Adherence and HIV Protection Thresholds for Emtricitabine and Tenofovir Disoproxil Fumarate Preexposure Prophylaxis among Cisgender Women: A Systematic Review.

PURPOSE OF REVIEW: Adherence-concentration-efficacy benchmarks have not been fully characterized for cisgender women using emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) oral daily pre-exposure prophylaxis (PrEP) for HIV prevention. RECENT FINDINGS: We conducted a systematic review to investigate current evidence on the adherence-concentration-efficacy relationship of tenofovir-diphosphate (TFV-DP) derived from FTC/TDF PrEP in dried blood spots (DBS) and peripheral mononuclear cells (PBMC) in cisgender women without HIV, including during pregnancy. We searched for completed and ongoing studies published before May 2024 in PubMed, Embase, Cochrane Library, CINAHL, and clinicaltrial.gov.  Overall, 11 studies assessing adherence benchmarks focusing on (n = 5) or involving (n = 6) cisgender women were included. Women-specific median steady-state TFV-DP concentration for daily dosing ranged from 17 to 51 fmol/106 in PBMC and 1389 to 1685 fmol/punch in DBS in non-pregnant women; 50 to 71 fmol/106 in PBMC and 583 to 965 fmol/punch in DBS in pregnant women; and 618 to 1406 fmol/punch in DBS in postpartum women. DBS TFV-DP levels were 14-43% lower in pregnancy versus postpartum or non-pregnant periods, but PBMC TFV-DP levels appear to be comparable. Clinical and modeling studies demonstrate effective HIV protection for women taking at least four doses/week of oral TDF-based PrEP, and emerging evidence suggests that systemic drug levels are more likely to be predictive of efficacy than local tissue levels at the site of exposure. The preponderance of emerging evidence points to comparable efficacy and similar adherence requirement for women as men among those with detectable drug levels, although there was an indication that the highest achievable efficacy may be reached at a lower adherence level in men than women. In this review, we found evidence that women-specific TFV-DP adherence benchmarks in DBS and PBMC are within range of US-based historical thresholds derived from healthy men and women. Emerging evidence suggests that imperfect but adequate adherence to oral FTC/TDF PrEP with at least four doses/week provides sufficient HIV protection in cisgender women as it does in MSM, but more data are still needed to refine intrinsic achievable efficacy estimates for cisgender women.

Effects of Freshwater Acidification on the Gut Microbial Community of Trachemys scripta elegans.

Freshwater acidification (FA) has become a global environmental problem, posing a potential threat to freshwater ecosystems. The gut microbiota plays a crucial role in the host's response and adaptation to new environments. In this study, we investigated the changes in microbial communities in Red-eared slider (Trachemys scripta elegans) under acidic conditions to reveal the ecological impacts of acidification on freshwater turtles. The results showed that there were significant differences in ß-diversity (p = 0.03), while there were no significant differences in the α-diversity of gut microbiota in T. s. elegans between the different levels of acidification (pH of 5.5, 6.5, 7.5). Both the Gut Microbiome Health Index (GMHI) and the Microbial Dysbiosis Index (MDI) exhibited significant differences when comparing environments with a pH of 5.5 to those with a pH of 6.5 (p < 0.01). A comparative analysis between pH levels of 5.5 and 6.5 also revealed substantial differences (p < 0.01). Likewise, a comparative analysis between pH levels of 6.5 and 7.5 also revealed substantial differences (p < 0.01). At the phylum level, Firmicutes, Fusobacteria, and Bacteroidota formed a major part of the gut microbial community, Fusobacteria showed significant differences in different acidity environments (p = 0.03). At the genus level, Cetobacterium, Turicibacter, unclassified Eubacteriaceae, and Anaerorhabdus_furcosa_group showed significant differences in different acidity environments. The pH reduced interactivity in the gut microbiota of T. s. elegans. In addition, LEfSe analysis and functional prediction revealed that the potentially_pathogenic and stress_tolerant functional characteristics also showed significant differences in different acidity environments. The findings underscore the pivotal role of the gut microbiota in T. s. elegans in response to freshwater acidification and provide a foundation for further exploration into the impacts of acidification on freshwater ecosystems.

Comparison of the intestinal flora of wild and artificial breeding green turtles (Chelonia mydas).

Gut microbes are pivotal reference indicators for assessing the health status of animals. Before introducing artificially bred species into the wild, examining their gut microbe composition is crucial to help mitigate potential threats posed to wild populations. However, gut microbiological trait similarities between wild and artificially bred green turtles remain unexplored. Therefore, this study compared the gut microbiological characteristics of wild and artificially bred green turtles (Chelonia mydas) through high-throughput Illumina sequencing technology. The α-diversity of intestinal bacteria in wild green turtles, as determined by Shannon and Chao indices, significantly surpasses that of artificial breeding green turtles (p < 0.01). However, no significant differences were detected in the fungal α-diversity between wild and artificially bred green turtles. Meanwhile, the ß-diversity analysis revealed significant differences between wild and artificially bred green turtles in bacterial and fungal compositions. The community of gut bacteria in artificially bred green turtles had a significantly higher abundance of Fusobacteriota including those belonging to the Paracoccus, Cetobacterium, and Fusobacterium genera than that of the wild green turtle. In contrast, the abundance of bacteria belonging to the phylum Actinobacteriota and genus Nautella significantly decreased. Regarding the fungal community, artificially bred green turtles had a significantly higher abundance of Fusarium, Sterigmatomyces, and Acremonium and a lower abundance of Candida and Rhodotorula than the wild green turtle. The PICRUSt2 analyses demonstrated significant differences in the functions of the gut bacterial flora between groups, particularly in carbohydrate and energy metabolism. Fungal functional guild analysis further revealed that the functions of the intestinal fungal flora of wild and artificially bred green turtles differed significantly in terms of animal pathogens-endophytes-lichen parasites-plant pathogens-soil saprotrophs-wood saprotrophs. BugBase analysis revealed significant potential pathogenicity and stress tolerance variations between wild and artificially bred green turtles. Collectively, this study elucidates the distinctive characteristics of gut microbiota in wild and artificially bred green turtles while evaluating their health status. These findings offer valuable scientific insights for releasing artificially bred green turtles and other artificially bred wildlife into natural habitats.

Simulations on coal water slurry gasification by molecular dynamics method with ReaxFF.

CONTEXT: Coal water slurry (CWS) is a new type of liquid coal product with low pollution, which is mainly used in the chemical industry to produce syngas (CO + H2). It is of great significance to study the microscopic mechanism of CWS gasification reaction for improving the efficiency of coal gasification. In this paper, the method of molecular dynamics based on reaction force fields (ReaxFF-MD) is used to study the gasification process of CWS/O2 system at different temperatures. The results show that, in the range of 1600-2400 K, the macromolecular network structure of lignite is decomposed into a large number of small molecular structures and a small number of light tar free radical fragments, and the types and quantities of reaction products increased rapidly. At 2400-4000 K, the free radical fragments of light tar are further decomposed and reacted with gasification agents, but the types and quantities of reaction products have little change. At 3600 K, a full gasification reaction occurred in the system, and the content of syngas is the highest. METHODS: The model was established and optimized by Materials Studio (MS) software. Based on ReaxFF-MD method, Lammps software was used to simulate the gasification process of CWS/O2 system, and the reaction force field files containing C, H, O, N, and S element were used. By calculating the activation energy of gasification reaction, the rationality of the model and calculation method was illustrated. The post-processing of the results was implemented using OVITO, ChemDraw software, and self-programmed Python scripts.

Identification of specific markers for human pluripotent stem cell-derived small extracellular vesicles.

Pluripotent stem cell-derived small extracellular vesicles (PSC-sEVs) have demonstrated great clinical translational potential in multiple aging-related degenerative diseases. Characterizing the PSC-sEVs is crucial for their clinical applications. However, the specific marker pattern of PSC-sEVs remains unknown. Here, the sEVs derived from two typical types of PSCs including induced pluripotent stem cells (iPSC-sEVs) and embryonic stem cells (ESC-sEVs) were analysed using proteomic analysis by liquid chromatography with tandem mass spectrometry (LC-MS/MS), and surface marker phenotyping analysis by nanoparticle flow cytometry (NanoFCM). A group of pluripotency-related proteins were found to be enriched in PSC-sEVs by LC-MS/MS and then validated by Western Blot analysis. To investigate whether these proteins were specifically expressed in PSC-sEVs, sEVs derived from seven types of non-PSCs (non-PSC-sEVs) were adopted for analysis. The results showed that PODXL, OCT4, Dnmt3a, and LIN28A were specifically enriched in PSC-sEVs but not in non-PSC-sEVs. Then, commonly used surface antigens for PSC identification (SSEA4, Tra-1-60 and Tra-1-81) and PODXL were gauged at single-particle resolution by NanoFCM for surface marker identification. The results showed that the positive rates of PODXL (>50%) and SSEA4 (>70%) in PSC-sEVs were much higher than those in non-PSC-sEVs (<10%). These results were further verified with samples purified by density gradient ultracentrifugation. Taken together, this study for the first time identified a cohort of specific markers for PSC-sEVs, among which PODXL, OCT4, Dnmt3a and LIN28A can be detected with Western Blot analysis, and PODXL and SSEA4 can be detected with NanoFCM analysis. The application of these specific markers for PSC-sEVs identification may advance the clinical translation of PSCs-sEVs.

[Inhibitory Effect of Metformin and Arsenic Trioxide on KG1a Cell Proliferation].

OBJECTIVE: To investigate the effect of metformin and arsenic trioxide on KG1a cells proliferation of acute myeloid leukemia and its possible mechanism. METHODS: CCK-8 method was used to detect the killing effect of metformin, arsenic trioxide and combined application on KG1a cells. Annexin V-FITC/PI Dual Stain Flow Cytometry was used to detect the effect of combined application on apoptosis of KG1a cells. Western blot was used to detect the expression of intracellular apoptosis-,autophagy-related protein. RESULTS: Metformin and arsenic trioxide alone or in combination could inhibit the proliferation of KG1a cells and induce apoptosis of KG1a cells, and the proliferation inhibition rate and apoptosis rate in the combined drug group were higher than those in the drug group alone(P <0.05). The combination of drugs induced upregulation of Caspase 8 protein and P62 protein expression and was higher than that in the drug group alone(P <0.05). CONCLUSION: Metformin can synergize with arsenic trioxide to kill KG1a cells, and its mechanism of action may be related to inducing apoptosis and enhancing autophagy.

JD-312 - A novel small molecule that facilitates cartilage repair and alleviates osteoarthritis progression.

Background: The chondrogenic differentiation of mesenchymal stem cells (MSCs) to enhance cartilage repair and regeneration is a promising strategy to alleviate osteoarthritis (OA) progression. Method: The potency of JD-312 in inducing chondrogenic differentiation of MSCs was assessed and verified. The efficacy of JD-312-treated MSCs was evaluated using a Sprague-Dawley rat DMM model. Additionally, the capacity of JD-312 to successfully recruit bone marrow-derived mesenchymal stem cells (BMSCs) for the treatment of OA in vitro was confirmed via intra-articular injection. The repair status of the articular cartilage was analyzed in vivo through histological examination. Result: In this study, we identify JD-312 as a novel non-toxic small molecule that can promote chondrogenic differentiation in human umbilical cord-derived MSCs (hUCMSCs) and human bone marrow MSCS (hBMSCs) in vitro. We also show that transient differentiation of MSCs with JD-312 prior to in vivo administration remarkably improves the regeneration of cartilage and promotes Col2a1 and Acan expression in rat models of DMM, in comparison to kartogenin (KGN) pre-treatment or MSCs alone. Furthermore, direct intra-articular injection of JD-312 in murine model of OA showed reduced loss of articular cartilage and improved pain parameters. Lastly, we identified that the effects of JD-312 are at least in part mediated via upregulation of genes associated with the focal adhesion, PI3K-Akt signaling and the ECM-receptor interaction pathways, and specifically cartilage oligomeric matrix protein (COMP) may play a vital role. Conclusion: Our study demonstrated that JD-312 showed encouraging repair effects for OA in vivo. The translational potential of this article: Together, our findings demonstrate that JD-312 is a promising new therapeutic molecule for cartilage regeneration with clinical potential.

Mind the Gap: Learning Modality-Agnostic Representations With a Cross-Modality UNet.

Cross-modality recognition has many important applications in science, law enforcement and entertainment. Popular methods to bridge the modality gap include reducing the distributional differences of representations of different modalities, learning indistinguishable representations or explicit modality transfer. The first two approaches suffer from the loss of discriminant information while removing the modality-specific variations. The third one heavily relies on the successful modality transfer, could face catastrophic performance drop when explicit modality transfers are not possible or difficult. To tackle this problem, we proposed a compact encoder-decoder neural module (cmUNet) to learn modality-agnostic representations while retaining identity-related information. This is achieved through cross-modality transformation and in-modality reconstruction, enhanced by an adversarial/perceptual loss which encourages indistinguishability of representations in the original sample space. For cross-modality matching, we propose MarrNet where cmUNet is connected to a standard feature extraction network which takes as inputs the modality-agnostic representations and outputs similarity scores for matching. We validated our method on five challenging tasks, namely Raman-infrared spectrum matching, cross-modality person re-identification and heterogeneous (photo-sketch, visible-near infrared and visible-thermal) face recognition, where MarrNet showed superior performance compared to state-of-the-art methods. Furthermore, it is observed that a cross-modality matching method could be biased to extract discriminant information from partial or even wrong regions, due to incompetence of dealing with modality gaps, which subsequently leads to poor generalization. We show that robustness to occlusions can be an indicator of whether a method can well bridge the modality gap. This, to our knowledge, has been largely neglected in the previous works. Our experiments demonstrated that MarrNet exhibited excellent robustness against disguises and occlusions, and outperformed existing methods with a large margin (>10%). The proposed cmUNet is a meta-approach and can be used as a building block for various applications.

Cotton GhNAC4 promotes drought tolerance by regulating secondary cell wall biosynthesis and ribosomal protein homeostasis.

Drought has a severe impact on the quality and yield of cotton. Deciphering the key genes related to drought tolerance is important for understanding the regulation mechanism of drought stress and breeding drought-tolerant cotton cultivars. Several studies have demonstrated that NAC transcription factors are crucial in the regulation of drought stress, however, the related functional mechanisms are still largely unexplored. Here, we identified that NAC transcription factor GhNAC4 positively regulated drought stress tolerance in cotton. The expression of GhNAC4 was significantly induced by abiotic stress and plant hormones. Silencing of GhNAC4 distinctly impaired the resistance to drought stress and overexpressing GhNAC4 in cotton significantly enhanced the stress tolerance. RNA-seq analysis revealed that overexpression of GhNAC4 enriched the expression of genes associated with the biosynthesis of secondary cell walls and ribosomal proteins. We confirmed that GhNAC4 positively activated the expressions of GhNST1, a master regulator reported previously in secondary cell wall formation, and two ribosomal protein-encoding genes GhRPL12 and GhRPL18p, by directly binding to their promoter regions. Overexpression of GhNAC4 promoted the expression of downstream genes associated with the secondary wall biosynthesis, resulting in enhancing secondary wall deposition in the roots, and silencing of GhRPL12 and GhRPL18p significantly impaired the resistance to drought stress. Taken together, our study reveals a novel pathway mediated by GhNAC4 that promotes secondary cell wall biosynthesis to strengthen secondary wall development and regulates the expression of ribosomal protein-encoding genes to maintain translation stability, which ultimately enhances drought tolerance in cotton.

No extraction? No problem. Direct to PCR processing of tongue swabs for diagnosis of tuberculosis disease as an alternative to sputum collection.

IMPORTANCE: Tuberculosis (TB) remains one of the world's leading infectious disease killers, despite available treatments. Although highly sensitive molecular diagnostics are available, expensive equipment and poor infrastructure have hindered their implementation in low-resource settings. Furthermore, the collection of sputum poses challenges as it is difficult for patients to produce and creates dangerous aerosols. This manuscript explores tongue swabs as a promising alternative to sputum collection. While previous studies have explored the sensitivity of tongue swabs as compared to sputum, existing literature has not addressed the need to standardize and simplify laboratory processing for easy implementation in high TB burden areas. This manuscript provides the first evidence that detection of TB from a tongue swab is possible without the use of DNA extraction or purification steps. The data provided in this manuscript will improve the collection and testing of tongue swabs for the diagnosis of TB disease.

Deubiquitylating Enzymes in Cancer and Immunity.

Deubiquitylating enzymes (DUBs) maintain relative homeostasis of the cellular ubiquitome by removing the post-translational modification ubiquitin moiety from substrates. Numerous DUBs have been demonstrated specificity for cleaving a certain type of ubiquitin linkage or positions within ubiquitin chains. Moreover, several DUBs perform functions through specific protein-protein interactions in a catalytically independent manner, which further expands the versatility and complexity of DUBs' functions. Dysregulation of DUBs disrupts the dynamic equilibrium of ubiquitome and causes various diseases, especially cancer and immune disorders. This review summarizes the Janus-faced roles of DUBs in cancer including proteasomal degradation, DNA repair, apoptosis, and tumor metastasis, as well as in immunity involving innate immune receptor signaling and inflammatory and autoimmune disorders. The prospects and challenges for the clinical development of DUB inhibitors are further discussed. The review provides a comprehensive understanding of the multi-faced roles of DUBs in cancer and immunity.

Comparative transcriptome analysis on candidate genes associated with fruiting body growth and development in Lyophyllum decastes.

Lyophyllum decastes is a mushroom that is highly regarded for its culinary and medicinal properties. Its delectable taste and texture make it a popular choice for consumption. To gain a deeper understanding of the molecular mechanisms involved in the development of the fruiting body of L. decastes, we used RNA sequencing to conduct a comparative transcriptome analysis. The analysis encompassed various developmental stages, including the vegetative mycelium, primordial initiation, young fruiting body, medium-size fruiting body, and mature fruiting body stages. A range of 40.1 to 60.6 million clean reads were obtained, and de novo assembly generated 15,451 unigenes with an average length of 1,462.68 bp. Functional annotation of transcriptomes matched 76.84% of the unigenes to known proteins available in at least one database. The gene expression analysis revealed a significant number of differentially expressed genes (DEGs) between each stage. These genes were annotated and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Highly differentially expressed unigenes were also identified, including those that encode extracellular enzymes, transcription factors, and signaling pathways. The accuracy of the RNA-Seq and DEG analyses was validated using quantitative PCR. Enzyme activity analysis experiments demonstrated that the extracellular enzymes exhibited significant differences across different developmental stages. This study provides valuable insights into the molecular mechanisms that underlie the development of the fruiting body in L. decastes.

GPRC5B protects osteoarthritis by regulation of autophagy signaling.

Osteoarthritis (OA) is one of the most common chronic diseases in the world. However, current treatment modalities mainly relieve pain and inhibit cartilage degradation, but do not promote cartilage regeneration. In this study, we show that G protein-coupled receptor class C group 5 member B (GPRC5B), an orphan G-protein-couple receptor, not only inhibits cartilage degradation, but also increases cartilage regeneration and thereby is protective against OA. We observed that Gprc5b deficient chondrocytes had an upregulation of cartilage catabolic gene expression, along with downregulation of anabolic genes in vitro. Furthermore, mice deficient in Gprc5b displayed a more severe OA phenotype in the destabilization of the medial meniscus (DMM) induced OA mouse model, with upregulation of cartilage catabolic factors and downregulation of anabolic factors, consistent with our in vitro findings. Overexpression of Gprc5b by lentiviral vectors alleviated the cartilage degeneration in DMM-induced OA mouse model by inhibiting cartilage degradation and promoting regeneration. We also assessed the molecular mechanisms downstream of Gprc5b that may mediate these observed effects and identify the role of protein kinase B (AKT)-mammalian target of rapamycin (mTOR)-autophagy signaling pathway. Thus, we demonstrate an integral role of GPRC5B in OA pathogenesis, and activation of GPRC5B has the potential in preventing the progression of OA.

Biomolecular condensates: Formation mechanisms, biological functions, and therapeutic targets.

Biomolecular condensates are cellular structures composed of membraneless assemblies comprising proteins or nucleic acids. The formation of these condensates requires components to change from a state of solubility separation from the surrounding environment by undergoing phase transition and condensation. Over the past decade, it has become widely appreciated that biomolecular condensates are ubiquitous in eukaryotic cells and play a vital role in physiological and pathological processes. These condensates may provide promising targets for the clinic research. Recently, a series of pathological and physiological processes have been found associated with the dysfunction of condensates, and a range of targets and methods have been demonstrated to modulate the formation of these condensates. A more extensive description of biomolecular condensates is urgently needed for the development of novel therapies. In this review, we summarized the current understanding of biomolecular condensates and the molecular mechanisms of their formation. Moreover, we reviewed the functions of condensates and therapeutic targets for diseases. We further highlighted the available regulatory targets and methods, discussed the significance and challenges of targeting these condensates. Reviewing the latest developments in biomolecular condensate research could be essential in translating our current knowledge on the use of condensates for clinical therapeutic strategies.

Multicolor, injectable BSA-based lanthanide luminescent hydrogels with biodegradability.

Protein hydrogels have attracted increasing attention because of their excellent biodegradability and biocompatibility, but frequently suffer from the single structures and functions. As a combination of luminescent materials and biomaterials, multifunctional protein luminescent hydrogels can exhibit wider applications in various fields. Herein, we report a novel, multicolor tunable, injectable, and biodegradable protein-based lanthanide luminescent hydrogel. In this work, urea was utilized to denature BSA to expose disulfide bonds, and tris(2-carboxyethyl)phosphine (TCEP) was employed to break the disulfide bonds in BSA to generate free thiols. A part of free thiols in BSA rearranged into disulfide bonds to form a crosslinked network. In addition, lanthanide complexes (Ln(4-VDPA)3), containing multiple active reaction sites, could react with the remaining thiols in BSA to form the second crosslinked network. The whole process avoids the use of nonenvironmentally friendly photoinitiators and free radical initiators. The rheological properties and structure of hydrogels were investigated, and the luminescent performances of hydrogels were studied in detail. Finally, the injectability and biodegradability of hydrogels were verified. This work will provide a feasible strategy for the design and fabrication of multifunctional protein luminescent hydrogels, which may have further applications in biomedicine, optoelectronics, and information technology.

Flexible Sweat Sensors: From Films to Textiles.

Flexible sweat sensors have found widespread potential applications for long-term wear and tracking and real-time monitoring of human health. However, the main substrate currently used in common flexible sweat sensors is thin film, which has disadvantages such as poor air permeability and the need for additional wearables. In this Review, the recent progress of sweat sensors has been systematically summarized by the types of monitoring methods of sweat sensors. In addition, this Review introduces and compares the performance of sweat sensors based on thin film and textile substrates such as fiber/yarn. Finally, opportunities and suggestions for the development of flexible sweat sensors are presented by summarizing the integration methods of sensors and human body monitoring sites.

Functional connectivity strength and topology differences in social phobia adolescents with and without ADHD comorbidity.

Social phobia (SP) is associated with changes in functional connectivity strength and topology. However, reported changes have been heterogeneous due to small sample sizes, inconsistent methodologies, and comorbidities, such as attention-deficit/hyperactivity disorder (ADHD), which has a high comorbidity rate with SP. Furthermore, there are few studies looking at SP in an adolescent population, a critical period for the development of the social brain. This project focuses on functional connectivity strength and topological differences in social phobia patients with and without ADHD comorbidity. We examined resting-state functional MRI images from 158 subjects, including 36 SP participants without ADHD comorbidity, 60 SP participants with ADHD comorbidity, and 62 healthy controls, with an overall average age of 14.16. We used a data-driven approach to examine impaired functional connectivity in a whole-brain analysis and higher-order topological differences in functional brain networks. We identified changes in the cerebellum and default mode network in social phobia patients as a whole, with the presence of ADHD comorbidity affecting various subsystems of the default mode network. Social phobia functional connectivity networks resembled random graphs, and local connectivity patterns in the superior occipital gyrus were different due to ADHD comorbidity. These alterations may indicate impairments in self-related processing, imagery, mentalizing, and predictive processes. We then used these changes in a linear support vector machine to distinguish between each pair of groups and achieved prediction accuracy significantly above chance rates. Our study extends prior research by showing that functional connectivity changes exist at adolescence, which are affected by ADHD comorbidity. As such, these results offer a new perspective in examining neurobiological changes in SP patients.