Variation and correlation between water retention capacity and gas permeability of compacted loess overburden during wetting-drying cycles.

Landfill gases can have numerous detrimental effects on the global climate and urban ecological environment. The protective efficacy of the final cover layer against landfill gases, following exposure to periodic natural meteorological changes during long-term service, remains unclear. This study conducted centrifuge tests and gas permeability tests on compacted loess. The experiments examined the impact and relationship of wetting-drying cycles and dry density on the soil water characteristic curve (SWCC) and gas permeability of compacted loess. Research findings reveal that during the dehumidification process of compacted loess, the gas permeability increases non-linearly, varying the gas permeability of soil with different densities to different extents under wetting-drying cycles. Two models were introduced to describe the impact of wetting-drying cycles on gas permeability of loess with various dry densities, where fitting parameters increased with the number of wetting-drying cycles. Sensitivity analysis of the parameters in the Parker-Van Genuchten-Mualem (P-VG-M) model suggests that parameter γ's accuracy should be ensured in practical applications. Finally, from a microstructural perspective, wetting-drying cycles cause dispersed clay and other binding materials coalesce to fill minuscule pores, leading to an increase in the effective pores responsible for the gas permeability of the soil. These research results offer valuable guidance for designing water retention and gas permeability in compacted loess cover layers under wetting-drying cycles.

Aptamer-Antibody Chimera Sensors for Sensitive, Rapid, and Reversible Molecular Detection in Complex Samples.

The development of receptors suitable for the continuous detection of analytes in complex, interferent-rich samples remains challenging. Antibodies are highly sensitive but difficult to engineer in order to introduce signaling functionality, while aptamer switches are easy to construct but often yield only a modest target sensitivity. We present here a programmable antibody and DNA aptamer switch (PANDAS), which combines the desirable properties of both receptors by using a nucleic acid tether to link an analyte-specific antibody to an internal strand-displacement (ISD)-based aptamer switch that recognizes the same target through different epitopes. The antibody increases PANDAS analyte binding due to its high affinity, and the effective concentration between the two receptors further enhances two-epitope binding and fluorescent aptamer signaling. We developed a PANDAS sensor for the clotting protein thrombin and show that a tuned design achieves a greater than 300-fold enhanced sensitivity compared to that of using an aptamer alone. This design also exhibits reversible binding, enabling repeated measurements with a temporal resolution of ∼10 min, and retains excellent sensitivity even in interferent-rich samples. With future development, this PANDAS approach could enable the adaptation of existing protein-binding aptamers with modest affinity to sensors that deliver excellent sensitivity and minute-scale resolution in minimally prepared biological specimens.

9-Azahomocubane.

Homocubane, a highly strained cage hydrocarbon, contains two very different positions for the introduction of a nitrogen atom into the skeleton, e. g., a position 1 exchange results in a tertiary amine whereas position 9 yields a secondary amine. Herein reported is the synthesis of 9-azahomocubane along with associated structural characterization, physical property analysis and chemical reactivity. Not only is 9-azahomocubane readily synthesized, and found to be stable as predicted, the basicity of the secondary amine was observed to be significantly lower than the structurally related azabicyclo[2.2.1]heptane, although similar to 1-azahomocubane.

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation.

The unusual and sterically constrained amino acid, seco-1-azacubane-2-carboxylic acid, was incorporated into a range of bioactive chemical templates, including enalaprilat, perindoprilat, endomorphin-2 and isoniazid, and subjected to biological testing. The endomorphin-2 derivative displayed increased activity at the δ opioid receptor, but a loss in activity was observed in the other cases, although human normal cell line evaluation suggests limited cytotoxic effects.

seco-1-Azacubane-2-carboxylic acid-Amide Bond Comparison to Proline.

seco-1-Azacubane-2-carboxylic acid, an unusual and sterically constrained amino acid, was found to undergo amide bond formation at both the N- and C-termini using proline based bioactive molecule templates as a concept platform.

Impact of digital health literacy on health-related quality of life in Chinese community-dwelling older adults: the mediating effect of health-promoting lifestyle.

Background: In the context of aging and digitalization, the development and application of digital health can help meet the growing health needs of older adults. Improving digital health literacy of older adults may be an effective way to alleviate the shortage of public health resources and improve their health-related quality of life (HRQoL). However, the impact of digital health literacy on HRQoL in older adults and the underlying mechanism remain unclear. This study intends to explore whether digital health literacy has an effect on HRQoL in community-dwelling older adults, and whether health-promoting lifestyle plays a mediating role between digital health literacy and HRQoL, while providing a theoretical basis for the scientific construction of HRQoL intervention programs for older adults. Methods: The cross-sectional study was conducted in Chongqing, China from September 2020 to April 2021. 572 community-dwelling older adults were surveyed by stratified sampling. Data on sociodemographic characteristics, digital health literacy, health-promoting lifestyle and HRQoL were collected. Univariate analysis was used to compare the differences in HRQoL among community-dwelling older adults with different sociodemographic characteristics. Pearson correlation analysis was used to explore the correlation between digital health literacy, health-promoting lifestyle and HRQoL. SPSS PROCESS macro was used to examine the mediating effect of health-promoting lifestyle between digital health literacy and HRQoL. Results: The mean score of HRQoL was 97.97 (SD 11.45). Univariate analysis showed that there were statistically significant differences in HRQoL among community-dwelling older adults with different gender, age, educational level, marital status, and monthly household income per capita (p < 0.05). There were positive correlations between digital health literacy, health-promoting lifestyle and HRQoL, with correlation coefficients ranging from 0.416 to 0.706 (p < 0.001). Digital health literacy was positively associated with HRQoL (ß = 0.210, p < 0.001), and health-promoting lifestyle mediated the relationship between digital health literacy and HRQoL, with an indirect effect of 0.175 (95% Bootstrap CI 0.135-0.214). Conclusion: Digital health literacy can affect HRQoL through the mediating effect of health-promoting lifestyle. It is suggested that relevant management institutions, communities and families should strengthen the cultivation of the digital health literacy of older adults, promote their development of health-promoting lifestyle, and ultimately improve HRQoL.

Perspectives on the popularization of smart senior care to meet the demands of older adults living alone in communities of Southwest China: A qualitative study.

Background: Older adults who live alone face challenges in daily life and in maintaining their health status quo. Currently, however, their growing demands cannot be satisfied with high quality; therefore, these demands expressed by elders may be settled in the form of smart senior care. Hence, the improvement in smart senior care may produce more positive meanings in promoting the health and sense of happiness among this elderly population. This study aimed to explore the perceptions of demands and satisfaction with regard to the provision of senior care services to the community-dwelling older adults who live alone in Southwest China, thus providing a reference for the popularization of smart senior care. Methods: This study adopted a qualitative descriptive approach on demands and the popularization of smart senior care. Semi-structured and in-depth individual interviews were conducted with 15 community-dwelling older adults who lived alone in Southwest China between March and May 2021. Thematic analysis was applied to analyze the data. Results: Through data analysis, three major themes and subcategories were generated: "necessities" (contradiction: more meticulous daily life care and higher psychological needs vs. the current lower satisfaction status quo; conflict: higher demands for medical and emergency care against less access at present), "feasibility" (objectively feasible: the popularization of smart devices and applications; subjectively feasible: interests in obtaining health information), and "existing obstacles" (insufficient publicity; technophobia; patterned living habits; and concerns). Conclusions: Smart senior care may resolve the contradiction that prevails between the shortage of medical resources and the increasing demands for eldercare. Despite several obstacles that stand in the way of the popularization of smart senior care, the necessities and feasibility lay the preliminary foundation for its development and popularization. Decision-makers, communities, developers, and providers should cooperate to make smart senior care more popular and available to seniors living alone, facilitating independence while realizing aging in place by promoting healthy aging.

Multitargeted Opioid Ligand Discovery as a Strategy to Retain Analgesia and Reduce Opioid-Related Adverse Effects.

The global "opioid crisis" has placed enormous pressure on the opioid ligand discovery community to produce novel opioid analgesics with superior opioid-related adverse-effect profiles compared with morphine. In this Perspective, the multitargeted opioid ligand strategy for the discovery of opioid analgesics with superior preclinical therapeutic indices relative to morphine is reviewed and discussed. Dual-targeted µ-opioid (MOP)/δ-opioid (DOP) ligands in which the in vitro DOP antagonist potency at least equals that of the MOP agonist activity, and are devoid of DOP or κ-opioid (KOP) agonist activity, are sufficiently promising candidates to warrant further investigation. Dual-targeted MOP/NOP partial agonists have superior preclinical therapeutic indices to morphine and/or fentanyl in nonhuman primates and are also considered promising. Based on the poor preclinical and clinical therapeutic indices of cebranopadol, which is a full agonist at MOP, DOP, and NOP receptors and a partial agonist at the KOP receptor, this pharmacologic template should be avoided.

Flow-Cell-Based Technology for Massively Parallel Characterization of Base-Modified DNA Aptamers.

Aptamers incorporating chemically modified bases can achieve superior affinity and specificity compared to natural aptamers, but their characterization remains a labor-intensive, low-throughput task. Here, we describe the "non-natural aptamer array" (N2A2) system, in which a minimally modified Illumina MiSeq instrument is used for the high-throughput generation and characterization of large libraries of base-modified DNA aptamer candidates based on both target binding and specificity. We first demonstrate the capability to screen multiple different base modifications to identify the optimal chemistry for high-affinity target binding. We next use N2A2 to generate aptamers that can maintain excellent specificity even in complex samples, with equally strong target affinity in both buffer and diluted human serum. For both aptamers, affinity was formally calculated with gold-standard binding assays. Given that N2A2 requires only minor mechanical modifications to the MiSeq, we believe that N2A2 offers a broadly accessible tool for generating high-quality affinity reagents for diverse applications.

Resistance of QYm.nau-2D to wheat yellow mosaic virus was derived from an alien introgression into common wheat.

KEY MESSAGE: The QYm.nau-2D locus conferring wheat yellow mosaic virus resistance is an exotic introgression and we developed 11 diagnostic markers tightly linked to QYm.nau-2D. Wheat yellow mosaic virus (WYMV) is a serious disease of winter wheat in China. Breeding resistant varieties is the most effective strategy for WYMV control. A WYMV resistant locus QYm.nau-2D on the chromosome arm 2DL has been repeatedly reported but the mapped region is large. In the present study, we screened recombinants using a biparental population and mapped QYm.nau-2D into an 18.8 Mb physical interval. By genome-wide association studies of 372 wheat varieties for WYMV resistance in four environments, we narrowed down QYm.nau-2D into a 16.4 Mb interval. Haplotype analysis indicated QYm.nau-2D were present as six different states due to recombination during hybridization breeding. QYm.nau-2D was finally mapped into a linkage block of 11.2 Mb. Chromosome painting using 2D specific probes and collinearity analysis among the published sequences corresponding to QYm.nau-2D region indicated the block was an exotic introgression. The Illumina-sequenced reads of four diploid Aegilops species were mapped to the sequence of Fielder, a variety having the introgression. The mapping reads were significantly increased at the putative introgression regions of Fielder. Ae. uniaristata (NN) had the highest mapping reads, suggesting that QYm.nau-2D was possibly an introgression from genome N. We investigated the agronomic performances of different haplotypes and observed no linkage drag of the alien introgression for the 15 tested traits. For marker-assisted selection of QYm.nau-2D, we developed 11 diagnostic markers tightly linked to the locus. This research provided a case study of an exotic introgression, which has been utilized in wheat improvement for WYMV resistance.

ARHGAP6 inhibits bladder cancer cell viability, migration, and invasion via ß-catenin signaling and enhances mitomycin C sensitivity.

The Rho/ROCK pathway regulates diverse cellular processes and contributes to the development and advancement of several types of human cancers. This study investigated the role of specific Rho GTPase-activating proteins (RhoGAP), ARHGAP6, in bladder cancer (BC). In this study, ARHGAP6 expression in BC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor-related function and the underlying molecular mechanism ARHGAP6 of in BC. The mRNA and protein levels of ARHGAP6 significantly reduced in human BC tissues and cell lines compared with corresponding adjacent non-cancerous tissues and normal urothelial cells. In vitro, ARHGAP6 overexpression markedly decreased the viability, migration, and invasion of BC cells. Interestingly, low ARHGAP6 expression in BC strongly correlated with poor patient survival and was highly associated with metastasis and ß-catenin signaling. Furthermore, ARHGAP6 expression strongly influenced the sensitivity of BC cells to mitomycin C treatment. Together, our results demonstrate that ARHGAP6 plays critical roles in regulating the proliferation, migration, invasion, and metastasis of BC cells possibly via the modulation of ß-catenin and strongly influences the chemosensitivity of BC cells.

Association of extreme precipitation with hospitalizations for acute myocardial infarction in Beijing, China: A time-series study.

Background: In the context of global climate changes, increasing extreme weather events have aroused great public concern. Limited evidence has focused on the association between extreme precipitation and hospitalizations for acute myocardial infarction (AMI). Our study aimed to examine the effect of extreme precipitation on AMI hospitalizations. Methods: Daily AMI hospitalizations, weather variables and air pollution data in Beijing from 2013 to 2018 were obtained. We used a time-series analysis with a distributed lag model to evaluate the association of extreme precipitation (≥95th percentile of daily precipitation) with AMI hospitalizations. Subgroup analysis was conducted to identify the vulnerable subpopulations and further assessed the attributable burden. Results: Extreme precipitation increased the risk of AMI hospitalizations with significant single-day effects from Lag 4 to Lag 11, and the maximum cumulative effects at Lag 0-14 (CRR = 1.177, 95% CI: 1.045, 1.326). Older people (≥65 years) and females were more vulnerable to extreme precipitation. The attributable fraction and numbers of extreme precipitation on AMI hospitalizations were 0.68% (95% CI: 0.20%, 1.12%) and 854 (95% CI: 244, 1,395), respectively. Conclusion: Extreme precipitation is correlated with a higher risk of AMI hospitalizations. The elderly (≥65 years) and females are more susceptible to AMI triggered by extreme precipitation.

The Application and Prospect of Mobile Health (mHealth) in Health Service for Older People Living Alone in Community: A Narrative Review.

As a result of improvements in life expectancy and reductions in fertility rate, the increasing world population ageing brings huge challenges for both developed and developing countries. Such factors as fewer children, migration of children and widowhood further increase the number of older people living alone. Older adults prefer age in place, which means care in the home. As the main place older people live in, care in community absolutely needs more attention. Optimizing health services for the elderly living in community is of positive significance to health promotion and happiness enhancement. But the traditional health service for the elderly has drawbacks of poor timeliness and high labor cost. The rapid development of modern science and technology make it possible to apply mHealth in health service for the elderly. At present, mHealth is relatively mature in the communities of developed countries. This article presents the application of mHealth in many developed countries, as references for developing countries.

Peripheral apoE4 enhances Alzheimer's pathology and impairs cognition by compromising cerebrovascular function.

The ε4 allele of the apolipoprotein E (APOE) gene, a genetic risk factor for Alzheimer's disease, is abundantly expressed in both the brain and periphery. Here, we present evidence that peripheral apoE isoforms, separated from those in the brain by the blood-brain barrier, differentially impact Alzheimer's disease pathogenesis and cognition. To evaluate the function of peripheral apoE, we developed conditional mouse models expressing human APOE3 or APOE4 in the liver with no detectable apoE in the brain. Liver-expressed apoE4 compromised synaptic plasticity and cognition by impairing cerebrovascular functions. Plasma proteome profiling revealed apoE isoform-dependent functional pathways highlighting cell adhesion, lipoprotein metabolism and complement activation. ApoE3 plasma from young mice improved cognition and reduced vessel-associated gliosis when transfused into aged mice, whereas apoE4 compromised the beneficial effects of young plasma. A human induced pluripotent stem cell-derived endothelial cell model recapitulated the plasma apoE isoform-specific effect on endothelial integrity, further supporting a vascular-related mechanism. Upon breeding with amyloid model mice, liver-expressed apoE4 exacerbated brain amyloid pathology, whereas apoE3 reduced it. Our findings demonstrate pathogenic effects of peripheral apoE4, providing a strong rationale for targeting peripheral apoE to treat Alzheimer's disease.

In vitro Anti-Hantavirus Activity of Protein Kinase Inhibitor 8G1 Targeting AKT/mTOR/eIF4E Signaling Pathway.

Hantaan virus (HTNV) is the main cause of hemorrhagic fever with renal syndrome (HFRS) around the world, which results in profound morbidity and mortality. However, there are currently no FDA-approved therapeutics or vaccines against HFRS. To find new anti-HTNV drugs, the inhibitory activity of 901 small molecule kinase inhibitors against HTNV is analyzed. Among these compounds, compound 8G1 inhibits HTNV with a relatively high inhibition rate and lower toxicity. The viral titer and nucleocapsid protein of HTNV are reduced after compound 8G1 treatment in a dose-dependent manner at concentrations ranging from 1 to 20 µM. In addition, the administration of compound 8G1 at the early stage of HTNV infection can inhibit the replication of HTNV. The molecular docking result reveals that compound 8G1 forms interactions with the key amino acid residues of serine/threonine-protein kinase B (Akt), which is responsible for the observed affinity. Then, the mammalian target of rapamycin (mTOR) and eukaryotic translation initiation factor 4E (eIF4E) signaling pathways are inhibited. Our results may help to design novel targets for therapeutic intervention against HTNV infection and to understand the anti-HTNV mechanism of protein kinase inhibitors.

Multi-omics analysis reveals expression complexity and functional diversity of mouse kinome.

Protein kinases are a crucial component of signaling pathways involved in a wide range of cellular responses, including growth, proliferation, differentiation, and migration. Systematic investigation of protein kinases is critical to better understand phosphorylation-mediated signaling pathways and may provide insights into the development of potential therapeutic drug targets. Here we perform a systems-level analysis of the mouse kinome by analyzing multi-omics data. We used bulk and single-cell transcriptomic data from the C57BL/6J mouse strain to define tissue- and cell-type-specific expression of protein kinases, followed by investigating variations in sequence and expression between C57BL/6J and DBA/2J strains. We then profiled a deep brain phosphoproteome from C57BL/6J and DBA/2J strains as well as their reciprocal hybrids to infer the activity of the mouse kinome. Finally, we performed phenome-wide association analysis using the BXD recombinant inbred (RI) mice (a cross between C57BL/6J and DBA/2J strains) to identify any associations between variants in protein kinases and phenotypes. Collectively, our study provides a comprehensive analysis of the mouse kinome by investigating genetic sequence variation, tissue-specific expression patterns, and associations with downstream phenotypes.

Design, synthesis and evaluation of alpha lipoic acid derivatives to treat multiple sclerosis-associated central neuropathic pain.

Multiple sclerosis-associated central neuropathic pain (MS-CNP) is difficult to alleviate with clinically used pain-killers and so there is a large unmet medical need for novel treatments for alleviating MS-CNP. Although (R)-alpha lipoic acid (ALA) evoked significant pain relief efficacy in a mouse model of multiple sclerosis-associated central neuropathic pain (MS-CNP), this dietary supplement has poor oral bioavailability due to low gastric stability. Eight ester prodrugs of the R enantiomer of ALA [(R)-ALA] were designed encompassing a range of biocompatible hydrophobic and hydrophilic features and synthesized in an effort to identify a prodrug candidate that was stable at gastric and upper gastrointestinal tract (GIT) pH, and that could be released (hydrolyzed by esterases) in the blood to (R)-ALA immediately after absorption into the portal vein (i.e., highly desirable features for pain relief development). These biocompatible hydrophobic and hydrophilic (R)-ALA pro-dugs underwent comprehensive preliminary screening to reveal PD-ALA4 HCl salt (10) as a promising candidate and PD-ALA 7 (8) could be a viable substitute, utilizing enzyme-free gastric and intestinal stability assessments, LogP evaluations, in vitro plasma stability and caco-2 cell monolayer permeability.

Current status and influencing factors of digital health literacy among community-dwelling older adults in Southwest China: a cross-sectional study.

BACKGROUND: The rapid development of digital health has reduced the time and cost of medical treatment, bringing efficient and economical benefits. However, older adults all over the world are deficient in digital health knowledge and skills to varying degrees. This study intends to investigate the current status and influencing factors of digital health literacy among community-dwelling older adults in Southwest China, so as to provide theoretical reference for global digital health researches and the construction of gerontological digital health service models. METHODS: A cross-sectional survey was conducted from September 2020 to April 2021 in Chongqing, China. 572 community-dwelling older adults (≥ 65 years) were surveyed by stratified sampling. Data on sociodemographic characteristics, Internet usage, attitude towards Internet health information and digital health literacy were collected. Wherein, the digital health literacy assessment adopted the Digital Health Literacy Assessment Scale for community-dwelling older adults, which was developed by the research group, proven to be with good internal consistency (0.941), split-half reliability (0.889), test-retest reliability (0.941), content validity (0.967), criterion validity (0.938) and construct validity. The influencing factors were explored by univariate analysis and multiple linear regression analysis. RESULTS: The average score of digital health literacy was 37.10 (SD 18.65). Univariate analysis showed that there were statistically significant differences in the comparison of digital health literacy according to 16 variables, such as different age and education levels. Multiple linear regression analysis showed that education level, marital status, self-rated health status, degree of health concerns, duration of Internet usage, time spent using the Internet per day, frequency of Internet usage, frequency of receiving guidance passively from family members, perceived usefulness, perceived ease of use and perceived reliability were positively correlated with digital health literacy, while age and perceived risk were negatively correlated with digital health literacy. CONCLUSION: The overall digital health literacy of community-dwelling older adults in Southwest China is relatively low. In the future, health professionals should fully consider the diverse influencing factors of digital health literacy, assess individual differences and provide targeted intervention programs. Meanwhile, global public health authorities should integrate health resources effectively, and seek health service models for older adults in line with the development of the digital age to narrow the digital divide.

Improving object detection quality with structural constraints.

Recent researches revealed object detection networks using the simple "classification loss + localization loss" training objective are not effectively optimized in many cases, while providing additional constraints on network features could effectively improve object detection quality. Specifically, some works used constraints on training sample relations to successfully learn discriminative network features. Based on these observations, we propose Structural Constraint for improving object detection quality. Structural constraint supervises feature learning in classification and localization network branches with Fisher Loss and Equi-proportion Loss respectively, by requiring feature similarities of training sample pairs to be consistent with corresponding ground truth label similarities. Structural constraint could be applied to all object detection network architectures with the assist of our Proxy Feature design. Our experiment results showed that structural constraint mechanism is able to optimize object class instances' distribution in network feature space, and consequently detection results. Evaluations on MSCOCO2017 and KITTI datasets showed that our structural constraint mechanism is able to assist baseline networks to outperform modern counterpart detectors in terms of object detection quality.

Associations between ambient temperature and adult asthma hospitalizations in Beijing, China: a time-stratified case-crossover study.

BACKGROUND: Studies on the associations between ambient temperature and asthma hospitalizations are limited, and the results are controversial. We aimed to assess the short-term effects of ambient temperature on the risk of asthma hospitalizations and quantify the hospitalization burdens of asthma attributable to non-optimal temperature in adults in Beijing, China. METHODS: We collected daily asthma hospitalizations, meteorological factors and air quality data in Beijing from 2012 to 2015. We applied a time-stratified case-crossover design and fitted a distributed lag non-linear model with a conditional quasi-Poisson regression to explore the association between ambient temperature and adult asthma hospitalizations. The effect modifications of these associations by gender and age were assessed by stratified analyses. We also computed the attributable fractions and numbers with 95% empirical confidence intervals (eCI) of asthma hospitalizations due to extreme and moderate temperatures. RESULTS: From 2012 to 2015, we identified a total of 18,500 hospitalizations for asthma among adult residents in Beijing, China. Compared with the optimal temperature (22 °C), the cumulative relative risk (CRR) over lag 0-30 days was 2.32 with a 95% confidence interval (CI) of 1.57-3.42 for extreme cold corresponding to the 2.5th percentile (- 6.5 °C) of temperature distribution and 2.04 (95% CI 1.52-2.74) for extreme heat corresponding to the 97.5th percentile (29 °C) of temperature distribution. 29.1% (95% eCI 17.5-38.0%) of adult asthma hospitalizations was attributable to non-optimum temperatures. Moderate cold temperatures yielded most of the burdens, with an attributable fraction of 20.3% (95% eCI 9.1-28.7%). The temperature-related risks of asthma hospitalizations were more prominent in females and younger people (19-64 years old). CONCLUSIONS: There was a U-shaped association between ambient temperature and the risk of adult asthma hospitalizations in Beijing, China. Females and younger patients were more vulnerable to the effects of non-optimum temperatures. Most of the burden was attributable to moderate cold. Our findings may uncover the potential impact of climate changes on asthma exacerbations.