Non-equilibrium structural and dynamic behaviors of active polymers in complex and crowded environments.

Active matter systems, which convert internal chemical energy or energy from the environment into directed motion, are ubiquitous in nature and exhibit a range of emerging non-equilibrium behaviors. However, most of the current works on active matter have been devoted to particles, and the study of active polymers has only recently come into the spotlight due to their prevalence within living organisms. The intricate interplay between activity and conformational degrees of freedom gives rise to novel structural and dynamical behaviors of active polymers. Research in active polymers remarkably broadens diverse concepts of polymer physics, such as molecular architecture, dynamics, scaling and so on, which is of significant importance for the development of new polymer materials with unique performance. Furthermore, active polymers are often found in strongly interacting and crowded systems and in complex environments, so that the understanding of this behavior is essential for future developments of novel polymer-based biomaterials. This review thereby focuses on the study of active polymers in complex and crowded environments, and aims to provide insights into the fundamental physics underlying the adaptive and collective behaviors far from equilibrium, as well as the open challenges that the field is currently facing.

Deconstructive and Divergent Synthesis of Bioactive Natural Products.

Natural products play a key role in innovative drug discovery. To explore the potential application of natural products and their analogues in pharmacology, total synthesis is a key tool that provides natural product candidates and synthetic analogues for drug development and potential clinical trials. Deconstructive synthesis, namely building new, challenging structures through bond cleavage of easily accessible moieties, has emerged as a useful design principle in synthesizing bioactive natural products. Divergent synthesis, namely synthesizing many natural products from a common intermediate, can improve the efficiency of chemical synthesis and generate libraries of molecules with unprecedented structural diversity. In this review, we will firstly introduce five recent and excellent examples of deconstructive and divergent syntheses of natural products (2021-2023). Then, we will summarize our previous work on the deconstructive and divergent synthesis of natural products to demonstrate the high efficiency and simplicity of these two strategies in the field of total synthesis.

Web-Based Cognitive Behavioral Therapy for Depression Among Homebound Older Adults: Development and Usability Study.

BACKGROUND: Homebound older adults are a high-risk group for depression. However, many of them face barriers to accessing evidence-supported mental health treatments. Digital mental health interventions can potentially improve treatment access, but few web-based interventions are explicitly tailored for depression in older adults. OBJECTIVE: This paper describes the development process of Empower@Home, a web-delivered intervention for depression in homebound older adults that is based on cognitive behavioral therapy, and reports on the outcomes of usability studies. METHODS: Empower@Home was developed in collaboration with community agencies, stakeholders, and older adults, guided by user-centered design principles. User needs were assessed through secondary data analysis, demographic and health profiles from administrative data, and interviews and surveys of community partners. A comparative usability evaluation was conducted with 10 older adults to assess the usability of Empower@Home compared to 2 similar programs. Field testing was conducted with 4 end users to detect additional usability issues. RESULTS: Feedback and recommendations from community partners heavily influenced the content and design of Empower@Home. The intervention consists of 9 sessions, including psychoeducation and an introduction to cognitive behavioral therapy skills and tools through short video clips, in-session exercises, an animated storyline, and weekly out-of-session home practice. A printed workbook accompanies the web-based lessons. In comparative usability testing (N=10), Empower@Home received a System Usability Scale score of 78 (SD 7.4), which was significantly higher than the 2 comparator programs (t9=3.28; P=.005 and t9=2.78; P=.011). Most participants, 80% (n=8), preferred Empower@Home over the comparators. In the longitudinal field test (n=4), all participants reported liking the program procedures and feeling confident in performing program-related tasks. The single-subject line graph showed an overall downward trend in their depression scores over time, offering an encouraging indication of the intervention's potential effects. CONCLUSIONS: Collaboration with community stakeholders and careful consideration of potential implementation issues during the design process can result in more usable, engaging, and effective digital mental health interventions.

Implementation of a Dyad-Based Intervention to Improve Antiretroviral Therapy Adherence Among HIV-Positive People Who Inject Drugs in Kazakhstan: A Randomized Trial.

Purpose: HIV-positive people who inject drugs (PWID) in Kazakhstan face many challenges to antiretroviral therapy (ART) adherence. Interventions that leverage social support from an intimate partner, family member, or friend may be effective in improving ART adherence among this population. The purpose of this paper is to describe the implementation process of a dyad-based intervention among HIV-positive PWID and their treatment support partners. Method: Sixty-six HIV-positive PWID and 66 of their treatment support partners will be enrolled in this pilot randomized controlled trial in Almaty, Kazakhstan, and randomized as dyads to receive an adapted version of the SMART Couples intervention or standard of care. Results: Several implementation strategies were used to facilitate intervention delivery, including remote delivery, training of staff, supervision, technical assistance, quality assurance, and collection of assessments through diverse sources. Discussion: This trial responds to a need for dyad-based ART adherence interventions adapted specifically for HIV-positive PWID.

Emerging antiviral therapies and drugs for the treatment of influenza.

INTRODUCTION: Both vaccines and antiviral drugs represent the mainstay for preventing and treating influenza. However, approved M2 ion channel inhibitors, neuraminidase inhibitors, polymerase inhibitors, and various vaccines cannot meet therapeutic needs because of viral resistance. Thus, the discovery of new targets for the virus or host and the development of more effective inhibitors are essential to protect humans from the influenza virus. AREAS COVERED: This review summarizes the latest progress in vaccines and antiviral drug research to prevent and treat influenza, providing the foothold for developing novel antiviral inhibitors. EXPERT OPINION: Vaccines embody the most effective approach to preventing influenza virus infection, and recombinant protein vaccines show promising prospects in developing next-generation vaccines. Compounds targeting the viral components of RNA polymerase, hemagglutinin and nucleoprotein, and the modification of trusted neuraminidase inhibitors are future research directions for anti-influenza virus drugs. In addition, some host factors affect the replication of virus in vivo, which can be used to develop antiviral drugs.

Tumor microenvironment-associated lactate metabolism regulates the prognosis and precise checkpoint immunotherapy outcomes of patients with lung adenocarcinoma.

BACKGROUND: Despite the wide clinical application of checkpoint inhibitor immunotherapy in lung adenocarcinoma, its limited benefit to patients remains puzzling to researchers. One of the mechanisms of immunotherapy resistance may be the dysregulation of lactate metabolism in the immunosuppressive tumor microenvironment (TME), which can inhibit dendritic cell maturation and prevent T-cell invasion into tumors. However, the key genes related to lactate metabolism and their influence on the immunotherapeutic effects in lung adenocarcinoma have not yet been investigated in depth. METHODS: In this study, we first surveyed the dysregulated expression of genes related to lactate metabolism in lung adenocarcinoma and then characterized their biological functions. Using machine learning methods, we constructed a lactate-associated gene signature in The Cancer Genome Atlas cohort and validated its effectiveness in predicting the prognosis and immunotherapy outcomes of patients in the Gene Expression Omnibus cohorts. RESULTS: A 7-gene signature based on the metabolomics related to lactate metabolism was found to be associated with multiple important clinical features of cancer and was an independent prognostic factor. CONCLUSIONS: These results suggest that rather than being simply a metabolic byproduct of glycolysis, lactate in the TME can affect immunotherapy outcomes. Therefore, the mechanism underlying this effect of lactate is worthy of further study.

Childhood adversity and cognitive impairment in later life.

Objectives: This study examined the association between childhood adversity and cognitive impairment in later life and explored the potential moderation effect of gender and race. Methods: The study sample included 15,133 participants of the Health and Retirement Study (1998-2016 surveys) who had complete data on key study measures and were more than 50. The outcome variable is a dichotomous indicator of cognitive impairment as assessed by the Telephone Interview for Cognitive Status for self-respondents and the 16-item Informant Questionnaire on Cognitive Decline in the Elderly for proxies. A total of six childhood adversity indicators included grade retention, parental substance abuse, physical abuse, trouble with the police, moving due to financial hardship, and receipt of help due to financial hardship in early life. The estimation of the association between childhood adversity and cognitive impairment involved Cox proportional hazards regression. Results: Grade retention had the largest effect on incident cognitive impairment (HR = 1.3, 95% CI = 1.23-1.38, p < 0.001), followed by physical abuse by a parent (HR = 1.10, 95% CI = 1.00-1.20, p = 0.001). The impact of grade retention was more detrimental to women than men (interaction term HR = 0.89, 95% CI = 0.80-1.00, p = 0.048, female as the reference). Parental substance abuse was associated with a lower risk of incident cognitive impairment for most racial groups (HR = 0.89, 95% CI = 0.83-0.95, p = 0.001), but this association was reversed in "non-Hispanic other" race, consisting mainly of Asians (HR = 1.54, 95% CI = 1.05-2.26, p = 0.025). Discussion: Some aspects of childhood adversity continue to harm cognitive functioning in later life, while some events may have the opposite effect, with evidence of heterogeneity across gender and race.

Leymus chinensis Adapts to Degraded Soil Environments by Changing Metabolic Pathways and Root Exudate Components.

Phytoremediation is a promising remediation strategy for degraded soil restoration. Root exudates are the main carrier substances for information communication and energy transfer between plant roots and soil, which play non-negligible roles in the restoration process. This work investigated the adaptation of Leymus chinensis root exudates to different degraded levels of soil and the mechanism of rhizosphere restoration in a 3-year degraded soil field study. We found that the soil quality at each degradation level significantly increased, with the soil organic matter (SOM) content slightly increasing by 1.82%, moderately increasing by 3.27%, and severely increasing by 3.59%, and there were significant increases in the contents of available nutrients such as available phosphorus (AP), ammonia nitrogen (AN), and nitrate nitrogen (NN). The physiological activities indicated that root tissue cells also mobilize oxidative stress to respond to the soil environment pressure. A total of 473 main components were obtained from root exudates by gas chromatography-time-of-flight mass spectrometry (GC-TOFMS), including acids, alcohols, carbohydrates, and other major primary metabolites. OPLS-DA revealed that soil degradation exerted an important influence on the metabolic characteristics of root exudates, and the numbers of both up- and downregulated metabolic characteristic peaks increased with the increase in the degree of degradation. Forty-three metabolites underwent clear changes, including some defense-related metabolites and osmotic adjustment substances that were significantly changed. These changes mainly mobilized a series of lipid metabolism pathways to maintain the fluidity of membrane function and help plants adapt to unfavorable soil environmental conditions. The PPP energy metabolism pathway was mobilized in response to slight degradation, and TCA energy pathways responded to the environmental pressure of severe soil degradation.

Internet-Based Psychotherapy Intervention for Depression Among Older Adults Receiving Home Care: Qualitative Study of Participants' Experiences.

BACKGROUND: Depression is common among homebound older adults. Internet-based cognitive behavioral therapy (iCBT) is a promising but understudied approach for treating depression among older adults with disabilities. OBJECTIVE: This study aims to understand the experiences of homebound older adults who participated in a pilot feasibility trial of an iCBT for depression. METHODS: The participants included 21 homebound older adults who participated in a generic iCBT program that was not specifically designed for older adults and 8 home care workers who assisted in the iCBT program. Informants completed semistructured individual interviews, which were transcribed verbatim and analyzed using methods informed by grounded theory. A hierarchical code structure of themes and subthemes was developed after an iterative process of constant comparisons and questionings of the initial codes. The data analysis was conducted by using dedoose, a web app for mixed methods research. RESULTS: Three themes and various subthemes emerged related to participants' experience of the iCBT intervention, as follows: intervention impact, which involved subthemes related to participants' perceived impact of the intervention; challenges and difficulties, which involved subthemes on the challenges and difficulties that participants experienced in the intervention; and facilitators, which involved subthemes on the factors that facilitated intervention use and engagement. CONCLUSIONS: iCBT is a promising intervention for homebound older adults experiencing depression. Home care workers reported improved relationships with their clients and that the program did not add a burden to their duties. Future programs should involve accessible technical features and age-adapted content to improve user experience, uptake, and adherence. TRIAL REGISTRATION: ClinicalTrials.gov NCT04267289; https://clinicaltrials.gov/ct2/show/NCT04267289.

A long-wavelength fluorescent probe with a large Stokes shift for lysosome-targeted imaging of Cys and GSH.

Biothiols including cysteine (Cys) and glutathione (GSH) are biological signaling molecules responsible for cell detoxification, cell metabolism and neutralization of reactive oxygen species. Here, we synthesized a long-wavelength fluorescent probe, DCIMA, for lysosome-targeted imaging of Cys and GSH in living cells. DCIMA is consisted of a dicyanoisophorone core modified with an acrylate group for biothiol detection through the Michael addition reaction and a morpholine group as the lysosome-targeting agent. The presence of the electron-donating morpholine group also enhances the intramolecular charge transfer mechanism of the probe, thereby enabling its long-wavelength fluorescence emission (670 nm) and large Stokes shift (180 nm). In concentration range of 0-30 µM, the probe was determined to react quickly with both Cys and GSH with low detection limits (<5 min, 35.2 nM for GSH and 34.8 nM for Cys) and achieve the sensitive fluorescence imaging of the biothiols located in the lysosomes of living cells.

Erratum to: Recruitment of Hard-to-Reach Older Adults in Technology-Based Mental Health Services Studies: Lessons Learned.

[This corrects the article DOI: 10.1093/geroni/igaa057.1328.].

Integrated 16S rRNA Gene Sequencing and LC-MS Analysis Revealed the Interplay Between Gut Microbiota and Plasma Metabolites in Rats With Ischemic Stroke.

Gut microbiome and plasma metabolome serve a role in the pathogenesis of ischemic stroke (IS). However, the relationship between the microbiota and metabolites remains unclear. This study aimed to reveal the specific asso-ciation between the microbiota and the metabolites in IS using integrated 16S rRNA gene sequencing and liquid chromatography-mass spectrometry (LC-MS) analysis. Male Sprague Dawley (SD) rats were divided into three groups: normal group (n = 8, Normal), model group (n = 9, IS), and sham-operated group (n = 8, Sham). Rats in the IS group were induced by middle cerebral artery occlusion (MCAO), and rats in the Sham group received an initial anesthesia and neck incision only. A neurological function test and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used to assess the IS rat model. Then, the plasma samples were analyzed using untargeted LC-MS. The cecum samples were collected and analyzed using 16S rRNA sequencing. Pearson correlation analysis was performed to explore the association between the gut microbiota and the plasma metabolites. The 16S rRNA sequencing showed that the composition and diversity of the microbiota in the IS and control rats were significantly different. Compared with the Sham group, the abundance of the Firmicutes phylum was decreased, whereas Proteobacteria and Deferribacteres were increased in the IS group. Ruminococcus_sp_15975 and Lachnospiraceae_UCG_001 might be considered as biomarkers for the IS and Sham groups, respectively. LC-MS analysis revealed that many metabolites, such as L-leucine, L-valine, and L-phenylalanine, displayed different patterns between the IS and Sham groups. Pathway analysis indicated that these metabolites were mainly involved in mineral absorption and cholinergic synapse. Furthermore, integrated analysis correlated IS-related microbes with metabolites. For example, Proteobacteria were positively correlated with L-phenylalanine, while they were negatively correlated with eicosapentaenoic acid (EPA). Our results provided evidence of the relationship between the gut microbiome and plasma metabolome in IS, suggesting that these microflora-related metabolites might serve as potential diagnostic and therapeutic markers.

Resveratrol induces PD-L1 expression through snail-driven activation of Wnt pathway in lung cancer cells.

PURPOSE: Recent clinical trials with agents targeting immune checkpoint pathway have emerged as an important therapeutic approach for a broad range of cancer types. Resveratrol has been shown to possess cancer preventive and therapeutic effects and has potential to be chemotherapeutic agent/adjuvant. Here, we assessed the effect of resveratrol on immune checkpoint pathways. METHODS: The expression patterns of Wnt components and PD-L1 were examined by Western blot, Chromatin immunoprecipitation (ChIP) was used for analysis of DNA-protein interaction, the promoter activity was determined by luciferase reporter assay, apoptosis was analyzed by flow cytometry and the ability of the resveratrol to modulate T cell function was assessed in a co-culture system. RESULTS: Although the dose-, and cell-type dependent effects of resveratrol on PD-L1 expression have been reported, we show here that resveratrol dose-dependently upregulates PD-L1 expression at the range of pharmacologic-achievable concentrations in lung cancer cells and that is essential for suppression of T-cell-mediated immune response. We also found that Wnt pathway is critical for mediating resveratrol-induced PD-L1 upregulation. Mechanistically, resveratrol activates SirT1 deacetylase to deacetylate and stabilize transcriptional factor Snail. Snail in turn inhibits transcription of Axin2, which leads in disassembly of destruction complex and enhanced binding of ß-catenin/TCF to PD-L1 promoter. CONCLUSION: We conclude that resveratrol is capable to suppress anti-tumor immunity by controlling mainly PD-L1 expression. This finding will extend the understanding of resveratrol in regulation of tumor immunity and is relevant to the debate on resveratrol supplements for lung cancer patients.

Modern Senicide in the Face of a Pandemic: An Examination of Public Discourse and Sentiment About Older Adults and COVID-19 Using Machine Learning.

OBJECTIVES: This study examined public discourse and sentiment regarding older adults and COVID-19 on social media and assessed the extent of ageism in public discourse. METHODS: Twitter data (N = 82,893) related to both older adults and COVID-19 and dated from January 23 to May 20, 2020, were analyzed. We used a combination of data science methods (including supervised machine learning, topic modeling, and sentiment analysis), qualitative thematic analysis, and conventional statistics. RESULTS: The most common category in the coded tweets was "personal opinions" (66.2%), followed by "informative" (24.7%), "jokes/ridicule" (4.8%), and "personal experiences" (4.3%). The daily average of ageist content was 18%, with the highest of 52.8% on March 11, 2020. Specifically, more than 1 in 10 (11.5%) tweets implied that the life of older adults is less valuable or downplayed the pandemic because it mostly harms older adults. A small proportion (4.6%) explicitly supported the idea of just isolating older adults. Almost three-quarters (72.9%) within "jokes/ridicule" targeted older adults, half of which were "death jokes." Also, 14 themes were extracted, such as perceptions of lockdown and risk. A bivariate Granger causality test suggested that informative tweets regarding at-risk populations increased the prevalence of tweets that downplayed the pandemic. DISCUSSION: Ageist content in the context of COVID-19 was prevalent on Twitter. Information about COVID-19 on Twitter influenced public perceptions of risk and acceptable ways of controlling the pandemic. Public education on the risk of severe illness is needed to correct misperceptions.

Dual Trajectories of Social Isolation and Dementia in Older Adults: A Population-Based Longitudinal Study.

Objectives: To identify the interrelations between the trajectories of social isolation and dementia in older adults. Methods: Data came from the National Health and Aging Trends Study 2011-2018 surveys. Group-based dual trajectory modeling was used to examine trajectories and their interrelations. Results: Four trajectories of social isolation-rarely isolated (62.2%), steady increase (13.5%), steady decrease (7.4%), and persistently isolated (16.9%) and dementia risk-persistently low risk (80.4%), increasing with early onset (3.9%), increasing with late onset (4.5%), and persistently high risk (11.2%) emerged. Two-thirds of the low-risk dementia group were in the rarely isolated group. The high-risk dementia group had the most overlap with the decreasing social isolation group (47%), followed by the persistently isolated group (28%). Conclusions: Social isolation and dementia mostly evolved in the same direction. However, the pattern of associations between these trajectories is intricate and may be reversed among long-term dementia survivors.

Research on the Effect of Molten Salt Ultrasonic Composite Cleaning for Paint Removal.

Aiming at paint removal on hydraulic cylinder, the effect of molten salt ultrasonic composite cleaning was studied. First, the mechanism of molten salt cleaning and ultrasonic cleaning was reviewed. To further describe the composite cleaning mechanism, the components and internal structure of paint were analyzed by scanning electron microscopy and Fourier transform infrared. Results showed that the paint had a significant layered structure. The total thickness was about 100 µm, and the main components were organic matters, including ester groups, epoxy groups, and aromatic compounds. Then, combining with thermal environment, cleaning medium's property, and ultrasound, the composite cleaning mechanism was described in terms of three aspects: thermal effect, chemical reaction, and ultrasonic effect. Besides, the reason why this composite cleaning had good effect on paint removal, compared to paint heated in air, was explained through dynamic analysis, which was the reduction of reaction activation energy from 114.4 kJ/mol of paint alone to 74.1 kJ/mol.

AND-Logic Based Fluorescent Probe for Selective Detection of Lysosomal Bisulfite in Living Cells.

Sulfur dioxide (SO2) plays significant roles in regulating cell apotosis and inflammation. However, there are complex interactions between small biomolecules in cells, and the identification of these coexisting biomarkers remains a challenge. Herein, we report an AND logic gate based fluorescent probe (NY-Lyso), operating by responding to pH differences between organelles in cell and selectively reacting with bisulfite (HSO3-). This approach allows the fluorescence of the probe to remain silent under neutral or alkaline conditions, notably, is activated by costimulation of lower pH and bisulfite. Furthermore, it was confirmed to be biocompatible and could be employed to monitor HSO3- in lysosomes of living cells. The proposed method demonstrated more practical and outstanding capabilities in targeted and real-time monitoring, providing an effective optical tool for biomarker sensing.

Bioactive Diterpenoids from the Leaves of Callicarpa macrophylla.

A phytochemical investigation of the leaves of Callicarpa macrophylla led to the isolation of five new diterpenoids (1-5), macrophypenes A-E, and nine known analogues (6-14). The structures of 1-5 were established on the basis of extensive analysis of NMR spectroscopic data, X-ray diffraction data, and experimental and calculated electronic circular dichroism spectra. Compound 1 is a spiroditerpenoid with a novel skeleton, and compound 5 is a rare ent-abietane diterpenoid possessing a peroxide bridge. Compounds 1, 5-7, and 11-14 stimulate nerve growth factor mediated neurite outgrowth from PC12 cells.

Bioactive clerodane diterpenoids from the twigs of Casearia balansae.

Eight new clerodane diterpenes, balanspenes A-H (1-8), along with two known analogues (9 and 10), were isolated from the twigs of Casearia balansae. The structures of 1-8 were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of compounds 1, 4, and 7 were confirmed by comparing their experimental CD spectra with those calculated by the time-dependent density functional theory method. Compounds 4-7, 9, and 10 were found to possess the property of being able to stimulate NGF-mediated neurite outgrowth from PC12 cells.

Characterization and NO inhibitory activities of chemical constituents from an edible plant Petasites tatewakianus.

Petasites tatewakianus is an edible plant belonging to the family Compositae. In our continuous search for NO inhibitors, which may be useful for the development of anti-inflammatory agents, the chemical constituents of the leaves of the edible plant P. tatewakianus were investigated. This phytochemical investigation led to the isolation of 3 new (1-3) and 10 known (4-13) sesquiterpenes and 2 other types of known compounds (14 and 15). Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic data analyses, and the absolute configurations of compounds 1 and 3 were confirmed by comparing their experimental CD spectra with those calculated by the time-dependent density functional theory (TDDFT) method. The following biological studies disclosed that these isolated compounds showed inhibitory activities on LPS-induced NO production in murine microglial BV-2 cells. The results of our phytochemical investigation, including two new bakkenolide sesquiterpenes (1 and 2), one new sesquiterpene with an unusual carbon skeleton (3), and the first report of compounds 5-7 and 10-15 from this species, further revealed the chemical composition of P. tatewakianus as an edible plant, and the biological studies implied that P. tatewakianus, containing bioactive substances with the inhibitory activities of NO production, was potentially beneficial to human health.