Objective:To investigate the protective function of tocilizumab in human cardiac myocytes ischemia-reperfusion injury.Methods:The human cardiac myocytes were treated by tocilizumab with different concentrations(1.0 mg...Objective:To investigate the protective function of tocilizumab in human cardiac myocytes ischemia-reperfusion injury.Methods:The human cardiac myocytes were treated by tocilizumab with different concentrations(1.0 mg/mL,3.0 mg/mL,5.0 mg/mL) for 24 h.then cells were cultured in ischemia environment for 24 h and reperfusion environment for 1 h.The MTT and flow cytometry were used to detect the proliferation and apoptosis of human cardiac myocytes,respectively.The mRNA and protein expressions of Bcl-2 and Bax were measured by qRT-PCR and western blot,respectively.Results:Compared to the negative group,pretreated by tocilizumab could significantly enhance the proliferation viability and suppress apoptosis of human cardiac myocytes after suffering ischemia reperfusion injury(P<0.05).The expression of Bcl-2 in tocilizumab treated group were higher than NC group(P<0.05).while the Bax expression were lower(P<0.05).Conclusions:Tocilizumab could significantly inhibit apoptosis and keep the proliferation viability of human cardiac myocytes after suffering ischemia reperfusion injury.Tocilizumab may obtain a widely application in the protection of ischemia reperfusion injury.展开更多
The pleiotropic functions of circulating high density lipoprotein(HDL) on peripheral vascular health are well established. HDL plays a pivotal role in reverse cholesterol transport and is also known to suppress inflam...The pleiotropic functions of circulating high density lipoprotein(HDL) on peripheral vascular health are well established. HDL plays a pivotal role in reverse cholesterol transport and is also known to suppress inflammation,endothelial activation and apoptosis in peripheral vessels. Although not expressed in the central nervous system, HDL has nevertheless emerged as a potential resilience factor for dementia in multiple epidemiological studies. Animal model data specifically support a role for HDL in attenuating the accumulation of P-amyloid within cerebral vessels concomitant with reduced neuroinflammation and improved cognitive performance. As the vascular contributions to dementia are increasingly appreciated, this review seeks to summarize recent literature focused on the vasoprotective properties of HDL that may extend to cerebral vessels, discuss potential roles of HDL in dementia relative to brainderived lipoproteins, identify gaps in current knowledge, and highlight new opportunities for research and discovery.展开更多
Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^...Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane.Na^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells.Therefo re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases.However,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell function.Our recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's disease.Stabilization of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these diseases.For this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell migration.Thus,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related pathogenesis.The potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.展开更多
Parkinson's disease(PD)is the most frequent movement disorder and the second most prevalent age-related neurodegenerative disease(ND)worldwide.From the clinical point of view,it is characterized by severe motor co...Parkinson's disease(PD)is the most frequent movement disorder and the second most prevalent age-related neurodegenerative disease(ND)worldwide.From the clinical point of view,it is characterized by severe motor complications,including uncontrollable resting tremors,rigidity,bradykinesia,and postural instability.展开更多
In the course of organic synthesis, particularly for multi-step synthesis or natural product total synthesis, the selection of appropriate protective groups for the intended functionality is crucial in order to achiev...In the course of organic synthesis, particularly for multi-step synthesis or natural product total synthesis, the selection of appropriate protective groups for the intended functionality is crucial in order to achieve chemoselective synthetic goals. The development of many useful protective groups has been reported based on the functionality of the anilino group. Herein, we discuss our study of various protective groups and the processes we used to establish compatibility with anilino functionality via the implementation of Oxone-mediated oxidative esterification in methanol. The results and the details of our experiments are reported herein.展开更多
Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone.Presently,no effective countermeasure exists,and ionizi...Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone.Presently,no effective countermeasure exists,and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity.The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy.Our studies revealed that P7C3 repressed ionizing radiation(IR)-induced osteoclastic activity,inhibited adipogenesis,and promoted osteoblastogenesis and mineral deposition in vitro.We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened,osteoporotic bone.However,the administration of P7C3 significantly inhibited osteoclastic activity,lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area,architecture,and mechanical strength.Our findings revealed significant enhancement of cellular macromolecule metabolic processes,myeloid cell differentiation,and the proteins LRP-4,TAGLN,ILK,and Tollip,with downregulation of GDF-3,SH2B1,and CD200.These proteins are key in favoring osteoblast over adipogenic progenitor differentiation,cell matrix interactions,and shape and motility,facilitating inflammatory resolution,and suppressing osteoclastogenesis,potentially via Wnt/β-catenin signaling.A concern was whether P7C3 afforded similar protection to cancer cells.Preliminarily,and remarkably,at the same protective P7C3 dose,a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro.Together,these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy,leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications.Our data uncover a new approach for the prevention of radiation-induced bone damage,and further work is needed to investigate its ability to selectively drive cancer cell death.展开更多
Glycosylation is a process that involves the addition of sugar moieties or glycans to different types of molecules,including proteins,lipids,and nucleic acids.Among these,protein glycosylation is one of the most preva...Glycosylation is a process that involves the addition of sugar moieties or glycans to different types of molecules,including proteins,lipids,and nucleic acids.Among these,protein glycosylation is one of the most prevalent forms of post-translational modification,playing a crucial role in biological complexity.With more than ten monosaccharides identified within mammalian brain cells and more than 1×1012 possible combinations,the heterogeneity of glycosylation is extensive(Conroy et al.,2021).The diversity of glycans and the complexity of their structures allow for a wide range of protein functions.N-glycans are one of the most abundant forms of glycans and are involved in various cellular functions.N-glycans can be added to proteins at specific sequons,Asn-X-Ser/Thr,and are classified into three main types in mature glycoproteins:high mannose,complex,and hybrid.High mannose N-glycans consist of 5-9 mannose residues linked to a chitobiose core and undergo processing into complex or hybrid forms in the Golgi apparatus(Varki et al.,2017).Complex N-glycans are more diverse and contain various branched structures such as antennae with fucose,galactose,and sialic acid residues.Hybrid N-glycans contain one or more complex branches in conjunction with an oligomannose branch(Fisher and Ungar,2016).Understanding the specific functions of these different types of N-glycans in protein regulation,folding,and function is an active area of research in the life sciences,including glycobiology.展开更多
Parkinson’s disease:Parkinson’s disease(PD) is the second most prevalent neurodegenerative disease,after Alzheimer’s disease,affecting 1%of the general population over the age of 65years.According to data from the ...Parkinson’s disease:Parkinson’s disease(PD) is the second most prevalent neurodegenerative disease,after Alzheimer’s disease,affecting 1%of the general population over the age of 65years.According to data from the World Health Organization(WHO),its prevalence has doubled in the past 25 years.In 2019,global estimates indicated over 8.5 million individuals with PD and it is suggested that PD caused 329000 deaths,an increase of over 100% since 2000(WHO,2022).展开更多
Ambroxol hydrochloride(2-amino-3,5-dibromo-N-methylbenzylamine hydrochloride)has been used as a mucolytic agent in the treatment of respiratory diseases since the late 1970s.Its effects on mucus membranes such as mucu...Ambroxol hydrochloride(2-amino-3,5-dibromo-N-methylbenzylamine hydrochloride)has been used as a mucolytic agent in the treatment of respiratory diseases since the late 1970s.Its effects on mucus membranes such as mucus disruption,increased mucus production,and low toxicity profile were addressed in its original German patent in 1966.These first described properties have kept Ambroxol available worldwide and over the counter in the pharmaceutical market to this day.展开更多
Background:Excessive heat exposure can lead to hyperthermia in humans,which impairs physical performance and disrupts cognitive function.While heat is a known physiological stressor,it is unclear how severe heat stres...Background:Excessive heat exposure can lead to hyperthermia in humans,which impairs physical performance and disrupts cognitive function.While heat is a known physiological stressor,it is unclear how severe heat stress affects brain physiology and function.Methods:Eleven healthy participants were subjected to heat stress from prolonged exercise or warm water immersion until their rectal temperatures(T_(re))attained 39.5℃,inducing exertional or passive hyperthermia,respectively.In a separate trial,blended ice was ingested before and during exercise as a cooling strategy.Data were compared to a control condition with seated rest(normothermic).Brain temperature(T_(br)),cerebral perfusion,and task-based brain activity were assessed using magnetic resonance imaging techniques.Results:T_(br)in motor cortex was found to be tightly regulated at rest(37.3℃±0.4℃(mean±SD))despite fluctuations in T_(re).With the development of hyperthermia,T_(br)increases and dovetails with the rising T_(re).Bilateral motor cortical activity was suppressed during high-intensity plantarflexion tasks,implying a reduced central motor drive in hyperthermic participants(T_(re)=38.5℃±0.1℃).Global gray matter perfusion and regional perfusion in sensorimotor cortex were reduced with passive hyperthermia.Executive function was poorer under a passive hyperthermic state,and this could relate to compromised visual processing as indicated by the reduced activation of left lateral-occipital cortex.Conversely,ingestion of blended ice before and during exercise alleviated the rise in both T_(re)and T_(bc)and mitigated heat-related neural perturbations.Conclusion:Severe heat exposure elevates T_(br),disrupts motor cortical activity and executive function,and this can lead to impairment of physical and cognitive performance.展开更多
BACKGROUND Chronic obstructive pulmonary disease(COPD)is a common respiratory disorder that affects the elderly population and increases the risk of postoperative pulmonary complications(PPCs)after major surgeries.Sev...BACKGROUND Chronic obstructive pulmonary disease(COPD)is a common respiratory disorder that affects the elderly population and increases the risk of postoperative pulmonary complications(PPCs)after major surgeries.Sevoflurane is a volatile anesthetic that has been shown to have anti-inflammatory and antioxidant properties and attenuate lung injury in animal models.AIM To evaluate the protective effect of sevoflurane on the lung function of elderly COPD patients undergoing total hip arthroplasty(THA).METHODS In this randomized controlled trial,we randomly assigned 120 elderly patients with COPD,who were scheduled for THA,to receive either sevoflurane(sevoflurane group)or propofol(propofol group)as the maintenance anesthetic.The primary outcome was the incidence of PPCs within seven days after surgery.The secondary outcomes were changes in the lung function parameters,inflammatory markers,oxidative stress markers,and postoperative pain scores.RESULTS The results showed that the incidence of PPCs was significantly lower in the sevoflurane group than in the propofol group(10%vs 25%,P=0.02).Furthermore,the decline in the forced expiratory volume in 1 s,forced vital capacity,and peak expiratory flow was significantly lesser in the sevoflurane group than in the propofol group at 24 h and 48 h after surgery(P<0.05).The interleukin-6,tumor necrosis factor-alpha,malondialdehyde,and 8-hydroxy-2α-deoxyguanosine levels were significantly lower in the sevoflurane group than in the propofol group at 24 h after surgery(P<0.05).The sevoflurane group showed significantly lower postoperative pain scores than the propofol group at 6 h,12 h,and 24 h after surgery(P<0.05).CONCLUSION Sevoflurane protects the lung function of elderly COPD patients undergoing THA under general anesthesia by reducing the incidence of PPCs,attenuating inflammatory and oxidative stress responses,and alleviating postoperative pain.展开更多
Prototype experiments were carried out on the explosion-proof performance of the RC blast wall.The mass of TNT detonated in the experiments is 5 kg and 20 kg respectively.The shock wave overpressure was tested in diff...Prototype experiments were carried out on the explosion-proof performance of the RC blast wall.The mass of TNT detonated in the experiments is 5 kg and 20 kg respectively.The shock wave overpressure was tested in different regions.The above experiments were numerically simulated,and the simulated shock wave overpressure waveforms were compared with that tested and given by CONWEP program.The results show that the numerically simulated waveform is slightly different from the test waveform,but similar to CONWEP waveform.Through dimensional analysis and numerical simulation under different working conditions,the equation for the attenuation rate of the diffraction overpressure behind the blast wall was obtained.According to the corresponding standards,the degree of casualties and the damage degree of the brick concrete building at a certain distance behind the wall can be determined when parameters are set.The above results can provide a reference for the design and construction of the reinforced concrete blast wall.展开更多
Our brain is constantly active.Even at rest,the brain carries out essential functions such as maintenance of resting potentials,subthreshold synaptic activity,and spiking activity related to information processing.Thi...Our brain is constantly active.Even at rest,the brain carries out essential functions such as maintenance of resting potentials,subthreshold synaptic activity,and spiking activity related to information processing.This resting activity can be assessed with several in vivo tools,such as resting-state functional magnetic resonance imaging.This technique measures subtle changes in blood flow,volume,and oxygenation that occur over time.Although vascular in nature,resting-state functional magnetic resonance imaging is considered a reliable proxy of neural activity and several studies have shown that the brain is functionally divided into interacting neural networks called the“functional connectome”.展开更多
Functional magnetic resonance imaging(fMRI)is a popular tool used to investigate not only how the brain responds to specific stimuli during sensorimotor or cognitive tasks,but also brain activity at rest.The physics b...Functional magnetic resonance imaging(fMRI)is a popular tool used to investigate not only how the brain responds to specific stimuli during sensorimotor or cognitive tasks,but also brain activity at rest.The physics beyond this approach is based on the analysis of the blood oxygenation level-dependent signal.展开更多
With the increase of life expectancy and population growth,neurodegenerative diseases have risen too and are projected to be a major health public concern by 2050.Neurodegenerative diseases are characterized by the pr...With the increase of life expectancy and population growth,neurodegenerative diseases have risen too and are projected to be a major health public concern by 2050.Neurodegenerative diseases are characterized by the progressive decline of cognitive function leading to the subsequent loss of autonomy.Although the underlying causes of neurodegeneration are not well understood,aging is the main risk factor.展开更多
BACKGROUND Left ventricular(LV)remodeling and diastolic function in people with heart failure(HF)are correlated with iron status;however,the causality is uncertain.This Mendelian randomization(MR)study investigated th...BACKGROUND Left ventricular(LV)remodeling and diastolic function in people with heart failure(HF)are correlated with iron status;however,the causality is uncertain.This Mendelian randomization(MR)study investigated the bidirectional causal relationship between systemic iron parameters and LV structure and function in a preserved ejection fraction population.METHODS Transferrin saturation(TSAT),total iron binding capacity(TIBC),and serum iron and ferritin levels were extracted as instrumental variables for iron parameters from meta-analyses of public genome-wide association studies.Individuals without myocardial infarction history,HF,or LV ejection fraction(LVEF)<50%(n=16,923)in the UK Biobank Cardiovascular Magnetic Resonance Imaging Study constituted the outcome dataset.The dataset included LV end-diastolic volume,LV endsystolic volume,LV mass(LVM),and LVM-to-end-diastolic volume ratio(LVMVR).We used a two-sample bidirectional MR study with inverse variance weighting(IVW)as the primary analysis method and estimation methods using different algorithms to improve the robustness of the results.RESULTS In the IVW analysis,one standard deviation(SD)increased in TSAT significantly correlated with decreased LVMVR(β=-0.1365;95%confidence interval[CI]:-0.2092 to-0.0638;P=0.0002)after Bonferroni adjustment.Conversely,no significant relationships were observed between other iron and LV parameters.After Bonferroni correction,reverse MR analysis showed that one SD increase in LVEF significantly correlated with decreased TSAT(β=-0.0699;95%CI:-0.1087 to-0.0311;P=0.0004).No heterogeneity or pleiotropic effects evidence was observed in the analysis.CONCLUSIONS We demonstrated a causal relationship between TSAT and LV remodeling and function in a preserved ejection fraction population.展开更多
In traditional finite-temperature Kohn–Sham density functional theory(KSDFT),the partial occupation of a large number of high-energy KS eigenstates restricts the use of first-principles molecular dynamics methods at ...In traditional finite-temperature Kohn–Sham density functional theory(KSDFT),the partial occupation of a large number of high-energy KS eigenstates restricts the use of first-principles molecular dynamics methods at extremely high temperatures.However,stochastic density functional theory(SDFT)can overcome this limitation.Recently,SDFT and the related mixed stochastic–deterministic density functional theory,based on a plane-wave basis set,have been implemented in the first-principles electronic structure software ABACUS[Q.Liu and M.Chen,Phys.Rev.B 106,125132(2022)].In this study,we combine SDFT with the Born–Oppenheimer molecular dynamics method to investigate systems with temperatures ranging from a few tens of eV to 1000 eV.Importantly,we train machine-learning-based interatomic models using the SDFT data and employ these deep potential models to simulate large-scale systems with long trajectories.Subsequently,we compute and analyze the structural properties,dynamic properties,and transport coefficients of warm dense matter.展开更多
Assume that L is a non-negative self-adjoint operator on L^(2)(ℝ^(n))with its heat kernels satisfying the so-called Gaussian upper bound estimate and that X is a ball quasi-Banach function space onℝ^(n) satisfying som...Assume that L is a non-negative self-adjoint operator on L^(2)(ℝ^(n))with its heat kernels satisfying the so-called Gaussian upper bound estimate and that X is a ball quasi-Banach function space onℝ^(n) satisfying some mild assumptions.Let HX,L(ℝ^(n))be the Hardy space associated with both X and L,which is defined by the Lusin area function related to the semigroup generated by L.In this article,the authors establish various maximal function characterizations of the Hardy space HX,L(ℝ^(n))and then apply these characterizations to obtain the solvability of the related Cauchy problem.These results have a wide range of generality and,in particular,the specific spaces X to which these results can be applied include the weighted space,the variable space,the mixed-norm space,the Orlicz space,the Orlicz-slice space,and the Morrey space.Moreover,the obtained maximal function characterizations of the mixed-norm Hardy space,the Orlicz-slice Hardy space,and the Morrey-Hardy space associated with L are completely new.展开更多
Several densities or probability laws of continuous random variables derive from the Euler Gamma function. These laws form the basis of sampling theory, namely hypothesis testing and estimation. Namely the gamma, beta...Several densities or probability laws of continuous random variables derive from the Euler Gamma function. These laws form the basis of sampling theory, namely hypothesis testing and estimation. Namely the gamma, beta, and Student law, through the chi-square law and the normal law are all distributions resulting from applications of Euleur functions.展开更多
The abalone shell,a composite material whose cross-section is composed of inorganic and organic layers,has high strength and toughness.Inspired by the abalone shell,several multi-layer composite plates with different ...The abalone shell,a composite material whose cross-section is composed of inorganic and organic layers,has high strength and toughness.Inspired by the abalone shell,several multi-layer composite plates with different layer sequences and thicknesses are studied as bullet-proof material in this paper.To investigate the ballistic performance of this multi-layer structure,the complete characterization model and related material parameters of large deformation,failure and fracture ofAl_(2)O_(3)ceramics andCarbon Fiber Reinforced Polymer(CFRP)are studied.Then,3D finite element models of the proposed composite plates with different layer sequences and thicknesses impacted by a 12.7 mm armor-piercing incendiary(API)are built using Abaqus to predict failure.The simulation results show that the CFRP/Al2O3 ceramic/Ultrahigh Molecular Weight Polyethylene(UHMWPE)/CFRP(1 mm/4 mm/4 mm/1 mm)composite is the optimized stack of layers.The simulation results under specified layer sequence and thickness have a reasonable correlation with the experimental results and reflect the failure and fracture of the multi-layer composite protective armor.展开更多
基金supported by a grant from the Health Department Foundation of Zhejiang Province(2010KYA102)
文摘Objective:To investigate the protective function of tocilizumab in human cardiac myocytes ischemia-reperfusion injury.Methods:The human cardiac myocytes were treated by tocilizumab with different concentrations(1.0 mg/mL,3.0 mg/mL,5.0 mg/mL) for 24 h.then cells were cultured in ischemia environment for 24 h and reperfusion environment for 1 h.The MTT and flow cytometry were used to detect the proliferation and apoptosis of human cardiac myocytes,respectively.The mRNA and protein expressions of Bcl-2 and Bax were measured by qRT-PCR and western blot,respectively.Results:Compared to the negative group,pretreated by tocilizumab could significantly enhance the proliferation viability and suppress apoptosis of human cardiac myocytes after suffering ischemia reperfusion injury(P<0.05).The expression of Bcl-2 in tocilizumab treated group were higher than NC group(P<0.05).while the Bax expression were lower(P<0.05).Conclusions:Tocilizumab could significantly inhibit apoptosis and keep the proliferation viability of human cardiac myocytes after suffering ischemia reperfusion injury.Tocilizumab may obtain a widely application in the protection of ischemia reperfusion injury.
文摘The pleiotropic functions of circulating high density lipoprotein(HDL) on peripheral vascular health are well established. HDL plays a pivotal role in reverse cholesterol transport and is also known to suppress inflammation,endothelial activation and apoptosis in peripheral vessels. Although not expressed in the central nervous system, HDL has nevertheless emerged as a potential resilience factor for dementia in multiple epidemiological studies. Animal model data specifically support a role for HDL in attenuating the accumulation of P-amyloid within cerebral vessels concomitant with reduced neuroinflammation and improved cognitive performance. As the vascular contributions to dementia are increasingly appreciated, this review seeks to summarize recent literature focused on the vasoprotective properties of HDL that may extend to cerebral vessels, discuss potential roles of HDL in dementia relative to brainderived lipoproteins, identify gaps in current knowledge, and highlight new opportunities for research and discovery.
基金supported by the National Natural Science Foundation of China,No.82173800 (to JB)Shenzhen Science and Technology Program,No.KQTD20200820113040070 (to JB)。
文摘Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane.Na^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells.Therefo re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases.However,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell function.Our recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's disease.Stabilization of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these diseases.For this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell migration.Thus,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related pathogenesis.The potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.
基金supported by Institute of Translational Pharmacology,National Research Council(IFT-CNR),Projects DSB.AD007.088 to AS。
文摘Parkinson's disease(PD)is the most frequent movement disorder and the second most prevalent age-related neurodegenerative disease(ND)worldwide.From the clinical point of view,it is characterized by severe motor complications,including uncontrollable resting tremors,rigidity,bradykinesia,and postural instability.
文摘In the course of organic synthesis, particularly for multi-step synthesis or natural product total synthesis, the selection of appropriate protective groups for the intended functionality is crucial in order to achieve chemoselective synthetic goals. The development of many useful protective groups has been reported based on the functionality of the anilino group. Herein, we discuss our study of various protective groups and the processes we used to establish compatibility with anilino functionality via the implementation of Oxone-mediated oxidative esterification in methanol. The results and the details of our experiments are reported herein.
基金funded by the Department of Internal Medicine,College of Medicine,University of Central Florida (Award#2508074)supported by the National Aeronautics and Space Administration [grant No.80NSSC21M0309]issued through the NASA Office of STEM Engagement。
文摘Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone.Presently,no effective countermeasure exists,and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity.The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy.Our studies revealed that P7C3 repressed ionizing radiation(IR)-induced osteoclastic activity,inhibited adipogenesis,and promoted osteoblastogenesis and mineral deposition in vitro.We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened,osteoporotic bone.However,the administration of P7C3 significantly inhibited osteoclastic activity,lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area,architecture,and mechanical strength.Our findings revealed significant enhancement of cellular macromolecule metabolic processes,myeloid cell differentiation,and the proteins LRP-4,TAGLN,ILK,and Tollip,with downregulation of GDF-3,SH2B1,and CD200.These proteins are key in favoring osteoblast over adipogenic progenitor differentiation,cell matrix interactions,and shape and motility,facilitating inflammatory resolution,and suppressing osteoclastogenesis,potentially via Wnt/β-catenin signaling.A concern was whether P7C3 afforded similar protection to cancer cells.Preliminarily,and remarkably,at the same protective P7C3 dose,a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro.Together,these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy,leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications.Our data uncover a new approach for the prevention of radiation-induced bone damage,and further work is needed to investigate its ability to selectively drive cancer cell death.
基金supported by the Institute for Basic Science(IBS-R001-D2-2022-A03).
文摘Glycosylation is a process that involves the addition of sugar moieties or glycans to different types of molecules,including proteins,lipids,and nucleic acids.Among these,protein glycosylation is one of the most prevalent forms of post-translational modification,playing a crucial role in biological complexity.With more than ten monosaccharides identified within mammalian brain cells and more than 1×1012 possible combinations,the heterogeneity of glycosylation is extensive(Conroy et al.,2021).The diversity of glycans and the complexity of their structures allow for a wide range of protein functions.N-glycans are one of the most abundant forms of glycans and are involved in various cellular functions.N-glycans can be added to proteins at specific sequons,Asn-X-Ser/Thr,and are classified into three main types in mature glycoproteins:high mannose,complex,and hybrid.High mannose N-glycans consist of 5-9 mannose residues linked to a chitobiose core and undergo processing into complex or hybrid forms in the Golgi apparatus(Varki et al.,2017).Complex N-glycans are more diverse and contain various branched structures such as antennae with fucose,galactose,and sialic acid residues.Hybrid N-glycans contain one or more complex branches in conjunction with an oligomannose branch(Fisher and Ungar,2016).Understanding the specific functions of these different types of N-glycans in protein regulation,folding,and function is an active area of research in the life sciences,including glycobiology.
基金Authors are also grateful to RHO’s postdoctoral contract (Ayuda IJC2020-045695-I financed by MCIN/AEI/10.13039/501100011033,European Union NextGeneration EU/PRTR)。
文摘Parkinson’s disease:Parkinson’s disease(PD) is the second most prevalent neurodegenerative disease,after Alzheimer’s disease,affecting 1%of the general population over the age of 65years.According to data from the World Health Organization(WHO),its prevalence has doubled in the past 25 years.In 2019,global estimates indicated over 8.5 million individuals with PD and it is suggested that PD caused 329000 deaths,an increase of over 100% since 2000(WHO,2022).
基金partly funded by the Clinician-Scientist grant(No.472-0-0)by the medical faculty of the University of Tübingen(to SCV).
文摘Ambroxol hydrochloride(2-amino-3,5-dibromo-N-methylbenzylamine hydrochloride)has been used as a mucolytic agent in the treatment of respiratory diseases since the late 1970s.Its effects on mucus membranes such as mucus disruption,increased mucus production,and low toxicity profile were addressed in its original German patent in 1966.These first described properties have kept Ambroxol available worldwide and over the counter in the pharmaceutical market to this day.
基金supported by Defence Innovative Research Program(DIRP)Grant(PA No.9015102335)from Defence Research&Technology Office,Ministry of Defence,Singapore。
文摘Background:Excessive heat exposure can lead to hyperthermia in humans,which impairs physical performance and disrupts cognitive function.While heat is a known physiological stressor,it is unclear how severe heat stress affects brain physiology and function.Methods:Eleven healthy participants were subjected to heat stress from prolonged exercise or warm water immersion until their rectal temperatures(T_(re))attained 39.5℃,inducing exertional or passive hyperthermia,respectively.In a separate trial,blended ice was ingested before and during exercise as a cooling strategy.Data were compared to a control condition with seated rest(normothermic).Brain temperature(T_(br)),cerebral perfusion,and task-based brain activity were assessed using magnetic resonance imaging techniques.Results:T_(br)in motor cortex was found to be tightly regulated at rest(37.3℃±0.4℃(mean±SD))despite fluctuations in T_(re).With the development of hyperthermia,T_(br)increases and dovetails with the rising T_(re).Bilateral motor cortical activity was suppressed during high-intensity plantarflexion tasks,implying a reduced central motor drive in hyperthermic participants(T_(re)=38.5℃±0.1℃).Global gray matter perfusion and regional perfusion in sensorimotor cortex were reduced with passive hyperthermia.Executive function was poorer under a passive hyperthermic state,and this could relate to compromised visual processing as indicated by the reduced activation of left lateral-occipital cortex.Conversely,ingestion of blended ice before and during exercise alleviated the rise in both T_(re)and T_(bc)and mitigated heat-related neural perturbations.Conclusion:Severe heat exposure elevates T_(br),disrupts motor cortical activity and executive function,and this can lead to impairment of physical and cognitive performance.
基金This study was registered in February 2018.Registration identification number is ChiCTR1900021234.
文摘BACKGROUND Chronic obstructive pulmonary disease(COPD)is a common respiratory disorder that affects the elderly population and increases the risk of postoperative pulmonary complications(PPCs)after major surgeries.Sevoflurane is a volatile anesthetic that has been shown to have anti-inflammatory and antioxidant properties and attenuate lung injury in animal models.AIM To evaluate the protective effect of sevoflurane on the lung function of elderly COPD patients undergoing total hip arthroplasty(THA).METHODS In this randomized controlled trial,we randomly assigned 120 elderly patients with COPD,who were scheduled for THA,to receive either sevoflurane(sevoflurane group)or propofol(propofol group)as the maintenance anesthetic.The primary outcome was the incidence of PPCs within seven days after surgery.The secondary outcomes were changes in the lung function parameters,inflammatory markers,oxidative stress markers,and postoperative pain scores.RESULTS The results showed that the incidence of PPCs was significantly lower in the sevoflurane group than in the propofol group(10%vs 25%,P=0.02).Furthermore,the decline in the forced expiratory volume in 1 s,forced vital capacity,and peak expiratory flow was significantly lesser in the sevoflurane group than in the propofol group at 24 h and 48 h after surgery(P<0.05).The interleukin-6,tumor necrosis factor-alpha,malondialdehyde,and 8-hydroxy-2α-deoxyguanosine levels were significantly lower in the sevoflurane group than in the propofol group at 24 h after surgery(P<0.05).The sevoflurane group showed significantly lower postoperative pain scores than the propofol group at 6 h,12 h,and 24 h after surgery(P<0.05).CONCLUSION Sevoflurane protects the lung function of elderly COPD patients undergoing THA under general anesthesia by reducing the incidence of PPCs,attenuating inflammatory and oxidative stress responses,and alleviating postoperative pain.
基金funded by Key R&D Projects in Hubei Province (Grant No.2020BCA084)Innovative Group Project of Hubei Natural Science Foundation (Grant No.2020CFA043)。
文摘Prototype experiments were carried out on the explosion-proof performance of the RC blast wall.The mass of TNT detonated in the experiments is 5 kg and 20 kg respectively.The shock wave overpressure was tested in different regions.The above experiments were numerically simulated,and the simulated shock wave overpressure waveforms were compared with that tested and given by CONWEP program.The results show that the numerically simulated waveform is slightly different from the test waveform,but similar to CONWEP waveform.Through dimensional analysis and numerical simulation under different working conditions,the equation for the attenuation rate of the diffraction overpressure behind the blast wall was obtained.According to the corresponding standards,the degree of casualties and the damage degree of the brick concrete building at a certain distance behind the wall can be determined when parameters are set.The above results can provide a reference for the design and construction of the reinforced concrete blast wall.
文摘Our brain is constantly active.Even at rest,the brain carries out essential functions such as maintenance of resting potentials,subthreshold synaptic activity,and spiking activity related to information processing.This resting activity can be assessed with several in vivo tools,such as resting-state functional magnetic resonance imaging.This technique measures subtle changes in blood flow,volume,and oxygenation that occur over time.Although vascular in nature,resting-state functional magnetic resonance imaging is considered a reliable proxy of neural activity and several studies have shown that the brain is functionally divided into interacting neural networks called the“functional connectome”.
文摘Functional magnetic resonance imaging(fMRI)is a popular tool used to investigate not only how the brain responds to specific stimuli during sensorimotor or cognitive tasks,but also brain activity at rest.The physics beyond this approach is based on the analysis of the blood oxygenation level-dependent signal.
基金supported by The David and Inez Myers Foundation,Beachwood,OH,USA(to DT)。
文摘With the increase of life expectancy and population growth,neurodegenerative diseases have risen too and are projected to be a major health public concern by 2050.Neurodegenerative diseases are characterized by the progressive decline of cognitive function leading to the subsequent loss of autonomy.Although the underlying causes of neurodegeneration are not well understood,aging is the main risk factor.
基金funded by the Key Research and Development of the Gansu Province(No.20YF8FA 079)the Construction Project of the Gansu Clinical Medical Research Center(No.18JR2FA003).
文摘BACKGROUND Left ventricular(LV)remodeling and diastolic function in people with heart failure(HF)are correlated with iron status;however,the causality is uncertain.This Mendelian randomization(MR)study investigated the bidirectional causal relationship between systemic iron parameters and LV structure and function in a preserved ejection fraction population.METHODS Transferrin saturation(TSAT),total iron binding capacity(TIBC),and serum iron and ferritin levels were extracted as instrumental variables for iron parameters from meta-analyses of public genome-wide association studies.Individuals without myocardial infarction history,HF,or LV ejection fraction(LVEF)<50%(n=16,923)in the UK Biobank Cardiovascular Magnetic Resonance Imaging Study constituted the outcome dataset.The dataset included LV end-diastolic volume,LV endsystolic volume,LV mass(LVM),and LVM-to-end-diastolic volume ratio(LVMVR).We used a two-sample bidirectional MR study with inverse variance weighting(IVW)as the primary analysis method and estimation methods using different algorithms to improve the robustness of the results.RESULTS In the IVW analysis,one standard deviation(SD)increased in TSAT significantly correlated with decreased LVMVR(β=-0.1365;95%confidence interval[CI]:-0.2092 to-0.0638;P=0.0002)after Bonferroni adjustment.Conversely,no significant relationships were observed between other iron and LV parameters.After Bonferroni correction,reverse MR analysis showed that one SD increase in LVEF significantly correlated with decreased TSAT(β=-0.0699;95%CI:-0.1087 to-0.0311;P=0.0004).No heterogeneity or pleiotropic effects evidence was observed in the analysis.CONCLUSIONS We demonstrated a causal relationship between TSAT and LV remodeling and function in a preserved ejection fraction population.
基金supported by the National Natural Science Foundation of China under Grant Nos.12122401 and 12074007.
文摘In traditional finite-temperature Kohn–Sham density functional theory(KSDFT),the partial occupation of a large number of high-energy KS eigenstates restricts the use of first-principles molecular dynamics methods at extremely high temperatures.However,stochastic density functional theory(SDFT)can overcome this limitation.Recently,SDFT and the related mixed stochastic–deterministic density functional theory,based on a plane-wave basis set,have been implemented in the first-principles electronic structure software ABACUS[Q.Liu and M.Chen,Phys.Rev.B 106,125132(2022)].In this study,we combine SDFT with the Born–Oppenheimer molecular dynamics method to investigate systems with temperatures ranging from a few tens of eV to 1000 eV.Importantly,we train machine-learning-based interatomic models using the SDFT data and employ these deep potential models to simulate large-scale systems with long trajectories.Subsequently,we compute and analyze the structural properties,dynamic properties,and transport coefficients of warm dense matter.
基金supported by the National Key Research and Development Program of China(2020YFA0712900)the National Natural Science Foundation of China(12371093,12071197,12122102 and 12071431)+2 种基金the Key Project of Gansu Provincial National Science Foundation(23JRRA1022)the Fundamental Research Funds for the Central Universities(2233300008 and lzujbky-2021-ey18)the Innovative Groups of Basic Research in Gansu Province(22JR5RA391).
文摘Assume that L is a non-negative self-adjoint operator on L^(2)(ℝ^(n))with its heat kernels satisfying the so-called Gaussian upper bound estimate and that X is a ball quasi-Banach function space onℝ^(n) satisfying some mild assumptions.Let HX,L(ℝ^(n))be the Hardy space associated with both X and L,which is defined by the Lusin area function related to the semigroup generated by L.In this article,the authors establish various maximal function characterizations of the Hardy space HX,L(ℝ^(n))and then apply these characterizations to obtain the solvability of the related Cauchy problem.These results have a wide range of generality and,in particular,the specific spaces X to which these results can be applied include the weighted space,the variable space,the mixed-norm space,the Orlicz space,the Orlicz-slice space,and the Morrey space.Moreover,the obtained maximal function characterizations of the mixed-norm Hardy space,the Orlicz-slice Hardy space,and the Morrey-Hardy space associated with L are completely new.
文摘Several densities or probability laws of continuous random variables derive from the Euler Gamma function. These laws form the basis of sampling theory, namely hypothesis testing and estimation. Namely the gamma, beta, and Student law, through the chi-square law and the normal law are all distributions resulting from applications of Euleur functions.
基金funded by the National Natural Science Foundation of China(W.Zhang,Grant No.12220101002)Shaanxi Provincial Key Science and Technology Innovation Team(Y.Xu,Grant No.2023-CX-TD-14)+1 种基金the Young Talent Fund of Association for Science and Technology in Shaanxi,China(D.Jia,Grant No.20230240)the Chinese Studentship Council(D.Jia,Grant No.201908060224).
文摘The abalone shell,a composite material whose cross-section is composed of inorganic and organic layers,has high strength and toughness.Inspired by the abalone shell,several multi-layer composite plates with different layer sequences and thicknesses are studied as bullet-proof material in this paper.To investigate the ballistic performance of this multi-layer structure,the complete characterization model and related material parameters of large deformation,failure and fracture ofAl_(2)O_(3)ceramics andCarbon Fiber Reinforced Polymer(CFRP)are studied.Then,3D finite element models of the proposed composite plates with different layer sequences and thicknesses impacted by a 12.7 mm armor-piercing incendiary(API)are built using Abaqus to predict failure.The simulation results show that the CFRP/Al2O3 ceramic/Ultrahigh Molecular Weight Polyethylene(UHMWPE)/CFRP(1 mm/4 mm/4 mm/1 mm)composite is the optimized stack of layers.The simulation results under specified layer sequence and thickness have a reasonable correlation with the experimental results and reflect the failure and fracture of the multi-layer composite protective armor.
