Development and experimental validation of computational methods for human antibody affinity enhancement.

High affinity is crucial for the efficacy and specificity of antibody. Due to involving high-throughput screens, biological experiments for antibody affinity maturation are time-consuming and have a low success rate. Precise computational-assisted antibody design promises to accelerate this process, but there is still a lack of effective computational methods capable of pinpointing beneficial mutations within the complementarity-determining region (CDR) of antibodies. Moreover, random mutations often lead to challenges in antibody expression and immunogenicity. In this study, to enhance the affinity of a human antibody against avian influenza virus, a CDR library was constructed and evolutionary information was acquired through sequence alignment to restrict the mutation positions and types. Concurrently, a statistical potential methodology was developed based on amino acid interactions between antibodies and antigens to calculate potential affinity-enhanced antibodies, which were further subjected to molecular dynamics simulations. Subsequently, experimental validation confirmed that a point mutation enhancing 2.5-fold affinity was obtained from 10 designs, resulting in the antibody affinity of 2 nM. A predictive model for antibody-antigen interactions based on the binding interface was also developed, achieving an Area Under the Curve (AUC) of 0.83 and a precision of 0.89 on the test set. Lastly, a novel approach involving combinations of affinity-enhancing mutations and an iterative mutation optimization scheme similar to the Monte Carlo method were proposed. This study presents computational methods that rapidly and accurately enhance antibody affinity, addressing issues related to antibody expression and immunogenicity.

Revolutionizing GPCR-ligand predictions: DeepGPCR with experimental validation for high-precision drug discovery.

G-protein coupled receptors (GPCRs), crucial in various diseases, are targeted of over 40% of approved drugs. However, the reliable acquisition of experimental GPCRs structures is hindered by their lipid-embedded conformations. Traditional protein-ligand interaction models falter in GPCR-drug interactions, caused by limited and low-quality structures. Generalized models, trained on soluble protein-ligand pairs, are also inadequate. To address these issues, we developed two models, DeepGPCR_BC for binary classification and DeepGPCR_RG for affinity prediction. These models use non-structural GPCR-ligand interaction data, leveraging graph convolutional networks and mol2vec techniques to represent binding pockets and ligands as graphs. This approach significantly speeds up predictions while preserving critical physical-chemical and spatial information. In independent tests, DeepGPCR_BC surpassed Autodock Vina and Schrödinger Dock with an area under the curve of 0.72, accuracy of 0.68 and true positive rate of 0.73, whereas DeepGPCR_RG demonstrated a Pearson correlation of 0.39 and root mean squared error of 1.34. We applied these models to screen drug candidates for GPR35 (Q9HC97), yielding promising results with three (F545-1970, K297-0698, S948-0241) out of eight candidates. Furthermore, we also successfully obtained six active inhibitors for GLP-1R. Our GPCR-specific models pave the way for efficient and accurate large-scale virtual screening, potentially revolutionizing drug discovery in the GPCR field.

Role of miRNAs in macrophage-mediated kidney injury.

Macrophages, crucial components of the human immune system, can be polarized into M1/M2 phenotypes, each with distinct functions and roles. Macrophage polarization has been reported to be significantly involved in the inflammation and fibrosis observed in kidney injury. MicroRNA (miRNA), a type of short RNA lacking protein-coding function, can inhibit specific mRNA by partially binding to its target mRNA. The intricate association between miRNAs and macrophages has been attracting increasing interest in recent years. This review discusses the role of miRNAs in regulating macrophage-mediated kidney injury. It shows how miRNAs can influence macrophage polarization, thereby altering the biological function of macrophages in the kidney. Furthermore, this review highlights the significance of miRNAs derived from exosomes and extracellular vesicles as a crucial mediator in the crosstalk between macrophages and kidney cells. The potential of miRNAs as treatment applications and biomarkers for macrophage-mediated kidney injury is also discussed.

A qualitative exploration of 40 Hz sound and music for older adults with mild cognitive impairment.

Emerging evidence suggests that 40 Hz auditory stimulation may benefit cognition. Nested within a randomized crossover trial, this qualitative study evaluates the acceptability and experience of three auditory interventions-self-selected music, 40 Hz sound, and a novel combination, termed 40 Hz music-in individuals with Mild Cognitive Impairment (MCI). Semi-structured interviews were conducted with individuals with MCI post-intervention exposure. Findings indicated a preference for self-selected music due to its memory-boosting and emotional benefits, while responses to 40 Hz sound were mixed, with several participants reporting discomfort. The composite 40 Hz music intervention showed promise, striking a balance by enhancing user experience and mitigating the 40 Hz sound's negative aspects. Engagement was influenced by personal music interests, listening routines, and support networks. This study highlights the potential of integrating 40 Hz sound with personalized music to offer a more acceptable 40 Hz auditory intervention for cognition in older adults with MCI.

Predictors of Usual and Peak Gait Speed in Community-Dwelling Older Adults With Mild-to-Moderate Alzheimer's Dementia.

Gait speed significantly affects functional status and health outcomes in older adults. This cross-sectional study evaluated cognitive and physical fitness contributors to usual and peak gait speed in persons with Alzheimer's dementia. Multiple hierarchal linear regression was used to obtain squared semipartial correlation coefficients (sr2) and effect sizes (Cohen's ƒ2). Participants (n = 90; 56% male) averaged 77.1 ± 6.6 years of age and 21.8 ± 3.4 on Mini-Mental State Examination. Demographic/clinical, physical fitness, and cognition variables explained 45% and 39% of variance in usual and peak gait speed, respectively. Muscle strength was the only significant contributor to both usual (sr2 = .175; Cohen's ƒ2 = 0.31; p < .001) and peak gait speed (sr2 = .11; Cohen's ƒ2 = 0.18; p < .001). Women who were "slow" walkers (usual gait speed <1.0 m/s) had significantly lower cardiorespiratory fitness and executive functioning compared with "fast" walkers. In conclusion, improving muscle strength may modify gait and downstream health outcomes in Alzheimer's dementia.

Association of Sleep and Physical Activity Among Older Adults and the Moderation of Chronotype.

This study aimed to examine the associations of both subjectively and objectively measured sleep with physical activity among older adults and to explore the possible moderating role of chronotype in these associations. We included baseline data of 116 community-dwelling older adults without dementia from three prior studies. Pittsburgh Sleep Quality Index and Actigraphy were used as subjective and objective sleep measures, respectively. Physical activity was assessed by the Physical Activity Scale for the Elderly. The Morningness-Eveningness Questionnaire was used to measure chronotype, which was further dichotomized into morning type and non-morning type. Multiple linear regressions were performed to examine the associations, controlling for demographic and health characteristics. We found that better subjective sleep quality, shorter actigraphy sleep duration, and higher actigraphy sleep efficiency were uniquely associated with greater physical activity. Being a morning type might alleviate the adverse association between poor subjective sleep quality and physical activity among older adults.

Assisted Relaxation Therapy for Insomnia in Older Adults With Mild Cognitive Impairment: A Pilot Study.

Insomnia symptoms are prevalent in older adults with mild cognitive impairment (MCI) and can pose treatment challenges. We tested the feasibility, acceptability, and preliminary efficacy of assisted relaxation therapy (ART) to improve insomnia symptoms in community-dwelling older adults with MCI. In this pilot RCT, 25 participants were assigned to intervention or control groups for 2 weeks. The final sample (n = 20) consisted of all Black, primarily female (70%) older adults (mean age 69.10; SD = 7.45) with mean Montreal Cognitive Assessment scores of 21.10 (SD = 2.49). Recruitment was timely; attrition was low (80%). Participants were able to use ART (average use 7.00; SD = 5.07 days). Participants in the ART group improved on Insomnia Severity Index (ISI) (- 7.10; 95% CI [-11.63, -2.55]; p = .004) compared to baseline. There were clinically meaningful mean change scores on ISI for the intervention group compared to the control (- 7.10 vs. - 4.33). Results provide justification for testing ART in a fully powered clinical trial.

Challenges and suggestions for exergaming program in exercise among older adults. / 运动游戏在老年人运动锻炼中面临的挑战及对策.

Engaging in physical activity and exercise is one of the important ways for health promotion. However, older adults are often physically inactive or have a sedentary lifestyle and have poor compliance with physical activity. Exergaming program with their unique advantages could make physical activity a more joyful experience and motivate older adults to participate in physical activity. Promoting older adults' health through engagement in exergaming programs is still in the early stage, and still faces many challenges. Analyzing the challenges and difficulties faced by exergaming program for older adults and exploring in-depth strategies to promote the implementation of exergaming program for older adults are of great significance for the design and implementation of sports games for older adults.

An mHealth-Facilitated Personalized Intervention for Physical Activity and Sleep in Community-Dwelling Older Adults.

This randomized controlled pilot trial tested the preliminary effect of a 24-week mHealth-facilitated, personalized intervention on physical activity (PA) and sleep in 21 community-dwelling older adults. The intervention included a personalized exercise prescription, training, goal setting, and financial incentives. mHealth strategies, including self-monitoring, motivational messages, activity reminders, and phone coaching, were used to facilitate PA participation. PA and sleep were measured using actigraphy and questionnaires at baseline and 8-, 16-, and 24-week visits. Participants in the intervention group had lower objective PA levels at 24 weeks than at 8 and 16 weeks, although levels of PA remained higher than at baseline. Compared with the control group, the intervention increased PA at 8, 16, and 24 weeks; improved subjective sleep quality at 16 and 24 weeks; and increased actigraphy-measured sleep duration and sleep efficiency at 24 weeks. mHealth PA interventions may benefit PA and sleep in older adults. Strategies for maintaining long-term PA behavioral changes are needed.

Promoting sleep in low-income older adults with disabilities: Comparing CAPABLE with a social engagement control.

Sleep plays a vital role in older adults' health. The Community Aging in Place-Advancing Better Living for Elders (CAPABLE) trial, conducted in Maryland between 2012 and 2016, is a 5-month biobehavioral environmental intervention study to reduce functional disabilities in 300 low-income older adults. Individual and environmental factors impacting sleep were addressed in CAPABLE. This secondary data analysis was to test the preliminary effect of CAPABLE on actigraph-measured sleep, compared with a social engagement control in 73 CAPABLE participants with pretest-posttest actigraph data. Participants in this analysis were aged 75.8±7.5 years; 86.3% of them were females and 84.9% were Black/African Americans. Both CAPABLE intervention and social engagement control improved sleep efficiency and reduced sleep onset latency. The effect of CAPABLE on sleep was comparable to social engagement. These findings underline the importance of promoting physical function and maintaining social activity for sleep in low-income older adults with disabilities.

A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008µM and 9.453 µM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.

Impact of Different Proportions of 2D and 3D Scaffolds on the Proliferation and Differentiation of Human Adipose-Derived Stem Cells.

PURPOSE: To observe the proliferation and differentiation of human adipose-derived stem cells (hADSCs) on 2D and 3D scaffolds, the sodium alginate and collagen interpenetrating network hydrogel were developed to determine optimal properties for bone tissue engineering. METHODS: Three groups of scaffold materials were prepared according to the ratio of sodium alginate to collagen: A (4:1), B (2:1), and C (1:1), respectively. For each group, gel beads (3D surfaces) and freeze-dried films (2D surfaces) were respectively prepared. For gel beads, hADSCs were mixed during the preparation of the beads, and then stem cells were applied to the surface of each film after freeze-drying and sterilization during the preparation of the freeze-dried films. Cell proliferation and osteogenic differentiation potential were detected by cell counting kit, viable/dead cell staining kit, quantitative reverse transcription polymerase chain reaction, and immunofluorescent staining, respectively. RESULTS: Results showed that cell proliferation rate progressively increased with the increase of collagen ratio, with group C of 3D surfaces of gel beads achieving the highest rate. In particular, highest cell viability on the 2D surfaces was achieved in group B. Differences in BGLAP and RUNX2 expression in hADSCs on 2D or 3D surfaces of the 3 groups were statistically significant. Particularly, BGLAP and RUNX2 gene expression levels were highest in group C of freeze-dried films and were highest in group B of gel beads. Furthermore, the trend of immunofluorescence expression of RUNX2 and osteocalcin expression were consistent with the genetic testing results. CONCLUSIONS: All data indicated that sodium alginate-collagen scaffolding materials had no adverse impact on the proliferation and osteogenic differentiation of hADSCs. Cell differentiation and proliferation of bone tissue engineering can be promoted with the use of sodium alginate and collagen interpenetrating network hydrogel, and the appropriate ratio of sodium alginate and collagen is 2:1.

Biogas energy generated from livestock manure in China: Current situation and future trends.

This article investigates the current status of the livestock industry (cattle, pigs, sheep, and poultry) in China and assesses the potential for biogas production from anaerobically digested livestock manure. According to calculation results based on the latest data of livestock released by the National Bureau of Statistics of China in 2018, China produced 2 × 1012 kg of manure pollution in 2017, with pig waste representing the largest single manure source. Biogas that can be converted from high organic containing manure is a kind of clean bioenergy with low carbon footprint. In 2017, the energy potential from manure-produced biogas was about 5.74 × 1012-6.73 × 1012 MJ, which corresponds to 4-5% of China's total energy demand. Correlation analysis between biogas production and the livestock industry showed that crop production had significant effects on manure-generated biogas production. However, it is necessary to address the challenges when applying AD technology. Bioenergy potential from manure will be lost during material collection and transportation. Although large-scale livestock farming remains controversial, this type of farming can improve the energy recovery rate of livestock manure. How to gain benefits and maintain sustainable development is also a bottleneck for AD promotion. Reducing energy input in AD projects as well as enhancing the efficiency of methanogenesis of livestock manure are key factors for achieving a high net output of biogas projects. More inclusive strategies and a broader vision should be adopted to allow stakeholders to benefit from manure-generated biogas projects.

Association of fear of falling with frailty in community-dwelling older adults: A cross-sectional study.

This study aimed to describe frailty and fear of falling and examine the cross-sectional association between frailty and fear of falling in community-dwelling older adults in China. We recruited 165 older adults from five selected communities in the five districts of Changchun, Jilin Province. Participants were asked to complete a demographic questionnaire, the Short Falls Efficacy Scale-International, and the Tilburg Frailty Indicator. We found that 60% of our participants were frail and that 81% reported a fear of falling. Using binary logistic regression, we found that the participants with fear of falling were 7.2 times more likely to be frail. These findings suggest that fear of falling should be regularly screened in clinical practice to help identify older adults with greater risks of frailty. Future longitudinal studies of larger sample size are needed to confirm the association. Moreover, frailty prevention programs that include strategies to reduce the fear of falling should be tested among community-dwelling older adults.

The effect of resistance training on sleep in Chinese older adults: A randomized controlled trial.

Sleep disturbances affect approximately half of the older adult population and add additional risks of developing Alzheimer's disease. This study is to test the effects of a 12-week resistance training (RT) program on sleep in older adults residing in an assisted living facility in China. A total of 62 eligible participants were randomly assigned to RT (n = 31) or control group (n = 31). Participants in RT group participated in three 1-hour moderate intensity RT sessions per week for 12 weeks (at least 48 h between sessions). In the overall sample, sleep efficiency increased (P < 0.01), wake after sleep onset (P < 0.01) decreased in participants in RT group at post-intervention, compared to control group. Similar results were found in participants with mild cognitive impairment (MCI). The findings support that RT improves sleep efficiency and decreases sleep fragmentation in older adults in general and in those with MCI.

Association of cardiovascular risk factor clustering and prehypertension among adults：Results from the China health and retirement longitudinal study baseline.

Background: Prehypertension is common in China, but its causes and associated factors have not been well studied. This study aimed to examine the age and gender-specific associations between CVD risk factor clustering and prehypertension among adults in China.Methods: This cross-sectional study used data from participants (n = 8735) aged over 45 in the China Health and Retirement Longitudinal Study (CHARLS) Baseline conducted from 2011-2012. The participants' data were collected using standard questionnaires, anthropometric, and biochemical tests. Logistic regression analyses were used to examine the associations between cardiovascular risk factors, their clustering and prehypertension.Results: Overall, 21.1%, 39.5%, 27.6% and 11.8% participants had 0, 1, 2, ≥ 3 CVD risk factors in prehypertension group, respectively. Diabetes and overweight/obesity were significantly associated with prehypertension (OR, 1.24; 95% confidence interval [CI], 1.06-1.44; OR, 1.55; 95% CI, 1.38-1.75) in the overall population, and diabetes was associated with prehypertension only in men (OR, 1.26; 95% CI, 1.00-1.58) and older adults (OR, 1.32; 95% CI, 1.03-1.69). Moreover, participants with 1, 2 and ≥3 risk factors had increased odds of having prehypertension (OR, 1.29; 95% CI, 1.12-1.49; OR, 1.59; 95% CI, 1.31-1.78; OR, 2.05; 95% CI, 1.66-2.53, respectively) and existed dose-response relationship, regardless of age and gender.Conclusions: This study indicated that CVD risk factor clustering was significantly associated with prehypertension and hypertension. These results provide valuable information for health professionals to better understand the impact of CVD risk factor clustering on prehypertension and hypertension.

Measuring the 'dose' of person-centred care in aged care: Development of staff and family questionnaires.

AIMS: To develop a theoretically and psychometrically sound instrument to measure the 'dose' of person-centred care practice in long-term care. BACKGROUND: Although person-centred care has been adopted for long-term care across the world, there is a lack of theory-based instruments to measure its impact. Two questionnaires were developed to measure person-centred care from the perspectives of staff and family based on current person-centred care frameworks: Kitwood, Nolan, and Eden Alternative. METHODS: Phase I: literature review and focus groups identified potential items for the questionnaires. Phase II: academic experts, local staff, and family members of residents assessed content validity. Phase III: psychometric testing. RESULTS: A 34-item staff questionnaire (Cronbach's Alpha = 0.942) with two factors "Making person-centredness real" and "Making the environment meaningful for life and work". A 30-item family questionnaire (Cronbach's Alpha = 0.947), with three factors "Staff care about what is meaningful to my family member", "Staff know and respect my family member", and "We are all part of a family". The factors did not directly reflect the theoretical constructs from Kitwood's and Nolan's work. CONCLUSION: Two instruments, capturing the 'dose' or active practice of delivering person-centred care, have demonstrated sound psychometric properties. The study contributes to understanding the theoretical components of person-centred care. IMPACT: The study addressed the lack of robust tools to measure how much person-centred care is taking place in aged care facilities. Staff and family questionnaires were produced based on strong theoretical foundations combining concepts of prominent person-centred theories and rigorous psychometric testing. The instruments can be used to determine if person-centred care makes a difference, to compare if person-centred care changes or develops over time or between facilities. Ultimately residents, families, and staff will benefit from the ability to measure how much person-centred care residents receive.

A personalized behavioral intervention implementing mHealth technologies for older adults: A pilot feasibility study.

Sedentary behavior has been associated with adverse health outcomes such as disturbed sleep in older adults. We conducted a single-group pretest and posttest study to evaluate the feasibility of a personalized behavioral intervention program using mobile health technology in improving physical activity and sleep in older adults. The four-week intervention included: personalized physical activity training, real-time physical activity self-monitoring, interactive prompts and feedback with a smartwatch, phone consultation with an exercise trainer and research team members, and weekly financial incentives for achieving weekly physical activity goals. Eight cognitively intact older adults were recruited and completed the study. Findings suggested that the intervention was feasible in this sample of older adults and provided favorable changes in levels of physical activity during the intervention and at post-intervention. Future studies will include a fully powered trial to evaluate the efficacy of this intervention in sedentary older adults.

The Relationship Between Midday Napping And Neurocognitive Function in Early Adolescents.

Objective/Background: The impact of midday napping on neurocognitive function in adolescents has not been well established. This study aimed to investigate the relationship between self-reported midday-napping behaviors and neurocognitive function in early adolescents. Participants: The sample was comprised of 363 early adolescents (12.00 ± 0.38 years old) from Jintan, China. Methods: Midday napping, nighttime sleep duration, and sleep quality were measured by self-reported questionnaires. Neurocognitive function was measured by the Penn Computerized Neurocognitive Battery (accuracy and reaction times). Generalized linear regression was used to analyze the relationships. Results: Sixty-four percent of our sample took more than 3 naps per week, and 70.11% reported nap durations of over 30 min. Participants with higher frequencies or longer durations of midday napping reported significantly better nighttime sleep quality (p < 0.05). Adjusted models showed that frequent nappers (5-7d/week) were significantly associated with heightened accuracy on tasks that measured sustained attention and nonverbal reasoning and faster reaction times on spatial memory compared with other frequency groups (ps < 0.05). For napping duration subgroups, early adolescents who took naps of any length were estimated to have faster reaction speeds on the sustained attention task compared with participants who never napped (ps < 0.05). However, only nappers with a moderate duration (31-60 min) tended to achieve both faster speeds (ß = -38.28, p = 0.02) and better accuracy (ß = 3.90, p = 0.04) on the sustained attention task. Conclusions: Our findings suggest that there is an association between habitual midday napping and neurocognitive function in early adolescents, especially in China, where midday napping is a cultural practice.

Vaccination with a DNA vaccine encoding CD317-targeting HBs antigen elicits enhanced immunity in mice.

BACKGROUND: Conventional hepatitis B virus (HBV) vaccines fail to induce protective antibody titers in 5-10% of immune-competent vaccines. Therefore, safe and effective HBV vaccines are still clinically needed. METHODS: In this study, we developed a plasmid DNA vaccine encoding CD317 single-chain fragment variable (α317scFv) linked with the hepatitis B surface antigen (HBsAg) and detected the humoral and cellular immune responses elicited by this vaccine in BALB/c mice. RESULTS: Vaccination with this fusion DNA vaccine in BALB/c mice induced more robust antiviral T cell and antibody immunity against HBsAg. Compared with mice vaccinated with control vaccine encoding HBsAg, the level of serum-circulating anti-HBsAg antibody (HBsAb) was nearly double in fusion DNA-vaccinated mice. More interesting, splenic lymphocytes isolated from fusion DNA-vaccinated mice showed more potent proliferation and IFN-γ production after being re-stimulated with recombinant HBsAg in vitro. And not only that, the cytotoxicity of fusion DNA vaccine-sensitized splenocytes was ∼3-fold higher than that of controls. CONCLUSION: Taken together, our results reveal that the fusion DNA vaccine can induce more effective immunological protection against HBV, and is a promising candidate for preventing HBV infection.