA dynamic PPI network of lung cancer associated with smoking was constructed by bioinformatic analysis using Human Protein Reference Database and Gene Expression Omnibus Database. Yu et al. used the support vector machine (SVM) model and found 520 dynamic proteins and 2754 static proteins and further predicted 7 dynamic PPI subnetworks for lung cancer patients with smoking history .Mathematical modeling is a time and cost-effective method that provides insight into underlying molecular reactions and biological processes as alternatives to conventional laboratory experiments . MathemaChmielecki et al. developed isogenic TKI-sensitive and TKI-resistant pairs of cell line that mimic the behavior of NSCLC with evolutionary cancer modeling . They coSince lung cancer is a heterogeneous disease, a comprehensive and in-depth discovery of lung cancer proteomic profiling is needed for precise target treatment. The microenvironment interface of the tumor cells and host cells directly impacts the tumor-host communication system by affecting signaling and growth factors, therefore cancer processing . To unde


Using next generation sequencing we have systematically analyzed a large cohort of 489 patients with bone marrow failure (BMF), including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), aplastic anemia (AA), and related conditions for the presence of germline (GL) alterations in Fanconi Anemia (FA) and telomerase genes. We have detected an increased frequency of heterozygous FA gene mutations in MDS and to lesser degree in AML suggesting that the presence of one normal allele may not be completely protective and indeed heterozygous FA lesions may have a long latency period before hematologic manifestation. In contrast, GL telomerase gene mutations were not associated with increased disease risk. When compared to large control cohorts, we have not detected an increased frequency of damaging variants among telomerase complex genes, including those previously believed to be involved in the pathogenesis of AA. Our results may suggest that while low penetrance and delayed disease onset can confound identification of genetic predisposition factors, GL FA alterations can be also associated with MDS. RUNX1 mutations are associated with thrombocytopenia and subsequent clonal evolution . All the variants from tested genes were extracted for further functional annotation and processing. Sequencing results were annotated using ANNOVAR, http://annovar.openbioinfromatics.org. Mutations that were predicted to be damaging/probably damaging by 4/5 algorithms  were prioritized for further analysis (tier1). This functional pre-processing analysis was also carried out on control population variants that were extracted from ExAC database. Ethnically matched population and the variants extracted that we analyzed were derived from ExAC database consisting 33370 normal, White/Caucassian individuals. For the purpose of this analysis, the candidate alterations were sub-classified to prioritize known disease-prone sequence alterations/mutations (OMIM/Rockefeller Fanconi mutation database)We used Exome Aggregation Consortium (ExAC), Cambridge, MA , according to the manufacturer's protocols. The captured targets were subjected to massive sequencing using Illumina HiSeq 2000 . Generation of .bam files with its preprocessing and detection of somatic point mutations/insertions and deletions was according with GATK best practices.Whole exome capture using SureSelect Human All Exon 50 Mb kit was used for targeted, exome capture according to the manufacture's protocol (SureSelectTargeted sequencing was completed using TruSeq Enrichment library (Illumina). Two panels were created, one for somatic mutations and one for GL variants. Somatic variants were reported previously . List oft-test  and Fisher's Exact test (for discrete data). Reported p-values here are not adjusted for multiple comparisons. Odds ratio were calculated as follows: number of patients with damaging variant multiplied by a number of normal individuals without damaging variants and divided by number of normal individuals with damaging variant multiplied by number of patients without damaging variants.For comparison between groups, with and without FA mutations, statistical analysis was performed using standard, unpaired, two sample


Major renal injuries follow ischemia reperfusion take place in two steps: one, ischemia (hypoxia) that induce ATP depletion and leads to epithelial tubular cells or endothelial cells injuries; and second, reperfusion that leads to oxidative stress, nitrosative stress and inflammation.Renal I/R (ischemia reperfusion) occurs in kidney surgeries such as partial nephrectomy or transplantation because of renal vessels ligation during the procedures. Ischemia (tissue hypoxia) leads to renal damages especially proximal convoluted tubules (PCT) injuries -3. SerioIschemia decreases ATP production and finally leads to tissue ATP depletion. ATP depletion leads to Rho GTPase inactivation that makes activation of ADF (Actin depolymerizing factor) or cofilin in the apical brush border of proximal tubules -6. ActivATP depletion also dissociates the actin-stabilizing proteins such as tropomyosin and ezrin , permittPCT cell death occurs from at least two cell death mechanisms, necrosis and apoptosis. Activation of cofilin after ATP depletion also can induce apoptosis by activating intrinsic pathway  and alsoChallenges for the future clinical use of apoptosis inhibition in acute kidney injury (AKI) include determining the best timing of therapy, optimizing the specificity of inhibitor, minimizing the extra renal adverse effects, and tubule-specific targeting of the apoptosis modulatory maneuvers . In my oInterruption of the apical cytoskeleton by ATP depletion also results in loss of tight junctions and adherents junctions between tubular cells and leads to tubular cells disconnection .Ischemia leads to disruption of at least two proteins, Na, K-ATPase and integrins. Deterioration of basolateral Na, K-ATPase in PCT is cause of increasing in excretion of sodium in tubular lumen . IntegriSome PCT cells maybe remain viable after I/R and undergo recovery. These cells show the appearance of dedifferentiated epithelial cells, and then the cells up regulate genes that encode some growth factors and undergo proliferation and undergo re-differentiation until the normal epithelium is restored .Cofilin also degrades actin cytoskeleton and junctional complexes in endothelial cells in experimental AKI  and leadAfter ischemia and restoration of blood flow, production of reactive oxygen species (ROS), such as superoxide, hydroxyl, H2O2 and activation of leukocytes and endothelial cells contribute to reperfusion injury .Decrease of innate antioxidant enzymes, increase of intracellular sodium and calcium, stimulation of NO synthetize, endonucleases and phospholipases also occur during reperfusion . Nitric Ischemic proximal tubule cells also generate mediators such as proinflammatory cytokines  and chemotactic cytokines such as monocyte chemo attractant protein-1 (MCP-1) and IL-8 .There are many studies that administration of antioxidant agent attenuated renal I/R injury -4,20. InAlthough many experimental studies show a decreased injury and preserved renal function after ROS inhibition by antioxidant agents, efficient treatments are still limited ,25. CurrIn summary major renal injuries follow I/R take place in two steps: one, ischemia (hypoxia) that induces ATP depletion and leads to epithelial tubular cells or endothelial cells injuries; and second, reperfusion that leads to oxidative stress, nitrosative stress and inflammation.With respect to above background may be said that the major trigger of pathogenesis in renal I/R are ATP depletion (Hypoxia), ROS and in follow activation of other pathogenetic pathways. By these insights the new suggestions introduce to investigate in animals and especially clinical trial in combat with renal I/R injuries.- Compensation of ATP depletion via pretreatment with ATP and AMP injection.- Inhibition of hypoxia through normobaric or hyperbaric hyperoxia pretreatment.- Administration of cofilin inhibitor or agents that inhibit actin–cofilin interaction before ischemia.- Use of powerful antioxidant agents that can increase activation of innate antioxidant enzymes and inhibit complement and inflammation.- Pretreatment with creatine or creatine phosphate.- Combination of mentioned suggestions.The author wants to thank from Bardia Tavafi and Rezvan Bagheri.Majid Tavafi is the single author of the manuscript.The author declare no competing interests.Ethical issues  have been completely observed by the author.None.


Overall Abstract: Dopamine plays a central role in shaping circuitry within the brain, thus affecting learning and behavior. It also plays a central role in schizophrenia and addiction. This panel will examine the impact of dopaminergic signaling on specific circuits that may create special vulnerability for the emergence of comorbidity between schizophrenia and addiction. The talks will include two presentations in clinical samples using molecular and functional imaging and two presentations in animal models.Jared Van Snellenberg will discuss connectivity of striatal substructures to the rest of the brain in drug free patients with schizophrenia and their relationship to abnormal cortical D2 signaling and psychotic symptoms. He will present recent unpublished work, motivated by pre-clinical studies with a D2 receptor over-expressing mouse model, using simultaneous multi-slice (multiband) functional MR imaging in these patients. These results suggest that unmedicated patients have altered connectivity between specific basal ganglia subnuclei, consistent with the animal model.Nora Volkow will focus on the role of bidirectional interactions between dopamine reward system and prefrontal regions in the addicted brain with emphasis on the role of D2 receptor signaling in the striatum. She will discuss the functional impact of these interactions on reward/motivation and executive-function networks and will discuss the variables that influence D2 receptor function including genes, sleep and social stressors and how they interact with drug exposures to provide resilience or vulnerability to substance use disorders or schizophrenia. Finally, she will discuss how this knowledge can be used to tailor interventions to remediate or buffer neurocircuity dysfunction triggered by drugs and for prevention.Bita Moghaddam will present an animal model of behaviorally induced dysfunction in the mesocortical circuit by using a task where actions are consistently rewarded but probabilistically punished. Spike activity and local field potentials are recorded during this task simultaneously from VTA and mPFC, two reciprocally connected mesocortical regions. Under no risk of punishment, a synchronous interaction at multiple time scales between PFC and VTA dopamine neurons is observed. This synchrony collapsed as a function of punishment contingency during reward-seeking actions, with risk of punishment diminishing VTA-driven neural synchrony between the two regions. These data reveal a dynamic coding scheme in VTA-mPFC neural circuits in representing aversion-based modulation of rewarded actions. These data suggest that driving VTA dopamine neurons by drugs of abuse may reverse the diminished synchrony and serve as self-medication in comorbid conditions.Finally, Aurelio Galli will discuss the structural, functional, and behavioral insights into the dopamine dysfunction of comorbid conditions as modeled by a deletion of the SLC6A3 affecting the function of the human dopamine transporter (hDAT). Genetic variants in hDAT have been associated with neuropsychiatric disorders. An in-frame deletion in hDAT at N336 (∆N336) leads to abnormal DA homeostasis. He demonstrated these dysfunctions in brains of Drosophila melanogaster expressing hDAT ∆N336. Furthermore, these flies are hyperactive and display fear and impaired social interactions, traits associated with impaired DA neurotransmission. Insights from X-ray crystallography, electron paramagnetic resonance, molecular dynamic simulations, electrophysiology and behaviors describe how a genetic variation causes DA dysfunction resulting in combined behavioral alterations and psychostimulant use.


The degree of inhospitable terrain encountered by migrating birds can dramatically affect migration strategies and their evolution as well as influence the way we develop our contemporary flyway conservation responses to protect them. We used telemetry data from 44 tagged individuals of four large-bodied, Arctic breeding waterbird species  to show for the first time that these birds fly non-stop over the Far East taiga forest, despite their differing ecologies and migration routes. This implies a lack of suitable taiga refuelling habitats for these long-distance migrants. These results underline the extreme importance of northeast China spring staging habitats and of Arctic areas prior to departure in autumn to enable birds to clear this inhospitable biome, confirming the need for adequate site safeguard to protect these populations throughout their annual cycle. WhateveThe 44 tagged individuals of four large-bodied, Arctic breeding waterbird species  flew non-stop over the Far East taiga forest, despite their differing ecologies and migration routes. These results underline the extreme importance of northeast China spring staging habitats and of Arctic areas prior to departure in autumn to enable birds to clear this inhospitable biome, confirming the need for adequate site management to protect these populations throughout their annual cycle.10.7717/peerj.4353/supp-1Supplemental Information 1Appendix A. Details of tracked birds and loggers.Appendix B. Detailed methods used to identify waterbird stopovers and flight segments.Appendix C. Relief map showing the relative elevated height above sea level of the taiga zone of Far Eastern Asia compared to that of Western Eurasia.Click here for additional data file.


Hereditary hemorrhagic telangiectasia is a rare autosomal dominant inherited disease that is usually complicated by visceral vascular malformations. Patients harboring such malformations are at increased risk of brain abscess formation, which despite advances in diagnostic and surgical methods remains a life threatening medical emergency with high mortality and morbidity rates. In the present report we describe a case of cerebral abscess due to silent pulmonary arteriovenous malformation (AVM) in a young patient previously undiagnosed for hereditary hemorrhagic telangiectasia syndrome (HHT). Hereditary hemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu syndrome is a rare systemic angiodysplasia inherited as an autosomal dominant disorder. Approximately 1% of patients with HHT are expected to develop a brain abscess . HoweverA 24-year-old male presented to the Emergency Department of Evangelismos Hospital, due to generalized tonic clonic seizures accompanied by fever, increasing right hemiparesis and motor dysphasia. Brain CT and MRI scans , revealeHereditary hemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu syndrome is a rare systemic angiodysplasia inherited as an autosomal dominant disorder. Four diagnostic criteria for HHT have been proposed i) epistaxis ii) telangiectasia on face, fingertips and nasal/oral mucosa iii) familial history of HHT and iv) visceral vascular anomalies including hepatic, pulmonary, spinal and cerebral arteriovenous malformations . DiagnosOur case illustrates that a brain abscess may be the first clinical manifestation of a nearly asymptomatic HHT patient. Furthermore patients with a history suggestive of HHT should be screened for the presence of visceral vascular malformations as they are at increased risk of brain abscess formation. In conclusion, it should be clearly pointed out not only to neurologists and neurosurgeons but to clinicians in general, that patients with signs suggestive of HHT and new onset of neurological symptoms, should be deemed to harbor a brain abscess until proven otherwise. This aggressive approach is mandated by the high prevalence and mortality associated with a brain abscess in this group of patients.


Background: Restless legs syndrome (RLS) is a relatively common neurological disorder affecting sleep and health-related quality of life. Neuroimaging studies, autopsy investigations and experimental studies using animal models have been conducted to investigate the potential causes of RLS, resulting in the generation of multiple pathophysiological hypotheses.Methods: This paper reviews the neurobiology and pharmacotherapy of RLS, with a critical analysis of the heterogeneity and methodological limitations of the existing scientific literature.Results: Although several neurotransmitter systems dysfunction and neuroanatomical abnormalities have been implicated in RLS pathogenesis, dopamine dysfunction within basal ganglia pathways, iron deficiency and opioid system abnormalities have consistently been found to be involved. Their involvement is further strengthened by the therapeutic effectiveness of dopaminergic agents, iron supplementation and opioid medications.Discussion: Converging evidence from neuroimaging, autoptic and animal studies points towards dopamine dysregulation and iron metabolism alterations as the main contributors to RLS pathophysiology. The possible interactions between different neurotransmitter systems should guide further neuropharmacological research in order to improve therapeutic efficacy for this disabling condition.


P. falciparum. We synthesized an artemisinin analogue withan alkyne tag, which can be coupled with biotin through click chemistry. Thisenabled selective purification and identification of 124 protein targets ofartemisinin. Many of these targets are critical for the parasite survival.In vitro assays confirmed the specific artemisinin bindingand inhibition of selected targets. We thus postulated that artemisinin killsthe parasite through disrupting its biochemical landscape. In addition, weshowed that artemisinin activation requires heme, rather than free ferrous iron,by monitoring the extent of protein binding using a fluorescent dye coupled withthe alkyne-tagged artemisinin. The extremely high level of heme released fromthe hemoglobin digestion by the parasite makes artemisinin exceptionally potentagainst late-stage parasites (trophozoite and schizont stages) compared toparasites at early ring stage, which have low level of heme, mainly derived fromendogenous synthesis. Such a unique activation mechanism also confersartemisinin with extremely high specificity against the parasites, while thehealthy red blood cells are unaffected. Our results provide a sound explanationof the MOA of artemisinin and its specificity against malaria parasites, whichmay benefit the optimization of treatment strategies and the battle against theemerging drug resistance.Artemisinin and its analogues are currently the most effective anti-malarialdrugs. The activation of artemisinin requires the cleavage of the endoperoxidebridge in the presence of iron sources. Once activated, artemisinins attackmacromolecules through alkylation and propagate a series of damages, leading toparasite death. Even though several parasite proteins have been reported asartemisinin targets, the exact mechanism of action (MOA) of artemisinin is stillcontroversial and its high potency and specificity against the malaria parasitecould not be fully accounted for. Recently, we have developed an unbiasedchemical proteomics approach to directly probe the MOA of artemisinin in Plasmodium falciparum, isresponsible for more than half-a-million deaths per year. Currently, artemisinin-basedcombination therapy is heavily relied to treat malaria. The artemisinin derivativesshare a unique endoperoxide bridge which has been suggested to be cleaved insideP. falciparum by iron sources (either heme or ferrous iron) torelease highly reactive carbon centered radicals. These radicals can modify and inhibitvarious parasite molecules, resulting in parasite death. Yet the precise MOA ofartemisinin has remained obscure. Recently, our group has developed an activity-basedartemisinin probe and revealed a broad spectrum of artemisinin targets that arepreviously unidentified. We have also provided multiple lines of evidences todemonstrate that heme, rather than free ferrous iron, is the predominant iron source forartemisinin activation. Notably, the parasite’s propagation largely relies on hemoglobindigestion, which releases high concentration of heme. Thus, such process makesartemisinin an extremely selective and potent anti-malarial drug. Once activated, thepromiscuous targeting of artemisinin disrupts the essential biological processes of theparasite, leading to its death. Furthermore, we have shown that the endogenouslysynthesized heme might play a key role in activating artemisinin at the parasite’s earlyring stage. These findings significantly enhance our understanding of artemisinin’s MOA,which may help to improve our treatment strategies against malaria, one of the mostdeadly diseases. The systematic identification of artemisinin targets providesinvaluable information for future anti-malarial drug development. Enhancing theartemisinin activation level at the early ring stage through modulation of theparasite’s heme synthesis pathway may pave a feasible way to curb the emergingartemisinin resistance in Southeast Asia due to K13 mutations, which result in aprolonged early ring stage that diminishes the drug’s killing effect. Another possibleapproach to overcome the artemisinin resistance might be to extend the length of drugtreatment. We anticipate that the thorough understanding of artemisinin’s MOA would helpto develop better strategies to treat malaria with better treatment schemes and betterdrugs or drug combinations. Our list of identified artemisinin targets also provides newavenues for studying, tracking and coping with the emerging resistance of this drug.The most pathogenic human malaria parasite,


Receptor tyrosine kinase (RTK) pathways serve as frequent oncogene drivers in solid cancers and small molecule and antibody-based inhibitors have been developed as targeted therapeutics for many of these oncogenic RTKs. In general, these drugs, when delivered as single agents in a manner consistent with the principles of precision medicine, induce tumor shrinkage but rarely complete tumor elimination. Moreover, acquired resistance of treated tumors is nearly invariant such that monotherapy strategies with targeted RTK drugs fail to provide long-term control or cures. The mechanisms mediating acquired resistance in tumors at progression treated with RTK inhibitors are relatively well defined compared to the molecular and cellular understanding of the cancer cells that persist early on therapy. We and others propose that these persisting cancer cells, termed “residual disease”, provide the reservoir from which acquired resistance eventually emerges. Herein, we will review the literature that describes rapid reprogramming induced upon inhibition of oncogenic RTKs in cancer cells as a mechanism by which cancer cells persist to yield residual disease and consider strategies for disrupting these intrinsic responses for future therapeutic gain. Receptor tyrosine kinases (RTKs) function as oncogene drivers in solid tumors through diverse mechanisms including mutation, amplification and autocrine/paracrine activation. As an example, lung adenocarcinomas (LUADs) harbor diverse oncogenic RTKs and many, such as EGFR, ALK, and ROS1 have approved tyrosine kinase inhibitors (TKIs) that induce dramatic tumor responses . AdditioOver the past decade, mechanisms mediating acquired resistance to RTK inhibitors have been investigated through analysis of tumor samples obtained at disease progression and represents a thoroughly reviewed topic –20. SeleA common feature of treatment failure with monotherapy, whether antimicrobial or anticancer, is the incomplete elimination of the bacterial or tumor cell targets , 23. TheAn extensive literature demonstrates the dynamic nature of the kinome, the subset of the genome encoding protein kinases , in respKlezcko et al.  analyzedThe literature reveals that altered gene transcription is not required for all rapid, TKI-induced reprogramming. Zhang et al.  used phoF1174L-positive human neuroblastoma cells [In addition to mechanisms involving rapidly induced bypass signaling, RTK inhibitor-induced epithelial to mesenchymal transition (EMT) has emerged as a mechanism of resistance, especially in response to EGFR inhibitors. EMT (reviewed in ) is an ima cells .Fig. 2PhBecause of the chronic method by which TKI-resistant cell lines exhibiting mesenchymal differentiation were selected, it is unclear if TKI-induced EMT represents a rapid reprogramming event. Anecdotally, cell morphology changes occur within weeks of TKI treatment . Also, oClinically, emergence of TKI-resistant EGFR mutant LUADs that exhibit small cell lung cancer (SCLC) lineage markers and heralded by RB1 and TP53 loss Fig.  has beenOverall, these studies indicate that, with sufficient foresight of specific bypass signaling pathways induced in response to TKI-stimulated cellular reprogramming, effective drug combinations could be designed and deployed to bring about greater tumor inhibition. However, in many cases, there appears to be significant diversity and/or redundancy in bypass pathway utilization in different cancer cell lines. For full implementation, the degree of variability in the reprogramming response across an oncogene-defined set of cancers will need to be fully understood. In this regard, a general caveat of the preclinical studies showing TKI-induced reprogramming is that the conclusions are frequently derived from a limited number of cell lines. As further developed below, it will be critical to interrogate the reprogrammed state in primary cancers under treatment to fully appreciate the heterogeneity of response. Moreover, if multiple mechanisms emerge in oncogene-defined cancer subsets, consideration must be given to biomarkers in pretreatment biopsies that may predict a specific reprogramming response.An alternative approach to combinations of RTK inhibitors with specific bypass pathway inhibitors is to target the driving RTK oncogene in combination with agents that block the reprogramming response at the transcriptional level. As an example, Stuhlmiller et al. demonstrated rapid lapatinib-induced reprogramming in a panel of ERBB2+ breast cancer cell lines . The adaStudies investigating reprogramming responses to RTK inhibitors in cancer cells addicted to specific oncogenic RTKs have tended to largely interpret the results from a cancer cell autonomous viewpoint. It is clear that RTK inhibitor-induced reprogramming induces secretion of myriad factors, some of which may signal in a paracrine fashion to the TME Fig. . In the A well-defined side effect of small molecule and antibody-based inhibitors of EGFR is an acneiform rash . The litFunctional genomics screens have been deployed to provide an unbiased approach to interrogating vulnerabilities in oncogene-driven cancer cells. To identify targets that could be inhibited in combination with EGFR-specific TKIs to yield deeper growth inhibition in EGFR mutant lung cancer cell lines, Casas-Selves et al.  used a gIn addition to oncogenic EGFR and distinct RTKs activated through gene-rearrangements, increased expression of the non-mutated RTK, FGFR1, is observed in lung cancers of all histologies –86, mesoA study by Harbinski et al.  used a cNumerous studies have examined mechanisms of acquired resistance presenting at tumor progression which likely reflect outgrowth of dominant evolutionarily-selected clones. By contrast, much less is known about signaling and transcriptional mechanisms in the setting of early residual disease following oncogene inhibition, in part because patient biopsies are rarely performed early during response to therapy . ObviousEarly Rebiopsy to Identify Biomarkers of Tumor Cell Survival Following EGFR TKI Therapy (NCT03042221)” will molecularly analyze paired baseline biopsy specimens from advanced stage EGFR mutant lung cancers and biopsies obtained following 2 weeks of EGFR TKI-targeted treatment with the intention to identify early adaptive mechanisms of cell survival in the setting of oncogene-targeted therapy. Preliminary RNAseq analysis of two sets of paired biopsies reveals evidence of both tumor cell autonomous and non-autonomous transcriptional responses [clinicaltrials.gov indicates other similar neoadjuvant trials based on oncogene-targeted agents have either been completed or are open and active (Surgery for Early Lung Cancer With Preoperative Erlotinib (Tarceva): A Clinical Phase II Trial (SELECT), NCT00462995 ; Study of TARCEVA (Erlotinib) as Adjuvant Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma, NCT01515137 ). These clinical protocols with specific intention to collect samples of tumors early during targeted therapy are anticipated to provide a clearer molecular understanding of residual cancer that will prompt informative laboratory studies.Similar “window of opportunity” trials are being launched to study remnant lung tumor samples after oncogene targeted therapies. McCoach and colleagues  are implesponses . AnalysiThe aforementioned clinical protocols will provide rich insight into the biology of residual disease and potentially drive reverse translational research  to exploThe clinical experience with TKI monotherapy in cancers bearing oncogenic RTKs highlights the importance of defining next-generation strategies that will reduce or eliminate acquired resistance. While serial deployment of 2nd and 3rd generation TKIs may increase the duration of response, resistance still eventually emerges due to residual disease. Based on the studies reviewed in this article, approaches whereby novel and rational “upfront” combinations of TKIs and drugs targeting signal pathways that prevent rapid tumor cell reprogramming must be identified and prioritized for preclinical testing. Evidence that blocking oncogenic pathways within cancer cells unleashes paracrine signaling between cancer cells and the TME, including the innate and adaptive immune systems, supports the continued development of transplantable murine cancer cell lines that faithfully represent oncogene-driven human cancers for subsequent analysis of the impact of TME-cancer cell crosstalk on TKI efficacy in fully immune competent hosts. This latter approach will permit rational evaluation of combinations of TKIs with drugs targeting TME pathways as well as approved and emerging immunotherapeutics. Finally, these studies must be accompanied by deep evaluation of molecular responses in primary human tumors early during TKI treatment to determine the kinetics of the processes as well as the degree of variation across tumor subtypes. Combined, these strategies may yield novel combination therapies that maximize the initial tumor shrinkage response, thereby leading to stable disease or perhaps cures.


The central nervous system (CNS) requires sophisticated regulation of neuronal activity. This modulation is partly accomplished by non-neuronal cells, characterized by the presence of transmembrane gap junctions (GJs) and hemichannels (HCs). This allows small molecule diffusion to guarantee neuronal synaptic activity and plasticity. Astrocytes are metabolically and functionally coupled to neurons by the uptake, binding and recycling of neurotransmitters. In addition, astrocytes release metabolites, such as glutamate, glutamine, D-serine, adenosine triphosphate (ATP) and lactate, regulating synaptic activity and plasticity by pre- and postsynaptic mechanisms. Uncoupling neuroglial communication leads to alterations in synaptic transmission that can be detrimental to neuronal circuit function and behavior. Therefore, understanding the pathways and mechanisms involved in this intercellular communication is fundamental for the search of new targets that can be used for several neurological disease treatments. This review will focus on molecular mechanisms mediating physiological and pathological coupling between astrocytes and neurons through GJs and HCs. Classical studies carried out by the end of 19th and during the 20th century classified astrocytes mainly based on their differences in morphology and localization into two different populations, protoplasmic and fibrous  to neurons, participate in the turnover of neurotransmitters such as glutamate and gamma-aminobutyric acid , adenosine triphosphate (ATP), glutamate, lactate and D-serine that diffuse through GJs to impact back on neuronal function . This specialized intercellular communication gives rise to a complex syncytial network that allows diffusion of several essential molecules for signaling and information processing  directly to the extracellular space. HCs also dock with other HCs or connexons of adjacent cell membranes to establish GJs  that spread from cell to cell. Presence of astrocytic calcium ions mobilizations suggests that glial cells may have some excitability and neuromodulator activities  that stratum radiatum astrocytes respond with an increase in [Ca2+]i when activated by ligands. Among the many receptors expressed in astroglial cells are purinergic  and metabotropic glutamate receptor (mGLURs) activation , inhibition of Cx43 HCs by mimetic peptide Gap26 reduces the amplitude of postsynaptic excitatory currents mediated by NMDA receptors and impairs long-term potentiation (LTP) induced by high-frequency stimulation , neurotransmitter release and uptake (Glutamate and GABA), and receptor stability (homeostatic plasticity).Astrocytes like neurons have complex morphologies characterized by the presence of processes that protrude into synapses. For synapses to work efficiently, astrocytes and neurons should have developed mechanisms controlling astrocytic processes extension into synapses, limiting astrocyte territories in the synaptic cleft, which is essential to re-uptake neurotransmitters without affecting synaptic transmission. Cx30 knockout mice show a decreased excitatory neurotransmission and impaired synaptic plasticity  and diacylglycerol , and non-dependent vesicular release. Astrocytes express Synaptotagmin IV (a Ca2+ sensor expressed in synaptic vesicles) and SNARE type proteins. Synaptotagmin IV knockdown experiments have revealed this Ca2+ sensor is involved in glutamate release from astrocytes  in astrocytes starts a cascade of events that stimulate membrane phospholipid hydrolysis to inositol triphosphate  has critical neuromodulator functions  that regulates blood vessel tone or by increasing glucose uptake from blood , requiring Na+/K+ ATPase activity. Furthermore, in astrocytes, this coupling demands glucose utilization and oxidation  transport , are responsible for maintaining extracellular glutamate concentrations within a range that permits normal excitatory neurotransmission , and nitric oxide (NO). These toxic molecular species can be released through HCs and propagated from damaged cells to healthy cells through GJs  and intracellular neurofibrillary tangles of hyperphosphorylated Tau protein, loss of synaptic connections, and oxidative stress increase leading to neuronal death  activation , Cx43 expression increased, and pre-treatment with Gap26 and Gap27 peptides powerfully decreased cerebral infarct volume and improved muscle strength, motor coordination and spatial memory skills. Furthermore, Gap26 treatment reduced Cx43 expression and astrocytosis after HI insult, suggesting Cx43 could be considered a therapeutic target ischemic or hypoxic disease treatment , Ca2+, and metabolic changes that stimulate the probability of pore opening (Retamal et al., During neural activity interglial communication regulates neurotransmitter and KLCM and AVR wrote the article and drew the figures. J-JS wrote the article and SLA conceptualized and wrote the article.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.