Perspectives on a peer-driven intervention to promote pre-exposure prophylaxis (PrEP) uptake among men who have sex with men in southern New England: a qualitative study.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is a highly effective pharmaceutical intervention that prevents HIV infection, but PrEP uptake across the US has been slow among men who have sex with men (MSM), especially among Black/African American (B/AA) and Hispanic /Latino (H/L) MSM. This study investigates the acceptability and essential components of a peer-driven intervention (PDI) for promoting PrEP uptake among MSM, with a specific focus on B/AA and H/L communities. METHODS: We conducted 28 semi-structured, qualitative interviews with MSM in southern New England to explore the components of a PDI, including attitudes, content, and effective communication methods. A purposive sampling strategy was used to recruit diverse participants who reflect the communities with the highest burden of HIV infection. RESULTS: Of 28 study participants, the median age was 28 years (interquartile range [IQR]: 25, 35). The sample comprised B/AA (39%, n = 11) and H/L (50%, n = 14) individuals. Notably, nearly half of the participants (46%) were current PrEP users. We found that many participants were in favor of using a PDI approach for promoting PrEP. Additionally, several participants showed interest in becoming peer educators themselves. They emphasized the need for strong communication skills to effectively teach others about PrEP. Moreover, participants noted that peer education should cover key topics like how PrEP works, how effective it is, and any possible side effects. CONCLUSIONS: Our study shows that effective PDIs, facilitated by well-trained peers knowledgeable about PrEP, could enhance PrEP uptake among MSM, addressing health disparities and potentially reducing HIV transmission in B/AA and H/L communities.

Clinical application of a modified wiltse approach in middle and lower thoracic vertebrae: a case-control study of thoracic fracture patients.

BACKGROUND: The Wiltse approach has been extensively employed in thoracolumbar surgeries due to its minimal muscle damage. However, in the middle and lower thoracic spine, the conventional Wiltse approach necessitates the severance of the latissimus dorsi and trapezius muscles, potentially leading to muscular injury. Consequently, we propose a modified Wiltse approach for the middle and lower thoracic vertebrae, which may further mitigate muscular damage. METHODS: From May 2018 to April 2022, 60 patients with spinal fractures in the middle and lower thoracic vertebrae (T5-12) were enrolled in this study. Thirty patients underwent surgery using the modified Wiltse approach (Group A), while the remaining 30 patients received traditional posterior surgery (Group B). The observation indices included operation time, intraoperative blood loss, incision length, number of C-arm exposures, postoperative drainage, postoperative ambulation time, discharge time, as well as preoperative and postoperative Cobb's angle, percentage of anterior vertebral body height (PAVBH), visual analog scale (VAS) Score, and Oswestry disability index (ODI). RESULTS: Compared to the traditional posterior approach, the modified Wiltse approach demonstrated significant advantages in operation time, intraoperative blood loss, length of incision, postoperative ambulation time, postoperative drainage, and discharge time, as well as postoperative VAS and ODI scores. No significant differences were observed between the two groups in terms of number of C-arm exposures, postoperative Cobb's angle, or postoperative PAVBH. CONCLUSION: We propose a modification of the Wiltse approach for the middle and lower thoracic vertebral regions, which may further minimize muscular damage and facilitate the recovery of patients who have undergone surgery in the middle and lower thoracic vertebrae.

Analysis of metastasis­related risk factors and clinical relevance in adult soft­tissue sarcoma.

Metastasis occurs in nearly 50% of cases of adult soft-tissue sarcoma (ASTS), leading to a dismal prognosis, with a 2-year survival rate of ~30%. Consequently, a prognostic model that incorporates metastatic characteristics may be instrumental in predicting survival time and in crafting optimal personalized therapeutic strategies for patients with ASTS. In the present study, a prognostic prediction model for ASTS was developed by examining genes that are differentially expressed between non-metastatic and metastatic patients in the Gene Expression Omnibus dataset. The prognostic model, which includes five featured genes [actin γ2 (ACTG2), apolipoprotein D, coatomer protein complex subunit γ2 imprinted transcript 1, collagen type VI α6 chain and osteomodulin], was further validated in patients with ASTS from the Cancer Genome Atlas dataset. Based on these five-gene signatures, patients were categorized into high- and low-risk groups. Functional and pathway analyses revealed disparities in stemness, extracellular matrix and cell adhesion-related pathways between the two risk groups, particularly noting the activation of the PI3K-Akt pathway in high-risk cases. Analysis of immune infiltration also revealed variations in immune microenvironment changes between the two risk groups. Immunohistochemical staining substantiated the prognostic significance of these gene signatures in a specific sarcoma subtype. Additionally, wound-healing and Transwell assays demonstrated that inhibition of ACTG2 by shRNAs curbed cell migration and invasion in a sarcoma HOS cell line, underscoring its role in sarcoma metastasis. In conclusion, the present study successfully developed and validated a metastasis-based prognosis prediction model. This model not only reliably forecasts the survival of patients with ASTS, but also may pave the way for further investigation into the processes underlying sarcoma metastasis, ultimately aiding in the design of tailored therapeutic regimens.

Functional Characterization of the Paeonia ostii P5CS Gene under Drought Stress.

With persistent elevation in global temperature, water scarcity becomes a major threat to plant growth and development, yield security, agricultural sustainability, and food production. Proline, as a key osmolyte and antioxidant, plays a critical role in regulating drought tolerance in plants, especially its key biosynthetic enzyme, delta-1-pyrroline-5-carboxylate synthase (P5CS), which always positively responds to drought stress. As an important woody oil crop, the expansion of Paeonia ostii cultivation needs to address the issue of plant drought tolerance. Here, we isolated a PoP5CS gene from P. ostii, with an open reading frame of 1842 bp encoding 613 amino acids. PoP5CS expression progressively increased in response to increasing drought stress, and it was localized in the cytoplasm. Silencing of PoP5CS in P. ostii reduced drought tolerance, accompanied by decreased proline content, elevated reactive oxygen species (ROS) accumulation, and increased relative electrical conductivity (REC) and malondialdehyde (MDA) levels. Conversely, overexpression of PoP5CS in Nicotiana tabacum plants enhanced drought resistance, manifested by increased proline levels, reduced ROS accumulation, and lower REC and MDA contents. This study isolates PoP5CS from P. ostii and validates its role in regulating drought tolerance, providing valuable genetic resources and theoretical insights for the development of drought-resistant P. ostii cultivars.

Synergistic actions of three MYB transcription factors underpin blotch formation in tree peony.

Blotches in floral organs attract pollinators and promote pollination success. Tree peony (Paeonia suffruticosa Andr.) is an internationally renowned cut flower with extremely high ornamental and economic value. Blotch formation on P. suffruticosa petals is predominantly attributed to anthocyanin accumulation. However, the endogenous regulation of blotch formation in P. suffruticosa remains elusive. Here, we identified the regulatory modules governing anthocyanin-mediated blotch formation in P. suffruticosa petals, which involves the transcription factors PsMYB308, PsMYBPA2, and PsMYB21. PsMYBPA2 activated PsF3H expression to provide sufficient precursor substrate for anthocyanin biosynthesis. PsMYB21 activated both PsF3H and PsFLS expression and promoted flavonol biosynthesis. The significantly high expression of PsMYB21 in non-blotch regions inhibited blotch formation by competing for anthocyanin biosynthesis substrates, while conversely, its low expression in the blotch region promoted blotch formation. PsMYB308 inhibited PsDFR and PsMYBPA2 expression to directly prevent anthocyanin-mediated blotch formation. Notably, a smaller blotch area, decreased anthocyanin content, and inhibition of anthocyanin structural gene expression were observed in PsMYBPA2-silenced petals, while the opposite phenotypes were observed in PsMYB308-silenced and PsMYB21-silenced petals. Additionally, PsMYBPA2 and PsMYB308 interacted with PsbHLH1-3, and their regulatory intensity on target genes was synergistically regulated by the PsMYBPA2-PsbHLH1-3 and PsMYB308-PsbHLH1-3 complexes. PsMYB308 also competitively bound to PsbHLH1-3 with PsMYBPA2 to fine-tune the regulatory network to prevent overaccumulation of anthocyanin in blotch regions. Overall, our study uncovers a complex R2R3-MYB transcriptional regulatory network that governs anthocyanin-mediated blotch formation in P. suffruticosa petals, providing insights into the molecular mechanisms underlying blotch formation in P. suffruticosa.

Identification and Functional Studies on the Role of PlSPL14 in Herbaceous Peony Stem Development.

Stem strength plays a crucial role in the growth and development of plants, as well as in their flowering and fruiting. It not only impacts the lodging resistance of crops, but also influences the ornamental value of ornamental plants. Stem development is closely linked to stem strength; however, the roles of the SPL transcription factors in the stem development of herbaceous peony (Paeonia lactiflora Pall.) are not yet fully elucidated. In this study, we obtained and cloned the full-length sequence of PlSPL14, encoding 1085 amino acids. Quantitative real-time PCR (qRT-PCR) analysis revealed that the expression level of PlSPL14 gradually increased with the stem development of P. lactiflora and was significantly expressed in vascular bundles. Subsequently, utilizing the techniques of virus-induced gene silencing (VIGS) and heterologous overexpression in tobacco (Nicotiana tabacum L.), it was determined that PlSPL14-silenced P. lactiflora had a thinner xylem thickness, a decreased stem diameter, and weakened stem strength, while PlSPL14-overexpressing tobacco resulted in a thicker xylem thickness, an increased stem diameter, and enhanced stem strength. Further screening of the interacting proteins of PlSPL14 using a yeast two-hybrid (Y2H) assay revealed an interactive relationship between PlSPL14 and PlSLR1 protein, which acts as a negative regulator of gibberellin (GA). Additionally, the expression level of PlSLR1 gradually decreased during the stem development of P. lactiflora. The above results suggest that PlSPL14 may play a positive regulatory role in stem development and act in the xylem, making it a potential candidate gene for enhancing stem straightness in plants.

Ultralow Power In-Sensor Neuronal Computing with Oscillatory Retinal Neurons for Frequency-Multiplexed, Parallel Machine Vision.

In-sensor and near-sensor computing architectures enable multiply accumulate operations to be carried out directly at the point of sensing. In-sensor architectures offer dramatic power and speed improvements over traditional von Neumann architectures by eliminating multiple analog-to-digital conversions, data storage, and data movement operations. Current in-sensor processing approaches rely on tunable sensors or additional weighting elements to perform linear functions such as multiply accumulate operations as the sensor acquires data. This work implements in-sensor computing with an oscillatory retinal neuron device that converts incident optical signals into voltage oscillations. A computing scheme is introduced based on the frequency shift of coupled oscillators that enables parallel, frequency multiplexed, nonlinear operations on the inputs. An experimentally implemented 3 × 3 focal plane array of coupled neurons shows that functions approximating edge detection, thresholding, and segmentation occur in parallel. An example of inference on handwritten digits from the MNIST database is also experimentally demonstrated with a 3 × 3 array of coupled neurons feeding into a single hidden layer neural network, approximating a liquid-state machine. Finally, the equivalent energy consumption to carry out image processing operations, including peripherals such as the Fourier transform circuits, is projected to be <20 fJ/OP, possibly reaching as low as 15 aJ/OP.

Exploring the therapeutic potential of urine-derived stem cell exosomes in temporomandibular joint osteoarthritis.

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative ailment that causes slow cartilage degeneration, aberrant bone remodeling, and persistent discomfort, leading to a considerable reduction in the patient's life quality. Current treatment options for TMJOA have limited efficacy. This investigation aimed to explore a potential strategy for halting or reversing the progression of TMJOA through the utilization of exosomes (EXOs) derived from urine-derived stem cells (USCs). The USC-EXOs were obtained through microfiltration and ultrafiltration techniques, followed by their characterization using particle size analysis, electron microscopy, and immunoblotting. Subsequently, an in vivo model of TMJOA induced by mechanical force was established. To assess the changes in the cartilage of TMJOA treated with USC-EXOs, we performed histology analysis using hematoxylin-eosin staining, immunohistochemistry, and histological scoring. Our findings indicate that the utilization of USC-EXOs yields substantial reductions in TMJOA, while concurrently enhancing the structural integrity and smoothness of the compromised condylar cartilage surface. Additionally, USC-EXOs exhibit inhibitory effects on osteoclastogenic activity within the subchondral bone layer of the condylar cartilage, as well as attenuated apoptosis in the rat TMJ in response to mechanical injury. In conclusion, USC-EXOs hold considerable promise as a potential therapeutic intervention for TMJOA.

Influence of sources and atmospheric processes on metal solubility in PM2.5 in urban Guangzhou, South China.

Water-soluble metals exert a significant influence on human and ecosystem health. In this study, a comprehensive investigation was undertaken to elucidate the solubilities of metals in PM2.5 and potential influencing factors during the dry season of 2019-2020 in urban Guangzhou, South China. The observed average solubility was <20 % for Al, Fe, Sn, and Ti; 20-40 % for V, Cr, Sb, Pb, and Ni; 40-60 % for Ba and Cu; and 60-80 % for Zn, As, Se, Cd, and Mn. Metals (Al, Ti, and Fe) originated from crustal sources (e.g., soil dust) have much lower solubilities than those (Mn, Zn, As, Se, Cd, and Ba) from fossil fuel combustion sources (e.g., traffic emission, coal combustion), suggesting the dominant role the metal sources played on solubility. Enhanced solubilities of Cu, As, Se, Cd, Sn, Sb, and Pb were associated with aerosol acidity, while those of V, Cr, Mn, Ni, Zn, and Ba were linked to organic acid complexation. For the three crustal metals, the solubilities of Al and Ti primarily depended on aerosol acidity, whereas the solubility of Fe depended on both aerosol acidity under pH < 2 conditions and organic acid complexation under pH > 2 conditions. These findings underscore the primary influence of inherent properties of the metals on their solubility and reveal the varying impacts of atmospheric physicochemical processes, with changes in their solubilities being <10 % for Cd, Sn, Sb, and Pb, 10-20 % for Cu, Cr, Mn, Ni, and Ba, and 20-30 % for As, Se, and Zn.

Phosphoglycerate mutase 5 exacerbates alcoholic cardiomyopathy in male mice by inducing prohibitin-2 dephosphorylation and impairing mitochondrial quality control.

BACKGROUND: The induction of mitochondrial quality control (MQC) mechanisms is essential for the re-establishment of mitochondrial homeostasis and cellular bioenergetics during periods of stress. Although MQC activation has cardioprotective effects in various cardiovascular diseases, its precise role and regulatory mechanisms in alcoholic cardiomyopathy (ACM) remain incompletely understood. METHODS: We explored whether two mitochondria-related proteins, phosphoglycerate mutase 5 (Pgam5) and prohibitin 2 (Phb2), influence MQC in male mice during ACM. RESULTS: Myocardial Pgam5 expression was upregulated in a male mouse model of ACM. Notably, following ACM induction, heart dysfunction was markedly reversed in male cardiomyocyte-specific Pgam5 knockout (Pgam5cKO) mice. Meanwhile, in alcohol-treated male mouse-derived neonatal cardiomyocytes, Pgam5 depletion preserved cell survival and restored mitochondrial dynamics, mitophagy, mitochondrial biogenesis and the mitochondrial unfolded protein response (mtUPR). We further found that in alcohol-treated cardiomyocyte, Pgam5 binds Phb2 and induces its dephosphorylation at Ser91. Alternative transduction of phospho-mimetic (Phb2S91D) and phospho-defective (Phb2S9A) Phb2 mutants attenuated and enhanced, respectively, alcohol-related mitochondrial dysfunction in cardiomyocytes. Moreover, transgenic male mice expressing Phb2S91D were resistant to alcohol-induced heart dysfunction. CONCLUSIONS: We conclude that ACM-induced Pgam5 upregulation results in Pgam5-dependent Phb2S91 dephosphorylation, leading to MQC destabilisation and mitochondrial dysfunction in heart. Therefore, modulating the Pgam5/Phb2 interaction could potentially offer a novel therapeutic strategy for ACM in male mice. HIGHLIGHTS: Pgam5 knockout attenuates alcohol-induced cardiac histopathology and heart dysfunction in male mice. Pgam5 KO reduces alcohol-induced myocardial inflammation, lipid peroxidation and metabolic dysfunction in male mice. Pgam5 depletion protects mitochondrial function in alcohol-exposed male mouse cardiomyocytes. Pgam5 depletion normalises MQC in ACM. EtOH impairs MQC through inducing Phb2 dephosphorylation at Ser91. Pgam5 interacts with Phb2 and induces Phb2 dephosphorylation. Transgenic mice expressing a Ser91 phospho-mimetic Phb2 mutant are resistant to ACM.

Effect of mutation of phaC on carbon supply, extracellular polysaccharide production, and pathogenicity of Xanthomonas oryzae pv. oryzae.

Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight in rice. Polyhydroxyalkanoates (PHAs) consitute a diverse group of biopolyesters synthesized by bacteria under nutrient-limited conditions. The phaC gene is important for PHA polymerization. We investigated the effects of phaC gene mutagensis in Xoo strain PXO99A. The phaC gene knock-out mutant exhibited reduced swarming ability relative to that of the wild-type. Under conditions where glucose was the sole sugar source, extracellular polysaccharide (EPS) production by ΔphaC declined by 44.8%. ΔphaC showed weak hypersensitive response (HR) induction in the leaves of non-host Nicotiana tabacum, concomitant with downregulation of hpa1 gene expression. When inoculated in rice leaves by the leaf-clipping method, ΔphaC displayed reduced virulence in terms of lesion length compared with the wild-type strain. The complemented strain showed no significant difference from the wild-type strain, suggesting that the deletion of phaC in Xoo induces significant alterations in various physiological and biological processes. These include bacterial swarming ability, EPS production, transcription of hrp genes, and glucose metabolism. These changes are intricately linked to the energy utilization and virulence of Xoo during plant infection. These findings revealed involvement of phaC in Xoo is in the maintaining carbon metabolism by functioning in the PHA metabolic pathway.

Electrospinning technology: a promising approach for tendon-bone interface tissue engineering.

The regeneration of tendon-bone interface tissue has become a topic of great interest in recent years. However, the complex nature of this interface has posed challenges in finding suitable solutions. Tissue engineering, with its potential to improve clinical outcomes and play a crucial role in musculoskeletal function, has been increasingly explored for tendon-bone interface regeneration. This review focuses on the research advancements of electrospinning technology in interface tissue engineering. By utilizing electrospinning, researchers have been able to fabricate scaffolds with tailored properties to promote the regeneration and integration of tendon and bone tissues. The review discusses the unique structure and function of the tendon-bone interface, the mechanisms involved in its healing, and the limitations currently faced in achieving successful regeneration. Additionally, it highlights the potential of electrospinning technology in scaffold fabrication and its role in facilitating the development of functional and integrated tendon-bone interface tissues. Overall, this review provides valuable insights into the application of electrospinning technology for tendon-bone interface tissue engineering, emphasizing its significance in addressing the challenges associated with regeneration in this complex interface.

Microplastics in heavy metal-contaminated soil drives bacterial community and metabolic changes.

Microplastic (MP) and heavy metal pollution in soil are global issues. When MPs invade the soil, they combine with heavy metals and adversely affect soil organisms. Six common MPs-polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyethylene terephthalate, and polytetrafluoroethylene-were selected for this study to examine the effects of various concentrations and MP types on the physicochemical properties, bacterial community, and soil metabolism of heavy metal-contaminated soil. MP enhanced predation and competition among heavy metal-contaminated soil bacteria. Heavy metal-MPs alter metabolites in lipid metabolism, other pathways, and the bacterial community. MP treatment promotes energy production and oxidative stress of soil bacteria to resist the toxicity of heavy metals and degrade MP pollution. In conclusion, MP treatment changed the metabolism of the microbiome in heavy metal-contaminated soil and increased the abundance of Proteobacteria that responded to MPs and heavy metal pollution by 11.54 % on average. This study explored bacteria for the ecological regeneration and provided ideas for MPs and heavy metal-contaminated soil remediation.

Proton-Induced Reversible Spin-State Switching in Octanuclear FeIII Spin-Crossover Metal-Organic Cages.

Responsive spin-crossover (SCO) metal-organic cages (MOCs) are emerging dynamic platforms with potential for advanced applications in magnetic sensing and molecular switching. Among these, FeIII-based MOCs are particularly noteworthy for their air stability, yet they remain largely unexplored. Herein, we report the synthesis of two novel FeIII MOCs using a bis-bidentate ligand approach, which exhibit SCO activity above room temperature. These represent the first SCO-active FeIII cages and feature an atypical {FeN6}-type coordination sphere, uncommon for FeIII SCO compounds. Our study reveals that these MOCs are sensitive to acid/base variations, enabling reversible magnetic switching in solution. The presence of multiple active proton sites within these SCO-MOCs facilitates multisite, multilevel proton-induced spin-state modulation. This behavior is observed at room temperature through 1H NMR spectroscopy, capturing the subtle proton-induced spin-state transitions triggered by pH changes. Further insights from extended X-ray absorption fine structure (EXAFS) and theoretical analyses indicate that these magnetic alterations primarily result from the protonation and deprotonation processes at the NH active sites on the ligands. These processes induce changes in the secondary coordination sphere, thereby modulating the magnetic properties of the cages. The capability of these FeIII MOCs to integrate magnetic responses with environmental stimuli underscores their potential as finely tunable magnetic sensors and highlights their versatility as molecular switches. This work paves the way for the development of SCO-active materials with tailored properties for applications in sensing and molecular switching.

High cadmium-accumulating Salix ecotype shapes rhizosphere microbiome to facilitate cadmium extraction.

Cadmium (Cd) contamination poses a significant threat to agricultural soils and food safety, necessitating effective remediation strategies. Salix species, with their high coverage and Cd accumulating capacity, hold promise for remediation efforts. The rhizosphere microbiome is crucial for enhancing Cd accumulating capacity for Salix. However, the mechanisms by how Salix interacts with its rhizosphere microbiome to enhance Cd extraction remains poorly understood. In this study, we compared the remediation performance of two Salix ecotypes: 51-3 (High Cd-accumulating Ecotype, HAE) and P646 (Low Cd-accumulating Ecotype, LAE). HAE exhibited notable advantages over LAE, with 10.80 % higher plant height, 43.80 % higher biomass, 20.26 % higher Cd accumulation in aboveground tissues (93.09 µg on average), and a superior Cd translocation factor (1.97 on average). Analysis of the rhizosphere bacterial community via 16S rRNA amplicon sequencing revealed that HAE harbored a more diverse bacterial community with a distinct composition compared to LAE. Indicator analysis identified 84 genera specifically enriched in HAE, predominantly belonging to Proteobacteria, Actinobacteria, and Firmicutes, including beneficial microbes such as Streptomyces, Bacillus, and Pseudomonas. Network analysis further elucidated three taxa groups specifically recruited by HAE, which were highly correlated with functional genes that associated with biosynthesis of secondary metabolites, glycan biosynthesis and metabolism, and metabolism of cofactors and vitamins. These functions contribute to enhancing plant growth, Cd uptake, and resistance to Cd in Salix. Overall, our findings highlight the importance of the rhizosphere microbiome in facilitating Cd extraction and provide insights into microbiome-based strategies for sustainable agricultural practices.

Long-Term HIV Pre-Exposure Prophylaxis Persistence and Reinitiation in Connecticut from 2012 to 2018.

HIV pre-exposure prophylaxis (PrEP) is a highly effective biomedical prevention for HIV infections. PrEP persistence is critical to achieving optimal protection against HIV infection. However, little is known about PrEP persistence in the United States. This study utilized the Connecticut All-Payer Claims Database (APCD) to identify PrEP persistence among patients who filled their PrEP prescriptions in the state. The authors identified 1,576 PrEP patients who picked up PrEP prescriptions and extracted medical and pharmacy claims to evaluate a longitudinal cohort during 2012-2018 based on the Connecticut APCD. Patients who did not pick up medication for one consecutive month (ie, 30 days) were defined as discontinuing PrEP. Kaplan-Meier Survival Curve and proportional hazard regression were used to describe PrEP persistence. Of the 1,576 patients who picked up PrEP prescriptions, the median age was 32.0 (interquartile range [IQR]: 22.0-44.0). The majority were male individuals (93%). Of 1,040 patients who discontinued PrEP, 702 (67.5%) restarted PrEP at least once. The median time of PrEP persistence was 3 months (IQR: 1-6 months) for initial PrEP use. The median time on PrEP was also around 3 months in the following episodes of PrEP use. Being female, being on parent's insurance, and having high co-pays were associated with shorter periods of PrEP persistence. PrEP persistence was low among patients who picked up PrEP prescriptions. Although many patients restarted PrEP, persistence remained low during follow-up PrEP use and possibly led to periods of increased HIV risk. Effective interventions are needed to improve PrEP persistence and reduce HIV incidence.

PoWRKY69-PoVQ11 module positively regulates drought tolerance by accumulating fructose in Paeonia ostii.

Drought is a detrimental environmental factor that restricts plant growth and threatens food security throughout the world. WRKY transcription factors play vital roles in abiotic stress response. However, the roles of IIe subgroup members from WRKY transcription factor family in soluble sugar mediated drought response are largely elusive. In this study, we identified a drought-responsive IIe subgroup WRKY transcription factor, PoWRKY69, from Paeonia ostii. PoWRKY69 functioned as a positive regulator in response to drought stress with nucleus expression and transcriptional activation activity. Silencing of PoWRKY69 increased plants sensitivity to drought stress, whereas conversely, overexpression of PoWRKY69 enhanced drought tolerance in plants. As revealed by yeast one-hybrid, electrophoretic mobility shift assay, and luciferase reporter assays, PoWRKY69 could directly bind to the W-box element of fructose-1,6-bisphosphate aldolase 5 (PoFBA5) promoter, contributing to a cascade regulatory network to activate PoFBA5 expression. Furthermore, virus-induced gene silencing and overexpression assays demonstrated that PoFBA5 functioned positively in response to drought stress by accumulating fructose to alleviate membrane lipid peroxidation and activate antioxidant defense system, these changes resulted in reactive oxygen species scavenging. According to yeast two-hybrid, bimolecular fluorescence complementation, and firefly luciferase complementation imaging assays, valine-glutamine 11 (PoVQ11) physically interacted with PoWRKY69 and led to an enhanced activation of PoWRKY69 on PoFBA5 promoter activity. This study broadens our understanding of WRKY69-VQ11 module regulated fructose accumulation in response to drought stress and provides feasible molecular measures to create novel drought-tolerant germplasm of P. ostii.

Src inhibition modulates AMBRA1-mediated mitophagy to counteract endothelial-to-mesenchymal transition in renal allograft fibrosis.

Chronic allograft dysfunction (CAD) poses a significant challenge in kidney transplantation, with renal vascular endothelial-to-mesenchymal transition (EndMT) playing a vital role. While renal vascular EndMT has been verified as an important contributing factor to renal allograft interstitial fibrosis/tubular atrophy in CAD patients, its underlying mechanisms remain obscure. Currently, Src activation is closely linked to organ fibrosis development. Single-cell transcriptomic analysis in clinical patients revealed that Src is a potential pivotal mediator in CAD progression. Our findings revealed a significant upregulation of Src which closely associated with EndMT in CAD patients, allogeneic kidney transplanted rats and endothelial cells lines. In vivo, Src inhibition remarkably alleviate EndMT and renal allograft interstitial fibrosis in allogeneic kidney transplanted rats. It also had a similar antifibrotic effect in two endothelial cell lines. Mechanistically, the knockout of Src resulted in an augmented AMBRA1-mediated mitophagy in endothelial cells. We demonstrate that Src knockdown upregulates AMBRA1 level and activates mitophagy by stabilizing Parkin's ubiquitination levels and mitochondrial translocation. Subsequent experiments demonstrated that the knockdown of the Parkin gene inhibited mitophagy in endothelial cells, leading to increased production of Interleukin-6, thereby inducing EndMT. Consequently, our study underscores Src as a critical mediator of renal vascular EndMT and allograft interstitial fibrosis, exerting its impact through the regulation of AMBRA1/Parkin-mediated mitophagy.

Identification of key genes for triacylglycerol biosynthesis and storage in herbaceous peony (Paeonia lactifolra Pall.) seeds based on full-length transcriptome.

BACKGROUND: The herbaceous peony (Paeonia lactiflora Pall.) is extensively cultivated in China due to its root being used as a traditional Chinese medicine known as 'Radix Paeoniae Alba'. In recent years, it has been discovered that its seeds incorporate abundant unsaturated fatty acids, thereby presenting a potential new oilseed plant. Surprisingly, little is known about the full-length transcriptome sequencing of Paeonia lactiflora, limiting research into its gene function and molecular mechanisms. RESULTS: A total of 484,931 Reads of Inserts (ROI) sequences and 1,455,771 full-Length non-chimeric reads (FLNC) sequences were obtained for CDS prediction, TF analysis, SSR analysis and lncRNA identification. In addition, gene function annotation and gene structure analysis were performed. A total of 4905 transcripts were related to lipid metabolism biosynthesis pathway, belonging to 28 enzymes. We use these data to identify 10 oleosin (OLE) and 5 diacylglycerol acyltransferase (DGAT) gene members after de-redundancy. The analysis of physicochemical properties and secondary structure showed them similarity in gene family respectively. The phylogenetic analysis showed that the distribution of OLE and DGAT family members was roughly the same as that of Arabidopsis. Quantitative real-time polymerase chain reaction (qRT-PCR) analyses revealed expression changes in different seed development stages, and showed a trend of increasing and then decreasing. CONCLUSION: In summary, these results provide new insights into the molecular mechanism of triacylglycerol (TAG) biosynthesis and storage during the seedling stage in Paeonia lactiflora. It provides theoretical references for selecting and breeding oil varieties and understanding the functions of oil storage as well as lipid synthesis related genes in Paeonia lactiflora.

Inhibition of ER stress using tauroursodeoxycholic acid rescues obesity-evoked cardiac remodeling and contractile anomalies through regulation of ferroptosis.

Interrupted ER homeostasis contributes to the etiology of obesity cardiomyopathy although it remains elusive how ER stress evokes cardiac anomalies in obesity. Our study evaluated the impact of ER stress inhibition on cardiac anomalies in obesity. Lean and ob/ob obese mice received chemical ER chaperone tauroursodeoxycholic acid (TUDCA, 50 mg/kg/d, p.o.) for 35 days prior to evaluation of glucose sensitivity, echocardiographic, myocardial geometric, cardiomyocyte mechanical and subcellular Ca2+ property, mitochondrial integrity, oxidative stress, apoptosis, and ferroptosis. Intracellular Ca2+ governing domains including sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) were monitored by45Ca2+uptake and immunoblotting. Our results noted that TUDCA alleviated myocardial remodeling (fibrosis, hypertrophy, enlarged LVESD), echocardiographic anomalies (compromised fractional shortening and ejection fraction), cardiomyocyte contractile dysfunction (amplitude and velocity of cell shortening, relengthening time) and intracellular Ca2+ anomalies (compromised subcellular Ca2+ release, clearance and SERCA function), mitochondrial damage (collapsed membrane potential, downregulated mitochondrial elements and ultrastructural alteration), ER stress (GRP78, eIF2α and ATF4), oxidative stress, apoptosis and ferroptosis [downregulated SLC7A11, GPx4 and upregulated transferrin receptor (TFRC)] without affecting global glucose sensitivity and serum Fe2+ in obese mice. Obesity-evoked change in HSP90, phospholamban and Na+-Ca2+ exchanger was spared by the chemical ER chaperone. Moreover, in vitro results noted that TUDCA, PERK inhibitor GSK2606414, TFRC neutralizing antibody and ferroptosis inhibitor LIP1 mitigated palmitic acid-elicited changes in lipid peroxidation and mechanical function. Our findings favored a role for ferroptosis in obesity cardiomyopathy downstream of ER stress.