Objective Arsenic(As) and fluoride(F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, lead...Objective Arsenic(As) and fluoride(F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level(microbiome and metabolome).Methods We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period.Results Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome, featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic(GABAergic) synapse, and arachidonic acid(AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated.Conclusion Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.展开更多
Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insu...Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.展开更多
Objective: To observe the relationship between the different stages of type 2 diabetes mellitus(T2DM)and the intestinal flora and verify its underlying mechanism.Methods: T2DM rats were generated by high-fat diet(HFD)...Objective: To observe the relationship between the different stages of type 2 diabetes mellitus(T2DM)and the intestinal flora and verify its underlying mechanism.Methods: T2DM rats were generated by high-fat diet(HFD) combined with intraperitoneal streptozotocin(STZ) injection. The rats were divided into four groups: the control group(fed with normal feed for1 month), the HFD group(fed with HFD for 1 month), the T2DM group(HFD combined with STZ and blood glucose ≥11.1 m M), and the unformed T2DM model(Un-mod) group(HFD combined with STZ and blood glucose <11.1 m M). Feces were collected, and bacterial communities in the fecal samples were analyzed by 16S r RNA gene sequencing. The content of short-chain fatty acids(SCFAs) in feces was measured by gas chromatography. Western blot and quantitative real-time polymerase chain reaction were used to detect the expression of G protein-coupled receptor 41(GPR41) and GPR43.Results: At different stages of T2DM, the intestinal flora and SCFAs content of rats were significantly decreased(all P <.05). Our results indicated that g__Prevotella had a significant negative correlation, and g__Ruminococcus_torques_group and g__lachnoclastic had a significant positive correlation with blood glucose. The content of SCFAs, in particular acetate and butyrate, in rat feces of different stages of T2DM were significantly reduced, as well as GPR41 and GPR43 expression. The results in the Un-mod group were similar to the T2DM group, and the expression of GPR41 and GPR43 proteins were significantly higher than those in the T2DM group(both P <.001).Conclusion: The intestinal flora-SCFAs-GPR41/GPR43 network may be important in the development of T2DM. Decreasing blood glucose levels by regulating the intestinal flora may become a new therapeutic strategy for T2DM, which has very important clinical and social values.展开更多
Approximately one third of renal cell carcinoma(RCC)patients have metastasis at the time of diagnosis,while one third of localized patients inevitably develop disease recurrence[1,2].To date,there are four drug combin...Approximately one third of renal cell carcinoma(RCC)patients have metastasis at the time of diagnosis,while one third of localized patients inevitably develop disease recurrence[1,2].To date,there are four drug combinations with immunotherapies which have been approved by the US Food and Drug Administration as first-line therapy in metastatic RCC(mRCC):pembrolizumab(anti-programmed cell death protein 1[anti-PD-1]antibody)plus axitinib(vascular endothelial growth factor receptor[VEGF-R]tyrosine kinase inhibitor[TKI]),avelumab(anti-PD-L1 antibody)plus axitinib,nivolumab(anti-PD-1 antibody)plus cabozantinib(multi-target TKI),and nivolumab plus ipilimumab(anticytotoxic T lymphocyte antigen 4 antibody),replacing monotherapies with TKIs targeting the VEGF-R pathway[1].展开更多
Multiple sclerosis(MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but...Multiple sclerosis(MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified. Epstein-Barr virus(EBV), vitamin D, and smoking are among the most well-established environmental risk factors in MS. Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. This review examines the role of EBV in MS pathophysiology and summarizes the recent clinical and radiological findings, with a focus on B-cells and in vivo imaging. Addressing the potential link between EBV and MS allows the better understanding of MS pathogenesis and helps to identify additional disease biomarkers that may be responsive to B-cell depleting intervention.展开更多
Xerostomia, or dry mouth, is a significant problem affecting quality of life in patients treated with radiation therapy for head and neck cancer. Strategies for reduction of xerostomia burden vary widely, with options...Xerostomia, or dry mouth, is a significant problem affecting quality of life in patients treated with radiation therapy for head and neck cancer. Strategies for reduction of xerostomia burden vary widely, with options including: sialagogue medications, saliva substitutes, acupuncture, vitamins, hyperbaric oxygen,submandibular gland transfer, and acupuncture or associated treatments. In this review, we sought to evaluate long-term outcomes of patients treated with various interventions for radiation-induced xerostomia. A literature search was performed using the terms "xerostomia" and "radiation" or "radiotherapy"; all prospective clinical trials were evaluated, and only studies that reported 1 year follow up were included. The search results yielded 2193 studies, 1977 of which were in English. Of those, 304 were clinical trials or clinical studies. After abstract review, 23 trials were included in the review evaluating the following treatment modalities: pilocarpine(three); cevimeline(one); amifostine(eleven);submandibular gland transfer(five); acupuncture like transcutaneous electrical nerve stimulation(ALTENS)(one); hyperbaric oxygen(one); and acupuncture(one). Pilocarpine, cevimeline, and amifostine have been shown in some studies to improve xerostomia outcomes, at the cost of toxicity. ALTENS has similar efficacy with fewer side effects. Submandibular gland transfer is effective but requires an elective surgery, and thus may not always be appropriate or practical.The use of intensity-modulated radiation therapy, in addition to dose deescalation in select patients, may result in fewer patients with late xerostomia,reducing the need for additional interventions.展开更多
Retinal disorders are a group of ocular diseases whose onset is associated with a number of aberrant molecular and cellular processes or physical damages that affect retinal structure and function resulting in neural ...Retinal disorders are a group of ocular diseases whose onset is associated with a number of aberrant molecular and cellular processes or physical damages that affect retinal structure and function resulting in neural and vascular degeneration in the retina.Current research has primarily focused on delaying retinal disease with minimal success in preventing or reversing neuronal degeneration.In this review,we explore a relatively new field of research involving circular RNAs,whose potential roles as biomarkers and mediators of retinal disease pathogenesis have only just emerged.While knowledge of circular RNAs function is limited given its novelty,current evidence has highlighted their roles as modulators of microRNAs,regulators of gene transcription,and biomarkers of disease development and progression.Here,we summarize how circular RNAs may be implicated in the pathogenesis of common retinal diseases including diabetic retinopathy,glaucoma,proliferative vitreoretinopathy,and age-related macular degeneration.Further,we explore the potential of circular RNAs as novel biomarkers and therapeutic targets for the diagnosis and treatment of retinal diseases.展开更多
The prone transpsoas approach is a relatively new technique to correct segmental kyphosis and global sagittal imbalance in a minimally invasive fashion. Here, we provide a detailed case report using the prone transpso...The prone transpsoas approach is a relatively new technique to correct segmental kyphosis and global sagittal imbalance in a minimally invasive fashion. Here, we provide a detailed case report using the prone transpsoas approach to address adjacent segment disease and flatback deformity. This technique allows considerable restoration of segmental lordosis with lateral interbody placement and posterior decompression and fusion using a single position approach. Our experience with the surgical technique and the advantages and challenges unique to this approach are discussed.展开更多
Langerhans cell histiocytosis(LCH)is a rare disease most commonly presenting in the pediatric population and characterized by neoplastic clonal proliferation of Langerhans dendritic cells with accumulation in various ...Langerhans cell histiocytosis(LCH)is a rare disease most commonly presenting in the pediatric population and characterized by neoplastic clonal proliferation of Langerhans dendritic cells with accumulation in various sites,including skeletal and visceral lesions.1 There are three levels of classification per the Histiocyte Society:single-system single-site(SS-s),single-system multiple-site(SS-m),and multisystem(MS).2 SS-s predominantly carries a better prognosis with more conservative treatment while MS requires a more aggressive treatment that is more likely to have an inferior outcome.展开更多
BACKGROUND Non-alcoholic fatty liver disease(NAFLD)has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation.In the United States alone,annual medical costs are approxim...BACKGROUND Non-alcoholic fatty liver disease(NAFLD)has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation.In the United States alone,annual medical costs are approximately 100 billion dollars.Unfortunately,there is no Federal Drug Administration(FDA)-approved medication for its treatment.However,various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD.It is valuable to have a compilation of the data available on their efficacy.AIM To assess the efficacy of cyclophilin inhibitors,fibroblast growth factor 21 analogs(FGF21),and dual and pan peroxisome proliferator-activated receptor(PPAR)agonists for treating NAFLD.METHODS A comprehensive literature search using keywords including cyclophilin inhibitor,FGF agonist,pan-PPAR agonists,dual-PPAR agonist,NAFLD,nonalcoholic steatohepatitis,and fatty liver was conducted on October 29,2022,in PubMed,EMBASE,Cochrane Library,Scopus and Web of Science.Animal and human research,case reports,and published articles in English from all countries with patients aged 18 and above were included.Only articles with a National Institutes of Health(NIH)Quality Assessment score of five or higher out of eight points were included.Articles that were narrative or systematic reviews,abstracts,not in English,focused on patients under 18 years old,did not measure outcomes of interest,were inaccessible,or had a low NIH Quality Assessment score were excluded.Each article was screened by two independent researchers evaluating relevance and quality.Resources were scored based on the NIH Quality Assessment Score;then,pertinent data was extracted in a spreadsheet and descriptively analyzed.RESULTS Of the 681 records screened,29 met the necessary criteria and were included in this review.These records included 12 human studies and 17 animal studies.Specifically,there were four studies on cyclophilin inhibitors,four on FGF agonists/analogs,eleven on pan-PPAR agonists,and ten on dual-PPAR agonists.Different investigational products were assessed:The most common cyclophilin inhibitor was NV556;FGF agonists and analogs was Efruxifermin;pan-PPAR agonists was Lanifibranor;and dual-PPAR agonists was Saroglitazar.All classes were found to be statistically efficacious for the treatment of NAFLD,with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan(P<0.05).CONCLUSION The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes,as well as good safety profiles(P<0.05).We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.展开更多
The author traces his experience with the application of computers in clinical microbiology over the past 60 years,specifically in directing clinicians to treat bacterial infections diagnosed by the laboratory and the...The author traces his experience with the application of computers in clinical microbiology over the past 60 years,specifically in directing clinicians to treat bacterial infections diagnosed by the laboratory and the antibacterial agent(s)that could be used to treat those infections.Appropriate use of antibiotics will result in reduced antimicrobial resistance,which is increasing worldwide.An early form of AI,Mycin(1976),a system based on rules provided by experts designed to propose antibiotic regimens for central nervous system infections,was never applied due to the limitations in the number of rules that could be incorporated into the clinical workflow.Machine learning(ML)was developed to overcome the limitations of expert systems.Several variables that influence the outcome bacteria/drug interaction,such as the source of the infection,absence of antimicrobial resistance markers,patients’health profile,and the historical susceptibility within the hospital and the local area are incorporated in the proposed comprehensive AI/ML program.The role of AI in the discovery of new antimicrobial agents is also addressed.展开更多
Axonal degeneration is a pivotal feature of many neurodegenerative conditions and substantially accounts for neurological morbidity. A widely used experimental model to study the mechanisms of axonal degeneration is W...Axonal degeneration is a pivotal feature of many neurodegenerative conditions and substantially accounts for neurological morbidity. A widely used experimental model to study the mechanisms of axonal degeneration is Wallerian degeneration (WD), which occurs after acute axonal injury. In the peripheral nervous system (PNS), WD is characterized by swift dismantling and clearance of injured axons with their myelin sheaths. This is a prerequisite for successful axonal regeneration. In the central nervous system (CNS), WD is much slower, which significantly contributes to failed axonal regeneration. Although it is well documented that Schwann cells (SCs) have a critical role in the regenerative potential of the PNS, to date we have only scarce knowledge as to how SCs 'sense' axonal injury and immediately respond to it. In this regard, it remains unknown as to whether SCs play the role of a passive bystander or an active director during the execution of the highly orchestrated disintegration program of axons. Older reports, together with more recent studies, suggest that SCs mount dynamic injury responses minutes after axonal injury, long before axonal breakdown occurs. The swift SC response to axonal injury could play either a pro degenerative role, or alternatively a supportive role, to the integrity of distressed axons that have not yet committed to degenerate. Indeed, supporting the latter concept, recent 昀ndings in a chronic PNS neurodegeneration model indicate that deactivation of a key molecule promoting SC injury responses exacerbates axonal loss. If this holds true in a broader spectrum of conditions, it may provide the grounds for the development of new glia-centric therapeutic approaches to counteract axonal loss.展开更多
Stereotactic body radiation therapy(SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer(NSCLC). A literature search primarily based on PubMed electronic datab...Stereotactic body radiation therapy(SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer(NSCLC). A literature search primarily based on PubMed electronic databases was completed in July 2018. Inclusion and exclusion criteria were determined prior to the search, and only prospective clinical trials were included. Nineteen trials from 2005 to 2018 met the inclusion criteria, reporting the outcomes of 1434 patients with central and peripheral early stage NSCLC. Patient eligibility,prescription dose and delivery, and follow up duration varied widely. Threeyears overall survival ranged from 43% to 95% with loco-regional control of up to 98% at 3 years. Up to 33% of patients failed distantly after SBRT at 3 years. SBRT was generally well tolerated with 10%-30% grade 3-4 toxicities and a few treatment-related deaths. No differences in outcomes were observed between conventionally fractionated radiation therapy and SBRT, central and peripheral lung tumors, or inoperable and operable patients. SBRT remains a reasonable treatment option for medically inoperable and select operable patients with early stage NSCLC. SBRT has shown excellent local and regional control with toxicity rates equivalent to surgery. Decreasing fractionation schedules have been consistently shown to be both safe and effective. Distant failure is common, and chemotherapy may be considered for select patients. However, the survival benefit of additional interventions, such as chemotherapy, for early stage NSCLC treated with SBRT remains unclear.展开更多
Large-scale epidemiological studies have found that hyperhomocysteinemia is a powerful, independent risk factor for Alzheimer's disease. Trillium tschonoskii maxim is a traditional Chinese medicine that is used to pr...Large-scale epidemiological studies have found that hyperhomocysteinemia is a powerful, independent risk factor for Alzheimer's disease. Trillium tschonoskii maxim is a traditional Chinese medicine that is used to promote memory. However, scientific understanding of its mechanism of action is limited. This report studied the potential neuroprotective effects of Trillium tschonoskii maxim extract against homocysteine-induced cognitive deficits. Rats were intravenously injected with homocysteine(400 μg/kg) for 14 days to induce a model of Alzheimer's disease. These rats were then intragastrically treated with Trillium tschonoskii maxim extract(0.125 or 0.25 g/kg) for 7 consecutive days. Open field test and Morris water maze test were conducted to measure spontaneous activity and learning and memory abilities. Western blot assay was used to detect the levels of Tau protein and other factors involved in Tau phosphorylation in the hippocampus. Immunohistochemical staining was used to examine Tau protein in the hippocampus. Golgi staining was applied to measure hippocampal dendritic spines. Our results demonstrated that homocysteine produced learning and memory deficits and increased levels of Tau phosphorylation, and diminished the activity of catalytic protein phosphatase 2A. The total number of hippocampal dendritic spines was also decreased. Trillium tschonoskii maxim extract treatment reversed the homocysteine-induced changes. The above results suggest that Trillium tschonoskii maxim extract can lessen homocysteine-induced abnormal Tau phosphorylation and improve cognitive deterioration such as that present in Alzheimer's disease.展开更多
Extract The contrary but interrelated processes of axon degeneration and regeneration are the yin and yang of many neurodegenerative conditions. Here we discuss recent evidence for metabolic cross-talk between glia an...Extract The contrary but interrelated processes of axon degeneration and regeneration are the yin and yang of many neurodegenerative conditions. Here we discuss recent evidence for metabolic cross-talk between glia and injured axons regulating these processes. We especially focus on potential bioenergetic mechanisms as to how axon-flanking glia may promote regeneration.展开更多
Neuropathic pain is a chronic syndrome caused by direct damage to or disease of the somatosensory nervous system. The lack of safe, adequate and sustained pain relief offered by present analgesic treatments is most al...Neuropathic pain is a chronic syndrome caused by direct damage to or disease of the somatosensory nervous system. The lack of safe, adequate and sustained pain relief offered by present analgesic treatments is most alarming. While many treatment options are available to manage chronic pain, such as antidepressants, nonsteroidal anti-inflammatory agents, opioids, and anticonvulsants, chronic neuropathic pain remains largely unmanaged. Compounding the dilemma of ineffective chronic pain treatments is the need to provide relief from suffering and yet not contribute to the scourge of drug abuse. A recent epidemic of addiction and accidental drug prescription overdoses parallel the increased use of opioid treatment, even though opioids are rarely an effective treatment of relieving chronic pain. To make matters worse, opioids may contribute to exacerbating pain, and side-effects such as cognitive impairment, nausea, constipation, development of tolerance, as well as their potential for addiction and overdose deaths exist. Clearly, there is an urgent need for alternative, nonopiate treatment of chronic pain. Innovative discoveries of pertinent brain mechanisms and functions are key to developing effective, safe treatments. Pioneering work has revealed the essential effects of the pleiotropic mediator tumor necrosis factor(TNF) on brain functioning. These studies establish that TNF inhibits norepinephrine release from hippocampal neurons, and show that excess TNF production within the hippocampus occurs during neuropathic pain, which mobilizes additional mechanisms that further inhibit norepinephrine release. Significantly, it has been verified that elevated levels of TNF in the brain are actually required for neuropathic pain development. Since TNF decreases norepinephrine release in the brain, enhanced TNF levels would prevent engagement of the norepinephrine descending inhibitory neuronal pain pathways. Increased levels of TNF in the brain are therefore critical to the development of neuropathic pain. Therefore, strategies that decrease this enhanced TNF expression in the brain will have superior analgesic efficacy. We propose this novel approach of targeting the pathologically high levels of brain TNF as an effective strategy in the treatment of the devastating syndrome of chronic pain.展开更多
Artificial intelligence(AI)is a complex concept,broadly defined in medicine as the development of computer systems to perform tasks that require human intelligence.It has the capacity to revolutionize medicine by incr...Artificial intelligence(AI)is a complex concept,broadly defined in medicine as the development of computer systems to perform tasks that require human intelligence.It has the capacity to revolutionize medicine by increasing efficiency,expediting data and image analysis and identifying patterns,trends and associations in large datasets.Within gastroenterology,recent research efforts have focused on using AI in esophagogastroduodenoscopy,wireless capsule endoscopy(WCE)and colonoscopy to assist in diagnosis,disease monitoring,lesion detection and therapeutic intervention.The main objective of this narrative review is to provide a comprehensive overview of the research being performed within gastroenterology on AI in esophagogastroduodenoscopy,WCE and colonoscopy.展开更多
Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy.However,the underlying mechanism remains elusive.We show here that...Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy.However,the underlying mechanism remains elusive.We show here that Pink1 knockout(KO)mice display defective dendritic spine maturation,reduced axonal synaptic vesicles,abnormal synaptic connection,and attenuated long-term synaptic potentiation(LTP).Drp1 activation via ^(S616) phosphorylation rescues deficits of spine maturation in Pink1 KO neurons.展开更多
Introduction:Primary succession on glacial forelands is increasingly relevant as rapid glacial retreat is exposing growing land areas to plant colonization.We investigated temporal trends,controls,and outcomes in flor...Introduction:Primary succession on glacial forelands is increasingly relevant as rapid glacial retreat is exposing growing land areas to plant colonization.We investigated temporal trends,controls,and outcomes in floral succession on a subarctic glacial foreland.Specifically,we examined changes in community composition(mosses,low shrubs,forbs,trees,and graminoids)over long-term(decadal)and short-term(<10 years)scales and attempted to identify the underlying processes responsible for the observed successional patterns.Methods:The study area was the foreland of the Skaftafellsjӧkull,located in Vatnajӧkull National Park near the south coast of Iceland.We established nine transect lines at varying distances from the ice front representing surfaces of age ranging from less than one decade to over 100 years.Each transect consisted of five measurement stations of 1 m2 where we measured vegetative cover(VC),species richness(SR),and species density(SD)and calculated species evenness(SE).Measurements were made initially in 2007 and repeated at the same geographic coordinates in 2014.Results:VC increased with distance from the ice front from 16%to over 90%.SR and SD increased from the youngest pioneer community through a mid-successional stage corresponding to an age of over 60 but less than 100 years.Increased VC but declining SR,SD,and SE characterized the oldest(over 100 years)bryophyte-dominated surfaces.Species turnover,which involved forbs almost exclusively,increased moderately from early through midsuccessional sites and declined on older sites.Comparison of the measurements made in 2014 to those made in 2007 demonstrates increased SR at mid-successional sites while SD remained relatively constant.Conclusion:At a small scale,colonization is controlled by local factors such as microtopography and aspect,particularly in proximity to the glacier.At the landscape level,changes in VC and community structure are controlled by time and nutrient availability.Low nutrient levels and limited site availability favor bryophyte dominance on the oldest surfaces.The greatest community-level changes observed over the 7-year interval were increases in surface cover by mosses and low shrubs,particularly in mid-successional and older sites.These changes suggest that the community on the oldest surfaces has not yet reached equilibrium.展开更多
基金supported by National Natural Science Foundation of China [No. 81773405 to Y.Q. and No. 82173644to X.Y.]Shanxi Natural Science Foundation of China [No.202203021211246 and No. 202103021224242]。
文摘Objective Arsenic(As) and fluoride(F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level(microbiome and metabolome).Methods We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period.Results Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome, featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic(GABAergic) synapse, and arachidonic acid(AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated.Conclusion Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.
文摘Type 1 diabetes(T1D)is a chronic autoimmune condition that destroys insulinproducing beta cells in the pancreas,leading to insulin deficiency and hyperglycemia.The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels.However,this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells.Recent research has explored the potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)as a novel intervention to modify the disease course and delay the onset of T1D.GLP-1RAs are medications initially developed for treating type 2 diabetes.They exert their effects by enhancing glucose-dependent insulin secretion,suppressing glucagon secretion,and slowing gastric emptying.Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D.This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D,possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells.This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification,which should open new avenues for preventing and treating T1D,improving the quality of life and long-term outcomes for individuals at risk of T1D.
基金supported by the National Natural Science Foundation of China (81973535 and 81773960)
文摘Objective: To observe the relationship between the different stages of type 2 diabetes mellitus(T2DM)and the intestinal flora and verify its underlying mechanism.Methods: T2DM rats were generated by high-fat diet(HFD) combined with intraperitoneal streptozotocin(STZ) injection. The rats were divided into four groups: the control group(fed with normal feed for1 month), the HFD group(fed with HFD for 1 month), the T2DM group(HFD combined with STZ and blood glucose ≥11.1 m M), and the unformed T2DM model(Un-mod) group(HFD combined with STZ and blood glucose <11.1 m M). Feces were collected, and bacterial communities in the fecal samples were analyzed by 16S r RNA gene sequencing. The content of short-chain fatty acids(SCFAs) in feces was measured by gas chromatography. Western blot and quantitative real-time polymerase chain reaction were used to detect the expression of G protein-coupled receptor 41(GPR41) and GPR43.Results: At different stages of T2DM, the intestinal flora and SCFAs content of rats were significantly decreased(all P <.05). Our results indicated that g__Prevotella had a significant negative correlation, and g__Ruminococcus_torques_group and g__lachnoclastic had a significant positive correlation with blood glucose. The content of SCFAs, in particular acetate and butyrate, in rat feces of different stages of T2DM were significantly reduced, as well as GPR41 and GPR43 expression. The results in the Un-mod group were similar to the T2DM group, and the expression of GPR41 and GPR43 proteins were significantly higher than those in the T2DM group(both P <.001).Conclusion: The intestinal flora-SCFAs-GPR41/GPR43 network may be important in the development of T2DM. Decreasing blood glucose levels by regulating the intestinal flora may become a new therapeutic strategy for T2DM, which has very important clinical and social values.
文摘Approximately one third of renal cell carcinoma(RCC)patients have metastasis at the time of diagnosis,while one third of localized patients inevitably develop disease recurrence[1,2].To date,there are four drug combinations with immunotherapies which have been approved by the US Food and Drug Administration as first-line therapy in metastatic RCC(mRCC):pembrolizumab(anti-programmed cell death protein 1[anti-PD-1]antibody)plus axitinib(vascular endothelial growth factor receptor[VEGF-R]tyrosine kinase inhibitor[TKI]),avelumab(anti-PD-L1 antibody)plus axitinib,nivolumab(anti-PD-1 antibody)plus cabozantinib(multi-target TKI),and nivolumab plus ipilimumab(anticytotoxic T lymphocyte antigen 4 antibody),replacing monotherapies with TKIs targeting the VEGF-R pathway[1].
文摘Multiple sclerosis(MS) is a disease of the central nervous system characterized by inflammation, demyelination, and neuronal damage. Environmental and genetic factors are associated with the risk of developing MS, but the exact cause still remains unidentified. Epstein-Barr virus(EBV), vitamin D, and smoking are among the most well-established environmental risk factors in MS. Infectious mononucleosis, which is caused by delayed primary EBV infection, increases the risk of developing MS. EBV may also contribute to MS pathogenesis indirectly by activating silent human endogenous retrovirus-W. The emerging B-cell depleting therapies, particularly anti-CD20 agents such as rituximab, ocrelizumab, as well as the fully human ofatumumab, have shown promising clinical and magnetic resonance imaging benefit. One potential effect of these therapies is the depletion of memory B-cells, the primary reservoir site where EBV latency occurs. In addition, EBV potentially interacts with both genetic and other environmental factors to increase susceptibility and disease severity of MS. This review examines the role of EBV in MS pathophysiology and summarizes the recent clinical and radiological findings, with a focus on B-cells and in vivo imaging. Addressing the potential link between EBV and MS allows the better understanding of MS pathogenesis and helps to identify additional disease biomarkers that may be responsive to B-cell depleting intervention.
文摘Xerostomia, or dry mouth, is a significant problem affecting quality of life in patients treated with radiation therapy for head and neck cancer. Strategies for reduction of xerostomia burden vary widely, with options including: sialagogue medications, saliva substitutes, acupuncture, vitamins, hyperbaric oxygen,submandibular gland transfer, and acupuncture or associated treatments. In this review, we sought to evaluate long-term outcomes of patients treated with various interventions for radiation-induced xerostomia. A literature search was performed using the terms "xerostomia" and "radiation" or "radiotherapy"; all prospective clinical trials were evaluated, and only studies that reported 1 year follow up were included. The search results yielded 2193 studies, 1977 of which were in English. Of those, 304 were clinical trials or clinical studies. After abstract review, 23 trials were included in the review evaluating the following treatment modalities: pilocarpine(three); cevimeline(one); amifostine(eleven);submandibular gland transfer(five); acupuncture like transcutaneous electrical nerve stimulation(ALTENS)(one); hyperbaric oxygen(one); and acupuncture(one). Pilocarpine, cevimeline, and amifostine have been shown in some studies to improve xerostomia outcomes, at the cost of toxicity. ALTENS has similar efficacy with fewer side effects. Submandibular gland transfer is effective but requires an elective surgery, and thus may not always be appropriate or practical.The use of intensity-modulated radiation therapy, in addition to dose deescalation in select patients, may result in fewer patients with late xerostomia,reducing the need for additional interventions.
基金supported,in part,by NIH/NEI Grants EY019949,EY025061,EY030970(to SXZ)a research grant NGR G2019302 from the Brightfocus Foundation(to SXZ)an Unrestricted Grant from Research to Prevent Blindness to the Department of Ophthalmology,the State University of New York at Buffalo.
文摘Retinal disorders are a group of ocular diseases whose onset is associated with a number of aberrant molecular and cellular processes or physical damages that affect retinal structure and function resulting in neural and vascular degeneration in the retina.Current research has primarily focused on delaying retinal disease with minimal success in preventing or reversing neuronal degeneration.In this review,we explore a relatively new field of research involving circular RNAs,whose potential roles as biomarkers and mediators of retinal disease pathogenesis have only just emerged.While knowledge of circular RNAs function is limited given its novelty,current evidence has highlighted their roles as modulators of microRNAs,regulators of gene transcription,and biomarkers of disease development and progression.Here,we summarize how circular RNAs may be implicated in the pathogenesis of common retinal diseases including diabetic retinopathy,glaucoma,proliferative vitreoretinopathy,and age-related macular degeneration.Further,we explore the potential of circular RNAs as novel biomarkers and therapeutic targets for the diagnosis and treatment of retinal diseases.
文摘The prone transpsoas approach is a relatively new technique to correct segmental kyphosis and global sagittal imbalance in a minimally invasive fashion. Here, we provide a detailed case report using the prone transpsoas approach to address adjacent segment disease and flatback deformity. This technique allows considerable restoration of segmental lordosis with lateral interbody placement and posterior decompression and fusion using a single position approach. Our experience with the surgical technique and the advantages and challenges unique to this approach are discussed.
文摘Langerhans cell histiocytosis(LCH)is a rare disease most commonly presenting in the pediatric population and characterized by neoplastic clonal proliferation of Langerhans dendritic cells with accumulation in various sites,including skeletal and visceral lesions.1 There are three levels of classification per the Histiocyte Society:single-system single-site(SS-s),single-system multiple-site(SS-m),and multisystem(MS).2 SS-s predominantly carries a better prognosis with more conservative treatment while MS requires a more aggressive treatment that is more likely to have an inferior outcome.
文摘BACKGROUND Non-alcoholic fatty liver disease(NAFLD)has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation.In the United States alone,annual medical costs are approximately 100 billion dollars.Unfortunately,there is no Federal Drug Administration(FDA)-approved medication for its treatment.However,various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD.It is valuable to have a compilation of the data available on their efficacy.AIM To assess the efficacy of cyclophilin inhibitors,fibroblast growth factor 21 analogs(FGF21),and dual and pan peroxisome proliferator-activated receptor(PPAR)agonists for treating NAFLD.METHODS A comprehensive literature search using keywords including cyclophilin inhibitor,FGF agonist,pan-PPAR agonists,dual-PPAR agonist,NAFLD,nonalcoholic steatohepatitis,and fatty liver was conducted on October 29,2022,in PubMed,EMBASE,Cochrane Library,Scopus and Web of Science.Animal and human research,case reports,and published articles in English from all countries with patients aged 18 and above were included.Only articles with a National Institutes of Health(NIH)Quality Assessment score of five or higher out of eight points were included.Articles that were narrative or systematic reviews,abstracts,not in English,focused on patients under 18 years old,did not measure outcomes of interest,were inaccessible,or had a low NIH Quality Assessment score were excluded.Each article was screened by two independent researchers evaluating relevance and quality.Resources were scored based on the NIH Quality Assessment Score;then,pertinent data was extracted in a spreadsheet and descriptively analyzed.RESULTS Of the 681 records screened,29 met the necessary criteria and were included in this review.These records included 12 human studies and 17 animal studies.Specifically,there were four studies on cyclophilin inhibitors,four on FGF agonists/analogs,eleven on pan-PPAR agonists,and ten on dual-PPAR agonists.Different investigational products were assessed:The most common cyclophilin inhibitor was NV556;FGF agonists and analogs was Efruxifermin;pan-PPAR agonists was Lanifibranor;and dual-PPAR agonists was Saroglitazar.All classes were found to be statistically efficacious for the treatment of NAFLD,with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan(P<0.05).CONCLUSION The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes,as well as good safety profiles(P<0.05).We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.
文摘The author traces his experience with the application of computers in clinical microbiology over the past 60 years,specifically in directing clinicians to treat bacterial infections diagnosed by the laboratory and the antibacterial agent(s)that could be used to treat those infections.Appropriate use of antibiotics will result in reduced antimicrobial resistance,which is increasing worldwide.An early form of AI,Mycin(1976),a system based on rules provided by experts designed to propose antibiotic regimens for central nervous system infections,was never applied due to the limitations in the number of rules that could be incorporated into the clinical workflow.Machine learning(ML)was developed to overcome the limitations of expert systems.Several variables that influence the outcome bacteria/drug interaction,such as the source of the infection,absence of antimicrobial resistance markers,patients’health profile,and the historical susceptibility within the hospital and the local area are incorporated in the proposed comprehensive AI/ML program.The role of AI in the discovery of new antimicrobial agents is also addressed.
基金supported by Muscular Dystrophy Association grants#292306 and#236648Empire State Development Corporation for HJKRI Grants W753 and U446+1 种基金Hunter’s Hope FoundationUniversity at Buffalo IMPACT funding
文摘Axonal degeneration is a pivotal feature of many neurodegenerative conditions and substantially accounts for neurological morbidity. A widely used experimental model to study the mechanisms of axonal degeneration is Wallerian degeneration (WD), which occurs after acute axonal injury. In the peripheral nervous system (PNS), WD is characterized by swift dismantling and clearance of injured axons with their myelin sheaths. This is a prerequisite for successful axonal regeneration. In the central nervous system (CNS), WD is much slower, which significantly contributes to failed axonal regeneration. Although it is well documented that Schwann cells (SCs) have a critical role in the regenerative potential of the PNS, to date we have only scarce knowledge as to how SCs 'sense' axonal injury and immediately respond to it. In this regard, it remains unknown as to whether SCs play the role of a passive bystander or an active director during the execution of the highly orchestrated disintegration program of axons. Older reports, together with more recent studies, suggest that SCs mount dynamic injury responses minutes after axonal injury, long before axonal breakdown occurs. The swift SC response to axonal injury could play either a pro degenerative role, or alternatively a supportive role, to the integrity of distressed axons that have not yet committed to degenerate. Indeed, supporting the latter concept, recent 昀ndings in a chronic PNS neurodegeneration model indicate that deactivation of a key molecule promoting SC injury responses exacerbates axonal loss. If this holds true in a broader spectrum of conditions, it may provide the grounds for the development of new glia-centric therapeutic approaches to counteract axonal loss.
文摘Stereotactic body radiation therapy(SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer(NSCLC). A literature search primarily based on PubMed electronic databases was completed in July 2018. Inclusion and exclusion criteria were determined prior to the search, and only prospective clinical trials were included. Nineteen trials from 2005 to 2018 met the inclusion criteria, reporting the outcomes of 1434 patients with central and peripheral early stage NSCLC. Patient eligibility,prescription dose and delivery, and follow up duration varied widely. Threeyears overall survival ranged from 43% to 95% with loco-regional control of up to 98% at 3 years. Up to 33% of patients failed distantly after SBRT at 3 years. SBRT was generally well tolerated with 10%-30% grade 3-4 toxicities and a few treatment-related deaths. No differences in outcomes were observed between conventionally fractionated radiation therapy and SBRT, central and peripheral lung tumors, or inoperable and operable patients. SBRT remains a reasonable treatment option for medically inoperable and select operable patients with early stage NSCLC. SBRT has shown excellent local and regional control with toxicity rates equivalent to surgery. Decreasing fractionation schedules have been consistently shown to be both safe and effective. Distant failure is common, and chemotherapy may be considered for select patients. However, the survival benefit of additional interventions, such as chemotherapy, for early stage NSCLC treated with SBRT remains unclear.
基金supported in part by grants from the National Natural Science Foundation of China,No.81260172,81660223the Opening Foundation of Hubei Key Laboratory of Biological Resource Protection and Utilization of China,No.PKLHB1318+2 种基金the Science and Technology Innovation Team Project of Hubei University for Nationalities of China,No.MY2011T005the Doctoral Fund of Hubei University for Nationalities of China,No.MY2012B015the Natural Science Foundation of Hubei Province of China,No.2017CFB451
文摘Large-scale epidemiological studies have found that hyperhomocysteinemia is a powerful, independent risk factor for Alzheimer's disease. Trillium tschonoskii maxim is a traditional Chinese medicine that is used to promote memory. However, scientific understanding of its mechanism of action is limited. This report studied the potential neuroprotective effects of Trillium tschonoskii maxim extract against homocysteine-induced cognitive deficits. Rats were intravenously injected with homocysteine(400 μg/kg) for 14 days to induce a model of Alzheimer's disease. These rats were then intragastrically treated with Trillium tschonoskii maxim extract(0.125 or 0.25 g/kg) for 7 consecutive days. Open field test and Morris water maze test were conducted to measure spontaneous activity and learning and memory abilities. Western blot assay was used to detect the levels of Tau protein and other factors involved in Tau phosphorylation in the hippocampus. Immunohistochemical staining was used to examine Tau protein in the hippocampus. Golgi staining was applied to measure hippocampal dendritic spines. Our results demonstrated that homocysteine produced learning and memory deficits and increased levels of Tau phosphorylation, and diminished the activity of catalytic protein phosphatase 2A. The total number of hippocampal dendritic spines was also decreased. Trillium tschonoskii maxim extract treatment reversed the homocysteine-induced changes. The above results suggest that Trillium tschonoskii maxim extract can lessen homocysteine-induced abnormal Tau phosphorylation and improve cognitive deterioration such as that present in Alzheimer's disease.
基金supported by grants from the National Institute of Health(R01NS111024)the Muscular Dystrophy Association(577844)+1 种基金Funding provided through the Empire State Development Corporation for Hunter James Kelly Research Institute grant nos.W753 and U446the Hunter’s Hope Foundation(to BB)。
文摘Extract The contrary but interrelated processes of axon degeneration and regeneration are the yin and yang of many neurodegenerative conditions. Here we discuss recent evidence for metabolic cross-talk between glia and injured axons regulating these processes. We especially focus on potential bioenergetic mechanisms as to how axon-flanking glia may promote regeneration.
文摘Neuropathic pain is a chronic syndrome caused by direct damage to or disease of the somatosensory nervous system. The lack of safe, adequate and sustained pain relief offered by present analgesic treatments is most alarming. While many treatment options are available to manage chronic pain, such as antidepressants, nonsteroidal anti-inflammatory agents, opioids, and anticonvulsants, chronic neuropathic pain remains largely unmanaged. Compounding the dilemma of ineffective chronic pain treatments is the need to provide relief from suffering and yet not contribute to the scourge of drug abuse. A recent epidemic of addiction and accidental drug prescription overdoses parallel the increased use of opioid treatment, even though opioids are rarely an effective treatment of relieving chronic pain. To make matters worse, opioids may contribute to exacerbating pain, and side-effects such as cognitive impairment, nausea, constipation, development of tolerance, as well as their potential for addiction and overdose deaths exist. Clearly, there is an urgent need for alternative, nonopiate treatment of chronic pain. Innovative discoveries of pertinent brain mechanisms and functions are key to developing effective, safe treatments. Pioneering work has revealed the essential effects of the pleiotropic mediator tumor necrosis factor(TNF) on brain functioning. These studies establish that TNF inhibits norepinephrine release from hippocampal neurons, and show that excess TNF production within the hippocampus occurs during neuropathic pain, which mobilizes additional mechanisms that further inhibit norepinephrine release. Significantly, it has been verified that elevated levels of TNF in the brain are actually required for neuropathic pain development. Since TNF decreases norepinephrine release in the brain, enhanced TNF levels would prevent engagement of the norepinephrine descending inhibitory neuronal pain pathways. Increased levels of TNF in the brain are therefore critical to the development of neuropathic pain. Therefore, strategies that decrease this enhanced TNF expression in the brain will have superior analgesic efficacy. We propose this novel approach of targeting the pathologically high levels of brain TNF as an effective strategy in the treatment of the devastating syndrome of chronic pain.
文摘Artificial intelligence(AI)is a complex concept,broadly defined in medicine as the development of computer systems to perform tasks that require human intelligence.It has the capacity to revolutionize medicine by increasing efficiency,expediting data and image analysis and identifying patterns,trends and associations in large datasets.Within gastroenterology,recent research efforts have focused on using AI in esophagogastroduodenoscopy,wireless capsule endoscopy(WCE)and colonoscopy to assist in diagnosis,disease monitoring,lesion detection and therapeutic intervention.The main objective of this narrative review is to provide a comprehensive overview of the research being performed within gastroenterology on AI in esophagogastroduodenoscopy,WCE and colonoscopy.
基金This work was supported by the National Natural Science Foundation of China(31730036,81861138012,81161120498,81429002,31330031,82171506,and 31872778)the Discipline Innovative Engineering Plan(111 Program)of China(B13036)+4 种基金a key laboratory grant from Hunan province(2016TP1006)Science and Technology Major Project of Hunan Provincial Science and Technology Department(2018SK1030)the Department of Science and Technology of Hunan Province(grant 2021DK2001,and innovative team program 2019RS1010)The innovative team program from Department of Science&Technology of Hunan Province(2019RS1010)The innovation-driven team project from Central South University(2020CX016),and Hunan 100 Talents Program.
文摘Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy.However,the underlying mechanism remains elusive.We show here that Pink1 knockout(KO)mice display defective dendritic spine maturation,reduced axonal synaptic vesicles,abnormal synaptic connection,and attenuated long-term synaptic potentiation(LTP).Drp1 activation via ^(S616) phosphorylation rescues deficits of spine maturation in Pink1 KO neurons.
文摘Introduction:Primary succession on glacial forelands is increasingly relevant as rapid glacial retreat is exposing growing land areas to plant colonization.We investigated temporal trends,controls,and outcomes in floral succession on a subarctic glacial foreland.Specifically,we examined changes in community composition(mosses,low shrubs,forbs,trees,and graminoids)over long-term(decadal)and short-term(<10 years)scales and attempted to identify the underlying processes responsible for the observed successional patterns.Methods:The study area was the foreland of the Skaftafellsjӧkull,located in Vatnajӧkull National Park near the south coast of Iceland.We established nine transect lines at varying distances from the ice front representing surfaces of age ranging from less than one decade to over 100 years.Each transect consisted of five measurement stations of 1 m2 where we measured vegetative cover(VC),species richness(SR),and species density(SD)and calculated species evenness(SE).Measurements were made initially in 2007 and repeated at the same geographic coordinates in 2014.Results:VC increased with distance from the ice front from 16%to over 90%.SR and SD increased from the youngest pioneer community through a mid-successional stage corresponding to an age of over 60 but less than 100 years.Increased VC but declining SR,SD,and SE characterized the oldest(over 100 years)bryophyte-dominated surfaces.Species turnover,which involved forbs almost exclusively,increased moderately from early through midsuccessional sites and declined on older sites.Comparison of the measurements made in 2014 to those made in 2007 demonstrates increased SR at mid-successional sites while SD remained relatively constant.Conclusion:At a small scale,colonization is controlled by local factors such as microtopography and aspect,particularly in proximity to the glacier.At the landscape level,changes in VC and community structure are controlled by time and nutrient availability.Low nutrient levels and limited site availability favor bryophyte dominance on the oldest surfaces.The greatest community-level changes observed over the 7-year interval were increases in surface cover by mosses and low shrubs,particularly in mid-successional and older sites.These changes suggest that the community on the oldest surfaces has not yet reached equilibrium.