Investigating the association between work family conflict (WFC) and generalized anxiety disorder (GAD) in an Australian community-based cohort study.

PURPOSE: Difficulties managing work and family demands are common and have been found to be associated with stress and poor mental health. However, very few studies have examined Work Family Conflict (WFC) in connection with diagnosable anxiety disorders (and none with Australian representative data). The current study investigated whether high WFC was significantly associated with a diagnosis of Generalised Anxiety Disorder (GAD) after controlling for a broad range of socio-demographic contextual factors, related psychosocial job, family and individual characteristics, and prior anxiety symptom history. METHODS: Data was analysed from an Australian population-based community cohort - the Personality and Total Health (PATH) Through Life project. Eligible participants (N = 1159) were employed full-time or part-time, with data collected by both online questionnaire and face-to-face interview. Presence of Generalised Anxiety Disorder (GAD) in the past 12-months was diagnosed by the GAD module in the Composite International Diagnostic Interview (CIDI) (based on DSM-IV criteria) and severe anxiety symptoms were measured using the Patient Health Questionnaire (PHQ) 7-item 'other anxiety' model. RESULTS: The findings consistently showed that those experiencing high WFC had higher odds of a GAD diagnosis (final adjusted model: CIDI: OR: 2.55, CI: 1.38-4.70) as well as clinical levels of anxiety symptoms (PHQ: OR:2.61, CI:1.44,4.72). This was the case after controlling for an extensive range of covariates. CONCLUSIONS: This is one of the first studies to show that WFC is associated with greater likelihood of GAD. The challenge of juggling both work and family can have far-reaching impacts - not just increasing distress broadly, but also potentially increasing the likelihood of clinically diagnosable anxiety.

Precise Modulation of Pericyte Dysfunction by a Multifunctional Nanoprodrug to Ameliorate Alzheimer's Disease.

Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a yet-untapped frontier for AD. Inspired by the elevation of vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species (ROS) levels in pericyte lesions, we fabricated a multifunctional nanoprodrug by conjugating the hybrid peptide VLC, a fusion of the VCAM-1 high-affinity peptide VHS and the neuroprotective apolipoprotein mimetic peptide COG1410, to curcumin (Cur) through phenylboronic ester bond (VLC@Cur-NPs) to alleviate complex pericyte-related pathological changes. Importantly, VLC@Cur-NPs effectively homed to pericyte lesions via VLC and released their contents upon ROS stimulation to maximize their regulatory effects. Consequently, VLC@Cur-NPs markedly increased pericyte regeneration to form a positive feedback loop and thus improved neurovascular function and ultimately alleviated memory defects in APP/PS1 transgenic mice. We present a promising therapeutic strategy for AD that can precisely modulate pericytes and has the potential to treat other cerebrovascular diseases.

Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis.

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer's disease (AD) collectively culminate in neuronal deterioration. In the context of AD, autophagy dysfunction, a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes. Therefore, multidimensional autophagy regulation strategies co-manipulating "autophagy induction" and "lysosome degradation" in dual targets (neuron and microglia) are more reliable for AD treatment. Accordingly, we designed an RP-1 peptide-modified reactive oxygen species (ROS)-responsive micelles (RT-NM) loading rapamycin or gypenoside XVII. Guided by RP-1 peptide, the ligand of receptor for advanced glycation end products (RAGE), RT-NM efficiently targeted neurons and microglia in AD-affected region. This nano-combination therapy activated the whole autophagy-lysosome pathway by autophagy induction (rapamycin) and lysosome improvement (gypenoside XVII), thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes, and promoting Aß phagocytosis. Resultantly, it decreased aberrant protein burden, alleviated neuroinflammation, and eventually ameliorated memory defects in 3 × Tg-AD transgenic mice. Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.

Human Umbilical Cord Mesenchymal Stem Cells Improve Lung Function in Chronic Obstructive Pulmonary Disease Rat Model Through Regulating Lung Microbiota.

BACKGROUND: The use of human umbilical cord mesenchymal stem cells (UC-MSCs) has shown promise in improving the pathophysiological characteristics of rats with chronic obstructive pulmonary disease (COPD). However, more research is needed to understand the exact mechanism behind their therapeutic effects and their impact on lung microbiota. METHODS: To investigate this, rats were randomly assigned to one of 3 groups: Control, COPD + vehicle, and COPD + UC-MSCs group. Lung function changes after UC-MSCs therapy were evaluated weekly for 6 weeks. Additionally, lactate dehydrogenase (LDH), TNF (tumor necrosis factor)-α, IL (interleukin)-6, and IL-1ß level in bronchoalveolar lavage fluid (BALF) were analyzed. Arterial blood gas and weight were recorded. Hematoxylin and eosin (HE) staining was used to examine lung pathology, while changes in the lung microbiota were evaluated through 16S rRNA sequencing. RESULTS: The administration of UC-MSCs in rats led to a progressive amelioration of COPD, as demonstrated by enhanced lung function and reduced inflammatory response. UC-MSCs treatment significantly altered the structure and diversity of the lung microbiota, effectively preventing microbiota dysbiosis. This was achieved by increasing the abundance of Bacteroidetes and reducing the levels of Proteobacteria. Additionally, treatment with UC-MSCs reduced the activation of pathways associated with COPD, including microbial metabolism, ABC transporters, and Quorum sensing. The group of UC-MSCs showed increased metabolic pathways, such as amino acid biosynthesis, purine metabolism, starch and sucrose metabolism, and biosynthesis of secondary metabolites, compared to the COPD group. CONCLUSIONS: The use of UC-MSCs was found to reduce inflammation and improve lung function in rats with COPD. The mechanism may be related to the lung microbiota, as UC-MSCs improved the communities of lung microbiota and regulated dysregulated metabolic pathways.

The target region focused imaging method for scanning ion conductance microscopy.

Scanning ion conductance microscopy (SICM) has developed rapidly and has wide applications in biomedicine, single-cell science and other fields. SICM scanning speed is limited by the conventional raster-type scanning method, which spends most of time on imaging the substrate and does not focus enough on the target area. In order to solve this problem, a target region focused (TRF) method is proposed, which can effectively avoid the scanning of unnecessary substrate areas and enables SICM to image the target area only to achieve high-speed and effective local scanning. TRF method and conventional hopping mode scanning method are compared in the experiments using breast cancer cells and rat basophilic leukemia cells as experimental materials. It was demonstrated that our method can reduce the scanning time for a single sample image significantly without losing scanning information or compromising the quality of imaging. The TRF method developed in this paper can provide an efficient and fast scanning strategy for improving the imaging performance of SICM systems, which can be applied to the dynamic features of cell samples in the fields of biology and pharmacology analysis.

Enhancing Triplet-Triplet Annihilation Upconversion of Pyrene Derivatives for Photoredox Catalysis via Molecular Engineering.

Triplet-triplet annihilation upconversion (TTA-UC) has the potential to enhance photoredox catalysis yield. It includes a sensitizer and an annihilator. Efficient and stable annihilators are essential for photoredox catalysis, yet only a few examples are reported. Herein, we designed four novel pyrene annihilators (1, 2, 3 and 4) via introducing aryl-alkynyl groups onto pyrene to systematically modulate their singlet and triplet energies. Coupled with platinum octaethylporphyrin (PtOEP), the TTA-UC efficiency is enhanced gradually as the number of aryl-alkynyl group increases. When combining 4 with palladium tetraphenyl-tetrabenzoporphyrin (PdTPTBP), we achieved the highest red-to-green upconversion efficiency (22.4±0.3 %) (out of a 50 % maximum) so far. Then, this pair was used to activate photooxidation of aryl boronic acid under red light (630 nm), which achieved a great improved reaction yield compared to that activated by green light directly. The results not only provide a design strategy for efficient annihilators, but also show the advantage of applying TTA-UC into improving the photoredox catalysis yield.

Dual Enzyme Cascade-Activated Popcorn-Like Nanoparticles Efficiently Remodeled Stellate Cells to Alleviate Pancreatic Desmoplasia.

In pancreatic cancer, excessive desmoplastic stroma severely impedes drug access to tumor cells. By reverting activated pancreatic stellate cells (PSCs) to quiescence, all-trans retinoic acid (ATRA) can attenuate their stromal synthesis and remodel the tumor-promoting microenvironment. However, its modulatory effects have been greatly weakened due to its limited delivery to PSCs. Therefore, we constructed a tripeptide RFC-modified gelatin/oleic acid nanoparticle (RNP@ATRA), which delivered ATRA in an enzyme-triggered popcorn-like manner and effectively resolved the delivery challenges. Specifically, surface RFC was cleaved by aminopeptidase N (APN) on the tumor endothelium to liberate l-arginine, generating nitric oxide (NO) for tumor-specific vasodilation. Then, massive nanoparticles were pushed from the vessels into tumors, showing 5.1- and 4.0-fold higher intratumoral accumulation than free ATRA and APN-inert nanoparticles, respectively. Subsequently, in the interstitium, matrix metalloproteinase-2-induced gelatin degradation caused RNP@ATRA to rapidly release ATRA, promoting its interstitial penetration and PSC delivery. Thus, activated PSCs were efficiently reverted to quiescence, and stroma secretion and vascular compression were reduced, thereby enhancing intratumoral delivery of small-molecule or nanosized chemotherapeutics. Ultimately, RNP@ATRA combined with chemotherapeutics markedly suppressed tumor growth and metastasis without causing additional toxicities. Overall, this work provides a potential nanoplatform for the efficient delivery of PSC-modifying agents in pancreatic cancer and other stroma-rich tumors.

Investigating the effects of solution viscosity on the stability and success rate of SECCM imaging.

Due to the capability of simultaneously detecting the morphology and electrochemical information of samples and limiting the electrochemical reaction to a range approximately the size of the inner diameter of the pipette tip opening, scanning electrochemical cell microscopy (SECCM) enables higher precision local electrochemical measurement and surface material delivery and has been demonstrating unique advantages and broad application prospects. However, the meniscus droplet at the pipette tip of SECCM is equivalent to the opening radius of the pipette tip, which is usually tens of nanometers to hundreds of nanometers. The tiny meniscus droplet makes it susceptible to evaporation and crystallization, which increases the likelihood of the pipette colliding with the sample during the scanning process, resulting in the failure of scanning. In this paper, the influence of solution viscosity on the shape variation of the droplet at the tip during the movement of the pipette of SECCM was studied by finite element analysis. It is proved that the increase of solution viscosity is helpful in reducing the shape variation of the droplet at the tip during the movement of the pipette. Then scanning experiments were carried out using a flat Au substrate and Au substrates with rounded triangle and rounded rectangular convex structures as the samples. According to the experimental results, increasing solution viscosity improves scanning success rates and scanning quality and effectively lowers the MSE of the scanning results. The experimental results also show that SECCM can image at a higher speed when the solution's viscosity increases since the deformation of the droplet at the tip is less than with a typical solution.

Enhancement of Microglia Functions by Developed Nano-Immuno-Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment.

Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy is explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia "restorer") and D PPA-1 peptide (immune checkpoint blockade) are integrated on a nano-immuno-synergist (D PAM@OA) to work coordinately. The self-assembled OA core is coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which D PPA-1 peptide is attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, D PAM@OA effectively promotes the recruitment and activation of effector T cells by inhibiting aberrant activation of Signal transducer and activator of transcription (STAT-3) pathway in microglia, and assists activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hinders malignant glioma progression and recurrence with or without temozolomide. The work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors.

Influence of outdoor meteorological parameters on the indoor environment of blast furnace yard.

The blast furnace tapping yard is a typical heavy-pollution industrial plant. Aiming at the problem of high temperature and high dust, the CFD model is established to simulate the coupling of indoor and outdoor wind environment, field measurement data are used to verify the simulation model, and then, the influence of outdoor meteorological parameters on the flow field and smoke emission of blast furnace discharge field is studied. The research results show that the impact of the outdoor wind environment on the air temperature, velocity, and PM2.5 concentration field in the workshop cannot be ignored, and the influence on dust removal in the blast furnace is significant. When the outdoor velocity increases or the temperature decreases, the ventilation volume in the workshop increases exponentially, the capture efficiency of PM2.5 by the dust cover gradually decreases, and the PM2.5 concentration in the working area gradually increases. The outdoor wind direction has the most significant influence on the ventilation volume of industrial plants and the capture rate of PM2.5 by a dust cover. For factories facing north from south, the southeast wind is an unfavorable wind direction with a small ventilation volume, and the concentration of PM2.5 in the area where workers are active exceeds 2.5 mg/m3. The concentration of the working area is affected by the dust removal hood and the outdoor wind environment. Therefore, outdoor meteorological conditions under the dominant wind direction in different seasons should be considered when designing the dust removal hood.

Quantile Regression for biomarkers in the UK Biobank.

Genome-wide association studies (GWAS) for biomarkers important for clinical phenotypes can lead to clinically relevant discoveries. GWAS for quantitative traits are based on simplified regression models modeling the conditional mean of a phenotype as a linear function of genotype. An alternative and easy to apply approach is quantile regression that naturally extends linear regression to the analysis of the entire conditional distribution of a phenotype of interest by modeling conditional quantiles within a regression framework. Quantile regression can be applied efficiently at biobank scale using standard statistical packages in much the same way as linear regression, while having some unique advantages such as identifying variants with heterogeneous effects across different quantiles, including non-additive effects and variants involved in gene-environment interactions; accommodating a wide range of phenotype distributions with invariance to trait transformation; and overall providing more detailed information about the underlying genotype-phenotype associations. Here, we demonstrate the value of quantile regression in the context of GWAS by applying it to 39 quantitative traits in the UK Biobank (n>300,000 individuals). Across these 39 traits we identify 7,297 significant loci, including 259 loci only detected by quantile regression. We show that quantile regression can help uncover replicable but unmodelled gene-environment interactions, and can provide additional key insights into poorly understood genotype-phenotype correlations for clinically relevant biomarkers at minimal additional cost.

Diagnosis, management, and prevention of malfunctions in anesthesia machines.

BACKGROUND: The anesthesia machine serves as a vital piece of lifesaving equipment. OBJECTIVE: To analyze incidents of failures in the Primus anesthesia machine and address these malfunctions to reduce recurrence of failure, save maintenance costs, enhance safety, and improve overall efficiency. METHODS: We conducted an analysis on the records pertaining to the maintenance and parts replacement of the Primus anesthesia machines used in the Department of Anaesthesiology at Shanghai Chest Hospital over the past two years to identify the most common causes of failure. This included an assessment of the damaged parts and degree of damage, as well as a review of factors that caused the fault. RESULTS: The main cause of the faults in the anesthesia machine was found to be air leakage and excessive humidity in the central air supply of the medical crane. The logistics department was instructed to increase inspections to check and ensure the quality of the central gas supply and ensure gas safety. CONCLUSION: Summarizing the methods for dealing with anesthesia machine faults can save hospitals a lot of money, ensure normal hospital and department maintenance, and provide a reference to repair such faults. The use of Internet of Things platform technology can continuously develop the direction of digitalization, automation, and intelligent management in each stage of the "whole life cycle" of anesthesia machine equipment.

The optimal pre-post allocation for randomized clinical trials.

BACKGROUND: In pre-post designs, analysis of covariance (ANCOVA) is a standard technique to detect the treatment effect with a continuous variable measured at baseline and follow-up. For measurements subject to a high degree of variability, it may be advisable to repeat the pre-treatment and/or follow-up assessments. In general, repeating the follow-up measurements is more advantageous than repeating the pre-treatment measurements, while the latter can still be valuable and improve efficiency in clinical trials. METHODS: In this article, we report investigations of using multiple pre-treatment and post-treatment measurements in randomized clinical trials. We consider the sample size formula for ANCOVA under general correlation structures with the pre-treatment mean included as the covariate and the mean follow-up value included as the response. We propose an optimal experimental design of multiple pre-post allocations under a specified constraint, that is, given the total number of pre-post treatment visits. The optimal number of the pre-treatment measurements is derived. For non-linear models, closed-form formulas for sample size/power calculations are generally unavailable, but we conduct Monte Carlo simulation studies instead. RESULTS: Theoretical formulas and simulation studies show the benefits of repeating the pre-treatment measurements in pre-post randomized studies. The optimal pre-post allocation derived from the ANCOVA extends well to binary measurements in simulation studies, using logistic regression and generalized estimating equations (GEE). CONCLUSIONS: Repeating baselines and follow-up assessments is a valuable and efficient technique in pre-post design. The proposed optimal pre-post allocation designs can minimize the sample size, i.e., achieve maximum power.

Occlusion of two semicircular canals does not disrupt normal hearing in adult mice.

Vertigo is a debilitating disease affecting 15-20% of adults worldwide. Vestibular peripheral vertigo is the most common cause of vertigo, often due to Meniere's disease and benign paroxysmal positional vertigo. Although some vertigo symptoms can be controlled by conservative treatment and/or vestibular rehabilitation therapy, these treatments do not work for some patients. Semicircular canal occlusion surgery has proven to be very effective for these patients with intractable vertigo. However, its application is limited due to concern that the procedure will disrupt normal hearing. In this study, we investigated if occlusion of two semicircular canals would jeopardize auditory function by comparing auditory function and hair cell morphology between the surgical and contralateral ears before and after the surgery in a mouse model. By measuring the auditory brainstem response and distortion product otoacoustic emission 4 weeks post-surgery, we show that auditory function does not significantly change between the surgical and contralateral ears. In addition, confocal imaging has shown no hair cell loss in the cochlear and vestibular sensory epithelia, and scanning electron microscopy also indicates normal stereocilia morphology in the surgical ear. More importantly, the endocochlear potential measured from the surgical ear is not significantly different than that seen in the contralateral ear. Our study suggests that occlusion of two semicircular canals does not disrupt normal hearing in the mouse model, providing a basis to extend the procedure to patients, even those with normal hearing, benefitting more patients with intractable vertigo attacks.

A subpopulation of agouti-related peptide neurons exciting corticotropin-releasing hormone axon terminals in median eminence led to hypothalamic-pituitary-adrenal axis activation in response to food restriction.

The excitatory action of gamma-aminobutyric-acid (GABA) in the median-eminence (ME) led to the steady-state release of corticotropin-releasing hormone (CRH) from CRH axon terminals, which modulates the hypothalamic-pituitary-adrenal (HPA) axis. However, in ME, the source of excitatory GABAergic input is unknown. We examined agouti-related peptide (AgRP) expressing neurons in the arcuate nucleus as a possible source for excitatory GABAergic input. Here, we show that a subpopulation of activated AgRP neurons directly project to the CRH axon terminals in ME elevates serum corticosterone levels in 60% food-restricted mice. This increase in serum corticosterone is not dependent on activation of CRH neuronal soma in the paraventricular nucleus. Furthermore, conditional deletion of Na+-K+-2Cl- cotransporter-1 (NKCC1), which promotes depolarizing GABA action, from the CRH axon terminals results in significantly lower corticosterone levels in response to food restriction. These findings highlight the important role of a subset of AgRP neurons in HPA axis modulation via NKCC1-dependent GABAergic excitation in ME.

WNK3 kinase maintains neuronal excitability by reducing inwardly rectifying K+ conductance in layer V pyramidal neurons of mouse medial prefrontal cortex.

The with-no-lysine (WNK) family of serine-threonine kinases and its downstream kinases of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1) may regulate intracellular Cl- homeostasis through phosphorylation of cation-Cl- co-transporters. WNK3 is expressed in fetal and postnatal brains, and its expression level increases during development. Its roles in neurons, however, remain uncertain. Using WNK3 knockout (KO) mice, we investigated the role of WNK3 in the regulation of the intracellular Cl- concentration ([Cl-]i) and the excitability of layer V pyramidal neurons in the medial prefrontal cortex (mPFC). Gramicidin-perforated patch-clamp recordings in neurons from acute slice preparation at the postnatal day 21 indicated a significantly depolarized reversal potential for GABAA receptor-mediated currents by 6 mV, corresponding to the higher [Cl-]i level by ~4 mM in KO mice than in wild-type littermates. However, phosphorylation levels of SPAK and OSR1 and those of neuronal Na+-K+-2Cl- co-transporter NKCC1 and K+-Cl- co-transporter KCC2 did not significantly differ between KO and wild-type mice. Meanwhile, the resting membrane potential of neurons was more hyperpolarized by 7 mV, and the minimum stimulus current necessary for firing induction was increased in KO mice. These were due to an increased inwardly rectifying K+ (IRK) conductance, mediated by classical inwardly rectifying (Kir) channels, in KO neurons. The introduction of an active form of WNK3 into the recording neurons reversed these changes. The potential role of KCC2 function in the observed changes of KO neurons was investigated by applying a selective KCC2 activator, CLP290. This reversed the enhanced IRK conductance in KO neurons, indicating that both WNK3 and KCC2 are intimately linked in the regulation of resting K+ conductance. Evaluation of synaptic properties revealed that the frequency of miniature excitatory postsynaptic currents (mEPSCs) was reduced, whereas that of inhibitory currents (mIPSCs) was slightly increased in KO neurons. Together, the impact of these developmental changes on the membrane and synaptic properties was manifested as behavioral deficits in pre-pulse inhibition, a measure of sensorimotor gating involving multiple brain regions including the mPFC, in KO mice. Thus, the basal function of WNK3 would be the maintenance and/or development of both intrinsic and synaptic excitabilities.

Cleavage of AUF1 by Coxsackievirus B Affects DDX5 Regulatory on Viral Replication through iTRAQ Proteomics Analysis.

Coxsackievirus B (CVB) 3C protease (3Cpro) plays a specific cleavage role on AU-rich binding factor (AUF1, also called hnRNP D), which consequently disputes the regulation of AUF1 on downstream molecules. In our study, the iTRAQ approach was first used to quantify the differentially expressed cellular proteins in AUF1-overexpressing HeLa cells, which provides straightforward insight into the role of AUF1 during viral infection. A total of 1,290 differentially expressed proteins (DEPs), including 882 upregulated and 408 downregulated proteins, were identified. The DEPs are involved in a variety of cellular processes via GO terms, protein-protein interactions, and a series of further bioinformatics analyses. Among the DEPs, some demonstrated important roles in cellular metabolism. In particular, DDX5 was further verified to be negatively regulated by AUF1 and increased in CVB-infected cells, which in turn promoted CVB replication. These findings provide potential novel ideas for exploring new antiviral therapy targets.

Analysis and research on the influence of music on students' mental health under the background of deep learning.

This paper makes a detailed analysis and discussion on the impact of music appreciation on college students' mental health and the influence of music appreciation on students' mental health, mental energy and mental structure. There has long been the idea of music promoting people's mental health, as well as related research in the field of music psychology. For this specific group of primary and secondary school students, it should be said that it is relatively rare to consider using music education to promote their mental health. This paper summarizes the advantages of deep learning over shallow learning, explains the necessity of introducing deep learning, and describes the data representation of deep learning and several typical deep learning models. This study adopts the method of multi-evidence to conduct in-depth research and analysis. On the basis of in-depth study and research, this paper analyzes and studies the impact of music on students' mental health, so as to lay a foundation for future research on students' mental health. In terms of influencing factors and strategies to promote students' in-depth learning, we should apply the research results to specific teaching situations with the help of advanced digital technology, and strive to combine theory with practice. The research shows that college students' mental health is an important part of quality education in Colleges and universities, and music education plays an important role in the implementation of quality education.

Cholinergic Neuron Targeting Nanosystem Delivering Hybrid Peptide for Combinatorial Mitochondrial Therapy in Alzheimer's Disease.

Mitochondrial dysfunction in neurons has recently become a promising therapeutic target for Alzheimer's disease (AD). Regulation of dysfunctional mitochondria through multiple pathways rather than antioxidation monotherapy indicates synergistic therapeutic effects. Therefore, we developed a multifunctional hybrid peptide HNSS composed of antioxidant peptide SS31 and neuroprotective peptide S14G-Humanin. However, suitable peptide delivery systems with excellent loading capacity and effective at-site delivery are still absent. Herein, the nanoparticles made of citraconylation-modified poly(ethylene glycol)-poly(trimethylene carbonate) polymer (PEG-PTMC(Cit)) exhibited desirable loading of HNSS peptide through electrostatic interactions. Meanwhile, based on fibroblast growth factor receptor 1(FGFR1) overexpression in both the blood-brain barrier and cholinergic neuron, an FGFR1 ligand-FGL peptide was modified on the nanosystem (FGL-NP(Cit)/HNSS) to achieve 4.8-fold enhanced accumulation in brain with preferred distribution into cholinergic neurons in the diseased region. The acid-sensitive property of the nanosystem facilitated lysosomal escape and intracellular drug release by charge switching, resulting in HNSS enrichment in mitochondria through directing of the SS31 part. FGL-NP(Cit)/HNSS effectively rescued mitochondria dysfunction via the PGC-1α and STAT3 pathways, inhibited Aß deposition and tau hyperphosphorylation, and ameliorated memory defects and cholinergic neuronal damage in 3xTg-AD mice. The work provides a potential platform for targeted cationic peptide delivery, harboring utility for peptide therapy in other neurodegenerative diseases.

DDX5: an expectable treater for viral infection- a literature review.

Background and Objective: DEAD-box protein (DDX)5 plays important roles in multiple aspects of cellular processes that require modulating RNA structure. Alongside the canonical role of DDX5 in RNA metabolism, many reports have shown that DDX5 influences viral infection by directly interacting with viral proteins. However, the functional role of DDX5 in virus-associated cancers, as well as the identity of DDX5 in virus infection-associated signaling pathways, has remained largely unexplained. Here, we further explore the precise functions of DDX5 and its potential targets for antiviral treatment. Methods: We searched the PubMed and PMC databases to identify studies on role of DDXs, especially DDX5, during various viral infection published up to May 2022. Key Content and Findings: DDX5 functions as both a viral infection helper and inhibitor, which depends on virus type. DDXs proteins have been identified to play roles on multiple aspects covering RNA metabolism and function. Conclusions: DDX5 influences viral pathogenesis by participating in viral replication and multiple viral infection-related signaling pathways, it also plays a double-edge sword role under different viral infection conditions. Deep investigation into the mechanism of DDX5 modulating immune response in host cells revealed that it holds highly potential usage for future antiviral therapy. We reviewed current studies to provide a comprehensive update of the role of DDX5 in viral infection.