Joint trajectories of pain, depression and frailty and associations with adverse outcomes among community-dwelling older adults: A longitudinal study.

This study aimed to examine joint trajectories of pain, depression and frailty and their associations with adverse outcomes. Four waves of national data from the China Health and Retirement Longitudinal Study (CHARLS 2011-2018) were used, involving 4217 participants aged ≥60 years. Joint trajectories were fit using parallel-process latent class growth analysis, and their associations with adverse outcomes were evaluated using modified Poisson regression. Four joint trajectories were identified. Compared with most favorable group, other three joint trajectory groups had higher risk of functional disability and hospitalization. Slowly progressive pain, depression and frailty and persistent combination of pain, depression and frailty were also associated with cognitive decline, while slowly reduced pain and depression but persistent frailty was associated with all-cause mortality. The findings highlight unique characteristics and health impacts of concurrent changes in pain, depression and frailty over time, implicating the integrated physical and psychological care for older adults.

The Current Position of Postoperative Radiotherapy for Salivary Gland Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Because of the rarity, heterogeneous histology, and diverse anatomical sites of salivary gland cancer (SGC), there are a limited number of clinical studies on its management. This study reports the cumulative evidence of postoperative radiotherapy (PORT) for SGC of the head and neck. METHODS: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases between 7th and 10th November 2023. RESULTS: A total of 2962 patients from 26 studies between 2007 and 2023 were included in this meta-analysis. The median RT dose was 64 Gy (range: 56-66 Gy). The median proportions of high-grade, pathological tumor stage 3 or 4 and pathological lymph node involvement were 42% (0-100%), 40% (0-77%), and 31% (0-75%). The pooled locoregional control rates at 3, 5, and 10 years were 92% (95% confidence interval [CI], 89-94%), 89% (95% CI, 86-93%), and 84% (95% CI, 73-92%), respectively. The pooled disease-free survival (DFS) rates at 3, 5, and 10 years were 77% (95% CI, 70-83%), 67% (95% CI, 60-74%), and 61% (95% CI, 55-67%), respectively. The pooled overall survival rates at 3, 5, and 10 years were 84% (95% CI, 79-88%), 75% (95% CI, 72-79%), and 68% (95% CI, 62-74%), respectively. Severe late toxicity ≥ grade 3 occurred in 7% (95% CI, 3-14%). CONCLUSION: PORT showed favorable long-term efficacy and safety in SGC, especially for patients with high-grade histology. Considering that DFS continued to decrease, further clinical trials exploring treatment intensification are warranted.

TracrRNA reprogramming enables direct PAM-independent detection of RNA with diverse DNA-targeting Cas12 nucleases.

Many CRISPR-Cas immune systems generate guide (g)RNAs using trans-activating CRISPR RNAs (tracrRNAs). Recent work revealed that Cas9 tracrRNAs could be reprogrammed to convert any RNA-of-interest into a gRNA, linking the RNA's presence to Cas9-mediated cleavage of double-stranded (ds)DNA. Here, we reprogram tracrRNAs from diverse Cas12 nucleases, linking the presence of an RNA-of-interest to dsDNA cleavage and subsequent collateral single-stranded DNA cleavage-all without the RNA necessarily encoding a protospacer-adjacent motif (PAM). After elucidating nuclease-specific design rules, we demonstrate PAM-independent RNA detection with Cas12b, Cas12e, and Cas12f nucleases. Furthermore, rationally truncating the dsDNA target boosts collateral cleavage activity, while the absence of a gRNA reduces background collateral activity and enhances sensitivity. Finally, we apply this platform to detect 16 S rRNA sequences from five different bacterial pathogens using a universal reprogrammed tracrRNA. These findings extend tracrRNA reprogramming to diverse dsDNA-targeting Cas12 nucleases, expanding the flexibility and versatility of CRISPR-based RNA detection.

Effectiveness of interventions for informal caregivers of community-dwelling frail older adults: A systematic review and meta-analysis.

AIM: Systematic reviews on interventions for informal caregivers of community-dwelling frail older adults were published over a decade ago and they mistook frailty for other severe age-related conditions like disability and dementia. Therefore, this study aimed to systematically synthesize these interventions supporting these caregivers identified by an acknowledged frailty assessment instrument and to examine their effectiveness on caregiver-related outcomes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Fourteen electronic databases, grey literature and reference lists were systematically searched for randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs) from inception to November 3, 2023. METHODS: Methodology quality and risk of bias were assessed. Data were meta-analysed using the Comprehensive Meta-Analysis, version 3.0. Studies and outcomes unsuitable for meta-analysis were summarized by narrative syntheses. RESULTS: Four studies consisting of three RCTs and one NRCT were included involving 350 participants. Interventions for caregivers of frail older adults included multicomponent interventions (n = 3) and education intervention (n = 1). Interventions had a moderate effect on reducing depression and showed nonsignificant effects on caregiver burden, caregiving time or quality of life (QoL). The PEDro scores for RCTs ranged from 6 to 8, indicating good methodologic quality, but were all judged as high risk of bias. The NRCT reported all methodologic aspects and was at low risk of bias. CONCLUSIONS: Few studies focus on interventions targeting caregivers of frail older adults, and their effectiveness may vary by outcomes. This review suggested the potential benefits of these interventions in reducing caregivers' depression. IMPACT: The differential effectiveness by outcomes and high risk of bias of studies implicate that more rigorous studies are warranted.

A review of factors affecting the soil microbial community structure in wetlands.

Microbial community in wetland soils is crucial for maintaining the stability of the wetland ecosystem. Nevertheless, the soil microbial community is sensitive to the environmental stress in wetlands. This leads to the possibility that the microbial community structure may be influenced by environmental factors. To gain an in-depth understanding in the response of microbial community structure in wetland soils under different environmental factors, this review comprehensively explores the factors of natural conditions (e.g., different types of wetland, soil physical and chemical properties, climate conditions), biological factors (e.g., plants, soil animals), and human activities (e.g., land use, soil pollution, grazing). Those factors can affect microbial community structure and activities in wetland soils through different ways such as (i) affecting the wetland soil environment in which soil microorganisms survived in, (ii) influencing the available nutrients (e.g., carbon, nitrogen) required for microbial activity, and (iii) the direct effects on soil microorganisms (toxicity or promotion of resistant species). This review can provide references for the conservation of microbial diversity in wetland soils, the maintenance of wetland ecosystem balance, and the wetland ecological restoration.

Single-Image SVBRDF Estimation Using Auxiliary Renderings as Intermediate Targets.

Recently, single-image SVBRDF capture is formulated as a regression problem, which uses a network to infer four SVBRDF maps from a flash-lit image. However, the accuracy is still not satisfactory since previous approaches usually adopt endto-end inference strategies. To mitigate the challenge, we propose "auxiliary renderings" as the intermediate regression targets, through which we divide the original end-to-end regression task into several easier sub-tasks, thus achieving better inference accuracy. Our contributions are threefold. First, we design three (or two pairs of) auxiliary renderings and summarize the motivations behind the designs. By our design, the auxiliary images are bumpiness-flattened or highlight-removed, containing disentangled visual cues about the final SVBRDF maps and can be easily transformed to the final maps. Second, to help estimate the auxiliary targets from the input image, we propose two mask images including a bumpiness mask and a highlight mask. Our method thus first infers mask images, then with the help of the mask images infers auxiliary renderings, and finally transforms the auxiliary images to SVBRDF maps. Third, we propose backbone UNets to infer mask images, and gated deformable UNets for estimating auxiliary targets. Thanks to the well designed networks and intermediate images, our method outputs better SVBRDF maps than previous approaches, validated by the extensive comparisonal and ablation experiments.

Crosslinking ability of hydrolyzed distarch phosphate and its stabilizing effect on rehydrated sea cucumber.

Effective crosslinking among food constituents has the potential to enhance their overall quality. Distarch phosphate (DSP), a common food additive employed as a thickening agent, bears a pre-crosslinked oligosaccharide (PCO) moiety within its molecular structure. Once this moiety is released, its double reducing end has the potential to undergo crosslinking with amino-rich macromolecules through Maillard reaction. In this study, hydrolyzed distarch phosphate (HDSP) was synthesized, and spectroscopic analysis verified the presence of PCO within HDSP. Preliminary validation experiment showed that HDSP could crosslink chitosan to form a hydrogel and significant browning was also observed during the process. Furthermore, rehydrated sea cucumber (RSC) crosslinked with HDSP exhibited a more intact appearance, higher mechanical strength, better color profile, and increased water-holding capacity. This series of results have confirmed that HDSP is capable to crosslink amino-rich macromolecules and form more stable three-dimensional network.

Iodine-doped carbon nanotubes boosting the adsorption effect and conversion kinetics of lithium-sulfur batteries.

Compared with lithium-ion batteries (LIBs), lithium-sulfur batteries (LSBs), based on electrochemical reactions involving multi-step 16-electron transformations provide higher specific capacity (1672 mAh g-1) and specific energy (2600 Wh kg-1), exhibiting great potential in the field of energy storage. However, the inherent insulation of sulfur, slow electrochemical reaction kinetics and detrimental shuttle-effect of lithium polysulfides (LiPSs) restrict the development of LSBs in practical applications. Herein, the iodine-doped carbon nanotubes (I-CNTs) is firstly reported as sulfur host material to the enhance the adsorption-conversion kinetics of LSBs. Iodine doping can significantly improve the polarity of I-CNTs. Iodine atoms with lone pair electrons (Lewis base) in iodine-doped CNTs can interact with lithium cations (Lewis acidic) in LiPSs, thereby anchoring polysulfides and suppressing subsequent shuttling behavior. Moreover, the charge transfer between iodine species (electron acceptor) and CNTs (electron donor) decreases the gap band and subsequently improves the conductivity of I-CNTs. The enhanced adsorption effect and conductivity are beneficial for accelerating reaction kinetics and enhancing electrocatalytic activity. The in-situ Raman spectroscopy, quasi in-situ electrochemical impedance spectroscopy (EIS) and Li2S potentiostatic deposition current-time (i-t) curves were conducted to verify mechanism of complex sulfur reduction reaction (SRR). Owing to above advantages, the I-CNTs@S composite cathode exhibits an ultrahigh initial capacity of 1326 mAh g-1 as well as outstanding cyclicability and rate performance. Our research results provide inspirations for the design of multifunctional host material for sulfur/carbon composite cathodes in LSBs.

Effects of (pre)frailty and cognitive reserve on mild cognitive impairment among community-dwelling older adults.

OBJECTIVE: We aimed to identify the effect of lifespan cognitive reserve and (pre)frailty on mild cognitive impairment (MCI) among older adults. MATERIALS AND METHODS: A total of 4420 older adults aged above 60 with intact cognition recruited in 2011/2012 were followed up in 2015 from the China Health and Retirement Longitudinal Study (CHARLS). The assessment of MCI was based on executive function, episodic memory, and visual-spatial ability. (Pre)frailty was assessed by the validated version of the Fried physical frailty phenotype scale. The lifespan cognitive reserve consisted of the highest educational level, occupational complexity, and participation in leisure activities. Modified Poisson regression models were used to identify the risk of MCI in relation to (pre)frailty and lifespan cognitive reserve index. We examined the interactions of (pre)frailty and lifespan cognitive reserve index on both additive and multiplicative scales. RESULTS: Baseline (pre)frailty significantly increased the risk of MCI after 3-4 years of follow-up, and high cognitive reserve protected individuals from the risk of MCI. There was an additive interaction between (pre)frailty and the low lifespan cognitive reserve (the relative excess interaction risk=1.08, 95 % CI= 0.25-1,91), but no multiplicative interaction (RR=0.95, 95 % CI= 0.67-1.37). The risk of MCI was larger among older adults with comorbid (pre)frailty and low cognitive reserve than those with each condition alone. CONCLUSION: Cognitive reserve attenuates the risk of MCI associated with (pre)frailty. This finding implicates the urgency for identifying and managing MCI among frail older adults who accumulate low cognitive reserve in the life course.

Does Social Support Moderate the Relationship Between Frailty and Functional Ability Trajectory Among Community-Dwelling Older Adults?

BACKGROUND: Functional ability is the important prerequisite to live independently and achieve aging in place, which depends on the complex interaction of intrinsic and extrinsic factors. Identifying the trends and influencing factors of functional ability would contribute to the accurate assessment and intervention of geriatric health. This study aimed to disentangle the moderating effect of 3 types of social support, namely objective support, subjective support, and support utilization, on the relationship between frailty and functional ability trajectories. METHODS: This was a secondary analysis using data from a prospective 3-wave study with a sample of 777 Chinese community-dwelling older adults. Social support was assessed using the Social Support Rating scale. Frailty was assessed using the FRAIL scale. Functional ability was measured by the Lawton Instrumental Activities of Daily Living scale. Latent growth curve models were implemented to test their relationships. RESULTS: Objective support but not subjective support or support utilization moderated on the relationship between frailty and functional ability slope. Functional ability decline over time was buffered by objective support among robust individuals but exacerbated among (pre)frail individuals. CONCLUSIONS: The moderating effect of social support on the relationship between frailty and functional ability trajectory varies by support types, which reminded that social support may be a promising intervention target to maintain functional independence for frail individuals, opening up a new perspective on social support in the field of disability prevention. Effective interventions should particularly address objective support in conjunction with empowering the frail older population to optimize the trajectory of functional ability.

Systematic interrogation of CRISPR antimicrobials in Klebsiella pneumoniae reveals nuclease-, guide- and strain-dependent features influencing antimicrobial activity.

CRISPR-Cas systems can be utilized as programmable-spectrum antimicrobials to combat bacterial infections. However, how CRISPR nucleases perform as antimicrobials across target sites and strains remains poorly explored. Here, we address this knowledge gap by systematically interrogating the use of CRISPR antimicrobials using multidrug-resistant and hypervirulent strains of Klebsiella pneumoniae as models. Comparing different Cas nucleases, DNA-targeting nucleases outperformed RNA-targeting nucleases based on the tested targets. Focusing on AsCas12a that exhibited robust targeting across different strains, we found that the elucidated modes of escape varied widely, restraining opportunities to enhance killing. We also encountered individual guide RNAs yielding different extents of clearance across strains, which were linked to an interplay between improper gRNA folding and strain-specific DNA repair and survival. To explore features that could improve targeting across strains, we performed a genome-wide screen in different K. pneumoniae strains that yielded guide design rules and trained an algorithm for predicting guide efficiency. Finally, we showed that Cas12a antimicrobials can be exploited to eliminate K. pneumoniae when encoded in phagemids delivered by T7-like phages. Altogether, our results highlight the importance of evaluating antimicrobial activity of CRISPR antimicrobials across relevant strains and define critical parameters for efficient CRISPR-based targeting.

Precise Capture and Dynamic Release of Circulating Liver Cancer Cells with Dual-Histidine-Based Cell Imprinted Hydrogels.

Circulating tumor cells (CTCs) detection presents significant advantages in diagnosing liver cancer due to its noninvasiveness, real-time monitoring, and dynamic tracking. However, the clinical application of CTCs-based diagnosis is largely limited by the challenges of capturing low-abundance CTCs within a complex blood environment while ensuring them alive. Here, an ultrastrong ligand, l-histidine-l-histidine (HH), specifically targeting sialylated glycans on the surface of CTCs, is designed. Furthermore, HH is integrated into a cell-imprinted polymer, constructing a hydrogel with precise CTCs imprinting, high elasticity, satisfactory blood compatibility, and robust anti-interference capacities. These features endow the hydrogel with excellent capture efficiency (>95%) for CTCs in peripheral blood, as well as the ability to release CTCs controllably and alive. Clinical tests substantiate the accurate differentiation between liver cancer, cirrhosis, and healthy groups using this method. The remarkable diagnostic accuracy (94%), lossless release of CTCs, material reversibility, and cost-effectiveness ($6.68 per sample) make the HH-based hydrogel a potentially revolutionary technology for liver cancer diagnosis and single-cell analysis.

Enteric coronavirus nsp2 is a virulence determinant that recruits NBR1 for autophagic targeting of TBK1 to diminish the innate immune response.

Non-structural protein 2 (nsp2) exists in all coronaviruses (CoVs), while its primary function in viral pathogenicity, is largely unclear. One such enteric CoV, porcine epidemic diarrhea virus (PEDV), causes high mortality in neonatal piglets worldwide. To determine the biological role of nsp2, we generated a PEDV mutant containing a complete nsp2 deletion (rPEDV-Δnsp2) from a highly pathogenic strain by reverse genetics, showing that nsp2 was dispensable for PEDV infection, while its deficiency reduced viral replication in vitro. Intriguingly, rPEDV-Δnsp2 was entirely avirulent in vivo, with significantly increased productions of IFNB (interferon beta) and IFN-stimulated genes (ISGs) in various intestinal tissues of challenged newborn piglets. Notably, nsp2 targets and degrades TBK1 (TANK binding kinase 1), the critical kinase in the innate immune response. Mechanistically, nsp2 induced the macroautophagy/autophagy process and recruited a selective autophagic receptor, NBR1 (NBR1 autophagy cargo receptor). NBR1 subsequently facilitated the K48-linked ubiquitination of TBK1 and delivered it for autophagosome-mediated degradation. Accordingly, the replication of rPEDV-Δnsp2 CoV was restrained by reduced autophagy and excess productions of type I IFNs and ISGs. Our data collectively define enteric CoV nsp2 as a novel virulence determinant, propose a crucial role of nsp2 in diminishing innate antiviral immunity by targeting TBK1 for NBR1-mediated selective autophagy, and pave the way to develop a new type of nsp2-based attenuated PEDV vaccine. The study also provides new insights into the prevention and treatment of other pathogenic CoVs.Abbreviations: 3-MA: 3-methyladenine; Baf A1: bafilomycin A1; CoV: coronavirus; CQ: chloroquine; dpi: days post-inoculation; DMVs: double-membrane vesicles; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; GIGYF2: GRB10 interacting GYF protein 2; hpi: hours post-infection; IFA: immunofluorescence assay; IFIH1: interferon induced with helicase C domain 1; IFIT2: interferon induced protein with tetratricopeptide repeats 2; IFITM1: interferon induced transmembrane protein 1; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; NBR1: NBR1 autophagy cargo receptor; nsp2: non-structural protein 2; OAS1: 2'-5'-oligoadenylate synthetase 1; PEDV: porcine epidemic diarrhea virus; PRRs: pattern recognition receptors; RIGI: RNA sensor RIG-I; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SQSTM1: sequestosome 1; TBK1: TANK binding kinase 1; TCID50: 50% tissue culture infectious doses; VSV: vesicular stomatitis virus.

Emotional "Contagion" in Piglets after Sensory Avoidance of Rewarding and Punishing Treatment.

In the pig farming industry, it is recommended to avoid groups when treating individuals to reduce adverse reactions in the group. However, can this eliminate the adverse effects effectively? Piglets were assigned to the Rewarding Group (RG), the Punishing Group (PG), and the Paired Control Group (PCG). There were six replicates in each group, with two paired piglets per replicate. One piglet of the RG and PG was randomly selected as the Treated pig (TP), treated with food rewards or electric shock, and the other as the Naive pig (NP). The NPs in the RG and PG were unaware of the treatment process, and piglets in the PCG were not treated. The behavior and heart rate changes of all piglets were recorded. Compared to the RG, the NPs in the PG showed longer proximity but less contact behavior, and the TPs in the PG showed more freezing behavior. The percentage change in heart rate of the NPs was synchronized with the TPs. This shows that after sensory avoidance, the untreated pigs could also feel the emotions of their peers and their emotional state was affected by their peers, and the negative emotions in the pigs lasted longer than the positive emotions. The avoidance process does not prevent the transfer of negative emotions to peers via emotional contagion from the stimulated pig.

Study on Inerting Characteristics of Gas Coal by the Inerting Concentration and Ratio of an Inert Gas Mixture.

To study the effect of the inert gas mixture concentration and ratio on the spontaneous combustion reaction of gas coal, a combination of experimental research and theoretical analysis was used to study the pyrolysis and combustion kinetics characteristics of gas coal and further explore the influence of inert gas on the inerting characteristics of gas coal. Research has shown that during the entire heating reaction process of gas coal, the concentration of inert gases has little effect on the drying and desorption stages, but there is a significant lag phenomenon in the characteristic temperature points of active decomposition and degassing stages. Under the same concentration of mixed inert gases, the higher the relative percentage content of CO2, the more significant the change and the better the inhibitory effect. The higher the volume fraction of the inert gas, the higher the cross-temperature point. In the late stage of rapid heating of coal samples, when the volume fraction of inert gas is 40%, the rate of temperature rise increases rapidly. In a pure air environment, CO begins to be released at 80 °C, and when the temperature rises to 130 ∼ 140 °C, the concentration of CO begins to rapidly increase. Under inert conditions, the higher the relative percentage content of inert gas is, the higher the temperature point at which CO is generated. When the experimental conditions are a mixture of 30% N2 and 10% CO2 as inert gas, the optimal inerting effect has been achieved. The research results provide a theoretical basis for determining the optimal ratio of inert gas inerting concentrations to achieve fire prevention and extinguishing.

Cost-Utility Analysis of Vericiguat in Heart Failure with Reduced Ejection Fraction After Worsening Heart Failure Events in China.

OBJECTIVE: Vericiguat is a new medication to demonstrate clinical efficacy in heart failure with reduced ejection fraction (HFrEF) after worsening heart failure (WHF) events, but its cost-utility was unknown. We aimed to assess the cost-utility of combining the application of vericiguat with standard treatment in HFrEF patients who had WHF events. METHODS: A multistate Markov model was implemented to mimic the economic results of HFrEF patients who had WHF events in China after receiving vericiguat or placebo. An analysis of cost-utility was conducted; most parameters were set according to the published studies and related databases. All the utilities and costs were decreased at a rate of 5% annually. The incremental cost-effectiveness ratios (ICERs) were the primary outcome measure. We also conducted sensitivity analyses. RESULTS: Over a 20 year lifetime horizon, additional use of vericiguat led to an elevated cost from US$9725.03 to US$20,660.76 at the current vericiguat costs. This was related to increased quality-adjusted life years (QALYs) from 2.50 to 2.66, along with an ICER of US$65,057.24 per QALY, which was over the willingness-to-pay (WTP) threshold of US$36,096.30 per QALY. If the vericiguat costs were discounted at 80%, it contributed to an ICER of US$12,226.77 per QALY. Additional use of vericiguat for patients with plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) of ≤ 5314 pg per ml produced an ICER of US$23,688.46 per QALY. The outcomes of the one-way sensitivity analysis showed the risk of death from cardiovascular disease in both groups was variable with the highest sensitivity. The probabilistic sensitivity analysis showed that 41.6% of the mimicked population receiving vericiguat combined with standard therapy was cost-effective at the WTP threshold of US$36,096.30 per QALY. CONCLUSIONS: From the perspective of Chinese public healthcare system, the combined use of vericiguat and standard treatment in patients with HFrEF following WHF events did not generate advantages in cost-utility in China but was a cost-effective therapeutic strategy for those who with plasma NT-proBNP of ≤ 5314 pg per ml.

Joint trajectories of loneliness, social isolation and sarcopenia and associations with adverse outcomes: A prospective cohort study.

This study aimed to examine joint trajectories of loneliness, social isolation and sarcopenia and their associations with adverse outcomes. A total of 4701 participants aged ≥60 years who had a baseline and at least one follow-up assessment of loneliness, social isolation and sarcopenia across 2011, 2013 and 2015 waves in China Health and Retirement Longitudinal Study. Adverse outcomes were obtained in 2018 wave. Joint trajectories were fit using the parallel process latent class growth analysis, and their associations with adverse outcomes were evaluated using modified Poisson regression. Joint trajectory patterns for social relationship and sarcopenia did not vary by the assessment for sarcopenia, but did vary by the assessment for social relationship. Older adults exhibit distinct joint trajectories and those with persistent combination of loneliness or social isolation and sarcopenia experience greatest risk of adverse outcomes. These findings implicate integration of health care and social care for community-dwelling older adults.

Exploring Novel Antidepressants Targeting G Protein-Coupled Receptors and Key Membrane Receptors Based on Molecular Structures.

Major Depressive Disorder (MDD) is a complex mental disorder that involves alterations in signal transmission across multiple scales and structural abnormalities. The development of effective antidepressants (ADs) has been hindered by the dominance of monoamine hypothesis, resulting in slow progress. Traditional ADs have undesirable traits like delayed onset of action, limited efficacy, and severe side effects. Recently, two categories of fast-acting antidepressant compounds have surfaced, dissociative anesthetics S-ketamine and its metabolites, as well as psychedelics such as lysergic acid diethylamide (LSD). This has led to structural research and drug development of the receptors that they target. This review provides breakthroughs and achievements in the structure of depression-related receptors and novel ADs based on these. Cryo-electron microscopy (cryo-EM) has enabled researchers to identify the structures of membrane receptors, including the N-methyl-D-aspartate receptor (NMDAR) and the 5-hydroxytryptamine 2A (5-HT2A) receptor. These high-resolution structures can be used for the development of novel ADs using virtual drug screening (VDS). Moreover, the unique antidepressant effects of 5-HT1A receptors in various brain regions, and the pivotal roles of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and tyrosine kinase receptor 2 (TrkB) in regulating synaptic plasticity, emphasize their potential as therapeutic targets. Using structural information, a series of highly selective ADs were designed based on the different role of receptors in MDD. These molecules have the favorable characteristics of rapid onset and low adverse drug reactions. This review offers researchers guidance and a methodological framework for the structure-based design of ADs.

Joint trajectories of physical frailty and social frailty and associations with adverse outcomes: A prospective cohort study.

BACKGROUND: We examined joint trajectories of physical frailty and social frailty as well as their associations with adverse outcomes. METHODS: We conducted a prospective cohort study by using five waves of national data from China Health and Retirement Longitudinal Study (CHARLS 2011-2020), involving 4531 participants aged ≥60 years. We identified 4-year trajectories at three examinations from 2011 to 2015 using parallel process latent class growth analysis. Adverse outcomes were obtained from 2015 to 2020 across two subsequent waves. We calculated hazard ratios (HR) using Cox proportional hazard models. We also conducted analyses by gender. RESULTS: Three joint trajectories were identified, including persistent absence of physical and social frailty (58.5 %), no physical frailty but social frailty (28.1 %), and persistent combination of physical and social frailty (13.4 %). Compared with persistent absence of physical and social frailty, no physical frailty but social frailty and persistent combination of physical and social frailty were associated with higher risk of instrumental activities of daily living (IADL) disability (HR = 1.182-2.020, 95 % CI: 1.014-2.416) and all-cause mortality (HR = 1.440-2.486, 95 % CI: 1.211-3.009). The persistent combination of physical and social frailty was also associated with ADL disability (HR = 2.412, 95 % CI: 1.999-2.911) and falls (HR = 1.410, 95 % CI: 1.196-1.662). Gender differences were observed in relationships between joint trajectories and adverse outcomes. CONCLUSION: Community-dwelling older adults exhibit distinct joint trajectories and those with persistent combination of physical and social frailty experience greatest risk of incident adverse outcomes. Clinical and public health measures targeting physical or social frailty should account for both and be gender-specific.