Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective d...Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.展开更多
BACKGROUND:Tracheal intubation(TI)is a fundamental procedure for securing the airway or assisting ventilation in emergency medicine.Tracheal intubation in the lateral position(TILP)has been utilized in clinical practi...BACKGROUND:Tracheal intubation(TI)is a fundamental procedure for securing the airway or assisting ventilation in emergency medicine.Tracheal intubation in the lateral position(TILP)has been utilized in clinical practice,demonstrating potential advantages in specific scenarios,including emergency settings.However,there is a lack of comprehensive reviews and practical protocols on TILP application.To address this gap,we performed a narrative review,and provided evidence-based recommendations to formulate a practice protocol,to assist clinicians to effectively apply TILP.METHODS:We conducted a narrative review of TILP applications and developed recommendations based on clinical research evidence and clinical experience.Delphi method was used among the TILP consortium to grade the strength of the recommendations and to help reach consensus.The practice protocols were formulated as warranted by advancements in medical knowledge,technology,and practice.RESULTS:This narrative review summarized the current evidence on TILP application,highlighting its safety,efficacy,challenges,and potential complications.In total,24 recommendations and a clinical protocol for TILP application in emergency patients were established.CONCLUSION:TILP is a valuable technique in emergency medicine.We reviewed its application in emergency settings and formulated recommendations along with a clinical practice protocol.Future studies are needed to evaluate the safety and efficacy of TILP,broaden its scope of application,and explore effective training protocols.展开更多
Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann c...Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be impaired.Recently,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported.This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such treatment.An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis.After initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and taurursodiol.The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function.We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in vitro.After a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered saline.None of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or changes in vital signs.Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend.A more sensitive in-house assay suggested possible inflammasome activation during the disease course.A trend for clinical stabilization was observed during the infusion period.Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles.Initial findings suggest that this approach is safe.展开更多
This paper presents the design of an asymmetrically variable wingtip anhedral angles morphing aircraft,inspired by biomimetic mechanisms,to enhance lateral maneuver capability.Firstly,we establish a lateral dynamic mo...This paper presents the design of an asymmetrically variable wingtip anhedral angles morphing aircraft,inspired by biomimetic mechanisms,to enhance lateral maneuver capability.Firstly,we establish a lateral dynamic model considering additional forces and moments resulting during the morphing process,and convert it into a Multiple Input Multiple Output(MIMO)virtual control system by importing virtual inputs.Secondly,a classical dynamics inversion controller is designed for the outer-loop system.A new Global Fast Terminal Incremental Sliding Mode Controller(NDO-GFTISMC)is proposed for the inner-loop system,in which an adaptive law is implemented to weaken control surface chattering,and a Nonlinear Disturbance Observer(NDO)is integrated to compensate for unknown disturbances.The whole control system is proven semiglobally uniformly ultimately bounded based on the multi-Lyapunov function method.Furthermore,we consider tracking errors and self-characteristics of actuators,a quadratic programmingbased dynamic control allocation law is designed,which allocates virtual control inputs to the asymmetrically deformed wingtip and rudder.Actuator dynamic models are incorporated to ensure physical realizability of designed allocation law.Finally,comparative experimental results validate the effectiveness of the designed control system and control allocation law.The NDO-GFTISMC features faster convergence,stronger robustness,and 81.25%and 75.0%reduction in maximum state tracking error under uncertainty compared to the Incremental Nonlinear Dynamic Inversion Controller based on NDO(NDO-INDI)and Incremental Sliding Mode Controller based on NDO(NDO-ISMC),respectively.The design of the morphing aircraft significantly enhances lateral maneuver capability,maintaining a substantial control margin during lateral maneuvering,reducing the burden of the rudder surface,and effectively solving the actuator saturation problem of traditional aircraft during lateral maneuvering.展开更多
Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves ...Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.展开更多
Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives ...Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives and may lead them to be confined to bed.However,the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear.To address this issue,we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022.A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis.We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients.Multiple factor analyses revealed that higher upper motor neuron scores(hazard ratio[HR]=1.05,95%confidence interval[CI]=1.01–1.09,P=0.018),onset in the left limb(HR=0.72,95%CI=0.58–0.89,P=0.002),and a horizontal pattern of progression(HR=0.46,95%CI=0.37–0.58,P<0.001)were risk factors for a shorter interval until bilateral limb involvement.The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients.These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.展开更多
Fluorescence lateral flow immunoassay(LFA)has emerged as a powerful tool for rapid screening of various biomarkers owing to its simplicity,sensitivity and flexibility.It is noteworthy that fluorescent probe mainly det...Fluorescence lateral flow immunoassay(LFA)has emerged as a powerful tool for rapid screening of various biomarkers owing to its simplicity,sensitivity and flexibility.It is noteworthy that fluorescent probe mainly determines the analytical performance of LFA.Due to the emission and excitation wavelengths are located in the visible region,most fluorophores are inevitably subject to light scattering and background autofluorescence.Herein,we reported a novel LFA sensor based on the second near-infrared(NIR-Ⅱ)fluorescent probe with excellent anti-interference capability.The designed NIR-Ⅱprobe was the Nd^(3+)and Yb^(3+)doped rare earth nanoparticles(RENPs)by employing Nd^(3+)as energy donor and Yb^(3+)as energy acceptor,which of the donor-acceptor energy transfer(ET)efficiency reached up to 80.7%.Meanwhile,relying on the convenient and effective encapsulation strategy of poly(lactic-co-glycolic acid)(PLGA)microspheres to RENPs,the surface functionalized NIR-Ⅱprobe(RE@PLGA)was obtained for subsequent bioconjugation.Benefiting from the optical advantages of NIR-Ⅱprobe,this proposed NIR-ⅡLFA displayed a good linear relationship ranging from 7 ng/mL to 200 ng/mL for the detection ofα-fetoprotein(AFP),an important biomarker of hepatocellular carcinoma(HCC).The limit of detection(LOD)was determined as low as 3.0 ng/m L,which was of 8.3 times lower than clinical cutoff value.It is promising that LFA sensor based on this efficient RENPs probe provides new opportunities for high sensitive detection of various biomarkers in biological samples.展开更多
Recent experiments have found that a liquid crystal elastomer(LCE)rod supported in the middle can rotate continuously under horizontal illumination due to the combined impacts of gravity and light-fueled lateral bend-...Recent experiments have found that a liquid crystal elastomer(LCE)rod supported in the middle can rotate continuously under horizontal illumination due to the combined impacts of gravity and light-fueled lateral bend-ing deformation.Similar to traditional gravity-driven systems,it is constrained by the direction of gravity and cannot be applied in microgravity environments.This study introduces a lateral constraint to a liquid crystal elastomer rod system,enabling self-rotation under lighting from any direction,including horizontal and vertical illumination.Through theoretical modeling,the results indicate that the system can steadily rotate under the combined impacts of lateral forces and vertical illumination.Factors like thermal energy flux,thermal conduc-tivity coefficient,the LCE rod length,contraction coefficient,and friction coefficient affect the angular velocity of the self-rotation.The numerical computations align closely with the experimental data.Our proposed steadily self-rotating system features a simple structure with constant self-rotation.It operates independently of gravity direction,making it an excellent choice for special environments,such as the microgravity conditions on the Moon.The lateral constraint strategy presented in this study offers a general approach to expanding the applica-tions of gravity-driven self-sustained motion,with promising potential,especially in microgravity settings,where its versatility under varying lighting conditions could yield valuable insights.展开更多
Leaves and glumes act as lateral organs and have essential effects on photosynthesis and seed morphology,thus affecting yield.However,the molecular mechanisms controlling their polarity development in rice still need ...Leaves and glumes act as lateral organs and have essential effects on photosynthesis and seed morphology,thus affecting yield.However,the molecular mechanisms controlling their polarity development in rice still need further study.Here,we isolated a polarity defect of lateral organs 1(pdl1)mutant in rice,which exhibits twisted/filamentous-shaped leaves and cracked/filamentous-shaped lemmas caused by defects in polarity development.PDL1 encodes a SUPPRESSOR OF GENE SILENCING 3 protein localized in the cytoplasmic granules.PDL1 is expressed in the shoot apical meristem,inflorescence meristem,floral meristem,and lateral organs including leaves and floral organs.PDL1 is involved in the synthesis of tasiR-ARF,which may subsequently modulate the expression of OsARFs.Meanwhile,the expression levels of abaxial miR165/166 and the adaxial identity genes OSHBs were respectively increased and reduced significantly.The results of this study clarify the molecular mechanism by which PDL1-mediated tasiR-ARF synthesis regulates the lateral organ polarity development in rice.展开更多
AIM:To evaluate the outcome and the degree of patient satisfaction with the reconstruction of full-thickness medial and central lower lid defects using a pendular flap of the remaining lateral part of the lower lid.ME...AIM:To evaluate the outcome and the degree of patient satisfaction with the reconstruction of full-thickness medial and central lower lid defects using a pendular flap of the remaining lateral part of the lower lid.METHODS:Totally 20 patients with full thickness medial or central lower lid defects that could not be repaired by direct closure with or without cantholysis.A sliding full-thickness composite flap was created from the lateral part of the remaining lid to cover the defect.The posterior lamella of the induced lateral defect was repaired by either a periosteal flap alone or in combination with a free tarsal graft.Postoperative cosmetic and functional outcomes were evaluated.RESULTS:The mean age of the patients was 46.3±18.1y(20-70y).The defects ranged from 30%-80%of the lid width and resulted from the excision of lid tumors in 11 patients(55%)and from trauma in 9(45%)patients.Postoperative complications included one case of lateral graft ectropion,2 cases of lid retraction and 3 cases of marginal graft necrosis.Most of the patients had an acceptable final cosmetic outcome.CONCLUSION:Reconstruction of moderate-sized defects in the medial/central lower lid via a sliding flap yielded acceptable cosmetic and functional outcomes with high patient satisfaction.Large defects≥50%of the horizontal length are at greater risk of complications.Reconstruction of medial defects by this technique was associated with a greater incidence of complications.展开更多
OBJECTIVE:To compare the changes in gait parameters before and after the treatment of lateral ankle sprain using the rotating-pulling-poking manipulation, and explore the potential bio-mechanical mechanism of this man...OBJECTIVE:To compare the changes in gait parameters before and after the treatment of lateral ankle sprain using the rotating-pulling-poking manipulation, and explore the potential bio-mechanical mechanism of this manipulation. METHODS:Forty patients with lateral ankle sprains were randomly divided into two groups in a 1∶1 ratio using a random number table. The experimental group were treated by rotating-pulling-poking manipulation and elastic bandage external fixation, while the control group were treated by ice compress and elastic bandage external fixation. The treatment courses of the two groups were both 2 weeks. We used a three-dimensional motion capture system for kinematic measurements and a Bertec gait analysis force measurement system for mechanical measurements, and compared the changes in gait parameters between the two groups of patients before and after treatment. RESULTS:Intragroup comparison showed that the support time, swing time, peak of back extension, peak of plantar flexion, peak of toe pedal force, and peak of heel landing force of the affected feet in the experimental group were significantly improved compared to those before treatment(P < 0.05). The swing time of the affected feet in the control group was significantly improved compared to that before treatment(P < 0.05). The inter group comparison showed that the gait speed, stride length, peak of back extension, peak of plantar flexion, peak of toe pedal force, and peak of heel landing force of the affected feet in the experimental group were significantly better than those in the control group(P < 0.05). CONCLUSIONS:The rotating-pulling-poking manipulation can effectively improve the patient's gait and range of motion of the affected ankle joint, and enhance the negative gravity in the vertical direction of the affected foot, and the braking and driving forces in the front and back directions. This may be the potential biomechanical mechanism of the rotating-pulling-poking manipulation for treating lateral ankle sprain.展开更多
Subduction zones are major convergent boundaries,where the downgoing oceanic plates usually form continuous tabular slabs extending deep into the Earth’s interior.However,many subducting slabs especially those with y...Subduction zones are major convergent boundaries,where the downgoing oceanic plates usually form continuous tabular slabs extending deep into the Earth’s interior.However,many subducting slabs especially those with young ages,exhibit complex geometry,with varying degrees of influence on the overlying continent and surface environment.To better understand the mechanism of such slab deformation,we apply four-dimensional finite element geodynamic models with data assimilation to investigate the evolution of the Cocos subduction in Central America,where a double-slab configuration with complex tearing has recently been observed.We reproduce the subduction history of the Cocos slab since the Eocene.During this period,multiple episodes of tearing occurred within the Cocos slab,starting at 25 Ma.We find that the ancient Farallon slab,subducted during the Mesozoic,enhances the lateral pressure gradient across the slab hinge,promoting eastward mantle flow and tearing of the Cocos slab.The repeated tearing and subduction of the young Cocos plate have shaped the complex slab configuration in the region.展开更多
The successful penetration of government,corporate,and organizational IT systems by state and non-state actors deploying APT vectors continues at an alarming pace.Advanced Persistent Threat(APT)attacks continue to pos...The successful penetration of government,corporate,and organizational IT systems by state and non-state actors deploying APT vectors continues at an alarming pace.Advanced Persistent Threat(APT)attacks continue to pose significant challenges for organizations despite technological advancements in artificial intelligence(AI)-based defense mechanisms.While AI has enhanced organizational capabilities for deterrence,detection,and mitigation of APTs,the global escalation in reported incidents,particularly those successfully penetrating critical government infrastructure has heightened concerns among information technology(IT)security administrators and decision-makers.Literature review has identified the stealthy lateral movement(LM)of malware within the initially infected local area network(LAN)as a significant concern.However,current literature has yet to propose a viable approach for resource-efficient,real-time detection of APT malware lateral movement within the initially compromised LAN following perimeter breach.Researchers have suggested the nature of the dataset,optimal feature selection,and the choice of machine learning(ML)techniques as critical factors for detection.Hence,the objective of the research described here was to successfully demonstrate a simplified lightweight ML method for detecting the LM of APT vectors.While the nearest detection rate achieved in the LM domain within LAN was 99.89%,as reported in relevant studies,our approach surpassed it,with a detection rate of 99.95%for the modified random forest(RF)classifier for dataset 1.Additionally,our approach achieved a perfect 100%detection rate for the decision tree(DT)and RF classifiers with dataset 2,a milestone not previously reached in studies within this domain involving two distinct datasets.Using the ML life cycle methodology,we deployed K-nearest neighbor(KNN),support vector machine(SVM),DT,and RF on three relevant datasets to detect the LM of APTs at the affected LAN prior to data exfiltration/destruction.Feature engineering presented four critical APT LM intrusion detection(ID)indicators(features)across the three datasets,namely,the source port number,the destination port number,the packets,and the bytes.This study demonstrates the effectiveness of lightweight ML classifiers in detecting APT lateral movement after network perimeter breach.It contributes to the field by proposing a non-intrusive network detection method capable of identifying APT malware before data exfiltration,thus providing an additional layer of organizational defense.展开更多
Lateral flow immunoassay(LFIA),a rapid detection technique noted for simplicity and economy,has showcased indispensable applicability in diverse domains such as disease screening,food safety,and environmental monitori...Lateral flow immunoassay(LFIA),a rapid detection technique noted for simplicity and economy,has showcased indispensable applicability in diverse domains such as disease screening,food safety,and environmental monitoring.Nevertheless,challenges still exist in detecting ultra-low concentration analytes due to the inherent sensitivity limitations of LFIA.Recently,significant advances have been achieved by integrating enzyme activity probes and transforming LFIA into a highly sensitive tool for rapidly detecting trace analyte concentrations.Specifically,modifying natural enzymes or engineered nanozymes allows them to function as immune probes,directly catalyzing the production of signal molecules or indirectly initiating enzyme activity.Therefore,the signal intensity and detection sensitivity of LFIA are markedly elevated.The present review undertakes a comprehensive examination of pertinent research literature,offering a systematic analysis of recently proposed enzyme-based signal amplification strategies.By way of comparative assessment,the merits and demerits of current approaches are delineated,along with the identification of research avenues that still need to be explored.It is anticipated that this critical overview will garner considerable attention within the biomedical and materials science communities,providing valuable direction and insight toward the advancement of high-performance LFIA technologies.展开更多
The heterostructures incorporated with two or more distinctive two-dimensional(2D)materials have attracted great attention be-cause they could give rise to enhanced prop-erty in comparison with their individual counte...The heterostructures incorporated with two or more distinctive two-dimensional(2D)materials have attracted great attention be-cause they could give rise to enhanced prop-erty in comparison with their individual counterparts.Here,a water-assisted two-step rapid physical vapor deposition(rPVD)method was explored and used to synthesize Bi_(2)Te_(3)-Sb_(2)Te_(3)lateral het-erostructures(LHS)successfully.The Bi_(2)Te_(3)-Sb_(2)Te_(3)LHS is in nearly uniform size,and grows along three particular orientations with the intersection angles of 120°.Inter-estingly,we found that the water molecules play a significant role in determining the growth orientation,namely whether it will grow along the vertical or lateral direction in 2D structure.Hence,a growth mechanism of LHS based on the water-assisted two-step rPVD was present,which can be used as a general strategy and extended to the growth of other 2D heterostruc-tures or homostructures,such as SnS-SnSe LHS and SnS-SnS lateral homostructures.Fur-thermore,the second-harmonic generation intensity of the Bi_(2)Te_(3)-Sb_(2)Te_(3)LHS is much stronger than that of the Bi_(2)Te_(3)/Sb_(2)Te_(3)vertical heterostructures(VHS).This work opens a new approach for the synthesis of water-assisted lateral 2D heterostructures or homostruc-tures and offers a new method to enhance the second-harmonic generation properties of topo-logical insulating materials.展开更多
文摘Amyotrophic lateral sclerosis is a devastating neurodegenerative disease for which the current treatment approaches remain severely limited.The principal pathological alterations of the disease include the selective degeneration of motor neurons in the brain,brainstem,and spinal cord,as well as abnormal protein deposition in the cytoplasm of neurons and glial cells.The biological markers under extensive scrutiny are predominantly located in the cerebrospinal fluid,blood,and even urine.Among these biomarke rs,neurofilament proteins and glial fibrillary acidic protein most accurately reflect the pathologic changes in the central nervous system,while creatinine and creatine kinase mainly indicate pathological alterations in the peripheral nerves and muscles.Neurofilament light chain levels serve as an indicator of neuronal axonal injury that remain stable throughout disease progression and are a promising diagnostic and prognostic biomarker with high specificity and sensitivity.However,there are challenges in using neurofilament light chain to diffe rentiate amyotrophic lateral sclerosis from other central nervous system diseases with axonal injury.Glial fibrillary acidic protein predominantly reflects the degree of neuronal demyelination and is linked to non-motor symptoms of amyotrophic lateral sclerosis such as cognitive impairment,oxygen saturation,and the glomerular filtration rate.TAR DNA-binding protein 43,a pathological protein associated with amyotrophic lateral sclerosis,is emerging as a promising biomarker,particularly with advancements in exosome-related research.Evidence is currently lacking for the value of creatinine and creatine kinase as diagnostic markers;however,they show potential in predicting disease prognosis.Despite the vigorous progress made in the identification of amyotrophic lateral sclerosis biomarkers in recent years,the quest for definitive diagnostic and prognostic biomarke rs remains a formidable challenge.This review summarizes the latest research achievements concerning blood biomarkers in amyotrophic lateral sclerosis that can provide a more direct basis for the differential diagnosis and prognostic assessment of the disease beyond a reliance on clinical manifestations and electromyography findings.
基金National Natural Science Foundation of China(U24A20714 to XMF and 82102238 to PC)。
文摘BACKGROUND:Tracheal intubation(TI)is a fundamental procedure for securing the airway or assisting ventilation in emergency medicine.Tracheal intubation in the lateral position(TILP)has been utilized in clinical practice,demonstrating potential advantages in specific scenarios,including emergency settings.However,there is a lack of comprehensive reviews and practical protocols on TILP application.To address this gap,we performed a narrative review,and provided evidence-based recommendations to formulate a practice protocol,to assist clinicians to effectively apply TILP.METHODS:We conducted a narrative review of TILP applications and developed recommendations based on clinical research evidence and clinical experience.Delphi method was used among the TILP consortium to grade the strength of the recommendations and to help reach consensus.The practice protocols were formulated as warranted by advancements in medical knowledge,technology,and practice.RESULTS:This narrative review summarized the current evidence on TILP application,highlighting its safety,efficacy,challenges,and potential complications.In total,24 recommendations and a clinical protocol for TILP application in emergency patients were established.CONCLUSION:TILP is a valuable technique in emergency medicine.We reviewed its application in emergency settings and formulated recommendations along with a clinical practice protocol.Future studies are needed to evaluate the safety and efficacy of TILP,broaden its scope of application,and explore effective training protocols.
基金support from the Miami Project to Cure Paralysis,the Buoniconti Fund,and the Interdisciplinary Stem Cell Institute(to AK,WDD,JDG,and ADL)the unconditional support of Dean Henri Ford of the Leonard M.Miller School of Medicine at the University of Miami.
文摘Schwann cells are essential for the maintenance and function of motor neurons,axonal networks,and the neuromuscular junction.In amyotrophic lateral sclerosis,where motor neuron function is progressively lost,Schwann cell function may also be impaired.Recently,important signaling and potential trophic activities of Schwann cell-derived exosomal vesicles have been reported.This case report describes the treatment of a patient with advanced amyotrophic lateral sclerosis using serial intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles,marking,to our knowledge,the first instance of such treatment.An 81-year-old male patient presented with a 1.5-year history of rapidly progressive amyotrophic lateral sclerosis.After initial diagnosis,the patient underwent a combination of generic riluzole,sodium phenylbutyrate for the treatment of amyotrophic lateral sclerosis,and taurursodiol.The patient volunteered to participate in an FDA-approved single-patient expanded access treatment and received weekly intravenous infusions of allogeneic Schwann cell-derived exosomal vesicles to potentially restore impaired Schwann cell and motor neuron function.We confirmed that cultured Schwann cells obtained from the amyotrophic lateral sclerosis patient via sural nerve biopsy appeared impaired(senescent)and that exposure of the patient’s Schwann cells to allogeneic Schwann cell-derived exosomal vesicles,cultured expanded from a cadaver donor improved their growth capacity in vitro.After a period of observation lasting 10 weeks,during which amyotrophic lateral sclerosis Functional Rating Scale-Revised and pulmonary function were regularly monitored,the patient received weekly consecutive infusions of 1.54×1012(×2),and then consecutive infusions of 7.5×1012(×6)allogeneic Schwann cell-derived exosomal vesicles diluted in 40 mL of Dulbecco’s phosphate-buffered saline.None of the infusions were associated with adverse events such as infusion reactions(allergic or otherwise)or changes in vital signs.Clinical lab serum neurofilament and cytokine levels measured prior to each infusion varied somewhat without a clear trend.A more sensitive in-house assay suggested possible inflammasome activation during the disease course.A trend for clinical stabilization was observed during the infusion period.Our study provides a novel approach to address impaired Schwann cells and possibly motor neuron function in patients with amyotrophic lateral sclerosis using allogeneic Schwann cell-derived exosomal vesicles.Initial findings suggest that this approach is safe.
基金supported by the National Natural Science Foundation of China(Nos.62103052 and No.52175214)。
文摘This paper presents the design of an asymmetrically variable wingtip anhedral angles morphing aircraft,inspired by biomimetic mechanisms,to enhance lateral maneuver capability.Firstly,we establish a lateral dynamic model considering additional forces and moments resulting during the morphing process,and convert it into a Multiple Input Multiple Output(MIMO)virtual control system by importing virtual inputs.Secondly,a classical dynamics inversion controller is designed for the outer-loop system.A new Global Fast Terminal Incremental Sliding Mode Controller(NDO-GFTISMC)is proposed for the inner-loop system,in which an adaptive law is implemented to weaken control surface chattering,and a Nonlinear Disturbance Observer(NDO)is integrated to compensate for unknown disturbances.The whole control system is proven semiglobally uniformly ultimately bounded based on the multi-Lyapunov function method.Furthermore,we consider tracking errors and self-characteristics of actuators,a quadratic programmingbased dynamic control allocation law is designed,which allocates virtual control inputs to the asymmetrically deformed wingtip and rudder.Actuator dynamic models are incorporated to ensure physical realizability of designed allocation law.Finally,comparative experimental results validate the effectiveness of the designed control system and control allocation law.The NDO-GFTISMC features faster convergence,stronger robustness,and 81.25%and 75.0%reduction in maximum state tracking error under uncertainty compared to the Incremental Nonlinear Dynamic Inversion Controller based on NDO(NDO-INDI)and Incremental Sliding Mode Controller based on NDO(NDO-ISMC),respectively.The design of the morphing aircraft significantly enhances lateral maneuver capability,maintaining a substantial control margin during lateral maneuvering,reducing the burden of the rudder surface,and effectively solving the actuator saturation problem of traditional aircraft during lateral maneuvering.
文摘Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.
基金supported by the National Natural Science Foundation of China,Nos.82071426,81873784Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(all to DF)。
文摘Amyotrophic lateral sclerosis is a rare neurodegenerative disease characterized by the involvement of both upper and lower motor neurons.Early bilateral limb involvement significantly affects patients'daily lives and may lead them to be confined to bed.However,the effect of upper and lower motor neuron impairment and other risk factors on bilateral limb involvement is unclear.To address this issue,we retrospectively collected data from 586 amyotrophic lateral sclerosis patients with limb onset diagnosed at Peking University Third Hospital between January 2020 and May 2022.A univariate analysis revealed no significant differences in the time intervals of spread in different directions between individuals with upper motor neuron-dominant amyotrophic lateral sclerosis and those with classic amyotrophic lateral sclerosis.We used causal directed acyclic graphs for risk factor determination and Cox proportional hazards models to investigate the association between the duration of bilateral limb involvement and clinical baseline characteristics in amyotrophic lateral sclerosis patients.Multiple factor analyses revealed that higher upper motor neuron scores(hazard ratio[HR]=1.05,95%confidence interval[CI]=1.01–1.09,P=0.018),onset in the left limb(HR=0.72,95%CI=0.58–0.89,P=0.002),and a horizontal pattern of progression(HR=0.46,95%CI=0.37–0.58,P<0.001)were risk factors for a shorter interval until bilateral limb involvement.The results demonstrated that a greater degree of upper motor neuron involvement might cause contralateral limb involvement to progress more quickly in limb-onset amyotrophic lateral sclerosis patients.These findings may improve the management of amyotrophic lateral sclerosis patients with limb onset and the prediction of patient prognosis.
基金supported by the National Natural Science Foundation of China(Nos.U2267221,22107029,22377135)the Bohai Rim Advanced Research Institute for Drug Discovery(No.LX215002)+5 种基金the Natural Science Foundation of Shandong Province(No.ZR2022QH212)the Taishan Scholars Program(No.tsqn202312305)the Young Elite Scientists Sponsorship Program by Chinese Chemical Societythe Fundamental Research Projects of Science&Technology Innovation and development Plan in Yantai City(No.2023JCYJ059)the Shandong Laboratory Program(No.SYS202205)the Shanghai Postdoctoral Excellence Program(No.2023704)。
文摘Fluorescence lateral flow immunoassay(LFA)has emerged as a powerful tool for rapid screening of various biomarkers owing to its simplicity,sensitivity and flexibility.It is noteworthy that fluorescent probe mainly determines the analytical performance of LFA.Due to the emission and excitation wavelengths are located in the visible region,most fluorophores are inevitably subject to light scattering and background autofluorescence.Herein,we reported a novel LFA sensor based on the second near-infrared(NIR-Ⅱ)fluorescent probe with excellent anti-interference capability.The designed NIR-Ⅱprobe was the Nd^(3+)and Yb^(3+)doped rare earth nanoparticles(RENPs)by employing Nd^(3+)as energy donor and Yb^(3+)as energy acceptor,which of the donor-acceptor energy transfer(ET)efficiency reached up to 80.7%.Meanwhile,relying on the convenient and effective encapsulation strategy of poly(lactic-co-glycolic acid)(PLGA)microspheres to RENPs,the surface functionalized NIR-Ⅱprobe(RE@PLGA)was obtained for subsequent bioconjugation.Benefiting from the optical advantages of NIR-Ⅱprobe,this proposed NIR-ⅡLFA displayed a good linear relationship ranging from 7 ng/mL to 200 ng/mL for the detection ofα-fetoprotein(AFP),an important biomarker of hepatocellular carcinoma(HCC).The limit of detection(LOD)was determined as low as 3.0 ng/m L,which was of 8.3 times lower than clinical cutoff value.It is promising that LFA sensor based on this efficient RENPs probe provides new opportunities for high sensitive detection of various biomarkers in biological samples.
基金supported by the University Natural Science Research Project of Anhui Province(Grant Nos.2022AH040042 and 2022AH020029)the National Natural Science Foundation of China(Grant No.12172001)+1 种基金Anhui Provincial Natural Science Foundation(Grant No.2208085Y01)the Housing and Urban-Rural Development Science and Technology Project of Anhui Province(Grant No.2022-YF069).
文摘Recent experiments have found that a liquid crystal elastomer(LCE)rod supported in the middle can rotate continuously under horizontal illumination due to the combined impacts of gravity and light-fueled lateral bend-ing deformation.Similar to traditional gravity-driven systems,it is constrained by the direction of gravity and cannot be applied in microgravity environments.This study introduces a lateral constraint to a liquid crystal elastomer rod system,enabling self-rotation under lighting from any direction,including horizontal and vertical illumination.Through theoretical modeling,the results indicate that the system can steadily rotate under the combined impacts of lateral forces and vertical illumination.Factors like thermal energy flux,thermal conduc-tivity coefficient,the LCE rod length,contraction coefficient,and friction coefficient affect the angular velocity of the self-rotation.The numerical computations align closely with the experimental data.Our proposed steadily self-rotating system features a simple structure with constant self-rotation.It operates independently of gravity direction,making it an excellent choice for special environments,such as the microgravity conditions on the Moon.The lateral constraint strategy presented in this study offers a general approach to expanding the applica-tions of gravity-driven self-sustained motion,with promising potential,especially in microgravity settings,where its versatility under varying lighting conditions could yield valuable insights.
基金supported by the National Natural Science Foundation of China(32470354,31900612,and 31971919)the Natural Science Foundation of Chongqing,China(cstc2020jcyj-jqX0020)+1 种基金the Foundation for Innovative Research Groups of the Natural Science Foundation of Chongqing,China(cstc2021jcyj-cxttX0004)the Chongqing Talent Program Foundation,China(cstc2024ycjhbgzxm0063)。
文摘Leaves and glumes act as lateral organs and have essential effects on photosynthesis and seed morphology,thus affecting yield.However,the molecular mechanisms controlling their polarity development in rice still need further study.Here,we isolated a polarity defect of lateral organs 1(pdl1)mutant in rice,which exhibits twisted/filamentous-shaped leaves and cracked/filamentous-shaped lemmas caused by defects in polarity development.PDL1 encodes a SUPPRESSOR OF GENE SILENCING 3 protein localized in the cytoplasmic granules.PDL1 is expressed in the shoot apical meristem,inflorescence meristem,floral meristem,and lateral organs including leaves and floral organs.PDL1 is involved in the synthesis of tasiR-ARF,which may subsequently modulate the expression of OsARFs.Meanwhile,the expression levels of abaxial miR165/166 and the adaxial identity genes OSHBs were respectively increased and reduced significantly.The results of this study clarify the molecular mechanism by which PDL1-mediated tasiR-ARF synthesis regulates the lateral organ polarity development in rice.
文摘AIM:To evaluate the outcome and the degree of patient satisfaction with the reconstruction of full-thickness medial and central lower lid defects using a pendular flap of the remaining lateral part of the lower lid.METHODS:Totally 20 patients with full thickness medial or central lower lid defects that could not be repaired by direct closure with or without cantholysis.A sliding full-thickness composite flap was created from the lateral part of the remaining lid to cover the defect.The posterior lamella of the induced lateral defect was repaired by either a periosteal flap alone or in combination with a free tarsal graft.Postoperative cosmetic and functional outcomes were evaluated.RESULTS:The mean age of the patients was 46.3±18.1y(20-70y).The defects ranged from 30%-80%of the lid width and resulted from the excision of lid tumors in 11 patients(55%)and from trauma in 9(45%)patients.Postoperative complications included one case of lateral graft ectropion,2 cases of lid retraction and 3 cases of marginal graft necrosis.Most of the patients had an acceptable final cosmetic outcome.CONCLUSION:Reconstruction of moderate-sized defects in the medial/central lower lid via a sliding flap yielded acceptable cosmetic and functional outcomes with high patient satisfaction.Large defects≥50%of the horizontal length are at greater risk of complications.Reconstruction of medial defects by this technique was associated with a greater incidence of complications.
基金the National Traditional Chinese Medicine Inheritance and Innovation Team Project:Traditional Chinese Medicine Innovation Team for Prevention and Treatment of Bone and Joint Degenerative Diseases (No. ZYYCXTD-C-202003)National Natural Science Foundation of China:the study on the Quantification and Mechanism of the rotating-pulling-poking manipulation in the Treatment of Lateral Ankle Sprain (No. 81473694)China Academy of Chinese Medical Sciences Science and Technology Innovation Project:Establishment and Promotion of a Simulation Operation Evaluation System for Rotating-pulling-poking Manipulation (CI2021A02015)。
文摘OBJECTIVE:To compare the changes in gait parameters before and after the treatment of lateral ankle sprain using the rotating-pulling-poking manipulation, and explore the potential bio-mechanical mechanism of this manipulation. METHODS:Forty patients with lateral ankle sprains were randomly divided into two groups in a 1∶1 ratio using a random number table. The experimental group were treated by rotating-pulling-poking manipulation and elastic bandage external fixation, while the control group were treated by ice compress and elastic bandage external fixation. The treatment courses of the two groups were both 2 weeks. We used a three-dimensional motion capture system for kinematic measurements and a Bertec gait analysis force measurement system for mechanical measurements, and compared the changes in gait parameters between the two groups of patients before and after treatment. RESULTS:Intragroup comparison showed that the support time, swing time, peak of back extension, peak of plantar flexion, peak of toe pedal force, and peak of heel landing force of the affected feet in the experimental group were significantly improved compared to those before treatment(P < 0.05). The swing time of the affected feet in the control group was significantly improved compared to that before treatment(P < 0.05). The inter group comparison showed that the gait speed, stride length, peak of back extension, peak of plantar flexion, peak of toe pedal force, and peak of heel landing force of the affected feet in the experimental group were significantly better than those in the control group(P < 0.05). CONCLUSIONS:The rotating-pulling-poking manipulation can effectively improve the patient's gait and range of motion of the affected ankle joint, and enhance the negative gravity in the vertical direction of the affected foot, and the braking and driving forces in the front and back directions. This may be the potential biomechanical mechanism of the rotating-pulling-poking manipulation for treating lateral ankle sprain.
基金supported by the Strategy Priority Research Program(Category B)of the Chinese Academy of Sciences(Grant No.XDB0710000)the National Natural Science Foundation of China(Grant No.92355302)supported by the National Supercomputer Center in Tianjin.
文摘Subduction zones are major convergent boundaries,where the downgoing oceanic plates usually form continuous tabular slabs extending deep into the Earth’s interior.However,many subducting slabs especially those with young ages,exhibit complex geometry,with varying degrees of influence on the overlying continent and surface environment.To better understand the mechanism of such slab deformation,we apply four-dimensional finite element geodynamic models with data assimilation to investigate the evolution of the Cocos subduction in Central America,where a double-slab configuration with complex tearing has recently been observed.We reproduce the subduction history of the Cocos slab since the Eocene.During this period,multiple episodes of tearing occurred within the Cocos slab,starting at 25 Ma.We find that the ancient Farallon slab,subducted during the Mesozoic,enhances the lateral pressure gradient across the slab hinge,promoting eastward mantle flow and tearing of the Cocos slab.The repeated tearing and subduction of the young Cocos plate have shaped the complex slab configuration in the region.
基金Rabdan Academy for funding the research presented in the paper.
文摘The successful penetration of government,corporate,and organizational IT systems by state and non-state actors deploying APT vectors continues at an alarming pace.Advanced Persistent Threat(APT)attacks continue to pose significant challenges for organizations despite technological advancements in artificial intelligence(AI)-based defense mechanisms.While AI has enhanced organizational capabilities for deterrence,detection,and mitigation of APTs,the global escalation in reported incidents,particularly those successfully penetrating critical government infrastructure has heightened concerns among information technology(IT)security administrators and decision-makers.Literature review has identified the stealthy lateral movement(LM)of malware within the initially infected local area network(LAN)as a significant concern.However,current literature has yet to propose a viable approach for resource-efficient,real-time detection of APT malware lateral movement within the initially compromised LAN following perimeter breach.Researchers have suggested the nature of the dataset,optimal feature selection,and the choice of machine learning(ML)techniques as critical factors for detection.Hence,the objective of the research described here was to successfully demonstrate a simplified lightweight ML method for detecting the LM of APT vectors.While the nearest detection rate achieved in the LM domain within LAN was 99.89%,as reported in relevant studies,our approach surpassed it,with a detection rate of 99.95%for the modified random forest(RF)classifier for dataset 1.Additionally,our approach achieved a perfect 100%detection rate for the decision tree(DT)and RF classifiers with dataset 2,a milestone not previously reached in studies within this domain involving two distinct datasets.Using the ML life cycle methodology,we deployed K-nearest neighbor(KNN),support vector machine(SVM),DT,and RF on three relevant datasets to detect the LM of APTs at the affected LAN prior to data exfiltration/destruction.Feature engineering presented four critical APT LM intrusion detection(ID)indicators(features)across the three datasets,namely,the source port number,the destination port number,the packets,and the bytes.This study demonstrates the effectiveness of lightweight ML classifiers in detecting APT lateral movement after network perimeter breach.It contributes to the field by proposing a non-intrusive network detection method capable of identifying APT malware before data exfiltration,thus providing an additional layer of organizational defense.
基金Financial supports from the National Natural Science Foundation of China(NSFC,Nos.52272144 and 22205048)Heilongjiang Provincial Natural Science Foundation of China(No.JQ2022E001)+3 种基金China Postdoctoral Science Foundation(Nos.2022M710931 and 2023T160154)Heilongjiang Postdoctoral Science Foundation(No.LBH-Z22010)Natural Science Foundation of Shandong Province(No.ZR2020ZD42)the Fundamental Research funds for the Central Universities are greatly acknowledged.
文摘Lateral flow immunoassay(LFIA),a rapid detection technique noted for simplicity and economy,has showcased indispensable applicability in diverse domains such as disease screening,food safety,and environmental monitoring.Nevertheless,challenges still exist in detecting ultra-low concentration analytes due to the inherent sensitivity limitations of LFIA.Recently,significant advances have been achieved by integrating enzyme activity probes and transforming LFIA into a highly sensitive tool for rapidly detecting trace analyte concentrations.Specifically,modifying natural enzymes or engineered nanozymes allows them to function as immune probes,directly catalyzing the production of signal molecules or indirectly initiating enzyme activity.Therefore,the signal intensity and detection sensitivity of LFIA are markedly elevated.The present review undertakes a comprehensive examination of pertinent research literature,offering a systematic analysis of recently proposed enzyme-based signal amplification strategies.By way of comparative assessment,the merits and demerits of current approaches are delineated,along with the identification of research avenues that still need to be explored.It is anticipated that this critical overview will garner considerable attention within the biomedical and materials science communities,providing valuable direction and insight toward the advancement of high-performance LFIA technologies.
基金supported by the Natural Science Foundation of Fujian Province of China(2022J01646)。
文摘The heterostructures incorporated with two or more distinctive two-dimensional(2D)materials have attracted great attention be-cause they could give rise to enhanced prop-erty in comparison with their individual counterparts.Here,a water-assisted two-step rapid physical vapor deposition(rPVD)method was explored and used to synthesize Bi_(2)Te_(3)-Sb_(2)Te_(3)lateral het-erostructures(LHS)successfully.The Bi_(2)Te_(3)-Sb_(2)Te_(3)LHS is in nearly uniform size,and grows along three particular orientations with the intersection angles of 120°.Inter-estingly,we found that the water molecules play a significant role in determining the growth orientation,namely whether it will grow along the vertical or lateral direction in 2D structure.Hence,a growth mechanism of LHS based on the water-assisted two-step rPVD was present,which can be used as a general strategy and extended to the growth of other 2D heterostruc-tures or homostructures,such as SnS-SnSe LHS and SnS-SnS lateral homostructures.Fur-thermore,the second-harmonic generation intensity of the Bi_(2)Te_(3)-Sb_(2)Te_(3)LHS is much stronger than that of the Bi_(2)Te_(3)/Sb_(2)Te_(3)vertical heterostructures(VHS).This work opens a new approach for the synthesis of water-assisted lateral 2D heterostructures or homostruc-tures and offers a new method to enhance the second-harmonic generation properties of topo-logical insulating materials.
