Altered physiology of gastrointestinal vagal afferents following neurotrauma

The adaptability of the central nervous system has been revealed in several model systems.Of particular interest to central nervous system-injured individuals is the ability for neural components to be modified for regain of function.In both types of neurotrauma,traumatic brain injury and spinal cord injury,the primary parasympathetic control to the gastrointestinal tract,the vagus nerve,remains anatomically intact.However,individuals with traumatic brain injury or spinal cord injury are highly susceptible to gastrointestinal dysfunctions.Such gastrointestinal dysfunctions attribute to higher morbidity and mortality following traumatic brain injury and spinal cord injury.While the vagal efferent output remains capable of eliciting motor responses following injury,evidence suggests impairment of the vagal afferents.Since sensory input drives motor output,this review will discuss the normal and altered anatomy and physiology of the gastrointestinal vagal afferents to better understand the contributions of vagal afferent plasticity following neurotrauma.

Role of aberrant Sonic hedgehog signaling pathway in cancers and developmental anomalies

Development is a sophisticated process maintained by various signal transduction pathways,including the Hedgehog(Hh)pathway.Several important functions are executed by the Hh signaling cascade such as organogenesis,tissue regeneration,and tissue homeostasis,among various others.Considering the multiple functions carried out by this pathway,any mutation causing aberrant Hh signaling may lead to myriad developmental abnormalities besides cancers.In the present review article,we explored a wide range of diseases caused by aberrant Hh signaling,including developmental defects and cancers.Finally,we concluded this mini-review with various treatment strategies for Hh-induced diseases.

Global health disparities in vulnerable populations of psychiatric patients during the COVID-19 pandemic

The coronavirus disease 2019 pandemic affects psychiatric patients disproportionately compared to the general population.In this narrative review,we examine the impact of the pandemic on significant global health disparities affecting vulnerable populations of psychiatric patients:People of diverse ethnic background and color,children with disabilities,sexual and gender minorities,pregnant women,mature adults,and those patients living in urban and rural communities.The identified disparities cause worsened mental health outcomes placing psychiatric patients at higher risk for depression,anxiety and posttraumatic stress disorder symptoms.Those psychiatric patients who are ethnic minorities display barriers to care,including collective trauma and structural racism.Sexual and gender minorities with mental illness face discrimination and limited access to treatment.Pregnant women with psychiatric diagnoses show higher exposure to domestic violence.Children with disabilities face a higher risk of worsening behavior.Mature adults with psychiatric problems show depression due to social isolation.Psychiatric patients who live in urban communities face pollutants and overcrowding compared to those living in rural communities,which face limited access to telehealth services.We suggest that social programs that decrease discrimination,enhance communal resilience,and help overcome systemic barriers of care should be developed to decrease global health disparities in vulnerable population.

Nerve growth factor in muscle afferent neurons of peripheral artery disease and autonomic function

In peripheral artery disease patients,the blood supply directed to the lower limbs is reduced.This results in severe limb ischemia and thereby enhances pain sensitivity in lower limbs.The painful perception is induced and exaggerate during walking,and is relieved by rest.This symptom is termed by intermittent claudication.The limb ischemia also amplifies autonomic responses during exercise.In the process of pain and autonomic responses originating exercising muscle,a number of receptors in afferent nerves sense ischemic changes and send signals to the central nervous system leading to autonomic responses.This review integrates recent study results in terms of perspectives including how nerve growth factor affects muscle sensory nerve receptors in peripheral artery disease and thereby alters responses of sympathetic nerve activity and blood pressure to active muscle.For the sensory nerve receptors,we emphasize the role played by transient receptor potential vanilloid type 1,purinergic P2X purinoceptor 3 and acid sensing ion channel subtype 3 in amplified sympathetic nerve activity responses in peripheral artery disease.

紫杉醇诱导的胰腺癌SW1990细胞凋亡过程中转录激活因子5和Bax表达水平的变化

目的转录激活因子5(Activating transcription factor 5,ATF5)是一个新的与肿瘤细胞分化、增殖及凋亡密切相关的因子。文中检测胰腺癌SW1990细胞中ATF5的表达,并进一步研究紫杉醇(Paclitaxel,PTX)诱导的人胰腺癌SW1990细胞凋亡的水平,及其与ATF5、Bax表达水平的相关性。方法 RT-PCR检测未经药物处理的SW1990细胞中ATF5 mRNA表达水平;以不同浓度的紫杉醇(0、6.25、12.5、25、50、100、200 nmol/L)作用SW1990细胞不同时间(0、6、12、24、48 h),噻唑蓝(MTT)比色法检测细胞增殖情况;用100 nmol/L紫杉醇作用SW1990细胞不同时间(0、12、24、48 h)后,观察形态学变化并用Annexin V/7-AAD双染法,流式细胞仪检测细胞凋亡情况;采用RT-PCR检测紫杉醇作用不同时间后ATF5、Bax的mRNA表达变化。结果胰腺癌SW1990细胞中表达ATF5。紫杉醇抑制胰腺癌SW1990细胞的增殖,并在一定范围内呈剂量、时间相关性。随着紫杉醇作用时间的增加,流式细胞仪检测凋亡率显著提高。半定量RT-PCR检测结果显示:ATF5、Bax mRNA表达均明显增强,且两者之间存在相关性(r=0.916,P<0.05)。结论 ATF5在胰腺癌SW1990细胞中高表达,并且在紫杉醇诱导的细胞凋亡过程中,表达量进一步上升,其变化趋势与Bax基因相似。提示ATF5参与紫杉醇诱导的细胞凋亡,并可能与Bax的凋亡途径存在相关性。

Investigating neurogenic bowel in experimental spinal cord injury: where to begin?

The devastating losses following traumatic spinal cord injury(SCI) encompass the motor, sensory and autonomic nervous systems. Neurogenic bowel is a slow transit colonic dysfunction marked by constipation, rectal evacuation difficulties, decreased anorectal sensation, fecal incontinence or some combination thereof. Furthermore, neurogenic bowel is one of the most prevalent comorbidities of SCI and is recognized by afflicted individuals and caregivers as a lifelong physical and psychological challenge that profoundly affects quality of life. The restoration of post-injury control of movement has received considerable scientific scrutiny yet the daily necessity of voiding the bowel and bladder remains critically under-investigated. Subsequently, physicians and caregivers are rarely presented with consistent, evidence-based strategies to successfully address the consequences of dysregulated voiding reflexes. Neurogenic bowel is commonly believed to result from the interruption of the supraspinal control of the spinal autonomic circuits regulating the colon. In this mini-review, we discuss the clinical challenges presented by neurogenic bowel and emerging pre-clinical evidence that is revealing that SCI also initiates functional remodeling of the colonic wall concurrent with a decrease in local enteric neurons. Since the enteric input to the colonic smooth muscle is the final common pathway for functional contractions of the colon, changes to the neuromuscular interface must first be understood in order to maximize the efficacy of therapeutic interventions targeting colonic dysfunction following SCI.

Targeted immunotherapy for non-small cell lung cancer

Targeted therapies that deliver the expected anti-tumor effects while mitigating the adverse effects are taking the cancer world by storm. The need for such therapies in non-small cell lung cancer(NSCLC), where systemic cytotoxic chemotherapies still remain the backbone of management, is felt more than ever before. Runway success of immunotherapies such as Ipilimumab for melanoma has brought excitement among oncologists. Immune-based treatments are in various stages of evaluation for NSCLC as well. Immunotherapies using strategies of antigen based or cell based vaccines, and blocking immune checkpoints are of substantial interest. Meaningful clinical responses are yet to be reaped from these new treatment modalities.

从组蛋白及组蛋白修饰看视网膜疾病

视网膜疾病包括年龄相关性黄斑变性（AMD）、糖尿病视网膜病变（DR）、视网膜色素上皮变性（RP）和营养不良、视网膜和脉络膜肿瘤等,是一组与视网膜及其神经和血管相关的疾病.尽管基因变异和单核苷酸多态性等遗传学因素所造成的基因表达的改变已被证明与这些疾病的发病机制有密切关系,但在基因序列不发生改变的情况下,长期内在及外在环境变化造成的可遗传性基因表达的改变正受到研究者的关注.近年来越来越多的证据支持至少部分视网膜疾病的发病机制与表观遗传,特别是组蛋白及组蛋白修饰有关.相关研究的进展使我们加深了对视网膜疾病病理机制的认识.

Stroke Prevention in Atrial Fibrillation:Current Strategies and Recommendations

Stroke is the most common complication of atrial fibrillation(AF).Guidelines recommend anticoagulant treatment in patients with CHA2DS2VASc scores of>2.Registry data suggests that almost half of patients who should be on therapeutic anticoagulation for stroke prevention in AF(SPAF)are not.Warfarin and more recently developed agents,the"novel anticoagulants"(NOACs)reduce the risk of embolic strokes.In addition,the NOACs also reduce intracranial hemorrhage(ICH)by over 50% compared to warfarin.Anticoagulation and bridging strategies involving cardioversion,catheter ablation,and invasive/surgical procedures are reviewed.The development of reversal agents for NOACs and the introduction of left atrial appendage occluding devices will evolve the use of newer strategies for preventing stroke in high risk AF patients.

Vacuole import and degradation pathway: Insights into a specialized autophagy pathway

Glucose deprivation induces the synthesis of pivotagluconeogenic enzymes such as fructose-1,6-bisphos-phatase, malate dehydrogenase, phosphoenolpyruvatecarboxykinase and isocitrate lyase in Saccharomycescerevisiae. However, following glucose replenishment,these gluconeogenic enzymes are inactivated and de-graded. Studies have characterized the mechanismsby which these enzymes are inactivated in response toglucose. The site of degradation of these proteins hasalso been ascertained to be dependent on the dura-tion of starvation. Glucose replenishment of short-termstarved cells results in these proteins being degradedin the proteasome. In contrast, addition of glucose tocells starved for a prolonged period results in theseproteins being degraded in the vacuole. In the vacuoledependent pathway, these proteins are sequestered inspecialized vesicles termed vacuole import and degra-dation (Vid). These vesicles converge with the endo-cytic pathway and deliver their cargo to the vacuolefor degradation. Recent studies have identified thatinternalization, as mediated by actin polymerization, isessential for delivery of cargo proteins to the vacuolefor degradation. In addition, components of the targetof rapamycin complex 1 interact with cargo proteins during glucose starvation. Furthermore, Tor1p dissoci-ates from cargo proteins following glucose replenish-ment. Future studies will be needed to elaborate on the importance of internalization at the plasma membrane and the subsequent import of cargo proteins into Vid vesicles in the vacuole dependent degradation pathway.

Human gingival tissue-derived mesenchymal stem cells inhibit proliferation and invasion of rheumatoid fibroblast-like synoviocytes via the CD39/CD73 signaling pathway

Background:Gingiva-derived mesenchymal stem cells(GMSCs)suppress immune and inflammatory responses in experimental arthritis models.Here,we determined whether GMSCs suppress the proliferation and invasion of rheumatoid arthritis fibroblast-like synoviocytes(RA FLSs).Methods:Surface markers of GMSCs were analyzed by flow cytometry.mRNA expression of matrix metalloproteinases and pro-inflammatory cytokine in RA FLSs was measured by quantitative polymerase chain reaction(PCR).RA FLS proliferation was analyzed by a 5-ethynyl-2′-deoxyuridine assay.To explore the molecular mechanisms,we assessed the effect of GMSCs on RA FLS proliferation by adding indoleamine-2,3-dioxygenase(IDO),CD39,or CD73 inhibitors.The invasion was analyzed by a transwell assay.The anti-inflammatory effects of GMSCs were assessed in a typeⅡcollagen-induced arthritis(CIA)mouse model.Results:Compared with human dermal fibroblast,GMSCs displayed a higher expression of CD39.Interleukin(IL)-8,IL-6,MMP-1,MMP-3,MMP-13,and monocyte chemoattractant protein-1 mRNA were all decreased in RA FLSs after incubation with GMSCs.GMSCs significantly reduced RA FLS proliferation in a dose-dependent manner in vitro,which was partly dependent on CD39/CD73 signaling.GMSCs significantly impeded the invasive capacity of RA FLSs in a dose-dependent manner in vitro.GMSCs infusion delayed arthritis onset and reduced arthritis scores in the CIA model.Conclusion:GMSCs are effective to inhibit the aggressive behavior of RA FLSs and treat experimental arthritis,implying their therapeutic potential in RA patients.

Response letter for “Mesenchymal stem cell secretome to control inflammation in allergic conjunctivitis”

Dr.Spampinato gave an insightful comment on'Mesenchymal stem cell secretome to control inflammation in allergic conjunctivitis'(1).Dr.Spampinato proposed that it is key to get the complete knowledge of mesenchymal stem cell(MSC)secretome composition in order to better understand MSC secretome and to achieve the best therapeutic effect of MSC secretome for clinic setting.

New insight into the oncogenic mechanism of the retroviral oncoprotein Tax

Human T cell leukemia virus type 1(HTLV-1),an etio-logical factor that causes adult T cell leukemia and lym-phoma(ATL),infects over 20 million people worldwide.About 1 million of HTLV-1-infected patients develop ATL,a highly aggressive non-Hodgkin's lymphoma without an effective therapy.The pX region of the HTLV-1 viral genome encodes an oncogenic protein,Tax,which plays a central role in transforming CD4+ T lymphocytes by deregulating oncogenic signaling pathways and promoting cell cycle progression.Expression of Tax following viral entry is critical for promoting survival and proliferation of human T cells and is required for initiation of oncogenesis.Tax exhibits diverse functions in host cells,and this oncoprotein primarily targets IκB kinase complex in the cytoplasm,resulting in persistent activation of NF-κB and upregulation of its responsive gene expressions that are crucial for T cell survival and cell cycle progression.We here review recent advances for the pathological roles of Tax in modulating IκB kinase activity.We also discuss our recent observation that Tax connects the IκB kinase complex to autophagy pathways.Understanding Tax-mediated pathogenesis will provide insights into development of new therapeutics in controlling HTLV-1-associated diseases.

Inhibition of smoothened decreases proliferation of Synoviocytes in rheumatoid arthritis

Fibroblast-like synoviocytes （FLSs） contribute to synovial hyperplasia in rheumatoid arthritis （RA）. Smoothened （Smo） is a key component of sonic hedgehog （Shh） signaling and contributes to tumor cell proliferation. The objective of this study was to investigate the role of Smo in RA synoviocyte proliferation. FLSs were isolated from RA synovium. Shh signaling was studied using a Smo antagonist （GDC-0449） and small interfering RNA （siRNA） targeting the Smo gene in FLSs. Cell proliferation was quantified by using kit-8 assay and cell cycle distribution and apoptosis were evaluated by flow cytometry. Cell cycle-related genes and proteins were detected by real-time PCR and western blot. FLSs treated with GDC-0449 or Smo-siRNA showed significantly decreased proliferation compared to controls （P〈0.05）. Incubation with GDC-0449 or transfection with Smo-siRNA resulted in a significant increase of G1 phase cells compared to controls （P 〈 0.05）. Cell cycle arrest was validated by the significant increase in cyclin D1 and E1 mRNA expression, decrease in cyclin-dependent kinase p21 mRNA expression in Smo-siRNA transfected cells （P 〈 0.05）. Protein expression of cyclin D1 was also downregulated after Smo gene knockdown （P 〈0.05）.The results suggest that Shh signaling plays an important role in RA-FLSs proliferation in a Smo-dependent manner and may contribute to synovial hyperplasia. Targeting Shh signaling may help control joint damage in patients with RA.

Data Do Not Support Effectiveness of Acupuncture for Improving Live Birth Rate in Women with Polycystic Ovary Syndrome

Recently, the arguments raised by Gang and Jing have been published in Chinese Journal of Integrative Medicine, concerning the randomized controlled trial （RCT） of our team published in JAMA. The conclusions of Gang and Jingo） result not only from misunderstanding of the aims of our study,） but also a lack of basic knowledge for the design of RCT and the limitations on the content, and hence the length, of the primary outcome article in high-impact journals （i.e. 2,500 words and a total of 5 figures/tables in JAMA）. We will address their main critiques point by point below.

Biomarkers for Primary Sjgren's Syndrome

Primary Sjogren＇s syndrome （pSS） is a systemic autoimmune disease with exocrine gland dysfunction and multi-organ involvement. Recent progress in understanding the pathogenesis of pSS offers an opportunity to find new biomarkers for the diagnosis and assessment of disease activity. Screening noninvasive biomarkers from the saliva and tears has significant potential. The need for specific and sensitive biomarker candidates in pSS is significant. This review aims to summarize recent advances in the identification of biomarkers of Sjogren syndrome, trying to identify reliable, sensitive, and specific biomarkers that can be used to guide treatment decisions.

HPV18 DNA replication inactivates the early promoter P_(55) activity and prevents viral E6 expression

Dear Editor,Human papillomaviruses(HPV)are a large group(>200genotypes)of small double-stranded DNA viruses(https://pave.niaid.nih.gov/).Although infections by most HPV types are asymptomatic,persistent infections in cervical and ano-genital epithelia by high-risk

A protocol to develop T helper and Treg cells in vivo

An understanding of the development and function of T helper(Th)1,Th17 and regulatory T(Treg)cells is critical toward revealing pro-inflammatory immune responses,especially in autoimmune diseases.However,there is no standard protocol to monitor the development of these cells over time in vivo.This protocol details a method to generate Th1,Th17,and Treg cells in a T cell-induced colitis model in vivo and monitor their dynamic changes,which can be used for further investigations in their development from naive CD4+T cells in specific gene knockouts and background strains.