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
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
The development of open-pit mines can adversely affect and even damage existing access tunnels. To ensure the safety and serviceability of them, it is essential to know potential adverse effects of the mining sequence...The development of open-pit mines can adversely affect and even damage existing access tunnels. To ensure the safety and serviceability of them, it is essential to know potential adverse effects of the mining sequence on existing tunnels such as displacements of the lining and additional loads on the lining. In this paper, three-dimensional numerical parametric study is performed to explore this complex interaction. This study investigates the effects of different parameters that may affect the tunnel response. These parameters are： excavation sequence method, horizontal/vertical stress ratio, slope angle, and tunnel diameter. This study shows that the mining sequence affects the stability of the tunnels. The open-pit mining activities lead to both higher axial forces in rock bolts and normal forces and bending moments in the lining. The results of the analysis also demonstrate that the mining sequence causes tunnel heave and significant tensile forces in the lining. Based on the study in this paper a better understanding of the interaction between oDen-oit minin~ seouence and tunnels will he ohtained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
Background:Early neurologic deterioration(END)may occur in patients with anterior circulation ischemic stroke(ACIS)after receiving endovascular treatment(EVT).Hemodynamic insufficiency,re-occlusion,and post-re-canaliz...Background:Early neurologic deterioration(END)may occur in patients with anterior circulation ischemic stroke(ACIS)after receiving endovascular treatment(EVT).Hemodynamic insufficiency,re-occlusion,and post-re-canalization hyper-perfusion are likely to play a critical role in END.We hypothesized that hemodynamic changes can predict END in patients with ACIS postsuccessful EVT using trans-cranial Doppler(TCD).Methods:We utilized a prospectively maintained database of ACIS patients treated with EVT between September 2016 and June 2018 in the Xuanwu Hospital,Capital Medical University.TCD parameters including peak systolic velocity(PSV),bilateral mean flow velocity(MFV),and pulse index(PI)were determined via the middle cerebral arteries within 72 h post-EVT.A logistic regression model was applied to detect independent predictors for END.Results:Totally,112 EVT patients were included in this study and 80/112 patients experienced successful re-canalization with<50%residual stenosis,while 17/80(21.3%)patients suffered END,for which vasogenic cerebral edema(11/17)was considered as a leading role and followed by symptomatic intra-cranial hemorrhage(4/17)and ischemia progression(2/17).For the 80 patients,the PSV(median:127 cm/s vs.116 cm/s,P=0.039),the ratio of ipsilateral-MFV/contra-lateral-MFV(iMFV/cMFV)(median:1.29 vs.1.02,P=0.036)and iMFV/mean blood pressure(MBP)(median:0.97 vs.0.79,P=0.008)in END patients were higher than those of non-END.Using the receiver-operating characteristic curve to obtain cut-off values for PSV,PI,iMFV/cMFV,and iMFV/MBP for END,we found that PI≥0.85(odds ratio:11.03,95%confidence interval:1.92–63.46,P=0.007)and iMFV/MBP≥0.84(odds ratio:9.20,95%confidence interval:2.07–40.84,P=0.004)were independent predictors of END in a multivariate logistic regression model,with a sensitivity of 82.4%and 76.5%and a specificity of 42.9%and 66.7%,respectively,and had the positive predictive values of 29.0%and 38.2%,and negative predictive values of 90.0%and 91.3%,with an area under the receiveroperat展开更多
In neurons,mitochondria are enriched to provide energy and calcium buffering required for synaptic transmission.Additionally,mitochondria localize to the synapse,where they are critical for the mobilization of reserve...In neurons,mitochondria are enriched to provide energy and calcium buffering required for synaptic transmission.Additionally,mitochondria localize to the synapse,where they are critical for the mobilization of reserve pool vesicles and for neurotransmitter release.Previously,functional defects in mitochondria were considered to be downstream effects of neurodegenerative diseases.However,more recent findings suggest mitochondria may serve as key mediators in the onset and progression of some types of neurodegeneration.In this review,we explore the possible roles of altered mitochondrial function and dynamics in the pathogenesis of neurodegenerative disorders,with a particular focus on Alzheimer’s disease(AD)and Parkinson’s disease(PD),which have highlighted the important role of mitochondria in neurodegeneration.While inheritable diseases like Charcot-Marie-Tooth disease type 2A are concretely linked to gene mutations affecting mitochondrial function,the cause of mitochondrial dysfunction in primarily sporadic diseases such as AD and PD is less clear.Neuronal death in PD is associated with defects in mitochondrial function and dynamics arising from mutations in proteins affecting these processes,including α-synuclein,DJ-1,LRRK2,Parkin and Pink1.In the case of AD,however,the connection between mitochondria and the onset of neurodegeneration has been less clear.Recent findings,however,have implicated altered function of ER-mitochondria contact sites and amyloid beta-and/or tau-induced defects in mitochondrial function and dynamics in the pathogenesis of AD,suggesting that mitochondrial defects may act as key mediators in the pathogenesis of AD as well.With recent findings at hand,it may be postulated that defects in mitochondrial processes comprise key events in the onset of neurodegeneration.展开更多
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
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
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
Big Data Analytics is an emerging field since massive storage and computing capabilities have been made available by advanced e-infrastructures.Earth and Environmental sciences are likely to benefit from Big Data Anal...Big Data Analytics is an emerging field since massive storage and computing capabilities have been made available by advanced e-infrastructures.Earth and Environmental sciences are likely to benefit from Big Data Analytics techniques supporting the processing of the large number of Earth Observation datasets currently acquired and generated through observations and simulations.However,Earth Science data and applications present specificities in terms of relevance of the geospatial information,wide heterogeneity of data models and formats,and complexity of processing.Therefore,Big Earth Data Analytics requires specifically tailored techniques and tools.The EarthServer Big Earth Data Analytics engine offers a solution for coverage-type datasets,built around a high performance array database technology,and the adoption and enhancement of standards for service interaction(OGC WCS and WCPS).The EarthServer solution,led by the collection of requirements from scientific communities and international initiatives,provides a holistic approach that ranges from query languages and scalability up to mobile access and visualization.The result is demonstrated and validated through the development of lighthouse applications in the Marine,Geology,Atmospheric,Planetary and Cryospheric science domains.展开更多
Pediatric autoimmune neuropsychiatric disorders associated with or without streptococcal and other bacterial infections (PANDAS/CANS) are emerging as a featured pediatric disorder. Although there is some controversy r...Pediatric autoimmune neuropsychiatric disorders associated with or without streptococcal and other bacterial infections (PANDAS/CANS) are emerging as a featured pediatric disorder. Although there is some controversy regarding treatment approaches, especially related to the behavioral sequelae, we have hypothesized in other published work that it is characterized by the rapid onset of Reward Deficiency Syndrome (RDS) in children. We propose utilizing a multi-systems biological approach involving the coupling of genetic addiction risk testing and pro-dopamine regulation (KB220/POLYGEN®) to help induce “dopamine homeostasis” in patients with PANDAS, especially those with known DNA-induced hypodopaminergia. This case study examines a 12-year-old Caucasian male with no prior psychiatric issues who presented with a sudden onset of severe anxiety, depression, emotional liability, and suicidal ideation. The patient underwent genotyping and the genetic addiction risk score (GARS) testing, which revealed risk polymorphisms in the dopamine D2 (-DRD2/ANKK (Taq1A), OPRM1 (A/G), DRD3 (C/T), and MAOA (4R) genes. These polymorphisms have been linked to hypodopaminergia. The patient was subsequently placed on research ID-KB220ZPBMPOLY (POLYGEN®), and albeit the possibility of bias, based upon self and parental assessment, a marked rapid improvement in psychiatric symptoms was observed. In the second phase of treatment (102 days utilizing KB220), the patient received standard antibody testing, which was positive for Lyme. Antibacterial therapy started immediately, and KB220z was discontinued to provide a wash-out period. A monotonic trend analysis was performed on each outcome measure, and a consistently decreasing trend was observed utilizing antibacterial therapy. Our recommendation, albeit only one case, is to utilize and further research a combined therapeutic approach, involving precision-guided DNA testing and pro-dopamine regulation along with antibacterial therapy, as well as glutathione to address offensive enhanced展开更多
A novel X-shaped variable stiffness vibration isolator(X-VSVI)is proposed.The Runge-Kutta method,harmonic balance method,and wavelet transform spectra are introduced to evaluate the performance of the X-VSVI under var...A novel X-shaped variable stiffness vibration isolator(X-VSVI)is proposed.The Runge-Kutta method,harmonic balance method,and wavelet transform spectra are introduced to evaluate the performance of the X-VSVI under various excitations.The layer number,the installation angle of the X-shaped structure,the stiffness,and the active control parameters are systematically analyzed.In addition,a prototype of the X-VSVI is manufactured,and vibration tests are carried out.The results show that the proposed X-VSVI has a superior adaptability to that of a traditional X-shaped mechanism,and shows excellent vibration isolation performance in response to different amplitudes and forms of excitations.Moreover,the vibration isolation efficiency of the device can be improved by appropriate adjustment of parameters.展开更多
To develop a knowledge-aware recommender system,a key issue is how to obtain rich and structured knowledge base(KB)information for recommender system(RS)items.Existing data sets or methods either use side information ...To develop a knowledge-aware recommender system,a key issue is how to obtain rich and structured knowledge base(KB)information for recommender system(RS)items.Existing data sets or methods either use side information from original RSs(containing very few kinds of useful information)or utilize a private KB.In this paper,we present KB4Rec v1.0,a data set linking KB information for RSs.It has linked three widely used RS data sets with two popular KBs,namely Freebase and YAGO.Based on our linked data set,we first preform qualitative analysis experiments,and then we discuss the effect of two important factors(i.e.,popularity and recency)on whether a RS item can be linked to a KB entity.Finally,we compare several knowledge-aware recommendation algorithms on our linked data set.展开更多
BACKGROUND Improved adenoma detection rate(ADR)has been demonstrated with artificial intelligence(AI)-assisted colonoscopy.However,data on the real-world appli-cation of AI and its effect on colorectal cancer(CRC)scre...BACKGROUND Improved adenoma detection rate(ADR)has been demonstrated with artificial intelligence(AI)-assisted colonoscopy.However,data on the real-world appli-cation of AI and its effect on colorectal cancer(CRC)screening outcomes is limited.AIM To analyze the long-term impact of AI on a diverse at-risk patient population undergoing diagnostic colonoscopy for positive CRC screening tests or sympt-oms.METHODS AI software(GI Genius,Medtronic)was implemented into the standard proced-ure protocol in November 2022.Data was collected on patient demographics,procedure indication,polyp size,location,and pathology.CRC screening outcomes were evaluated before and at different intervals after AI introduction with one year of follow-up.RESULTS We evaluated 1008 colonoscopies(278 pre-AI,255 early post-AI,285 established post-AI,and 190 late post-AI).The ADR was 38.1%pre-AI,42.0%early post-AI(P=0.77),40.0%established post-AI(P=0.44),and 39.5%late post-AI(P=0.77).There were no significant differences in polyp detection rate(PDR,baseline 59.7%),advanced ADR(baseline 16.2%),and non-neoplastic PDR(baseline 30.0%)before and after AI introduction.CONCLUSION In patients with an increased pre-test probability of having an abnormal colonoscopy,the current generation of AI did not yield enhanced CRC screening metrics over high-quality colonoscopy.Although the potential of AI in colonoscopy is undisputed,current AI technology may not universally elevate screening metrics across all situations and patient populations.Future studies that analyze different AI systems across various patient populations are needed to determine the most effective role of AI in optimizing CRC screening in clinical practice.展开更多
The purpose of the present study was to analyze the clinical phenotypes of a girl with oculo-facio-cardio-dental(OFCD)syndrome and to identify the potential pathogenic mutation responsible for her disease. The patient...The purpose of the present study was to analyze the clinical phenotypes of a girl with oculo-facio-cardio-dental(OFCD)syndrome and to identify the potential pathogenic mutation responsible for her disease. The patient underwent detailed clinical examinations and phenotype data were collected over a follow-up period of 9 years. Mutation analysis of the candidate gene BCOR was performed with polymerase chain reaction and Sanger sequencing. BCOR of 60 unrelated normal individuals were also sequenced as a control group. Clinical phenotyping and follow-up study results indicate that this patient had multiple system anomalies including ocular, facial, cardiac, dental, and limb malformations. In addition, papilloma of the choroid plexus was identified, which represents the first report of this phenotype in an OFCD patient. A novel deletion mutation, c.1296 delT in exon4 of the BCOR gene, was identified in this patient and was not found in her parents or in 60 normal unrelated individuals. This deletion was a frameshift mutation and is proposed to encode a premature stop codon, thus producing a truncated protein. Our patient fitted the diagnostic criteria for OFCD syndrome and we report the first papilloma of the choroid plexus in an OFCD patient, expanding the recognized phenotypic spectrum of this disease. Meanwhile, we identified a novel deletion mutation that may cause OFCD syndrome.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
Humans are exposed to radiofrequency electromagnetic fields （RFEMF） from various sources （e.g., mobile and cordless phones, base stations, TV and radio transmitters, wifi adapters）. So far, there is no evidence th...Humans are exposed to radiofrequency electromagnetic fields （RFEMF） from various sources （e.g., mobile and cordless phones, base stations, TV and radio transmitters, wifi adapters）. So far, there is no evidence that would indicate that RFEMF exposure is causing adverse health effects with respect to cancer, sleep disorder, headache, etc. Some results of in vitro and in vivo experiments revealed negative effects on male fertility. When looking at those studies in detail, many problems are identified with respect to correct dosimetry and proper experimental design. This field of research is notoriously difficult for various reasons, and experiments should be planned and performed with experts from the respective areas.展开更多
Arctic Ocean gateway fluxes play a crucial role in linking the Arctic with the global ocean and affecting climate and marine ecosystems.We reviewed past studies on Arctic-Subarctic ocean linkages and examined their ch...Arctic Ocean gateway fluxes play a crucial role in linking the Arctic with the global ocean and affecting climate and marine ecosystems.We reviewed past studies on Arctic-Subarctic ocean linkages and examined their changes and driving mechanisms.Our review highlights that radical changes occurred in the inflows and outflows of the Arctic Ocean during the 2010s.Specifically,the Pacific inflow temperature in the Bering Strait and Atlantic inflow temperature in the Fram Strait hit record highs,while the Pacific inflow salinity in the Bering Strait and Arctic outflow salinity in the Davis and Fram straits hit record lows.Both the ocean heat convergence from lower latitudes to the Arctic and the hydrological cycle connecting the Arctic with Subarctic seas were stronger in 2000-2020 than in 1980-2000.CMIP6 models project a continuing increase in poleward ocean heat convergence in the 21st century,mainly due to warming of inflow waters.They also predict an increase in freshwater input to the Arctic Ocean,with the largest increase in freshwater export expected to occur in the Fram Strait due to both increased ocean volume export and decreased salinity.Fram Strait sea ice volume export hit a record low in the 2010s and is projected to continue to decrease along with Arctic sea ice decline.We quantitatively attribute the variability of the volume,heat,and freshwater transports in the Arctic gateways to forcing within and outside the Arctic based on dedicated numerical simulations and emphasize the importance of both origins in driving the variability.展开更多
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The development of open-pit mines can adversely affect and even damage existing access tunnels. To ensure the safety and serviceability of them, it is essential to know potential adverse effects of the mining sequence on existing tunnels such as displacements of the lining and additional loads on the lining. In this paper, three-dimensional numerical parametric study is performed to explore this complex interaction. This study investigates the effects of different parameters that may affect the tunnel response. These parameters are： excavation sequence method, horizontal/vertical stress ratio, slope angle, and tunnel diameter. This study shows that the mining sequence affects the stability of the tunnels. The open-pit mining activities lead to both higher axial forces in rock bolts and normal forces and bending moments in the lining. The results of the analysis also demonstrate that the mining sequence causes tunnel heave and significant tensile forces in the lining. Based on the study in this paper a better understanding of the interaction between oDen-oit minin~ seouence and tunnels will he ohtained
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.
文摘Background:Early neurologic deterioration(END)may occur in patients with anterior circulation ischemic stroke(ACIS)after receiving endovascular treatment(EVT).Hemodynamic insufficiency,re-occlusion,and post-re-canalization hyper-perfusion are likely to play a critical role in END.We hypothesized that hemodynamic changes can predict END in patients with ACIS postsuccessful EVT using trans-cranial Doppler(TCD).Methods:We utilized a prospectively maintained database of ACIS patients treated with EVT between September 2016 and June 2018 in the Xuanwu Hospital,Capital Medical University.TCD parameters including peak systolic velocity(PSV),bilateral mean flow velocity(MFV),and pulse index(PI)were determined via the middle cerebral arteries within 72 h post-EVT.A logistic regression model was applied to detect independent predictors for END.Results:Totally,112 EVT patients were included in this study and 80/112 patients experienced successful re-canalization with<50%residual stenosis,while 17/80(21.3%)patients suffered END,for which vasogenic cerebral edema(11/17)was considered as a leading role and followed by symptomatic intra-cranial hemorrhage(4/17)and ischemia progression(2/17).For the 80 patients,the PSV(median:127 cm/s vs.116 cm/s,P=0.039),the ratio of ipsilateral-MFV/contra-lateral-MFV(iMFV/cMFV)(median:1.29 vs.1.02,P=0.036)and iMFV/mean blood pressure(MBP)(median:0.97 vs.0.79,P=0.008)in END patients were higher than those of non-END.Using the receiver-operating characteristic curve to obtain cut-off values for PSV,PI,iMFV/cMFV,and iMFV/MBP for END,we found that PI≥0.85(odds ratio:11.03,95%confidence interval:1.92–63.46,P=0.007)and iMFV/MBP≥0.84(odds ratio:9.20,95%confidence interval:2.07–40.84,P=0.004)were independent predictors of END in a multivariate logistic regression model,with a sensitivity of 82.4%and 76.5%and a specificity of 42.9%and 66.7%,respectively,and had the positive predictive values of 29.0%and 38.2%,and negative predictive values of 90.0%and 91.3%,with an area under the receiveroperat
文摘In neurons,mitochondria are enriched to provide energy and calcium buffering required for synaptic transmission.Additionally,mitochondria localize to the synapse,where they are critical for the mobilization of reserve pool vesicles and for neurotransmitter release.Previously,functional defects in mitochondria were considered to be downstream effects of neurodegenerative diseases.However,more recent findings suggest mitochondria may serve as key mediators in the onset and progression of some types of neurodegeneration.In this review,we explore the possible roles of altered mitochondrial function and dynamics in the pathogenesis of neurodegenerative disorders,with a particular focus on Alzheimer’s disease(AD)and Parkinson’s disease(PD),which have highlighted the important role of mitochondria in neurodegeneration.While inheritable diseases like Charcot-Marie-Tooth disease type 2A are concretely linked to gene mutations affecting mitochondrial function,the cause of mitochondrial dysfunction in primarily sporadic diseases such as AD and PD is less clear.Neuronal death in PD is associated with defects in mitochondrial function and dynamics arising from mutations in proteins affecting these processes,including α-synuclein,DJ-1,LRRK2,Parkin and Pink1.In the case of AD,however,the connection between mitochondria and the onset of neurodegeneration has been less clear.Recent findings,however,have implicated altered function of ER-mitochondria contact sites and amyloid beta-and/or tau-induced defects in mitochondrial function and dynamics in the pathogenesis of AD,suggesting that mitochondrial defects may act as key mediators in the pathogenesis of AD as well.With recent findings at hand,it may be postulated that defects in mitochondrial processes comprise key events in the onset of neurodegeneration.
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.
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the European Community under grant agreement 283610 EarthServer.
文摘Big Data Analytics is an emerging field since massive storage and computing capabilities have been made available by advanced e-infrastructures.Earth and Environmental sciences are likely to benefit from Big Data Analytics techniques supporting the processing of the large number of Earth Observation datasets currently acquired and generated through observations and simulations.However,Earth Science data and applications present specificities in terms of relevance of the geospatial information,wide heterogeneity of data models and formats,and complexity of processing.Therefore,Big Earth Data Analytics requires specifically tailored techniques and tools.The EarthServer Big Earth Data Analytics engine offers a solution for coverage-type datasets,built around a high performance array database technology,and the adoption and enhancement of standards for service interaction(OGC WCS and WCPS).The EarthServer solution,led by the collection of requirements from scientific communities and international initiatives,provides a holistic approach that ranges from query languages and scalability up to mobile access and visualization.The result is demonstrated and validated through the development of lighthouse applications in the Marine,Geology,Atmospheric,Planetary and Cryospheric science domains.
文摘Pediatric autoimmune neuropsychiatric disorders associated with or without streptococcal and other bacterial infections (PANDAS/CANS) are emerging as a featured pediatric disorder. Although there is some controversy regarding treatment approaches, especially related to the behavioral sequelae, we have hypothesized in other published work that it is characterized by the rapid onset of Reward Deficiency Syndrome (RDS) in children. We propose utilizing a multi-systems biological approach involving the coupling of genetic addiction risk testing and pro-dopamine regulation (KB220/POLYGEN®) to help induce “dopamine homeostasis” in patients with PANDAS, especially those with known DNA-induced hypodopaminergia. This case study examines a 12-year-old Caucasian male with no prior psychiatric issues who presented with a sudden onset of severe anxiety, depression, emotional liability, and suicidal ideation. The patient underwent genotyping and the genetic addiction risk score (GARS) testing, which revealed risk polymorphisms in the dopamine D2 (-DRD2/ANKK (Taq1A), OPRM1 (A/G), DRD3 (C/T), and MAOA (4R) genes. These polymorphisms have been linked to hypodopaminergia. The patient was subsequently placed on research ID-KB220ZPBMPOLY (POLYGEN®), and albeit the possibility of bias, based upon self and parental assessment, a marked rapid improvement in psychiatric symptoms was observed. In the second phase of treatment (102 days utilizing KB220), the patient received standard antibody testing, which was positive for Lyme. Antibacterial therapy started immediately, and KB220z was discontinued to provide a wash-out period. A monotonic trend analysis was performed on each outcome measure, and a consistently decreasing trend was observed utilizing antibacterial therapy. Our recommendation, albeit only one case, is to utilize and further research a combined therapeutic approach, involving precision-guided DNA testing and pro-dopamine regulation along with antibacterial therapy, as well as glutathione to address offensive enhanced
基金Project supported by the National Natural Science Foundation of China(Nos.12022213,12002329,U23A2066,12272240,and 12002217)。
文摘A novel X-shaped variable stiffness vibration isolator(X-VSVI)is proposed.The Runge-Kutta method,harmonic balance method,and wavelet transform spectra are introduced to evaluate the performance of the X-VSVI under various excitations.The layer number,the installation angle of the X-shaped structure,the stiffness,and the active control parameters are systematically analyzed.In addition,a prototype of the X-VSVI is manufactured,and vibration tests are carried out.The results show that the proposed X-VSVI has a superior adaptability to that of a traditional X-shaped mechanism,and shows excellent vibration isolation performance in response to different amplitudes and forms of excitations.Moreover,the vibration isolation efficiency of the device can be improved by appropriate adjustment of parameters.
基金The work was partially supported by National Natural Science Foundation of China under the grant numbers 61872369,61832017 and 61502502.
文摘To develop a knowledge-aware recommender system,a key issue is how to obtain rich and structured knowledge base(KB)information for recommender system(RS)items.Existing data sets or methods either use side information from original RSs(containing very few kinds of useful information)or utilize a private KB.In this paper,we present KB4Rec v1.0,a data set linking KB information for RSs.It has linked three widely used RS data sets with two popular KBs,namely Freebase and YAGO.Based on our linked data set,we first preform qualitative analysis experiments,and then we discuss the effect of two important factors(i.e.,popularity and recency)on whether a RS item can be linked to a KB entity.Finally,we compare several knowledge-aware recommendation algorithms on our linked data set.
基金This study was approved by the Institutional Review Board(IRB number:18CR-31902-01)of the Lundquist Institute at Harbor-UCLA.
文摘BACKGROUND Improved adenoma detection rate(ADR)has been demonstrated with artificial intelligence(AI)-assisted colonoscopy.However,data on the real-world appli-cation of AI and its effect on colorectal cancer(CRC)screening outcomes is limited.AIM To analyze the long-term impact of AI on a diverse at-risk patient population undergoing diagnostic colonoscopy for positive CRC screening tests or sympt-oms.METHODS AI software(GI Genius,Medtronic)was implemented into the standard proced-ure protocol in November 2022.Data was collected on patient demographics,procedure indication,polyp size,location,and pathology.CRC screening outcomes were evaluated before and at different intervals after AI introduction with one year of follow-up.RESULTS We evaluated 1008 colonoscopies(278 pre-AI,255 early post-AI,285 established post-AI,and 190 late post-AI).The ADR was 38.1%pre-AI,42.0%early post-AI(P=0.77),40.0%established post-AI(P=0.44),and 39.5%late post-AI(P=0.77).There were no significant differences in polyp detection rate(PDR,baseline 59.7%),advanced ADR(baseline 16.2%),and non-neoplastic PDR(baseline 30.0%)before and after AI introduction.CONCLUSION In patients with an increased pre-test probability of having an abnormal colonoscopy,the current generation of AI did not yield enhanced CRC screening metrics over high-quality colonoscopy.Although the potential of AI in colonoscopy is undisputed,current AI technology may not universally elevate screening metrics across all situations and patient populations.Future studies that analyze different AI systems across various patient populations are needed to determine the most effective role of AI in optimizing CRC screening in clinical practice.
基金supported by Beijing New Star of Science and Technology (H020821380190, Z131102000413025)Fund of Work Committee for Women and Children of China State Department (2014108)+1 种基金National Natural Science Foundation (30471861)Beijing Institute of Ophthalmology Leading Programme (201515)
文摘The purpose of the present study was to analyze the clinical phenotypes of a girl with oculo-facio-cardio-dental(OFCD)syndrome and to identify the potential pathogenic mutation responsible for her disease. The patient underwent detailed clinical examinations and phenotype data were collected over a follow-up period of 9 years. Mutation analysis of the candidate gene BCOR was performed with polymerase chain reaction and Sanger sequencing. BCOR of 60 unrelated normal individuals were also sequenced as a control group. Clinical phenotyping and follow-up study results indicate that this patient had multiple system anomalies including ocular, facial, cardiac, dental, and limb malformations. In addition, papilloma of the choroid plexus was identified, which represents the first report of this phenotype in an OFCD patient. A novel deletion mutation, c.1296 delT in exon4 of the BCOR gene, was identified in this patient and was not found in her parents or in 60 normal unrelated individuals. This deletion was a frameshift mutation and is proposed to encode a premature stop codon, thus producing a truncated protein. Our patient fitted the diagnostic criteria for OFCD syndrome and we report the first papilloma of the choroid plexus in an OFCD patient, expanding the recognized phenotypic spectrum of this disease. Meanwhile, we identified a novel deletion mutation that may cause OFCD syndrome.
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Humans are exposed to radiofrequency electromagnetic fields （RFEMF） from various sources （e.g., mobile and cordless phones, base stations, TV and radio transmitters, wifi adapters）. So far, there is no evidence that would indicate that RFEMF exposure is causing adverse health effects with respect to cancer, sleep disorder, headache, etc. Some results of in vitro and in vivo experiments revealed negative effects on male fertility. When looking at those studies in detail, many problems are identified with respect to correct dosimetry and proper experimental design. This field of research is notoriously difficult for various reasons, and experiments should be planned and performed with experts from the respective areas.
基金Q.W.was supported by the German Helmholtz Climate Initiative REKLIM(Regional Climate Change and Humans)and the German Federal Ministry for Education and Research(BMBF)within the EPICA project(grant no.03F0889A)Q.S.was supported by the Taishan Scholars Program(no.tsqn202211264)+7 种基金the Shandong Provincial Natural Science Foundation(ZR2022JQ17).S.W.was supported by the National Natural Science Foundation of China(grant no.42005044).G.S.was supported by the German Research Foundation(DFG,Deutsche Forschungsgemeinschaft)through the Transregional Collaborative Research Center TRR 172“(AC)3-Arctic Amplification”(grant no.268020496)the European Union’s Horizon 2020 research and innovation programme via project CRiceS(grant no.101003826).The Bering Strait work is supported by NSF-OPP Arctic Observing Network grants 1758565 and 2153942.P.G.M.was supported by the Natural Sciences and Engineering Research Council of Canada via research grant rgpin227438-09.The Fram Strait Arctic Outflow Observatory is supported by the Norwegian Polar Institute and by the Norwegian Research Council through the FRIPRO program(FreshArc,grant 286971).C.M.L.and the Davis Strait observing system are supported by the U.S.National Science Foundation Arctic Observing Network under grant 1902595.
文摘Arctic Ocean gateway fluxes play a crucial role in linking the Arctic with the global ocean and affecting climate and marine ecosystems.We reviewed past studies on Arctic-Subarctic ocean linkages and examined their changes and driving mechanisms.Our review highlights that radical changes occurred in the inflows and outflows of the Arctic Ocean during the 2010s.Specifically,the Pacific inflow temperature in the Bering Strait and Atlantic inflow temperature in the Fram Strait hit record highs,while the Pacific inflow salinity in the Bering Strait and Arctic outflow salinity in the Davis and Fram straits hit record lows.Both the ocean heat convergence from lower latitudes to the Arctic and the hydrological cycle connecting the Arctic with Subarctic seas were stronger in 2000-2020 than in 1980-2000.CMIP6 models project a continuing increase in poleward ocean heat convergence in the 21st century,mainly due to warming of inflow waters.They also predict an increase in freshwater input to the Arctic Ocean,with the largest increase in freshwater export expected to occur in the Fram Strait due to both increased ocean volume export and decreased salinity.Fram Strait sea ice volume export hit a record low in the 2010s and is projected to continue to decrease along with Arctic sea ice decline.We quantitatively attribute the variability of the volume,heat,and freshwater transports in the Arctic gateways to forcing within and outside the Arctic based on dedicated numerical simulations and emphasize the importance of both origins in driving the variability.
