Organic Semiconducting Sono-Metallo-Detonated Immunobombs for Ultrasensitized Domestication of Immunosuppressive Cells.

Cancer immunotherapy harnesses the immune system to combat cancer, yet tumors often evade immune surveillance through immunosuppressive cells. Herein, we report an organic semiconducting sono-metallo-detonated immunobomb (SMIB) to spatiotemporally tame immunosuppressive cells in situ. SMIB consists of an amphiphilic semiconducting polymer (SP) with a repeatable thiophene-based Schiff base serving as an iron ion chelator (Fe3+). SMIB increases sonochemical activity through iron chelation and reduces immunosuppressive cell differentiation with metals and sonochemicals, thereby decreasing the irradiation dose. Upon ultrasound irradiation, SMIB acts as a sono-metallo-detonated immunobomb and inhibits Tregs via the mTOR pathway and M2 macrophage polarization through GPX4 regulation. Ultrasensitized sono-generated reactive oxygen species also promote activation of antigen-presenting cells in deep solid tumors (1 cm), resulting in cytotoxic T cell infiltration and enhanced antitumor efficacy. This platform provides a versatile approach for synergistic sono- and metalloregulation of immunosuppressive cells in situ.

Effects of Bright Light Therapy on Agitation Among Older Adults Living with Dementia in Macao: A Pilot Study.

A randomized controlled trial was conducted to examine the effects of bright light therapy on agitation in older adults with dementia in Macao. This study involved 31 participants: 10 in the outdoor light treatment group, 11 in the indoor light-box treatment group, and 10 in the control group. Significant reductions in agitation were observed in the two treatment groups over four weeks compared to the control group. However, no statistical difference in cognitive function between experimental and control groups was found. This study supports the use of bright light therapy to reduce agitation in older people with dementia.

Ceftazidime-Avibactam Combination Therapy versus Monotherapy for the Treatment Carbapenem-Resistant Gram-Negative Bacterial Infections: A Retrospective Observational Study.

Purpose: Since the introduction of ceftazidime-avibactam (CZA) in the Chinese market, accumulating clinical evidence has substantiated its efficacy in the treatment of infections caused by carbapenem-resistant gram-negative bacteria (CR-GNB). Nevertheless, an ongoing debate persists concerning the choice between monotherapy and combination therapy when devising clinical anti-infection protocols. Patients and Methods: This retrospective, single-center observational study enrolled patients with CR-GNB infections who received CZA treatment between December 2019 and August 2023. The primary outcome assessed was 30-day mortality, and the secondary outcome measured was 14-day bacterial clearance. A multivariate Cox regression model was used to identify variables that were independently associated with 30-day mortality rate. Results: Eighty-three patients were enrolled in the study; of which, 45 received CZA monotherapy, whereas 38 received combination therapy. The overall 30-day mortality rate was 31.3%, and no significant difference was observed in the 30-day mortality rates between the CZA combination therapy and monotherapy groups (31.6% vs 31.1%, p=0.963). After adjustment by propensity score matching, the 30-day mortality rate was not significantly different between the two groups (28.6% vs 31.4%, p=0.794). Multivariate COX analysis revealed that age and SOFA score were independent predictors of 30-day mortality. Conclusion: Combination therapy with CZA and other antimicrobials was not found to have an advantage over monotherapy in reducing the 30-day mortality rate.

The relationship between marital status and cognitive impairment in Chinese older adults: the multiple mediating effects of social support and depression.

BACKGROUND: Marital status is a potentially essential factor for cognitive impairment. Relevant research examining the potential pathways through which the marital status of spouseless older people is associated with cognitive impairment needs to be more adequate. Therefore, this study aims to investigate the serial mediating effects of various forms of social support and depression between marital status and cognitive impairment in older Chinese people. METHODS: This study involved a secondary analysis of data from the 2014-2018 wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), with a total of 2,647 Chinese older adults and 53.6% being males. Mediation analysis using the SPSS process macro was conducted. RESULTS: The results indicated that marital status was significantly predictive of cognitive impairment among older people, and those with a spouse exhibited higher cognitive functioning. Informal social support and depression were found to play partial mediating roles in the association between marital status and cognitive impairment. The findings also revealed that marital status was unrelated to formal social support, and no association between formal social support and cognitive impairment was found. CONCLUSIONS: The study findings highlight the need for social service providers to design programs for promoting connections associated with informal support to reduce their risk of depression and cognitive impairment and for policymakers to develop effective formal social support systems for older people without spouses. This study indicated that older people could regain the benefits of marriage to lower the risk of depression and improve their mental health.

Genome-Wide Association Study of Xian Rice Grain Shape and Weight in Different Environments.

Drought is one of the key environmental factors affecting the growth and yield potential of rice. Grain shape, on the other hand, is an important factor determining the appearance, quality, and yield of rice grains. Here, we re-sequenced 275 Xian accessions and then conducted a genome-wide association study (GWAS) on six agronomic traits with the 404,411 single nucleotide polymorphisms (SNPs) derived by the best linear unbiased prediction (BLUP) for each trait. Under two years of drought stress (DS) and normal water (NW) treatments, a total of 16 QTLs associated with rice grain shape and grain weight were detected on chromosomes 1, 2, 3, 4, 5, 7, 8, 11, and 12. In addition, these QTLs were analyzed by haplotype analysis and functional annotation, and one clone (GSN1) and five new candidate genes were identified in the candidate interval. The findings provide important genetic information for the molecular improvement of grain shape and weight in rice.

Genome-wide association and epistasis studies reveal the genetic basis of saline-alkali tolerance at the germination stage in rice.

Introduction: Saline-alkali stress is one of the main abiotic factors limiting rice production worldwide. With the widespread use of rice direct seeding technology, it has become increasingly important to improve rice saline-alkali tolerance at the germination stage. Methods: To understand the genetic basis of saline-alkali tolerance and facilitate breeding efforts for developing saline-alkali tolerant rice varieties, the genetic basis of rice saline-alkali tolerance was dissected by phenotyping seven germination-related traits of 736 diverse rice accessions under the saline-alkali stress and control conditions using genome-wide association and epistasis analysis (GWAES). Results: Totally, 165 main-effect quantitative trait nucleotides (QTNs) and 124 additional epistatic QTNs were identified as significantly associated with saline-alkali tolerance, which explained a significant portion of the total phenotypic variation of the saline-alkali tolerance traits in the 736 rice accessions. Most of these QTNs were located in genomic regions either harboring saline-alkali tolerance QTNs or known genes for saline-alkali tolerance reported previously. Epistasis as an important genetic basis of rice saline-alkali tolerance was validated by genomic best linear unbiased prediction in which inclusion of both main-effect and epistatic QTNs showed a consistently better prediction accuracy than either main-effect or epistatic QTNs alone. Candidate genes for two pairs of important epistatic QTNs were suggested based on combined evidence from the high-resolution mapping plus their reported molecular functions. The first pair included a glycosyltransferase gene LOC_Os02g51900 (UGT85E1) and an E3 ligase gene LOC_Os04g01490 (OsSIRP4), while the second pair comprised an ethylene-responsive transcriptional factor, AP59 (LOC_Os02g43790), and a Bcl-2-associated athanogene gene, OsBAG1 (LOC_Os09g35630) for salt tolerance. Detailed haplotype analyses at both gene promoter and CDS regions of these candidate genes for important QTNs identified favorable haplotype combinations with large effects on saline-alkali tolerance, which can be used to improve rice saline-alkali tolerance by selective introgression. Discussion: Our findings provided saline-alkali tolerant germplasm resources and valuable genetic information to be used in future functional genomic and breeding efforts of rice saline-alkali tolerance at the germination stage.

Can Population Mobility Make Cities More Resilient? Evidence from the Analysis of Baidu Migration Big Data in China.

Knowledge spillover and capital agglomeration caused by population migration behavior are of great significance for improving the carrying capacity and adaptability of the urban economy and promoting high-quality economic development. Based on the big data collected on urban migration during the Spring Festival travel period, this paper constructs geographic, economic and geo-economic matrices, introduces two instrumental variables, and uses a spatial econometric model to investigate the mechanism between population mobility and urban economic resilience. The results show that (1) urban economic resilience exhibits spatial correlation, and the correlation order is geo-economic matrix > economic matrix > geography matrix; (2) the economic resilience of inflow areas is significantly affected by the net inflow of population, and the urban economic resilience index increases by 0.36−0.56% when the population mobility index increases by one unit; (3) in the case of economic and geo-economic matrices, there is a spatial interaction relationship of neighbor-companion in the mechanism of population migration on urban economic resilience; and (4) the mechanism is significantly impacted by innovation input and fixed asset investment, with positive moderating effects. In the geographical and economic matrices, the innovation input effect has a negative externality, while in the economic and geo-economic matrices, the fixed asset investment effect has a positive externality.

Comparative transcriptome analysis reveals the molecular mechanism of salt tolerance in Apocynum venetum.

Apocynum venetum is a traditional Chinese medicinal herb with tolerance to various abiotic stresses, especially, salinity. However, only a few studies have investigated the salt-tolerant mechanism of this non-halophyte under salt stress at phenotypic and physiological levels. To explore the molecular mechanism of salinity tolerance in A. venetum, the global transcriptome profiles of seedling leaves under different salt-stress durations, using 200 mM NaCl, were analyzed. De novo assembly of approximately 715 million high-quality reads and approximately 105.61 Gb sequence data was performed. In total, 2822 differentially expressed genes (DEGs) were identified. DEGs were significantly enriched in flavonoid metabolism-related pathways such as "flavonoid biosynthesis" and "phenylpropanoid biosynthesis". Most of these DEGs were downregulated under salt stress. However, genes encoding the non-selective cation channels and antioxidants were upregulated under salt stress, whereas most cell wall-related DEGs were downregulated. Consequently, the concentration of flavonoids decreased, whereas that of Na+ increased with exposure time. Thus, we hypothesized that the accumulation of Na+ in the leaves, which resulted in reduced flavonoid concentration under salt stress, directly led to a decrease in the salt tolerance of A. venetum. This was verified by overexpressing four flavonoid synthesis pathway genes in Arabidopsis. The transgenic plants showed higher salt tolerance than the wild-type plants due to the accumulation of total flavonoids. These physiological and transcriptome analyses of A. venetum revealed major molecular underpinnings contributing to the responses of A. venetum to salt stress, thereby improving our understanding of the molecular mechanisms underlying salt tolerance in A. venetum and plants in general. The findings serve as a basis for functional studies on and engineering strategies for plant salinity tolerance.

Sustained Release Systems for Delivery of Therapeutic Peptide/Protein.

Peptide/protein therapeutics have been significantly applied in the clinical treatment of various diseases such as cancer, diabetes, etc. owing to their high biocompatibility, specificity, and therapeutic efficacy. However, due to their immunogenicity, instability stemming from its complex tertiary and quaternary structure, vulnerability to enzyme degradation, and rapid renal clearance, the clinical application of protein/peptide therapeutics is significantly confined. Though nanotechnology has been demonstrated to prevent enzyme degradation of the protein therapeutics and thus enhance the half-life, issues such as initial burst release and uncontrollable release kinetics are still unsolved. Moreover, the traditional administration method results in poor patient compliance, limiting the clinical application of protein/peptide therapeutics. Exploiting the sustained-release formulations for more controllable delivery of protein/peptide therapeutics to decrease the frequency of injection and enhance patient compliance is thus greatly meaningful. In this review, we comprehensively summarize the substantial advancements of protein/peptide sustained-release systems in the past decades. In addition, the advantages and disadvantages of all these sustained-release systems in clinical application together with their future challenges are also discussed in this review.

Ceftazidime-Avibactam Resistance in Klebsiella pneumoniae Sequence Type 11 Due to a Mutation in Plasmid-Borne bla kpc-2 to bla kpc-33, in Henan, China.

PURPOSE: Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a serious problem worldwide. Herein, we describe the evolution of ceftazidime-avibactam (CZA) resistance by sequencing clinical isolates from a patient with CRKP infection undergoing CZA treatment. PATIENTS AND METHODS: In this study, six CRKP strains were isolated from sputum and blood samples of a patient with CRKP infection after intracerebral hemorrhage. Two strains were selected for whole-genome analysis. RESULTS: Drug susceptibility testing showed that the MIC of CZA for CRKP strains isolated after 6 days of CZA treatment was 64-fold higher than that for three CRKP strains isolated before CZA treatment (4 vs >256 µg/mL), whereas the MIC of imipenem and meropenem was 128-fold (>32 vs 0.25 µg/mL) and 16-fold (> 32 vs 2 µg/mL) lower relatively, respectively. Multilocus sequence typing showed that all six CRKP strains isolated from the patient were ST11 and pulsed-field gel electrophoresis confirmed that they were of the same clone. Two strains were selected for whole-genome analysis. The aspartic acid residue at position 179 in the Ω loop was replaced by a tyrosine residue in the resistant strain, and the plasmid carried a bla KPC-2 to bla KPC-33 mutation. The results of the modified carbapenem inactivation method and the carbapenemase inhibitor enhancement and colloidal gold enzyme immunochromatographic assays for bla KPC-33 were negative. CONCLUSION: This is the first report from Henan to show that treatment with CZA for 6 days can cause mutations and change the phenotype from CZA sensitive to resistant. Therefore, routine testing for drug susceptibility and carbapenemase phenotypes should be conducted during treatment with CZA, and genotype determination is essential.

Recent advances of nanomedicine-based strategies in diabetes and complications management: Diagnostics, monitoring, and therapeutics.

Diabetes mellitus (DM) is a metabolic disorder characterized by the presence of chronic hyperglycemia driven by insulin deficiency or resistance, imposing a significant global burden affecting 463 million people worldwide in 2019. This review has comprehensively summarized the application of nanomedicine with accurate, patient-friendly, real-time properties in the field of diabetes diagnosis and monitoring, and emphatically discussed the unique potential of various nanomedicine carriers (e.g., polymeric nanoparticles, liposomes, micelles, microparticles, microneedles, etc.) in the management of diabetes and complications. Novel delivery systems have been developed with improved pharmacokinetics and pharmacodynamics, excellent drug biodistribution, biocompatibility, and therapeutic efficacy, long-term action safety, as well as the improved production methods. Furthermore, the effective nanomedicine for the treatment of several major diabetic complications with significantly improved life qualities of diabetic patients were discussed in detail. Going through the literature review, several critical issues of the nanomedicine-based strategies applications need to be addressed such as stabilities and long-term safety effects in vivo, the deficiency of standard for formulation administration, feasibility of scale-up, etc. Overall, the review provides an insight into the design, advantages and limitations of novel nanomedicine application in the diagnostics, monitoring, and therapeutics of DM.

Polycyclic aromatic hydrocarbons exposure and early miscarriage in women undergoing in vitro fertilization-embryo transfer.

Various factors have been reported to be associated with early miscarriages, including microbial infection, chemical toxicity, maternal disorders and genetic abnormalities. In the present study, a prospective cohort study was conducted to investigate whether urinary concentrations of hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) were associated with early pregnancy loss in women undergoing in vitro fertilization-embryo transfer (IVF-ET). Risk of spontaneous pregnancy loss in patients exposed to PAHs was analysed using 40 patients who had experienced early pregnancy loss compared to 40 who had normal live births. Single spot morning urine samples were collected from each patient 30 days after embryo transfer when clinical pregnancy was confirmed and ten urinary OH-PAHs were measured. After adjustment for age and BMI using a Log Binomial Model, only 2 + 3-PHE was found to be associated positively with early miscarriage. Using Receiver Operating Characteristic (ROC) curve analysis, the Area Under the Curve (AUC) was 0.78 (p＜0.001), suggesting that 2 + 3-PHE might provide a potential biomarker to predict the miscarriage risk in patients exposed to high level of PAHs.

Trends in global clinical trial registration: an analysis of numbers of registered clinical trials in different parts of the world from 2004 to 2013.

OBJECTIVES: To analyse developments (and their causes) in the number and proportion of clinical trials that were registered in different parts of the world after the International Committee of Medical Journal Editors (ICMJE) announced in 2004 that it would require registration of clinical trials as a condition for publication. SETTING: The International Clinical Trials Registry Platform (ICTRP). DESIGN: The ICTRP database was searched for all clinical trials that were registered up to 31 December 2013. RESULTS: The ICTRP database contained data on 186,523 interventional clinical trials. The annual number of registered clinical trials increased from 3294 in 2004 to 23,384 in 2013. Relative to the number of clinical trial research publications, the global number of registered clinical trials increased fivefold between 2004 and 2013, rising particularly strongly between 2004 and 2005. In certain regions, especially Asia, the annual number of registered trials increased more gradually and continued to increase up to 2013. In India and Japan, two countries with marked but more gradual increases, these increases only happened after several local measures were implemented that encouraged and enforced registration. In most regions, there was a trend toward trials being registered at local registries. CONCLUSIONS: Clinical trial registration has greatly improved transparency in clinical trial research. However, these improvements have not taken place equally in all parts of the world. Achieving compliance with registration requires a coalescence of global and local measures, and remains a key challenge in many countries. Poor quality of registered trial data and the inaccessibility of trial protocols, results and participant-level data further undermine the potential benefits of clinical trial registration. National and regional registries and the ICTRP have played a leading role in achieving the successes of trial registration to date and should be supported in addressing these challenges in the future.