Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects...Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).展开更多
Background: The successful treatment of military combat casualties with penetrating injuries is significantly dependent on the time needed to get the patient to an adequate treatment facility. Profound hypothermia ind...Background: The successful treatment of military combat casualties with penetrating injuries is significantly dependent on the time needed to get the patient to an adequate treatment facility. Profound hypothermia induced suspended animation for delayed resuscitation(SADR) is a novel approach for inducing cardiac arrest and buying additional time for such injuries. However, the time used to safely administer circulatory arrest(CA) is controversial. The goal of this study was to evaluate the safety of hypothermia-induced SADR over 90 and 120 min time intervals.Methods: Sixteen male BAMA minipigs were randomized into two groups: CA90 group(90 min, n =8) and CA120 group(120 min, n =8). Cannulation of the right common carotid arteries and internal jugular veins was performed to establish cardiopulmonary bypass for each animal. Through the perfusion of cold organ preservation solution(OPS), cardioplegia and profound hypothermia(15℃) were induced. After CA, cardiopumonary bypass(CPB) was restarted, and the animals were gradually re-warmed and resuscitated. The animals were assisted with ventilators until spontaneous breathing was achieved. The index of hemodynamic perioperative serum chemistry values [alanine transaminase(ALT), aspartate aminotransferase(AST), creatinine(CR), lactic dehydrogenase(LDH) and troponin T(TnT)] and survival were observed from pre-operation to 7 days post-operation.Results: Fifteen animals were enrolled in the experiment, while 1 animal in CA120 group died from surgical error. All 8 animals in CA90 group recovered, with only 1 animal displaying mild disability. However, in CA120 group, only 2 animals survived with severe disability, and the other 5 animals died after 2 days post-operation. In CA90 group, the perioperative serum chemistry values increased at 1 day post-operation(ALT 84.43±18.65 U/L; AST 88.99±23.19 U/L; Cr 87.90±24.49μmol/L; LDH 1894.13±322.26 U/L; TnT 0.849±0.135 ng/ml) but decreased to normal or almost normal levels at 7 days post-operation(ALT 52.48±9.04 U/L; AST 75.23±21.46 U/L; Cr 82.69±18.41μmol/L; LDH 944.67±834.32 U/L; TnT 0.336±0.076 ng/ml).Conclusion: Profound hypothermia-induced SADR is an effective method for inducing cardiac arrest. Our results indicate that inducing CA for 90 min(at 15℃) is safer than doing so for 120 min. Our results indicate that 120 min of CA at 15℃ is dangerous and can result in high mortality and severe neurological complications. Further experimentation is needed to determine whether 120 min of CA at temperatures lower than 15℃ can lead to safe recovery.展开更多
AIM: To assess the safety of therapeutic hypothermia(TH) concerning arrhythmias we analyzed serial electrocardiograms(ECG) during TH.METHODS: All patients recovered from a cardiac arrest with Glasgow < 9 at admissi...AIM: To assess the safety of therapeutic hypothermia(TH) concerning arrhythmias we analyzed serial electrocardiograms(ECG) during TH.METHODS: All patients recovered from a cardiac arrest with Glasgow < 9 at admission were treated with induced mild TH to 32-34℃. TH was obtained with cool fluid infusion or a specific intravascular device. Twelvelead ECG before,during,and after TH,as well as ECG telemetry data was recorded in all patients. From a total of 54 patients admitted with cardiac arrest during the study period,47 patients had the 3 ECG and telemetry data available. ECG analysis was blinded and performed with manual caliper by two independent cardiologists from blinded copies of original ECG,recorded at 25 mm/s and 10 mm/m V. Coronary care unit staff analyzed ECG telemetry for rhythm disturbances. Variables measured in ECG were rhythm,RR,PR,QT and corrected QT(QTc by Bazett formula,measured in lead v2) intervals,QRS duration,presence of Osborn's J wave and U wave,as well as ST segment displacement and T wave amplitude in leads Ⅱ,v2 and v5.RESULTS: Heart rate went down an average of 19 bpm during hypothermia and increased again 16 bpm with rewarming(P < 0.0005,both). There was a nonsignificant prolongation of the PR interval during TH and a significant decrease with rewarming(P = 0.041). QRS duration significantly prolonged(P = 0.041) with TH and shortened back(P < 0.005) with rewarming. QTc interval presented a mean prolongation of 58 ms(P < 0.005) during TH and a significant shortening with rewarming of 22.2 ms(P = 0.017). Osborn or J wave was found in 21.3% of the patients. New arrhythmias occurred in 38.3% of the patients. Most frequent arrhythmia was non-sustained ventricular tachycardia(19.1%),followed by severe bradycardia or paced rhythm(10.6%),accelerated nodal rhythm(8.5%) and atrial fibrillation(6.4%). No life threatening arrhythmias(sustained ventricular tachycardia,polymorphic ventricular tachycardia or ventricular fibrillation) occurred during TH. CONCLUSION: A 38.3% of patients had cardiac arrhythmias during TH but without life-threatening arrhythmias. A concern may rise when inducing TH to patients with long QT syndrome.展开更多
Background:Ondansetron and hypothermia are both known to induce bradycardia or QT interval prolongation,thus placing affected patients at risk of cardiac arrest.Case Report:Herein,we report the case of a 97-year-old w...Background:Ondansetron and hypothermia are both known to induce bradycardia or QT interval prolongation,thus placing affected patients at risk of cardiac arrest.Case Report:Herein,we report the case of a 97-year-old woman who initially presented with confusion and hypothermia,and experienced severe bradycardia and asystolic cardiac arrest after a 4 mg intravenous ondansetron bolus injection.Conclusion:Ondansetron is associated with bradycardia and QTc prolongation,both of which might be further exacerbated by hypothermia.Clinicians should be aware that administering ondansetron in patients with hypothermia might further increase the risk of adverse cardiac events and eventual cardiac arrest.展开更多
This editorial addresses the growing concern of herb-induced liver injury(HILI),focusing on a unique case of Skullcap-induced HILI report.This editorial underscore the significant mortality rate linked to Skullcap-ind...This editorial addresses the growing concern of herb-induced liver injury(HILI),focusing on a unique case of Skullcap-induced HILI report.This editorial underscore the significant mortality rate linked to Skullcap-induced HILI,emphasizing the importance of vigilant monitoring and intervention.As herbal supplement usage rises,collaboration among clinicians and researchers is crucial to comprehend and address the complexities of HILI,particularly those involving Skullcap.展开更多
Objective To investigate the role of moderate h.vpothennia in the lung inflammation of rat acute lung injury induced by lipopolysaccharide(LPS). Methods A rat model of acute lung injury (ALl) was established by in-tin...Objective To investigate the role of moderate h.vpothennia in the lung inflammation of rat acute lung injury induced by lipopolysaccharide(LPS). Methods A rat model of acute lung injury (ALl) was established by in-tin-tracheal instillation of lipopolysaccharide ( 1.5 mg/kg, 0.5 ml) at 16 h after LPS ( 1.0 mg/kg) intraperitoneal adrninis-tmtion. Thirty-four male Sprague Dawley rats were randomly divided into four groups: control group, receiving saline only;LPS group, receiving LPS; hypothennia group, treated with hypothennia without LPS; LPS + hypothennia group, treated with LPS and cooled to 32.5℃-33.0℃ as PaO2/FiO2. was below 300 mmHg. Hemodynamics and blood gases were record-ed every hour throughout the study. Rats were killed 4 h after ALl, and lung lavage was performed to measure the tumor ne-crosis factor α(TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) concentrations in bronchoalveolar lavage fluid (BALF) by using enzyme-linked immunosorbent assay (ELISA). Results PaO2/FiO2 was significantly decreased and PaCO2 was increased in the LPS group as compared to their baseline values( P<0.01). Treatment with hypothermia inhib-ited the increase in PaCO2( P<0.05) but had no effect on PaO2/FiO2 in the presence of LPS. The administration of LPS significantly increased the concentrations of TNF-α, IL-6 and IL-10 in BALF as compared to the control experiment( P<0.05, P<0.01 ). Moderate hypothermia reduced the expressions of TNF-α and IL-6 ( P<0.01 ) but had no effect on the production of IL-10 ( P>0.05). Conclusion Moderate hypothermia significantly inhibits proinflammatory cytokine ex-pressions in lipopolysaccharide-induced acute lung injury.展开更多
Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate recovery.Only a few studies have attempted to use transplanted cells a...Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate recovery.Only a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury microenvironment.Here,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord injury.Induced neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury model.Basso,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion core.Examination of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the microenvironment.Altogether,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion site.Graft-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.展开更多
The study presents a comprehensive coupled thermo-bio-chemo-hydraulic(T-BCH)modeling framework for stabilizing soils using microbially induced calcite precipitation(MICP).The numerical model considers relevant multiph...The study presents a comprehensive coupled thermo-bio-chemo-hydraulic(T-BCH)modeling framework for stabilizing soils using microbially induced calcite precipitation(MICP).The numerical model considers relevant multiphysics involved in MICP,such as bacterial ureolytic activities,biochemical reactions,multiphase and multicomponent transport,and alteration of the porosity and permeability.The model incorporates multiphysical coupling effects through well-established constitutive relations that connect parameters and variables from different physical fields.It was implemented in the open-source finite element code OpenGeoSys(OGS),and a semi-staggered solution strategy was designed to solve the couplings,allowing for flexible model settings.Therefore,the developed model can be easily adapted to simulate MICP applications in different scenarios.The numerical model was employed to analyze the effect of various factors,including temperature,injection strategies,and application scales.Besides,a TBCH modeling study was conducted on the laboratory-scale domain to analyze the effects of temperature on urease activity and precipitated calcium carbonate.To understand the scale dependency of MICP treatment,a large-scale heterogeneous domain was subjected to variable biochemical injection strategies.The simulations conducted at the field-scale guided the selection of an injection strategy to achieve the desired type and amount of precipitation.Additionally,the study emphasized the potential of numerical models as reliable tools for optimizing future developments in field-scale MICP treatment.The present study demonstrates the potential of this numerical framework for designing and optimizing the MICP applications in laboratory-,prototype-,and field-scale scenarios.展开更多
Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regen...Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regeneration via cell replacement.However,the neural regeneration efficiency of induced neural stem cells remains limited.In this study,we explored differentially expressed genes and long non-coding RNAs to clarify the mechanism underlying the neurogenesis of induced neural stem cells.We found that H19 was the most downregulated neurogenesis-associated lnc RNA in induced neural stem cells compared with induced pluripotent stem cells.Additionally,we demonstrated that H19 levels in induced neural stem cells were markedly lower than those in induced pluripotent stem cells and were substantially higher than those in induced neural stem cell-derived neurons.We predicted the target genes of H19 and discovered that H19 directly interacts with mi R-325-3p,which directly interacts with Ctbp2 in induced pluripotent stem cells and induced neural stem cells.Silencing H19 or Ctbp2 impaired induced neural stem cell proliferation,and mi R-325-3p suppression restored the effect of H19 inhibition but not the effect of Ctbp2 inhibition.Furthermore,H19 silencing substantially promoted the neural differentiation of induced neural stem cells and did not induce apoptosis of induced neural stem cells.Notably,silencing H19 in induced neural stem cell grafts markedly accelerated the neurological recovery of closed head injury mice.Our results reveal that H19 regulates the neurogenesis of induced neural stem cells.H19 inhibition may promote the neural differentiation of induced neural stem cells,which is closely associated with neurological recovery following closed head injury.展开更多
Induced abortion signifies that pregnancy has been tempered with. Abortion is the removal of an embryo or fetus weighing less than 500 grams from its mother. It can either be spontaneous (unprompted) or induced. Abort...Induced abortion signifies that pregnancy has been tempered with. Abortion is the removal of an embryo or fetus weighing less than 500 grams from its mother. It can either be spontaneous (unprompted) or induced. Abortion remains one of the leading causes of maternal deaths in developing countries with induced abortion being the key cause. In 2014 from January to August, 9 abortion related deaths occurred in Botswana. There are several reasons female students in tertiary institutions resort to seeking induced abortion which include the socio-demographics like age and socio-economic factors like financial instability. Parental fears, unintended pregnancy and pressure from the partner also force females to terminate pregnancy. Induced abortion has claimed many women’s lives especially in developing countries with very restrictive abortion laws like Botswana as women do not access safe abortion care services. The study intends to establish the determinants of induced abortion among female students in selected tertiary learning institutions in Gaborone City, Botswana. It concentrated primarily on determining the prevalence of induced abortion. This was a descriptive cross-sectional study using both quantitative and qualitative data collection techniques. Systematic random sampling technique was used to come up with 278 participants. Prior to commencement of data collection, all ethical and logistical prerequisites were satisfied. Informed consent was solicited from all the study participants and the purpose of the study was fully explained. A self-administered questionnaire was used to collect data. Microsoft Excel spread sheet was used to code, clean, and enter the data, which was then exported for analysis to the statistical package for social sciences version 24. Frequency distribution tables, percentages graphs, and pie charts were used to illustrate the descriptive information. The study revealed that prevalence of induced abortion among female students in Gaborone City is 7.9%. They even suggested that induced abortion be liberalized. Age was the only socio-demographic factor associated with induced abortion with p = 0.047 using Chi Square test χ<sup>2</sup> = 7.609, df = 3. The study findings concluded that female students resort to induced abortion as a result of pressure from both parents and male partners especially when the pregnancy is unintended. The study recommends that the abortion law in Botswana be made liberal to ease access to safe abortion care services. It also recommends that contraceptive commodities should consistently be available in public health facilities.展开更多
Blasting in surface mines aims to fragment rock masses to a proper size.However,flyrock is an undesirable effect of blasting that can result in human injuries.In this study,support vector regression(SVR)is combined wi...Blasting in surface mines aims to fragment rock masses to a proper size.However,flyrock is an undesirable effect of blasting that can result in human injuries.In this study,support vector regression(SVR)is combined with four algorithms:gravitational search algorithm(GSA),biogeography-based optimization(BBO),ant colony optimization(ACO),and whale optimization algorithm(WOA)for predicting flyrock in two surface mines in Iran.Additionally,three other methods,including artificial neural network(ANN),kernel extreme learning machine(KELM),and general regression neural network(GRNN),are employed,and their performances are compared to those of four hybrid SVR models.After modeling,the measured and predicted flyrock values are validated with some performance indices,such as root mean squared error(RMSE).The results revealed that the SVR-WOA model has the most optimal accuracy,with an RMSE of 7.218,while the RMSEs of the KELM,GRNN,SVR-GSA,ANN,SVR-BBO,and SVR-ACO models are 10.668,10.867,15.305,15.661,16.239,and 18.228,respectively.Therefore,combining WOA and SVR can be a valuable tool for accurately predicting flyrock distance in surface mines.展开更多
Drug-induced liver injury(DILI)is a major problem in the United States,commonly leading to hospital admission.Diagnosing DILI is difficult as it is a diagnosis of exclusion requiring a temporal relationship between dr...Drug-induced liver injury(DILI)is a major problem in the United States,commonly leading to hospital admission.Diagnosing DILI is difficult as it is a diagnosis of exclusion requiring a temporal relationship between drug exposure and liver injury and a thorough work up for other causes.In addition,DILI has a very variable clinical and histologic presentation that can mimic many different etiologies of liver disease.Objective scoring systems can assess the probability that a drug caused the liver injury but liver biopsy findings are not part of the criteria used in these systems.This review will address some of the recent updates to the scoring systems and the role of liver biopsy in the diagnosis of DILI.展开更多
Boulder spacing in mountain rivers and near-wake flow zones within the boulder array is very useful for fish habitat and growth of aquatic organisms.The present study aims to investigate how the boulder array and spac...Boulder spacing in mountain rivers and near-wake flow zones within the boulder array is very useful for fish habitat and growth of aquatic organisms.The present study aims to investigate how the boulder array and spacing influence the near-bed flow structures in a gravel-bed stream.Boulders are staggered over a gravel-bed stream with three different inter-boulder spacing namely(a)large(b)medium and(c)small spacing.An acoustic Doppler velocimeter was used for flow measurements in a rectangular channel and the results were compared with those acquired from numerical simulation.The time-averaged velocity profiles at the near-wake flow zones of boulders experience maximum flow retardation which is an outcome of the boulder-induced form roughness.The ratio of velocity differences associated to form and skin roughness and its positive magnitude reveals the dominance of form roughness closest to the boulders.Form roughness computed is 1.75 to 2 times higher than the skin roughness at the near-wake flow region.In particular,the collective immobile boulders placed at different inter-boulder spacings developed high and low bed shear stresses closest to the boulders.The low bed shear stresses characterised by a secondary peak developed at the trough location of the boulders is attributed to the skin shear stress.Further,the spatial averaging of time-averaged flow quantities gives additional impetus to present an improved illustration of fluid shear stresses.The formation of form-induced shear stress is estimated to be 17%to 23%of doubleaveraged Reynolds shear stress and partially compensates for the damping of time-averaged Reynolds shear stress in the interfacial sub-layer.The quadrant analysis of spatial velocity fluctuations depicts that the form-induced shear stresses are dominant in the interfacial sub-layer and have no significance above the gravel-bed surface.展开更多
Evaluating the physical mechanisms that link hydraulic fracturing(HF) operations to induced earthquakes and the anticipated form of the resulting events is significant in informing subsurface fluid injection operation...Evaluating the physical mechanisms that link hydraulic fracturing(HF) operations to induced earthquakes and the anticipated form of the resulting events is significant in informing subsurface fluid injection operations. Current understanding supports the overriding role of the effective stress magnitude in triggering earthquakes, while the impact of change rate of effective stress has not been systematically addressed. In this work, a modified critical stiffness was brought up to investigate the likelihood, impact,and mitigation of induced seismicity during and after hydraulic fracturing by developing a poroelastic model based on rate-and-state fraction law and linear stability analysis. In the new criterion, the change rate of effective stress was considered a key variable to explore the evolution of this criterion and hence the likelihood of instability slip of fault. A coupled fluid flow-deformation model was used to represent the entire hydraulic fracturing process in COMSOL Multiphysics. The possibility of triggering an earthquake throughout the entire hydraulic fracturing process, from fracturing to cessation, was investigated considering different fault locations, orientations, and positions along the fault. The competition between the effects of the magnitude and change rate of effective stress was notable at each fracturing stage. The effective stress magnitude is a significant controlling factor during fracturing events, with the change rate dominating when fracturing is suddenly started or stopped. Instability dominates when the magnitude of the effective stress increases(constant injection at each fracturing stage) and the change rate of effective stress decreases(the injection process is suddenly stopped). Fracturing with a high injection rate, a fault adjacent to the hydraulic fracturing location and the position of the junction between the reservoir and fault are important to reduce the Coulomb failure stress(CFS) and enhance the critical stiffness as the significant disturbance of stresses at these positions in the coupled process. Therefore,notable attention should be given to the injection rate during fracturing, fault position, and position along faults as important considerations to help reduce the potential for induced seismicity. Our model was verified and confirmed using the case of the Longmaxi Formation in the Sichuan Basin, China, in which the reported microseismic data were correlated with high critical stiffness values. This work supplies new thoughts of the seismic risk associated with HF engineering.展开更多
Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells ...Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.展开更多
Midbrain dopaminergic neurons play an important role in the etiology of neurodevelopmental and neurodegenerative diseases.They also represent a potential source of transplanted cells for therapeutic applications.In vi...Midbrain dopaminergic neurons play an important role in the etiology of neurodevelopmental and neurodegenerative diseases.They also represent a potential source of transplanted cells for therapeutic applications.In vitro differentiation of functional midbrain dopaminergic neurons provides an accessible platform to study midbrain neuronal dysfunction and can be used to examine obstacles to dopaminergic neuronal development.Emerging evidence and impressive advances in human induced pluripotent stem cells,with tuned neural induction and differentiation protocols,makes the production of induced pluripotent stem cell-derived dopaminergic neurons feasible.Using SB431542 and dorsomorphin dual inhibitor in an induced pluripotent stem cell-derived neural induction protocol,we obtained multiple subtypes of neurons,including 20%tyrosine hydroxylase-positive dopaminergic neurons.To obtain more dopaminergic neurons,we next added sonic hedgehog(SHH)and fibroblast growth factor 8(FGF8)on day 8 of induction.This increased the proportion of dopaminergic neurons,up to 75%tyrosine hydroxylase-positive neurons,with 15%tyrosine hydroxylase and forkhead box protein A2(FOXA2)co-expressing neurons.We further optimized the induction protocol by applying the small molecule inhibitor,CHIR99021(CHIR).This helped facilitate the generation of midbrain dopaminergic neurons,and we obtained 31-74%midbrain dopaminergic neurons based on tyrosine hydroxylase and FOXA2 staining.Thus,we have established three induction protocols for dopaminergic neurons.Based on tyrosine hydroxylase and FOXA2 immunostaining analysis,the CHIR,SHH,and FGF8 combined protocol produces a much higher proportion of midbrain dopaminergic neurons,which could be an ideal resource for tackling midbrain-related diseases.展开更多
BACKGROUND Human induced pluripotent stem cell(hiPSC)technology is a valuable tool for generating patient-specific stem cells,facilitating disease modeling,and invest-igating disease mechanisms.However,iPSCs carrying ...BACKGROUND Human induced pluripotent stem cell(hiPSC)technology is a valuable tool for generating patient-specific stem cells,facilitating disease modeling,and invest-igating disease mechanisms.However,iPSCs carrying specific mutations may limit their clinical applications due to certain inherent characteristics.AIM To investigate the impact of MERTK mutations on hiPSCs and determine whether hiPSC-derived extracellular vesicles(EVs)influence anomalous cell junction and differentiation potential.METHODS We employed a non-integrating reprogramming technique to generate peripheral blood-derived hiPSCs with and hiPSCs without a MERTK mutation.Chromo-somal karyotype analysis,flow cytometry,and immunofluorescent staining were utilized for hiPSC identification.Transcriptomics and proteomics were employed to elucidate the expression patterns associated with cell junction abnormalities and cellular differentiation potential.Additionally,EVs were isolated from the supernatant,and their RNA and protein cargos were examined to investigate the involvement of hiPSC-derived EVs in stem cell junction and differentiation.RESULTS The generated hiPSCs,both with and without a MERTK mutation,exhibited normal karyotype and expressed pluripotency markers;however,hiPSCs with a MERTK mutation demonstrated anomalous adhesion capability and differentiation potential,as confirmed by transcriptomic and proteomic profiling.Furthermore,hiPSC-derived EVs were involved in various biological processes,including cell junction and differentiation.CONCLUSION HiPSCs with a MERTK mutation displayed altered junction characteristics and aberrant differentiation potential.Furthermore,hiPSC-derived EVs played a regulatory role in various biological processes,including cell junction and differentiation.展开更多
In recent years,the mining depth of steeply inclined coal seams in the Urumqi mining area has gradually increased.Local deformation of mining coal-rock results in frequent rockbursts.This has become a critical issue t...In recent years,the mining depth of steeply inclined coal seams in the Urumqi mining area has gradually increased.Local deformation of mining coal-rock results in frequent rockbursts.This has become a critical issue that affects the safe mining of deep,steeply inclined coal seams.In this work,we adopt a perspective centered on localized deformation in coal-rock mining and systematically combine theoretical analyses and extensive data mining of voluminous microseismic data.We describe a mechanical model for the urgently inclined mining of both the sandwiched rock pillar and the roof,explaining the mechanical response behavior of key disaster-prone zones within the deep working face,affected by the dynamics of deep mining.By exploring the spatial correlation inherent in extensive microseismic data,we delineate the“time-space”response relationship that governs the dynamic failure of coal-rock during the progression of the sharply inclined working face.The results disclose that(1)the distinctive coal-rock occurrence structure characterized by a“sandwiched rock pillar-B6 roof”constitutes the origin of rockburst in the southern mining area of the Wudong Coal Mine,with both elements presenting different degrees of deformation localization with increasing mining depth.(2)As mining depth increases,the bending deformation and energy accumulation within the rock pillar and roof show nonlinear acceleration.The localized deformation of deep,steeply inclined coal-rock engenders the spatial superposition of squeezing and prying effects in both the strike and dip directions,increasing the energy distribution disparity and stress asymmetry of the“sandwiched rock pillar-B3+6 coal seam-B6 roof”configuration.This makes worse the propensity for frequent dynamic disasters in the working face.(3)The developed high-energy distortion zone“inner-outer”control technology effectively reduces high stress concentration and energy distortion in the surrounding rock.After implementation,the average apparent resistivity in the rock pillar and B6 roof substantially increased by 430%and 300%,respectively,thus guaranteeing the safe and efficient development of steeply inclined coal seams.展开更多
The application of mathematical modeling to biological fluids is of utmost importance, as it has diverse applicationsin medicine. The peristaltic mechanism plays a crucial role in understanding numerous biological flo...The application of mathematical modeling to biological fluids is of utmost importance, as it has diverse applicationsin medicine. The peristaltic mechanism plays a crucial role in understanding numerous biological flows. In thispaper, we present a theoretical investigation of the double diffusion convection in the peristaltic transport of aPrandtl nanofluid through an asymmetric tapered channel under the combined action of thermal radiation andan induced magnetic field. The equations for the current flow scenario are developed, incorporating relevantassumptions, and considering the effect of viscous dissipation. The impact of thermal radiation and doublediffusion on public health is of particular interest. For instance, infrared radiation techniques have been used totreat various skin-related diseases and can also be employed as a measure of thermotherapy for some bones toenhance blood circulation, with radiation increasing blood flow by approximately 80%. To solve the governingequations, we employ a numerical method with the aid of symbolic software such as Mathematica and MATLAB.The velocity, magnetic force function, pressure rise, temperature, solute (species) concentration, and nanoparticlevolume fraction profiles are analytically derived and graphically displayed. The results outcomes are compared withthe findings of limiting situations for verification.展开更多
The South China Sea is a hotspot for regional climate research.Over the past 40 years,considerable improvement has been made in the development and utilization of the islands in the South China Sea,leading to a substa...The South China Sea is a hotspot for regional climate research.Over the past 40 years,considerable improvement has been made in the development and utilization of the islands in the South China Sea,leading to a substantial change in the land-use of the islands.However,research on the impact of human development on the local climate of these islands is lacking.This study analyzed the characteristics of local climate changes on the islands in the South China Sea based on data from the Yongxing Island Observation Station and ERA5 re-analysis.Furthermore,the influence of urbanization on the local climate of the South China Sea islands was explored in this study.The findings revealed that the 10-year average temperature in Yongxing Island increased by approximately 1.11℃from 1961 to 2020,and the contribution of island development and urbanization to the local warming rate over 60 years was approximately 36.2%.The linear increasing trend of the annual hot days from 1961–2020 was approximately 14.84 days per decade.The diurnal temperature range exhibited an increasing trend of 0.05℃per decade,whereas the number of cold days decreased by 1.06days per decade.The rapid increase in construction on Yongxing Island from 2005 to 2021 led to a decrease in observed surface wind speed by 0.32 m s^(-1)per decade.Consequently,the number of days with strong winds decreased,whereas the number of days with weak winds increased.Additionally,relative humidity exhibited a rapid decline from 2001 to 2016 and then rebounded.The study also found substantial differences between the ERA5 re-analysis and observation data,particularly in wind speed and relative humidity,indicating that the use of re-analysis data for climate resource assessment and climate change evaluation on island areas may not be feasible.展开更多
基金supported by the Natural Science Foundation of Shandong Province of China,No.ZR2015HM023(to MSW)the Science and Technology Plan Project of Qingdao City of China,No.19-6-1-50-nsh(to MSW)
文摘Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).
基金supported by the Major Project for Equipment Development of PLA in 2013(ASY135001)the National High Technology Research and Development Program of China(2015AA020312)
文摘Background: The successful treatment of military combat casualties with penetrating injuries is significantly dependent on the time needed to get the patient to an adequate treatment facility. Profound hypothermia induced suspended animation for delayed resuscitation(SADR) is a novel approach for inducing cardiac arrest and buying additional time for such injuries. However, the time used to safely administer circulatory arrest(CA) is controversial. The goal of this study was to evaluate the safety of hypothermia-induced SADR over 90 and 120 min time intervals.Methods: Sixteen male BAMA minipigs were randomized into two groups: CA90 group(90 min, n =8) and CA120 group(120 min, n =8). Cannulation of the right common carotid arteries and internal jugular veins was performed to establish cardiopulmonary bypass for each animal. Through the perfusion of cold organ preservation solution(OPS), cardioplegia and profound hypothermia(15℃) were induced. After CA, cardiopumonary bypass(CPB) was restarted, and the animals were gradually re-warmed and resuscitated. The animals were assisted with ventilators until spontaneous breathing was achieved. The index of hemodynamic perioperative serum chemistry values [alanine transaminase(ALT), aspartate aminotransferase(AST), creatinine(CR), lactic dehydrogenase(LDH) and troponin T(TnT)] and survival were observed from pre-operation to 7 days post-operation.Results: Fifteen animals were enrolled in the experiment, while 1 animal in CA120 group died from surgical error. All 8 animals in CA90 group recovered, with only 1 animal displaying mild disability. However, in CA120 group, only 2 animals survived with severe disability, and the other 5 animals died after 2 days post-operation. In CA90 group, the perioperative serum chemistry values increased at 1 day post-operation(ALT 84.43±18.65 U/L; AST 88.99±23.19 U/L; Cr 87.90±24.49μmol/L; LDH 1894.13±322.26 U/L; TnT 0.849±0.135 ng/ml) but decreased to normal or almost normal levels at 7 days post-operation(ALT 52.48±9.04 U/L; AST 75.23±21.46 U/L; Cr 82.69±18.41μmol/L; LDH 944.67±834.32 U/L; TnT 0.336±0.076 ng/ml).Conclusion: Profound hypothermia-induced SADR is an effective method for inducing cardiac arrest. Our results indicate that inducing CA for 90 min(at 15℃) is safer than doing so for 120 min. Our results indicate that 120 min of CA at 15℃ is dangerous and can result in high mortality and severe neurological complications. Further experimentation is needed to determine whether 120 min of CA at temperatures lower than 15℃ can lead to safe recovery.
文摘AIM: To assess the safety of therapeutic hypothermia(TH) concerning arrhythmias we analyzed serial electrocardiograms(ECG) during TH.METHODS: All patients recovered from a cardiac arrest with Glasgow < 9 at admission were treated with induced mild TH to 32-34℃. TH was obtained with cool fluid infusion or a specific intravascular device. Twelvelead ECG before,during,and after TH,as well as ECG telemetry data was recorded in all patients. From a total of 54 patients admitted with cardiac arrest during the study period,47 patients had the 3 ECG and telemetry data available. ECG analysis was blinded and performed with manual caliper by two independent cardiologists from blinded copies of original ECG,recorded at 25 mm/s and 10 mm/m V. Coronary care unit staff analyzed ECG telemetry for rhythm disturbances. Variables measured in ECG were rhythm,RR,PR,QT and corrected QT(QTc by Bazett formula,measured in lead v2) intervals,QRS duration,presence of Osborn's J wave and U wave,as well as ST segment displacement and T wave amplitude in leads Ⅱ,v2 and v5.RESULTS: Heart rate went down an average of 19 bpm during hypothermia and increased again 16 bpm with rewarming(P < 0.0005,both). There was a nonsignificant prolongation of the PR interval during TH and a significant decrease with rewarming(P = 0.041). QRS duration significantly prolonged(P = 0.041) with TH and shortened back(P < 0.005) with rewarming. QTc interval presented a mean prolongation of 58 ms(P < 0.005) during TH and a significant shortening with rewarming of 22.2 ms(P = 0.017). Osborn or J wave was found in 21.3% of the patients. New arrhythmias occurred in 38.3% of the patients. Most frequent arrhythmia was non-sustained ventricular tachycardia(19.1%),followed by severe bradycardia or paced rhythm(10.6%),accelerated nodal rhythm(8.5%) and atrial fibrillation(6.4%). No life threatening arrhythmias(sustained ventricular tachycardia,polymorphic ventricular tachycardia or ventricular fibrillation) occurred during TH. CONCLUSION: A 38.3% of patients had cardiac arrhythmias during TH but without life-threatening arrhythmias. A concern may rise when inducing TH to patients with long QT syndrome.
文摘Background:Ondansetron and hypothermia are both known to induce bradycardia or QT interval prolongation,thus placing affected patients at risk of cardiac arrest.Case Report:Herein,we report the case of a 97-year-old woman who initially presented with confusion and hypothermia,and experienced severe bradycardia and asystolic cardiac arrest after a 4 mg intravenous ondansetron bolus injection.Conclusion:Ondansetron is associated with bradycardia and QTc prolongation,both of which might be further exacerbated by hypothermia.Clinicians should be aware that administering ondansetron in patients with hypothermia might further increase the risk of adverse cardiac events and eventual cardiac arrest.
文摘This editorial addresses the growing concern of herb-induced liver injury(HILI),focusing on a unique case of Skullcap-induced HILI report.This editorial underscore the significant mortality rate linked to Skullcap-induced HILI,emphasizing the importance of vigilant monitoring and intervention.As herbal supplement usage rises,collaboration among clinicians and researchers is crucial to comprehend and address the complexities of HILI,particularly those involving Skullcap.
文摘Objective To investigate the role of moderate h.vpothennia in the lung inflammation of rat acute lung injury induced by lipopolysaccharide(LPS). Methods A rat model of acute lung injury (ALl) was established by in-tin-tracheal instillation of lipopolysaccharide ( 1.5 mg/kg, 0.5 ml) at 16 h after LPS ( 1.0 mg/kg) intraperitoneal adrninis-tmtion. Thirty-four male Sprague Dawley rats were randomly divided into four groups: control group, receiving saline only;LPS group, receiving LPS; hypothennia group, treated with hypothennia without LPS; LPS + hypothennia group, treated with LPS and cooled to 32.5℃-33.0℃ as PaO2/FiO2. was below 300 mmHg. Hemodynamics and blood gases were record-ed every hour throughout the study. Rats were killed 4 h after ALl, and lung lavage was performed to measure the tumor ne-crosis factor α(TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) concentrations in bronchoalveolar lavage fluid (BALF) by using enzyme-linked immunosorbent assay (ELISA). Results PaO2/FiO2 was significantly decreased and PaCO2 was increased in the LPS group as compared to their baseline values( P<0.01). Treatment with hypothermia inhib-ited the increase in PaCO2( P<0.05) but had no effect on PaO2/FiO2 in the presence of LPS. The administration of LPS significantly increased the concentrations of TNF-α, IL-6 and IL-10 in BALF as compared to the control experiment( P<0.05, P<0.01 ). Moderate hypothermia reduced the expressions of TNF-α and IL-6 ( P<0.01 ) but had no effect on the production of IL-10 ( P>0.05). Conclusion Moderate hypothermia significantly inhibits proinflammatory cytokine ex-pressions in lipopolysaccharide-induced acute lung injury.
基金supported by the Stem Cell and Translation National Key Project,No.2016YFA0101403(to ZC)the National Natural Science Foundation of China,Nos.82171250 and 81973351(to ZC)+6 种基金the Natural Science Foundation of Beijing,No.5142005(to ZC)Beijing Talents Foundation,No.2017000021223TD03(to ZC)Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan,No.CIT&TCD20180333(to ZC)Beijing Municipal Health Commission Fund,No.PXM2020_026283_000005(to ZC)Beijing One Hundred,Thousand,and Ten Thousand Talents Fund,No.2018A03(to ZC)the Royal Society-Newton Advanced Fellowship,No.NA150482(to ZC)the National Natural Science Foundation of China for Young Scientists,No.31900740(to SL)。
文摘Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate recovery.Only a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury microenvironment.Here,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord injury.Induced neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury model.Basso,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion core.Examination of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the microenvironment.Altogether,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion site.Graft-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.
基金support from the OpenGeoSys communitypartially funded by the Prime Minister Research Fellowship,Ministry of Education,Government of India with the project number SB21221901CEPMRF008347.
文摘The study presents a comprehensive coupled thermo-bio-chemo-hydraulic(T-BCH)modeling framework for stabilizing soils using microbially induced calcite precipitation(MICP).The numerical model considers relevant multiphysics involved in MICP,such as bacterial ureolytic activities,biochemical reactions,multiphase and multicomponent transport,and alteration of the porosity and permeability.The model incorporates multiphysical coupling effects through well-established constitutive relations that connect parameters and variables from different physical fields.It was implemented in the open-source finite element code OpenGeoSys(OGS),and a semi-staggered solution strategy was designed to solve the couplings,allowing for flexible model settings.Therefore,the developed model can be easily adapted to simulate MICP applications in different scenarios.The numerical model was employed to analyze the effect of various factors,including temperature,injection strategies,and application scales.Besides,a TBCH modeling study was conducted on the laboratory-scale domain to analyze the effects of temperature on urease activity and precipitated calcium carbonate.To understand the scale dependency of MICP treatment,a large-scale heterogeneous domain was subjected to variable biochemical injection strategies.The simulations conducted at the field-scale guided the selection of an injection strategy to achieve the desired type and amount of precipitation.Additionally,the study emphasized the potential of numerical models as reliable tools for optimizing future developments in field-scale MICP treatment.The present study demonstrates the potential of this numerical framework for designing and optimizing the MICP applications in laboratory-,prototype-,and field-scale scenarios.
基金supported by the National Natural Science Foundation of China,Nos.82271397(to MG),82001293(to MG),82171355(to RX),81971295(to RX)and 81671189(to RX)。
文摘Stem cell-based therapies have been proposed as a potential treatment for neural regeneration following closed head injury.We previously reported that induced neural stem cells exert beneficial effects on neural regeneration via cell replacement.However,the neural regeneration efficiency of induced neural stem cells remains limited.In this study,we explored differentially expressed genes and long non-coding RNAs to clarify the mechanism underlying the neurogenesis of induced neural stem cells.We found that H19 was the most downregulated neurogenesis-associated lnc RNA in induced neural stem cells compared with induced pluripotent stem cells.Additionally,we demonstrated that H19 levels in induced neural stem cells were markedly lower than those in induced pluripotent stem cells and were substantially higher than those in induced neural stem cell-derived neurons.We predicted the target genes of H19 and discovered that H19 directly interacts with mi R-325-3p,which directly interacts with Ctbp2 in induced pluripotent stem cells and induced neural stem cells.Silencing H19 or Ctbp2 impaired induced neural stem cell proliferation,and mi R-325-3p suppression restored the effect of H19 inhibition but not the effect of Ctbp2 inhibition.Furthermore,H19 silencing substantially promoted the neural differentiation of induced neural stem cells and did not induce apoptosis of induced neural stem cells.Notably,silencing H19 in induced neural stem cell grafts markedly accelerated the neurological recovery of closed head injury mice.Our results reveal that H19 regulates the neurogenesis of induced neural stem cells.H19 inhibition may promote the neural differentiation of induced neural stem cells,which is closely associated with neurological recovery following closed head injury.
文摘Induced abortion signifies that pregnancy has been tempered with. Abortion is the removal of an embryo or fetus weighing less than 500 grams from its mother. It can either be spontaneous (unprompted) or induced. Abortion remains one of the leading causes of maternal deaths in developing countries with induced abortion being the key cause. In 2014 from January to August, 9 abortion related deaths occurred in Botswana. There are several reasons female students in tertiary institutions resort to seeking induced abortion which include the socio-demographics like age and socio-economic factors like financial instability. Parental fears, unintended pregnancy and pressure from the partner also force females to terminate pregnancy. Induced abortion has claimed many women’s lives especially in developing countries with very restrictive abortion laws like Botswana as women do not access safe abortion care services. The study intends to establish the determinants of induced abortion among female students in selected tertiary learning institutions in Gaborone City, Botswana. It concentrated primarily on determining the prevalence of induced abortion. This was a descriptive cross-sectional study using both quantitative and qualitative data collection techniques. Systematic random sampling technique was used to come up with 278 participants. Prior to commencement of data collection, all ethical and logistical prerequisites were satisfied. Informed consent was solicited from all the study participants and the purpose of the study was fully explained. A self-administered questionnaire was used to collect data. Microsoft Excel spread sheet was used to code, clean, and enter the data, which was then exported for analysis to the statistical package for social sciences version 24. Frequency distribution tables, percentages graphs, and pie charts were used to illustrate the descriptive information. The study revealed that prevalence of induced abortion among female students in Gaborone City is 7.9%. They even suggested that induced abortion be liberalized. Age was the only socio-demographic factor associated with induced abortion with p = 0.047 using Chi Square test χ<sup>2</sup> = 7.609, df = 3. The study findings concluded that female students resort to induced abortion as a result of pressure from both parents and male partners especially when the pregnancy is unintended. The study recommends that the abortion law in Botswana be made liberal to ease access to safe abortion care services. It also recommends that contraceptive commodities should consistently be available in public health facilities.
文摘Blasting in surface mines aims to fragment rock masses to a proper size.However,flyrock is an undesirable effect of blasting that can result in human injuries.In this study,support vector regression(SVR)is combined with four algorithms:gravitational search algorithm(GSA),biogeography-based optimization(BBO),ant colony optimization(ACO),and whale optimization algorithm(WOA)for predicting flyrock in two surface mines in Iran.Additionally,three other methods,including artificial neural network(ANN),kernel extreme learning machine(KELM),and general regression neural network(GRNN),are employed,and their performances are compared to those of four hybrid SVR models.After modeling,the measured and predicted flyrock values are validated with some performance indices,such as root mean squared error(RMSE).The results revealed that the SVR-WOA model has the most optimal accuracy,with an RMSE of 7.218,while the RMSEs of the KELM,GRNN,SVR-GSA,ANN,SVR-BBO,and SVR-ACO models are 10.668,10.867,15.305,15.661,16.239,and 18.228,respectively.Therefore,combining WOA and SVR can be a valuable tool for accurately predicting flyrock distance in surface mines.
文摘Drug-induced liver injury(DILI)is a major problem in the United States,commonly leading to hospital admission.Diagnosing DILI is difficult as it is a diagnosis of exclusion requiring a temporal relationship between drug exposure and liver injury and a thorough work up for other causes.In addition,DILI has a very variable clinical and histologic presentation that can mimic many different etiologies of liver disease.Objective scoring systems can assess the probability that a drug caused the liver injury but liver biopsy findings are not part of the criteria used in these systems.This review will address some of the recent updates to the scoring systems and the role of liver biopsy in the diagnosis of DILI.
文摘Boulder spacing in mountain rivers and near-wake flow zones within the boulder array is very useful for fish habitat and growth of aquatic organisms.The present study aims to investigate how the boulder array and spacing influence the near-bed flow structures in a gravel-bed stream.Boulders are staggered over a gravel-bed stream with three different inter-boulder spacing namely(a)large(b)medium and(c)small spacing.An acoustic Doppler velocimeter was used for flow measurements in a rectangular channel and the results were compared with those acquired from numerical simulation.The time-averaged velocity profiles at the near-wake flow zones of boulders experience maximum flow retardation which is an outcome of the boulder-induced form roughness.The ratio of velocity differences associated to form and skin roughness and its positive magnitude reveals the dominance of form roughness closest to the boulders.Form roughness computed is 1.75 to 2 times higher than the skin roughness at the near-wake flow region.In particular,the collective immobile boulders placed at different inter-boulder spacings developed high and low bed shear stresses closest to the boulders.The low bed shear stresses characterised by a secondary peak developed at the trough location of the boulders is attributed to the skin shear stress.Further,the spatial averaging of time-averaged flow quantities gives additional impetus to present an improved illustration of fluid shear stresses.The formation of form-induced shear stress is estimated to be 17%to 23%of doubleaveraged Reynolds shear stress and partially compensates for the damping of time-averaged Reynolds shear stress in the interfacial sub-layer.The quadrant analysis of spatial velocity fluctuations depicts that the form-induced shear stresses are dominant in the interfacial sub-layer and have no significance above the gravel-bed surface.
基金funded by the joint fund of the National Key Research and Development Program of China(No.2021YFC2902101)National Natural Science Foundation of China(Grant No.52374084)+1 种基金Open Foundation of National Energy shale gas R&D(experiment) center(2022-KFKT-12)the 111 Project(B17009)。
文摘Evaluating the physical mechanisms that link hydraulic fracturing(HF) operations to induced earthquakes and the anticipated form of the resulting events is significant in informing subsurface fluid injection operations. Current understanding supports the overriding role of the effective stress magnitude in triggering earthquakes, while the impact of change rate of effective stress has not been systematically addressed. In this work, a modified critical stiffness was brought up to investigate the likelihood, impact,and mitigation of induced seismicity during and after hydraulic fracturing by developing a poroelastic model based on rate-and-state fraction law and linear stability analysis. In the new criterion, the change rate of effective stress was considered a key variable to explore the evolution of this criterion and hence the likelihood of instability slip of fault. A coupled fluid flow-deformation model was used to represent the entire hydraulic fracturing process in COMSOL Multiphysics. The possibility of triggering an earthquake throughout the entire hydraulic fracturing process, from fracturing to cessation, was investigated considering different fault locations, orientations, and positions along the fault. The competition between the effects of the magnitude and change rate of effective stress was notable at each fracturing stage. The effective stress magnitude is a significant controlling factor during fracturing events, with the change rate dominating when fracturing is suddenly started or stopped. Instability dominates when the magnitude of the effective stress increases(constant injection at each fracturing stage) and the change rate of effective stress decreases(the injection process is suddenly stopped). Fracturing with a high injection rate, a fault adjacent to the hydraulic fracturing location and the position of the junction between the reservoir and fault are important to reduce the Coulomb failure stress(CFS) and enhance the critical stiffness as the significant disturbance of stresses at these positions in the coupled process. Therefore,notable attention should be given to the injection rate during fracturing, fault position, and position along faults as important considerations to help reduce the potential for induced seismicity. Our model was verified and confirmed using the case of the Longmaxi Formation in the Sichuan Basin, China, in which the reported microseismic data were correlated with high critical stiffness values. This work supplies new thoughts of the seismic risk associated with HF engineering.
基金supported by the National Natural Science Foundation of China,Nos.82271397(to MG),82001293(to MG),82171355(to RX),81971295(to RX),and 81671189(to RX)。
文摘Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair.We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling,influencing their activation such that they can promote neurological recovery.However,the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear.In this study,we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-αexpression but suppressed insulin-like growth factor-1 expression.However,recombinant complement receptor 2-conjugated Crry(CR2-Crry)reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia,CXCL12,and tumor necrosis factor-α.Additionally,we observed that,in response to stimulation(including stimulation by CXCL12 secreted by activated microglia),CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4,Crry,and Akt signaling to modulate microglial activation.In agreement with these in vitro experimental results,we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation,leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice.Notably,these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury,cerebral edema,and neurological disorders post–closed head injury.In conclusion,our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry,thereby promoting induced neural stem cell–mediated improvement of neuronal injury,cerebral edema,and neurological disorders following closed head injury.
基金supported by the National Natural Science Foundation of China,No.81771222(to LS)Guangzhou Key Research Program on Brain Science,Nos.202007030011,202206060001(to LS)the Program of Introducing Talents of Discipline to Universities of China,No.B14036(to KFS)。
文摘Midbrain dopaminergic neurons play an important role in the etiology of neurodevelopmental and neurodegenerative diseases.They also represent a potential source of transplanted cells for therapeutic applications.In vitro differentiation of functional midbrain dopaminergic neurons provides an accessible platform to study midbrain neuronal dysfunction and can be used to examine obstacles to dopaminergic neuronal development.Emerging evidence and impressive advances in human induced pluripotent stem cells,with tuned neural induction and differentiation protocols,makes the production of induced pluripotent stem cell-derived dopaminergic neurons feasible.Using SB431542 and dorsomorphin dual inhibitor in an induced pluripotent stem cell-derived neural induction protocol,we obtained multiple subtypes of neurons,including 20%tyrosine hydroxylase-positive dopaminergic neurons.To obtain more dopaminergic neurons,we next added sonic hedgehog(SHH)and fibroblast growth factor 8(FGF8)on day 8 of induction.This increased the proportion of dopaminergic neurons,up to 75%tyrosine hydroxylase-positive neurons,with 15%tyrosine hydroxylase and forkhead box protein A2(FOXA2)co-expressing neurons.We further optimized the induction protocol by applying the small molecule inhibitor,CHIR99021(CHIR).This helped facilitate the generation of midbrain dopaminergic neurons,and we obtained 31-74%midbrain dopaminergic neurons based on tyrosine hydroxylase and FOXA2 staining.Thus,we have established three induction protocols for dopaminergic neurons.Based on tyrosine hydroxylase and FOXA2 immunostaining analysis,the CHIR,SHH,and FGF8 combined protocol produces a much higher proportion of midbrain dopaminergic neurons,which could be an ideal resource for tackling midbrain-related diseases.
基金Supported by the National Natural Science Foundation of China,No.82125007Beijing Natural Science Foundation,No.Z200014.
文摘BACKGROUND Human induced pluripotent stem cell(hiPSC)technology is a valuable tool for generating patient-specific stem cells,facilitating disease modeling,and invest-igating disease mechanisms.However,iPSCs carrying specific mutations may limit their clinical applications due to certain inherent characteristics.AIM To investigate the impact of MERTK mutations on hiPSCs and determine whether hiPSC-derived extracellular vesicles(EVs)influence anomalous cell junction and differentiation potential.METHODS We employed a non-integrating reprogramming technique to generate peripheral blood-derived hiPSCs with and hiPSCs without a MERTK mutation.Chromo-somal karyotype analysis,flow cytometry,and immunofluorescent staining were utilized for hiPSC identification.Transcriptomics and proteomics were employed to elucidate the expression patterns associated with cell junction abnormalities and cellular differentiation potential.Additionally,EVs were isolated from the supernatant,and their RNA and protein cargos were examined to investigate the involvement of hiPSC-derived EVs in stem cell junction and differentiation.RESULTS The generated hiPSCs,both with and without a MERTK mutation,exhibited normal karyotype and expressed pluripotency markers;however,hiPSCs with a MERTK mutation demonstrated anomalous adhesion capability and differentiation potential,as confirmed by transcriptomic and proteomic profiling.Furthermore,hiPSC-derived EVs were involved in various biological processes,including cell junction and differentiation.CONCLUSION HiPSCs with a MERTK mutation displayed altered junction characteristics and aberrant differentiation potential.Furthermore,hiPSC-derived EVs played a regulatory role in various biological processes,including cell junction and differentiation.
基金financially supported by the Major Program of the National Natural Science Foundation of China(No.52394191)the Outstanding Ph.D Dissertation Cultivating Program of Xi’an University of Science and Technology(No.PY22001)the National Foundation for studying abroad(No.[2022]87)。
文摘In recent years,the mining depth of steeply inclined coal seams in the Urumqi mining area has gradually increased.Local deformation of mining coal-rock results in frequent rockbursts.This has become a critical issue that affects the safe mining of deep,steeply inclined coal seams.In this work,we adopt a perspective centered on localized deformation in coal-rock mining and systematically combine theoretical analyses and extensive data mining of voluminous microseismic data.We describe a mechanical model for the urgently inclined mining of both the sandwiched rock pillar and the roof,explaining the mechanical response behavior of key disaster-prone zones within the deep working face,affected by the dynamics of deep mining.By exploring the spatial correlation inherent in extensive microseismic data,we delineate the“time-space”response relationship that governs the dynamic failure of coal-rock during the progression of the sharply inclined working face.The results disclose that(1)the distinctive coal-rock occurrence structure characterized by a“sandwiched rock pillar-B6 roof”constitutes the origin of rockburst in the southern mining area of the Wudong Coal Mine,with both elements presenting different degrees of deformation localization with increasing mining depth.(2)As mining depth increases,the bending deformation and energy accumulation within the rock pillar and roof show nonlinear acceleration.The localized deformation of deep,steeply inclined coal-rock engenders the spatial superposition of squeezing and prying effects in both the strike and dip directions,increasing the energy distribution disparity and stress asymmetry of the“sandwiched rock pillar-B3+6 coal seam-B6 roof”configuration.This makes worse the propensity for frequent dynamic disasters in the working face.(3)The developed high-energy distortion zone“inner-outer”control technology effectively reduces high stress concentration and energy distortion in the surrounding rock.After implementation,the average apparent resistivity in the rock pillar and B6 roof substantially increased by 430%and 300%,respectively,thus guaranteeing the safe and efficient development of steeply inclined coal seams.
基金Institutional Fund Projects under No.(IFP-A-2022-2-5-24)by Ministry of Education and University of Hafr Al Batin,Saudi Arabia.
文摘The application of mathematical modeling to biological fluids is of utmost importance, as it has diverse applicationsin medicine. The peristaltic mechanism plays a crucial role in understanding numerous biological flows. In thispaper, we present a theoretical investigation of the double diffusion convection in the peristaltic transport of aPrandtl nanofluid through an asymmetric tapered channel under the combined action of thermal radiation andan induced magnetic field. The equations for the current flow scenario are developed, incorporating relevantassumptions, and considering the effect of viscous dissipation. The impact of thermal radiation and doublediffusion on public health is of particular interest. For instance, infrared radiation techniques have been used totreat various skin-related diseases and can also be employed as a measure of thermotherapy for some bones toenhance blood circulation, with radiation increasing blood flow by approximately 80%. To solve the governingequations, we employ a numerical method with the aid of symbolic software such as Mathematica and MATLAB.The velocity, magnetic force function, pressure rise, temperature, solute (species) concentration, and nanoparticlevolume fraction profiles are analytically derived and graphically displayed. The results outcomes are compared withthe findings of limiting situations for verification.
基金National Natural Science Foundation of China(U21A6001,42075059)Specific Research Fund of The Innovation Platform for Academicians of Hainan Province(YSPTZX202143)+1 种基金Guangdong Major Project of Basic and Applied Basic Research(2020B0301030004)Science and Technology Project of Guangdong Meteorological Service(GRMC2020M29)。
文摘The South China Sea is a hotspot for regional climate research.Over the past 40 years,considerable improvement has been made in the development and utilization of the islands in the South China Sea,leading to a substantial change in the land-use of the islands.However,research on the impact of human development on the local climate of these islands is lacking.This study analyzed the characteristics of local climate changes on the islands in the South China Sea based on data from the Yongxing Island Observation Station and ERA5 re-analysis.Furthermore,the influence of urbanization on the local climate of the South China Sea islands was explored in this study.The findings revealed that the 10-year average temperature in Yongxing Island increased by approximately 1.11℃from 1961 to 2020,and the contribution of island development and urbanization to the local warming rate over 60 years was approximately 36.2%.The linear increasing trend of the annual hot days from 1961–2020 was approximately 14.84 days per decade.The diurnal temperature range exhibited an increasing trend of 0.05℃per decade,whereas the number of cold days decreased by 1.06days per decade.The rapid increase in construction on Yongxing Island from 2005 to 2021 led to a decrease in observed surface wind speed by 0.32 m s^(-1)per decade.Consequently,the number of days with strong winds decreased,whereas the number of days with weak winds increased.Additionally,relative humidity exhibited a rapid decline from 2001 to 2016 and then rebounded.The study also found substantial differences between the ERA5 re-analysis and observation data,particularly in wind speed and relative humidity,indicating that the use of re-analysis data for climate resource assessment and climate change evaluation on island areas may not be feasible.