Intranasal administration of stem cell-derived exosomes for central nervous system diseases

Exosomes,lipid bilayer-enclosed small cellular vesicles,are actively secreted by various cells and play crucial roles in intercellular communication.These nanosized vesicles transport internalized proteins,mRNA,miRNA,and other bioactive molecules.Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders.These exosomes exhibit multifaceted properties including antiapoptotic,anti-inflammatory,neurogenic,and vasculogenic effects.Furthermore,exosomes offer several advantages over stem cell therapy,such as high preservation capacity,low immunogenicity,the ability to traverse the blood-brain barrier,and the potential for drug encapsulation.Consequently,researchers have turned their attention to exosomes as a novel therapeutic avenue.Nonetheless,akin to the limitations of stem cell treatment,the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application.To overcome this hurdle,intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system.By exploiting the olfactory and trigeminal nerve axons,this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier.Notably,exosomes,owing to their small size,can readily access the nerve pathways using this method.As a result,intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments.In this comprehensive review,we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases.Furthermore,we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

Hypothalamic circuits and aging:keeping the circadian clock updated

Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.

Advances in Polysaccharide-Based Microneedle Systems for the Treatment of Ocular Diseases

The eye,a complex organ isolated from the systemic circulation,presents significant drug delivery challenges owing to its protective mechanisms,such as the blood-retinal barrier and corneal impermeability.Conventional drug administration methods often fail to sustain therapeutic levels and may compromise patient safety and compliance.Polysaccharidebased microneedles(PSMNs)have emerged as a transformative solution for ophthalmic drug delivery.However,a comprehensive review of PSMNs in ophthalmology has not been published to date.In this review,we critically examine the synergy between polysaccharide chemistry and microneedle technology for enhancing ocular drug delivery.We provide a thorough analysis of PSMNs,summarizing the design principles,fabrication processes,and challenges addressed during fabrication,including improving patient comfort and compliance.We also describe recent advances and the performance of various PSMNs in both research and clinical scenarios.Finally,we review the current regulatory frameworks and market barriers that are relevant to the clinical and commercial advancement of PSMNs and provide a final perspective on this research area.

Strengthening pharmacotherapy research for COVID-19-induced pulmonary fibrosis

The global spread of severe acute respiratory syndrome coronavirus 2 has resulted in a significant number of individuals developing pulmonary fibrosis(PF),an irreversible lung injury.This condition can manifest within a short inter-val following the onset of pneumonia symptoms,sometimes even within a few days.While lung transplantation is a potentially lifesaving procedure,its limited availability,high costs,intricate surgeries,and risk of immunological rejection present significant drawbacks.The optimal timing of medication administration for coronavirus disease 2019(COVID-19)-induced PF remains controversial.Despite this,it is crucial to explore pharmacotherapy interventions,involving early and preventative treatment as well as pharmacotherapy options for advanced-stage PF.Additionally,studies have demonstrated disparities in anti-fibrotic treatment based on race and gender factors.Genetic mutations may also impact therapeutic efficacy.Enhancing research efforts on pharmacotherapy interventions,while considering relevant pharmacological factors and optimizing the timing and dosage of medication administration,will lead to enhanced,personalized,and fair treatment for individuals impacted by COVID-19-related PF.These measures are crucial in lessening the burden of the disease on healthcare systems and improving patients'quality of life.

Ancylostoma ceylanicum and other zoonotic canine hookworms:neglected public and animal health risks in the Asia-Pacific region

Zoonotic hookworm infections remain a significant public health problem,causing nearly 500 milion cases globally and approximately four million disability-adjusted life years lost annually.More than one-fth of these cases are attrib-uted to Ancylostoma ceylanicum,an emerging zoonotic health issue in the Asia-Pacific region.This review presents key research gaps regarding the epidemiology,diagnosis,control,prevention and elimination of A.ceylanicum and other canine zoonotic hookworms as neglected health threats.A.ceylanicum is the second most prevalent human hook-worm in the region;it is the most common hookworm among dogs and cats-reservoirs of zoonotic infections.Previous population genetic and phylogenetic analyses revealed that A.ceylanicum has three possible transmis-sion dynamics:zoonotic,animal-only,and human-only pathways.The actual burden of zoonotic ancylostomiasis in most endemic countries remains unknown due to the use of parasitological techniques(e.g.,Kato-Katz thick smear and floatation techniques)that have reduced diagnostic performance and do not allow accurate species identifica-tion in helminth surveys.The emergence of benzimidazole resistance in soil-transmitted helminths(STHs),includ-ing hookworms,is a concern due to the protracted implementation of mass drug administration(MDA).Resistance is conferred by single nucleotide polymorphisms(SNPs)that occur in theβ-tubulin isotype 1 gene.These mutations have been reported in drug-resistant A.caninum but have not been found in A.ceylanicum in the field.A.ceylanicum remains understudied in the Asia-Pacific region.The zoonotic nature of the parasite warrants investigation of its occur-rence in human and animal reservoir hosts to understand the dynamics of zoonotic transmission in different endemic foci.The detection of benzimidazole resistance-associated SNPs in zoonotic hookworms from Asia-Pacific countries has yet to be thoroughly explored.Considering the high level of hookworm endemicity in the region,the circulation of resistant isolates between humans and animals potentially presents a significant One Health threat that can under-mine current MDA and proposed animal deworming-based control efforts.

Repurposing Loperamide as an Anti-Infection Drug for the Treatment of Intracellular Bacterial Pathogens

Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular infection.Herein,we applied a cell-based screening approach to a US Food and Drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.

Ophthalmic complications of injectable facial fillers

The recently published mini-review article by Miotti et al is an effort to clarify various aspects regarding the choice between fat grafts and fillers in facial aesthetic surgery.One of the complications associated with the administration of fillers is the possibility of vascular injury and spread of the dermal filler into the orbit,causing unexpected effects at a site distant from that of the initial injection,including ophthalmoplegia,ptosis and even visual compromise.Acute vision loss following filler injection is a devastating complication,occurring in up to 0.0008%of cases.The greatest risk of this complication occurs with nasal augmentation,followed by glabellar wrinkle treatment.While injected autologous fat predominantly occludes the proximal portion of the ophthalmic artery,hyaluronic acid fillers obstruct the ophthalmic artery comparatively distally.Treatment interventions include thrombolysis,hyperbaric oxygen therapy,oral aspirin,cobamamide and acetazolamide and administration of corticosteroids.However,most studies show a poor prognosis in the form of partial or no recovery of vision.Hence,prevention is of paramount importance.A high index of suspicion is also warranted on the part of both those administering as well as receiving injections of facial fillers to prevent potentially vision-threatening complications of this seemingly innocuous procedure.

Flexner's legacy and the future of medical education:Embracing challenge and opportunity

This editorial comments on the article by Alzerwi.We focus on the development course,present challenges,and future perspectives of medical education.Modern medical education is gradually undergoing significant and profound changes worldwide.The emergence of new ideas,methodologies,and techniques has created opportunities for medical education developments and brought new concerns and challenges,ultimately promoting virtuous progress in medical education reform.The sustainable development of medical education needs joint efforts and support from governments,medical colleges,hospitals,researchers,administrators,and educators.

Innovation Analysis of Rural Agricultural Economic Management Model in the Context of the Belt and Road Initiative

[Objectives]To explore innovative strategies for rural agricultural economic development in the context of the Belt and Road Initiative.[Methods]This research adopts the method of literature review and field research,systematically combs the research results related to the Belt and Road Initiative and rural agricultural economic management,and deeply understands the actual situation of rural agricultural economic management.[Results]The research shows that in the context of the Belt and Road Initiative,the rural agricultural economy is facing new development opportunities and challenges,but there are also some problems.In the new period,we should accelerate the innovative development of rural agricultural economy by promoting market-oriented reform,strengthening scientific and technological innovation,optimizing the industrial structure,deepening international cooperation and other measures.The Belt and Road Initiative provides an important opportunity for the innovation of rural agricultural economic management.Rural agricultural economic management should be actively integrated into the Belt and Road construction to improve the level of rural agricultural economic management.[Conclusions]This study provides useful exploration and reference for the innovation of rural agricultural economic management models,which helps to promote the healthy development of rural agricultural economy and achieve the goal of rural revitalization.

Optimization and Construction of Collaborative Office under the Background of Smart Campus in Universities

At present, with the continuous development of technologies such as the Internet, big data, and artificial intelligence, smart campuses in universities are being rapidly constructed. Improving the informatization level of administrative management work is also an important content. The collaborative office work in multiple departments requires more standardized, convenient, intelligent, and secure office systems. In response to this issue, this article analyzes the optimization and construction process of collaborative office systems based on the development of university informatization, summarizes the operational results, and explores the prospects of smart office.

Economic Coercion Inhibits Sustainable Global Growth

The Biden administration’s tariff hikes on Chinese products came,unsurprisingly,a month or so before the first 2024 presidential debate between incumbent U.S.President Joe Biden and former President Donald Trump.They are thus preparing to play the China card once more.Biden has announced tariff increases across key sectors,purportedly to“protect American workers and businesses from China’s unfair trade practices,”according to the White House.The White House Fact Sheet also emphasizes the Biden administration’s creation of jobs in key sectors,as a countermeasure to the Trump administration’s failed China strategy to increase American exports and boost American manufacturing.The administration’s political agenda is thus laid bare.

Problem Analysis and Effective Strategies of Ecological Civilization Education for Undergraduates in the New Age

The ecological civilization in the new age is one important aspect for undergraduates.We must enhance the concept of their civilization and improve the quality of civilization.Carrying out ecological civilization education in colleges and universities has a practical significance for enriching the contents of ideological and political education to realize their all-round development.Nowadays,some undergraduates lack awareness of ecological civilization and ignore its importance.For this reason,undergraduates need to pay attention to ecological civilization and improve their own ecological civilization literacy to promote the all-round development in qualities in the new age.This paper mainly analyzes the current problems in undergraduates’ecological civilization education and explores effective strategies to solve the current problems in undergraduates’ecological civilization education.The strategies include integrating ecological civilization resources,innovating methods of ecological civilization,strengthening ecological educator team construction,embodying ecological culture in campus construction and creating the atmosphere,emphasizing innovative practices for ecological civilization,strengthening publicity of social-ecological civilization,and attaching importance to family education of ecological civilization.

The Development Trend of Enterprise Business Administration and the Innovation of Management Mode

In the context of the new period,the continuous growth of social and economic levels and the rapid update of information technology have significantly impacted the business management of Chinese enterprises,presenting substantial challenges.The intensification of market competition exerts development pressure on many enterprises,and coupled with the unstable strength of some businesses,numerous problems in business management arise.These issues hinder the smooth execution of various business activities.Therefore,it is crucial to ensure effective business administration to conduct different business activities in an orderly manner,promptly avoid adverse risks,and strengthen control over multiple factors.The innovation and improvement of business administration are of great significance for enhancing the management level and market competitiveness of modern enterprises,accelerating their healthy development,and creating numerous opportunities.Consequently,this paper analyzes and explores the development trends of enterprise business administration and the innovation of management models for reference.

The basic core traditional C hinese medicine for the prevention and treatment of COVID-19 and its active mechanisms

Background:COVID-19 has had a dramatic impact on human health,economies,societies,and livelihoods around the world.Traditional Chinese medicine(TCM)formulae have played an important role in the prevention and treatment of COVID-19.WHO evaluated the role of TCM in treating of COVID-19 and encouraged other countries to promote the use of TCM formulae.However,the key is to find the basic core traditional Chinese medicine(BC-TCM)among those formulae.Methods:For the first time,we mined the data of TCM formulae in CNIPA and analyzed herb characteristics and association rules.We then determined the BC-TCM and screened main compounds and therapeutic targets.Finally,the potential molecular mechanisms were explored by using enrichment analyses and molecular docking.Results:This study screened 123 patented TCM formulae,including 312 herbs.According to frequency statistics and association rules,nine herbs(Gan Cao,Jin Yinhua,Guang Huoxiang,Fu Ling,Huang Qi,Jie Geng,Lian Qiao,Cang Zhu,Ku Xingren)were selected as the BC-TCM.The BC-TCM involved 166 main compounds and 48 therapeutic targets.The active compounds Hederagenin,Spinasterol,Beta-sitosterol,and Liquiritin had high binding activity to the COVID-19 targets 3CL,ACE2,and core targets RELA,HSP90AA1,STAT3,MAPK3,and TP53 according to molecular docking results.Interestingly,Hederagenin might be a potential compound for the prevention and treatment of COVID-19.Conclusion:Our research predicted and confirmed the preventive therapeutic effect of BC-TCM on COVID-19.This has the potential to broaden the scope of TCM,guide people in using clinical formulae,and provide valuable insights for future TCM discovery research.

Exploring Corporate Tax Compliance in the Era of Digital Tax Collection and Administration:Insights from the“Golden Tax Phase Four”Project

This article primarily examines the current state of tax collection and management,alongside other associated issues.It integrates insights from China’s“14th Five-Year Plan”and anticipates the imminent implementation of the“Golden Tax Phase Four.”With this backdrop,the article offers recommendations for advancing the reform of the tax collection and management system,fostering the development of intelligent taxation,and accelerating the modernization of tax collection and management in China.

结核病患者手机应用程序督导服药的应用及其影响因素

目的分析上海市2021年新发非利福平耐药肺结核患者手机应用程序(application,APP)督导服药的应用情况及其影响因素,为进一步优化手机APP督导管理方式的应用策略提供依据。方法通过易督导患者管理系统(e-Patient Service System,e-PSS)平台收集患者管理数据,通过《中国疾病预防控制信息系统》结核病子系统收集患者性别、年龄组、职业、户籍、病原学结果等信息。对手机APP督导管理应用情况及相关影响因素进行统计分析。采用卡方检验和多因素非条件logistic回归分析结核病患者使用手机APP督导服药的影响因素。结果2021年上海市采用e-PSS平台管理患者2687例,其中使用手机APP督导服药的患者790例,占29.4%。使用手机APP督导服药的患者总体服药率为99.8%,总体规则服药率为99.5%,坚持打卡率为24.1%。多因素分析结果显示,病原学结果阳性(OR值为2.328,95%CI为1.474~3.825)及阴性(OR值为1.699,95%CI为1.067~2.809),年龄60岁及以下(≤20岁、>20~40岁、>40~60岁的OR值分别为11.017、16.864、9.002,95%CI分别为3.793~40.430、6.881~55.914、3.674~29.837),职业为农民(OR值为1.801,95%CI为1.289~2.519)的患者更倾向于使用手机APP进行服药管理。结论结核病患者日常服药管理应针对不同类型人群采用不同的督导管理方式,对于>20~40岁年龄组、病原学阳性、职业为农民、有合并症的结核病患者,社区医生可以优先推荐使用手机APP进行服药管理。

Exploring the potential to enhance drug distribution in the brain subregion via intranasal delivery of nanoemulsion in combination with borneol as a guider

The number of people with Alzheimer’s disease(AD)is increasing annually,with the nidus mainly concentrated in the cortex and hippocampus.Despite of numerous efforts,effective treatment of AD is still facing great challenges due to the blood brain barrier(BBB)and limited drug distribution in the AD nidus sites.Thus,in this study,using vinpocetine(VIN)as a model drug,the objective is to explore the feasibility of tackling the above bottleneck via intranasal drug delivery in combination with a brain guider,borneol(BOR),using nanoemulsion(NE)as the carrier.First of all,the NE were prepared and characterized.In vivo behavior of the NE after intranasal administration was investigated.Influence of BOR dose,BOR administration route on drug brain targeting behavior was evaluated,and the influence of BOR addition on drug brain subregion distribution was probed.It was demonstrated that all the NE had comparable size and similar retention behavior after intranasal delivery.Compared to intravenous injection,improved brain targeting effect was observed by intranasal route,and drug targeting index(DTI)of the VIN–NE group was 154.1%,with the nose-to-brain direct transport percentage(DTP)35.1%.Especially,remarkably enhanced brain distribution was achieved after BOR addition in the NE,with the extent depending on BOR dose.VIN brain concentration was the highest in the VIN-1-BOR-NE group at BOR dose of 1 mg/kg,with the DTI reaching 596.1%and the DTP increased to 83.1%.BOR could exert better nose to brain delivery when administrated together with the drug via intranasal route.Notably,BOR can remarkably enhance drug distribution in both hippocampus and cortex,the nidus areas of AD.In conclusion,in combination with intranasal delivery and the intrinsic brain guiding effect of BOR,drug distribution not only in the brain but also in the cortex and hippocampus can be enhanced significantly,providing the perquisite for improved therapeutic efficacy of AD.

Application of Tranexamic Acid in Shoulder Arthroscopic Surgery:A Randomised Controlled Trial

Objective To explore the optimal administration route of tranexamic acid(TXA)in shoulder arthroscopic surgery.Methods Patients undergoing arthroscopic rotator cuff repair were randomly divided into four groups:control group(without TXA treatment),intravenous group(TXA was intravenously administered 10 minutes before surgery),irrigation group(TXA was added to the irrigation fluid during subacromial decompression and acromioplasty),and intravenous plus irrigation group(TXA was applied both intravenously and via intra-articular irrigation).The primary outcome was visual clarity assessed with visual analog scale(VAS)score,and the secondary outcomes included irrigation fluid consumption and time to subacromial decompression and acromioplasty procedure.Results There were 134 patients enrolled in the study,including 33 in the control group,35 in the intravenous group,32 in the irrigation group,and 34 in the intravenous plus irrigation group.The median and interquartile range of VAS scores for the intravenous,irrigation,and intravenous plus irrigation groups were 2.70(2.50,2.86)(Z=-3.677,P=0.002),2.67(2.50,2.77)(Z=-3.058,P<0.001),and 2.91(2.75,3.00)(Z=-6.634,P<0.001),respectively,significantly higher than that of the control group[2.44(2.37,2.53)].Moreover,the control group consumed more irrigation fluid than the intravenous group,irrigation group,and intravenous plus irrigation group(all P<0.05).The intravenous plus irrigation group consumed less irrigation fluid than either the intravenous group or the irrigation group(both P<0.001).There was no difference in subacromial decompression and acromioplasty operative time among the four groups.Conclusion TXA applied both topically and systematically can improve intraoperative visual clarity,and the combined application is more effective.

拜登政府对华气候政策的竞争逻辑

Climate change is a core issue on which China and the United States(US)are relatively willing to cooperate.Compared with Barack Obama,Joe Biden has incorporated additional elements of climate governance into the competitive track.His administration has attached increased importance to reciprocity and uniformity in sharing responsibilities,relied heavily on coercion and inducement as methods for advancing relevant policy agendas,and focused on the clean technology sector in a bid to decouple from China.The competitive logic of the climate policy pursued by the Biden administration has spotlighted its objectives:to seek leadership in global climate governance,to serve America's value-oriented diplomacy by manipulating ideologies in the realm of climate governance,and to sustain a relative dominant position in the climate governance system.To a certain extent,the competitive measures by the Biden administration have shaped the external environment of China's development and its participation in global climate governance.However,they can hardly achieve the core objective of serving America's strategic competition against China.Such a competitive climate policy will destabilize the strategic relationship between China and the US,impeding breakthroughs that resemble the Paris Agreement in the multilateral climate process.

Research on the intelligent internet nursing model based on the child respiratory and asthma control test scale for asthma management of preschool children

BACKGROUND Childhood asthma is a common respiratory ailment that significantly affects preschool children.Effective asthma management in this population is particularly challenging due to limited communication skills in children and the necessity for consistent involvement of a caregiver.With the rise of digital healthcare and the need for innovative interventions,Internet-based models can potentially offer relatively more efficient and patient-tailored care,especially in children.AIM To explore the impact of an intelligent Internet care model based on the child respiratory and asthma control test(TRACK)on asthma management in preschool children.METHODS The study group comprised preschoolers,aged 5 years or younger,that visited the hospital's pediatric outpatient and emergency departments between January 2021 and January 2022.Total of 200 children were evenly and randomly divided into the observation and control groups.The control group received standard treatment in accordance with the 2016 Guidelines for Pediatric Bronchial Asthma and the Global Initiative on Asthma.In addition to above treatment,the observation group was introduced to an intelligent internet nursing model,emphasizing the TRACK scale.Key measures monitored over a six-month period included the frequency of asthma attack,emergency visits,pulmonary function parameters(FEV1,FEV1/FVC,and PEF),monthly TRACK scores,and the SF-12 quality of life assessment.Post-intervention asthma control rates were assessed at six-month follow-up.RESULTS The observation group had fewer asthma attacks and emergency room visits than the control group(P<0.05).After six months of treatment,the children in both groups had higher FEV1,FEV1/FVC,and PEF(P<0.05).Statistically significant differences were observed between the two groups(P<0.05).For six months,children in the observation group had a higher monthly TRACK score than those in the control group(P<0.05).The PCS and MCSSF-12 quality of life scores were relatively higher than those before the nursing period(P<0.05).Furthermore,the groups showed statistically significant differences(P<0.05).The asthma control rate was higher in the observation group than in the control group(P<0.05).CONCLUSION TRACK based Intelligent Internet nursing model may reduce asthma attacks and emergency visits in asthmatic children,improve lung function,quality of life,and the TRACK score and asthma control rate.The effect of nursing was significant,allowing for development of an asthma management model.