Factors associated with antiretroviral treatment adherence among people living with HIV in Guangdong Province, China: a cross sectional analysis.

BACKGROUND: Understanding factors associated with antiretroviral treatment (ART) adherence is crucial for ART success among people living with HIV (PLHIV) in the "test and treat" era. Multiple psychosocial factors tend to coexist and have a syndemic effect on ART adherence. We aimed to explore factors associated with ART adherence and the syndemic effect of multiple psychosocial factors on ART adherence among PLHIV newly starting ART in Guangdong Province, China. METHODS: Newly diagnosed PLHIV from six cities in Guangdong Province were recruited between May 2018 and June 2019, and then followed up from May 2019 to August 2020. Baseline and follow-up data were collected from a questionnaire and the national HIV surveillance system, the follow-up data of which were analyzed in this study. A Center for Adherence Support Evaluation (CASE) index > 10 points was defined as optimal ART adherence, which was measured via participants' self-reported adherence during follow-up survey. Multivariable logistic regression was used to identify factors associated with ART adherence. Exploratory factor analysis (EFA) and multi-order latent variable structural equation modeling (SEM) were performed to explore the syndemic effect of multiple psychosocial factors on ART adherence. RESULTS: A total of 734 (68.53%) follow-up participants were finally included in this study among the 1071 baseline participants, of whom 91.28% (670/734) had self-reported optimal ART adherence. Unemployment (aOR = 1.75, 95%CI: 1.01-3.02), no medication reminder (aOR = 2.28, 95%CI: 1.09-4.74), low medication self-efficacy (aOR = 2.28, 95%CI: 1.27-4.10), low social cohesion (aOR = 1.82, 95%CI: 1.03-3.19), no social participation (aOR = 5.65, 95%CI: 1.71-18.63), and ART side effects (aOR = 0.46, 95%CI: 0.26-0.81) were barriers to optimal ART adherence. The EFA and second-order latent variable SEM showed a linear relationship (standardized coefficient = 0.43, P < 0.001) between ART adherence and the latent psychosocial (syndemic) factor, which consisted of the three latent factors of medication beliefs and self-efficacy (standardized coefficient = 0.65, P < 0.001), supportive environment (standardized coefficient = 0.50, P < 0.001), and negative emotions (standardized coefficient=-0.38, P < 0.01). The latent factors of medication beliefs and self-efficacy, supportive environment, and negative emotions explained 42.3%, 25.3%, and 14.1% of the variance in the latent psychosocial factor, respectively. CONCLUSIONS: About nine out of ten PLHIV on ART in Guangdong Province self-reported optimal ART adherence. However, more efforts should be made to address barriers to optimal ART adherence.

EZH2 G553C significantly increases the risk of brain metastasis from lung cancer due to salt bridge instability.

BACKGROUND: The incidence and mortality of lung cancer is the highest in China and the world. Brain is the most common distant metastasis site of lung cancer. Its transfer mechanism and predictive biomarkers are still unclear. EZH2 participates in the catalysis of transcriptional inhibition complex, mediates chromatin compactness, leads to the silencing of its downstream target genes, participates in the silencing of multiple tumor suppressor genes, and is related to cell proliferation, apoptosis and cycle regulation. In physiology, EZH2 has high activity in stem cells or progenitor cells, inhibits genes related to cell cycle arrest and promotes self-renewal. To detect the expression and mutation of EZH2 gene in patients with brain metastasis of lung cancer, and provide further theoretical basis for exploring the pathogenesis of brain metastasis of lung cancer and finding reliable biomarkers to predict brain metastasis of lung cancer. METHODS: This study investigated susceptible genes for brain metastasis of lung cancer. The second-generation sequencing technology was applied to screen the differential genes of paired samples (brain metastasis tissues, lung cancer tissues and adjacent tissues) of lung cancer patients with brain metastasi. RESULTS: It revealed that there was a significant difference in the G553C genotype of EZH2 between lung cancer brain metastasis tissues and lung cancer tissues (p = 0.045). The risk of lung cancer brain metastasis in G allele carriers was 2.124 times higher than that in C allele carriers. Immunohistochemistry showed that compared with lung cancer patients and lung cancer patients with brain metastasis, the expression level of EZH2 in lung cancer tissues of lung cancer patients was significantly higher than that in adjacent lung tissues (p < 0.0001), and higher than that in brain metastasis tissues (p = 0.0309). RNA in situ immunohybridization showed that EZH2 mRNA expression was gradually high in lung cancer adjacent tissues, lung cancer tissues and lung cancer brain metastasis tissues. CONCLUSIONS: EZH2 G553C polymorphism contributes to the prediction of brain metastasis of lung cancer, in which G allele carriers are more prone to brain metastasis.

The activation of LBH-CRYAB signaling promotes cardiac protection against I/R injury by inhibiting apoptosis and ferroptosis.

Myocardial ischemia-reperfusion (I/R) injury stands out among cardiovascular diseases, and current treatments are considered unsatisfactory. For cardiomyocytes (CMs) in ischemic tissues, the upregulation of Limb-bud and Heart (LBH) and αB-crystallin (CRYAB) and their subsequent downregulation in the context of cardiac fibrosis have been verified in our previous research. Here, we focused on the effects and mechanisms of activated LBH-CRYAB signaling on damaged CMs during I/R injury, and confirmed the occurrence of mitochondrial apoptosis and ferroptosis during I/R injury. The application of inhibitors, ectopic expression vectors, and knockout mouse models uniformly verified the role of LBH in alleviating both apoptosis and ferroptosis of CMs. p53 was identified as a mutual downstream effector for both LBH-CRYAB-modulated apoptosis and ferroptosis inhibition. In mouse models, LBH overexpression was confirmed to exert enhanced cardiac protection against I/R-induced apoptosis and ferroptosis, suggesting that LBH could serve as a promising target for the development of I/R therapy.

High-Speed and Accurate Diagnosis of Gastrointestinal Disease: Learning on Endoscopy Images Using Lightweight Transformer with Local Feature Attention.

In response to the pressing need for robust disease diagnosis from gastrointestinal tract (GIT) endoscopic images, we proposed FLATer, a fast, lightweight, and highly accurate transformer-based model. FLATer consists of a residual block, a vision transformer module, and a spatial attention block, which concurrently focuses on local features and global attention. It can leverage the capabilities of both convolutional neural networks (CNNs) and vision transformers (ViT). We decomposed the classification of endoscopic images into two subtasks: a binary classification to discern between normal and pathological images and a further multi-class classification to categorize images into specific diseases, namely ulcerative colitis, polyps, and esophagitis. FLATer has exhibited exceptional prowess in these tasks, achieving 96.4% accuracy in binary classification and 99.7% accuracy in ternary classification, surpassing most existing models. Notably, FLATer could maintain impressive performance when trained from scratch, underscoring its robustness. In addition to the high precision, FLATer boasted remarkable efficiency, reaching a notable throughput of 16.4k images per second, which positions FLATer as a compelling candidate for rapid disease identification in clinical practice.

Adropin deficiency worsens TNBS-induced colitis.

The aim of this study was to describe the effects of adropin deficiency on the distribution, phenotype and pathological phenotype of macrophages in colonic and mesenteric tissues of AdrKO (Enho-/-) mice, so as to explore the mechanism of adropin deficiency in spontaneous and experimental colitis. In this study, RNA-seq and metabonomics were used to screen the regulatory mechanism of adropin on the phenotypic transformation of macrophages. We found that adropin levels in active UC patients were significantly lower than those in normal subjects and remission UC patients, and at the same time, a large number of proinflammatory M1-type macrophages were infiltrated in the mesenteric tissue of colonic tissues from UC and CD patients. At the same time, spontaneous colitis occurred in Enho-/- (adropin-deficient)C57BL/6 mice, and there was an imbalance of M2 â†’ M1 polarization of macrophages in colon and mesentery of Enho-/- mice. In vivo, it has showed that adropin deficiency could exacerbate the pathological phenotype of colitis induced by TNBS. In vitro, adropin was used to intervene RAW264.7 macrophages, and then combined analysis of RNA-seq and metabolomics demonstrated that adropin regulated lipid metabolism of macrophages through PPARγ, thus promoting the repolarization of macrophages from M1 to M2. Adropin deficiency led to an imbalance in the phenotypic distribution of macrophages infiltrating the colon and mesenteric tissues, namely, an increase in M1 type, which led to the occurrence and development of colitis.

Calcitonin gene-related peptide: a potential protective agent in cerebral ischemia-reperfusion injury.

Ischemic stroke is the most common type of cerebrovascular disease with high disability and mortality rates, which severely burdens patients, their families, and society. At present, thrombolytic therapy is mainly used for the treatment of ischemic strokes. Even though it can achieve a good effect, thrombolytic recanalization can cause reperfusion injury. Calcitonin gene-related peptide (CGRP) is a neuropeptide that plays a neuroprotective role in the process of ischemia-reperfusion injury. By combining with its specific receptors, CGRP can induce vasodilation of local cerebral ischemia by directly activating the cAMP-PKA pathway in vascular smooth muscle cells and by indirectly activating the NO-cGMP pathway in an endothelial cell-dependent manner,thus rapidly increasing ischemic local blood flow together with reperfusion. CGRP, as a key effector molecule of neurogenic inflammation, can reduce the activation of microglia, downregulates Th1 classical inflammation, and reduce the production of TNF-α, IL-2, and IFN-γ and the innate immune response of macrophages, leading to the reduction of inflammatory factors. CGRP can reduce the overexpression of the aquaporin-4 (AQP-4) protein and its mRNA in the cerebral ischemic junction, and play a role in reducing cerebral edema. CGRP can protect endothelial cells from angiotensin II by reducing the production of oxidants and protecting antioxidant defense. Furthermore, CGRP-upregulated eNOS can further induce VEGF expression, which then promotes the survival and angiogenesis of vascular endothelial cells. CGRP can also reduce apoptosis by promoting the expression of Bcl-2 and inhibiting the expression of caspase-3. These effects suggest that CGRP can reduce brain injury and repair damaged nerve function. In this review, we focused on the role of CGRP in cerebral ischemia-reperfusion injury.

Proton pump inhibitors affect sperm parameters by regulating aquaporins.

Proton pump inhibitors (PPIs) were one of the most commonly used drugs in daily life. The adverse effects of long-term use of PPIs have aroused widespread controversy. It was of great significance to explore the molecular mechanism of sperm abnormality caused by PPIs. The PPI group was given omeprazole by gavage for 28 days. After the omeprazole intervention, the caudal epididymis was dissected to obtain sperms, and the sperm was counted through the microscope, as the acrosomal integrity was observed through PNA-FITC staining. The expression of aquaporins were detected by immunofluorescence and western blot in the testis, epididymis and spermatozoa. The liver cytochrome enzyme was evaluated by immunohistochemistry and western blot. We detected the serum estrogen level by ELISA, and the level of alanine transaminase (ALT) were detected through microplate method. The sperm count in PPI group was less than control group (p < 0.05), and the sperm acrosin integrity in PPI group was lower than control group (p < 0.05). In the testis, the expression of aquaporin 3 and aquaporin 8 in PPI group was higher than control group (p < 0.05), while the expression of aquaporin 7 was lower than control group (p < 0.05). In the epididymal and sperm, the expression of aquaporin 3 and aquaporin 7 in PPI group was higher than control group (p < 0.05), while the expression of aquaporin 8 in PPI group was lower than control group (p < 0.05). Meanwhile, the liver cytochrome enzyme in PPI group were lower than control group (p < 0.05), and estrogen and ALT in PPI group were higher than control group (p < 0.05). PPI may lead to the up-regulation of estrogen by inhibiting the activity of cytochrome enzyme, and then lead to the dysfunction of sperm parameters and acrosin integrity by affecting aquaporins function.

Female BMI has an effect on oocyte gene expression pattern.

Purpose: To explore the mechanisms by which abnormal female BMI affects oocyte quality, particularly whether it involves the alteration of gene expression patterns and how these patterns may impact clinical outcomes. Methods: In Part 1, we performed a retrospective study to compare the clinical outcomes between the female BMI ≥25 kg/m2 and female BMI ≤20 kg/m2 groups. In Part 2, we performed the transcriptome analyses based on the GSE87201 dataset. Results: In Part 1, among the clinical outcomes, only the grade 1-2 embryo rate at day 3 of ICSI cycles was significantly different between the two BMI groups; the other outcomes were not. In Part 2, compared with the BMI ≤20 kg/m2 group, the oocyte gene expression pattern of the BMI ≥25 kg/m2 group seemed to result in better oocyte tolerance to exogenous stress, such as intracytoplasmic sperm injection (ICSI). It seemed to explain the result of Part 1 that the BMI ≥25 kg/m2 group had better day-3 embryo quality after ICSI than the BMI ≤20 kg/m2 group. Conclusions: Abnormal female BMI affects oocyte quality by altering the gene expression patterns of oocytes. While a female BMI ≥25 kg/m2 is known to have certain detrimental effects on ART, our findings suggest that it can also confer some benefits to oocytes.

Effect of COVID-19 inactivated vaccine on peripheral blood anti-ß2-GPI antibody and outcomes in vitro fertilization-embryo transplantation.

Corona Virus Disease 2019 (COVID-19) is an acute respiratory infection and a global public health event. The level of aß2GPI is significantly up-regulated in COVID-19 patients. The impact of inactivated vaccination against COVID-19 on aß2GPI and in vitro fertilization and embryo transfer (IVF-ET) remains unknown amidst the universal administration of COVID-19 vaccines. We conducted a retrospective study to assess the impact of COVID-19 inactivated vaccination on aß2GPI levels and its effect on superovulation and pregnancy outcomes. We found aß2GPI level is significantly up-regulated after vaccination. There was no statistical difference in mature egg rate, 2PN fertilization rate, day 3 high-quality embryo rate, blastocyst formation rate, embryo implantation rate and miscarriage rate between the vaccine group and control group. Our findings showed vaccination with COVID-19 inactivated vaccine can elevate the level of aß2GPI in peripheral blood but have no effect on the outcomes of controlled ovarian hyperstimulation and pregnancy in IVF-ET.

An Actinic Keratosis Auxiliary Diagnosis Method Based on an Enhanced MobileNet Model.

Actinic keratosis (AK) is a common precancerous skin lesion with significant harm, and it is often confused with non-actinic keratoses (NAK). At present, the diagnosis of AK mainly depends on clinical experience and histopathology. Due to the high difficulty of diagnosis and easy confusion with other diseases, this article aims to develop a convolutional neural network that can efficiently, accurately, and automatically diagnose AK. This article improves the MobileNet model and uses the AK and NAK images in the HAM10000 dataset for training and testing after data preprocessing, and we performed external independent testing using a separate dataset to validate our preprocessing approach and to demonstrate the performance and generalization capability of our model. It further compares common deep learning models in the field of skin diseases (including the original MobileNet, ResNet, GoogleNet, EfficientNet, and Xception). The results show that the improved MobileNet has achieved 0.9265 in accuracy and 0.97 in Area Under the ROC Curve (AUC), which is the best among the comparison models. At the same time, it has the shortest training time, and the total time of five-fold cross-validation on local devices only takes 821.7 s. Local experiments show that the method proposed in this article has high accuracy and stability in diagnosing AK. Our method will help doctors diagnose AK more efficiently and accurately, allowing patients to receive timely diagnosis and treatment.

Analysis of serum metabolome of laborers exposure to welding fume.

OBJECTIVE: Welding fume exposure is inevitable of welding workers and poses a severe hazard to their health since welding is a necessary industrial process. Thus, preclinical diagnostic symptoms of worker exposure are of great importance. The aim of this study was to screen serum differential metabolites of welding fume exposure based on UPLC-QTOF-MS/MS. METHODS: In 2019, 49 participants were recruited at a machinery manufacturing factory. The non-target metabolomics technique was used to clarify serum metabolic signatures in people exposed to welding fume. Differential metabolites were screened by OPLS-DA analysis and Student's t-test. The receiver operating characteristic curve evaluated the discriminatory power of differential metabolites. And the correlations between differential metabolites and metal concentrations in urine and whole blood were analyzed utilizing Pearson correlation analysis. RESULTS: Thirty metabolites were increased significantly, and 5 metabolites were decreased. The differential metabolites are mainly enriched in the metabolism of arachidonic acid, glycero phospholipid, linoleic acid, and thiamine. These results observed that lysophosphatidylcholine (20:1/0:0) and phosphatidylglycerol(PGF1α/16:0) had a tremendous anticipating power with relatively increased AUC values (AUC > 0.9), and they also presented a significant correlation of Mo concentrations in whole blood and Cu concentrations in urine, respectively. CONCLUSION: The serum metabolism was changed significantly after exposure to welding fume. Lysophosphatidylcholine (20:1/0:0) and phosphatidylglycerol (PGF1α/16:0) may be a potential biological mediator and biomarker for laborers exposure to welding fume.

The effect of ionomycin-induced oocyte activation on multiple morphological abnormalities of the sperm flagella.

Artificial oocyte activation (AOA) is considered an effective method to improve clinical outcomes in patients with some forms of male factor infertility and does not increase the risk of birth defects. However, the effects of AOA on patients with multiple morphological abnormalities of the sperm flagella (MMAF) caused by a DNAH1 mutation are still unknown. To explore the effects, our study analyzed a case with MMAF due to DNAH1 homozygous mutation that underwent testicular sperm extraction (TESE) combined with intracytoplasmic sperm injection (ICSI). The case had 28 MII oocytes. The 28 oocytes were divided randomly and equally into AOA and non-AOA groups. Ionomycin was used for AOA. We compared the clinical outcomes of two groups and selected three blastulation failure embryos from each group for transcriptome analysis (Data can be accessed through GSE216618). Differentially expressed genes (DEGs) were determined with an adjusted p-value <0.05 and a |log2-fold change| ≥1. The comparison of clinical outcomes showed that the two pronuclei (2PN) rate and grade 1-2 embryo rate at day 3 were not significantly different between the two groups. Transcriptome analyses of blastulation failed embryos showed that the use of AOA had potential risks of chromosome structure defects, transcriptional regulation defects, and epigenetic defects. In conclusion, when the case with MMAF due to DNAH1 mutation underwent TESE-ICSI, ionomycin-induced oocyte activation could not improve the clinical outcomes and introduced the risks of chromosome structure defect, transcriptional regulation defect, and epigenetic defect.

Calcium/calmodulin-dependent serine protein kinase exacerbates mitochondrial calcium uniporter-related mitochondrial calcium overload by phosphorylating α-synuclein in Parkinson's disease.

α-Synuclein phosphorylation and mitochondrial calcium homeostasis are important mechanisms underlying mitochondrial dysfunction in Parkinson's disease, but the network regulating these mechanisms remains unclear. We identified the role of key phosphokinases and the pathological effects of α-synuclein phosphorylation on mitochondrial calcium influx and mitochondrial function in Parkinson's disease. The function of the key phosphokinase, calcium/calmodulin-dependent serine protein kinase, was investigated through loss- and gain-of-function experiments using a cell model of Parkinson's disease. The regulation of mitochondrial calcium uniporter-mediated mitochondrial calcium influx by calcium/calmodulin-dependent serine protein kinase was explored using a cellular model of Parkinson's disease. Coimmunoprecipitation experiments and α-synuclein mutation were used to explore the mechanism through which calcium/calmodulin-dependent serine protein kinase regulates mitochondrial calcium uniporter-mediated mitochondrial calcium influx and exacerbates mitochondrial damage in Parkinson's disease. Here, we show the pathogenic role of calcium/calmodulin-dependent serine protein kinase in Parkinson's disease progression. Calcium/calmodulin-dependent serine protein kinase phosphorylated α-synuclein to activate mitochondrial calcium uniporter and thus increase mitochondrial calcium influx, and these effects were blocked by α-synuclein S129A mutant expression. Furthermore, the calcium/calmodulin-dependent serine protein kinase inhibitor CASK-IN-1 exerted neuroprotective effects in Parkinson's disease. Collectively, our results suggest that calcium/calmodulin-dependent serine protein kinase phosphorylates α-synuclein to activate the mitochondrial calcium uniporter and thereby causes mitochondrial calcium overload and mitochondrial damage in Parkinson's disease. We elucidated a new role of calcium/calmodulin-dependent serine protein kinase in Parkinson's disease and revealed the potential therapeutic value of targeting calcium/calmodulin-dependent serine protein kinase in Parkinson's disease treatment.

Selective deficiency of UCP-1 and adropin may lead to different subtypes of anti-neutrophil cytoplasmic antibody-associated vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that is prone to respiratory and renal failures. Its major target antigens are serine protease 3 (PR3) and myeloperoxidase (MPO), but the determinants of PR3 and MPO subtypes are still unclear. Uncoupling protein-1 (UCP-1) and adropin (Adr) regulate mutually and play an important role in endothelial cell injury. In this study, adropin and UCP-1 knockout (AdrKO and UCP-1-KO) models were established on the basis of C57BL/6 J mice. The results showed that UCP-1-KO and AdrKO mice similar to AAV: significant inflammatory cell infiltration, vascular wall damage, and erythrocyte extravasation. The pathological basis of AdrKO was that endothelial cells adhered and activated neutrophils to release MPO, and the core gene was peroxisome proliferator-activated receptor gamma (PPARG). However, UCP-1-KO induced PR3 release, and the accumulation and expression of tissue factor on the vascular wall, and the core gene was peroxisome proliferator-activated receptor delta (PPARD). The present study verified that the subtypes of AAV may be genetically different diseases and it also provide novel experimental evidence for clinical differentiation of the two subtypes.

Lnc-HZ03 promotes TRBP-mediated splicing of pre-miR-hz03 to generate miR-hz03 in human trophoblast cells.

Benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) leads to dysfunctions of human trophoblast cells and further induces miscarriage. In our previous study, we have found that lnc-HZ03 and miR-hz03 are upregulated in BPDE-exposed human trophoblast cells and in recurrent miscarriage tissues; and the upregulated miR-hz03 caused by lnc-HZ03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. However, how lnc-HZ03 upregulates miR-hz03 is completely unknown. In this study, we find that lnc-HZ03 upregulates the expression level of a transcription factor TFIID (a TATA-binding protein) and promotes TFIID-mediated transactivation response element RNA-binding protein (TRBP) transcription. Subsequently, the upregulated TRBP promotes the maturation of miR-hz03 by splicing its precursor pre-miR-hz03 in human trophoblast cells. In BPDE-exposed trophoblast cells or in recurrent miscarriage tissues, lnc-HZ03 was upregulated, which accelerates the TFIID-mediated TRBP transcription and thus promotes TRBP-mediated miR-HZ03 maturation. Subsequently, the upregulated miR-hz03 further promotes the apoptosis of human trophoblast cells and induces miscarriage. This work provides new insights into the regulation of miRNA expression levels by lncRNAs in BPDE-exposed human trophoblast cells.

A Macrophage Membrane-Polymer Hybrid Biomimetic Nanoplatform for Therapeutic Delivery of Somatostatin Peptide to Chronic Pancreatitis.

The clinical translation of therapeutic peptides is generally challenged by multiple issues involving absorption, distribution, metabolism and excretion. In this study, a macrophage membrane-coated poly(lactic-co-glycolic acid) (PLGA) nanodelivery system was developed to enhance the bioavailability of the somatostatin (SST) peptide, which faces the hurdles of short half-life and potential side effects in the treatment of chronic pancreatitis. Using a facile nanoprecipitation strategy, SST was loaded in the nanoparticles with an encapsulation efficiency (EE) and a loading efficiency (LE) of 73.68 ± 3.56% and 1.47 ± 0.07%, respectively. The final formulation of SST-loaded nanoparticles with the camouflage of macrophage membrane (MP-SST) showed a mean diameter of 151 ± 4 nm and an average zeta potential of −29.6 ± 0.3 mV, which were stable long term during storage. With an above 90% cell viability, a hemolysis level of about 2% (<5%) and a preference for being ingested by activated endothelial cells compared to macrophages, the membrane−polymer hybrid nanoparticle showed biocompatibility and targeting capability in vitro. After being intravenously administered to mice with chronic pancreatitis, the MP-SST increased the content of SST in the serum (123.6 ± 13.6 pg/mL) and pancreas (1144.9 ± 206.2 pg/g) compared to the treatment of (Dulbecco's phosphate-buffered saline) DPBS (61.7 ± 6.0 pg/mL in serum and 740.2 ± 172.4 pg/g in the pancreas). The recovery of SST by MP-SST downregulated the expressions of chronic pancreatitis-related factors and alleviated the histologic severity of the pancreas to the greatest extent compared to other treatment groups. This augmentation of SST therapeutic effects demonstrated the superiority of integrating the synthetic polymer with biological membranes in the design of nanoplatforms for advanced and smart peptide delivery. Other peptides like SST can also be delivered via the membrane−polymer hybrid nanosystem for the treatment of diseases, broadening and promoting the potential clinical applications of peptides as therapeutics.

Limb-Bud and Heart (LBH) Upregulation in Cardiomyocytes under Hypoxia Promotes the Activation of Cardiac Fibroblasts via Exosome Secretion.

The activation of cardiac fibroblasts (CFs) after myocardial infarction (MI) is essential for post-MI infarct healing, during which the regulation of transforming growth factor beta1 (TGF-ß1) signaling is predominant. We have demonstrated that TGF-ß1-mediated upregulation of LBH contributes to post-MI CF activation via modulating αB-crystallin (CRYAB), after being upregulated by TGF-ß1. In this study, the effect of LBH-CRYAB signaling on the cardiac microenvironment via exosome communication and the corresponding mechanisms were investigated. The upregulation of LBH and CRYAB was verified in both cardiomyocytes (CMs) and CFs in hypoxic, post-MI peri-infarct tissues. CM-derived exosomes were isolated and identified, and LBH distribution was elevated in exosomes derived from LBH-upregulated CMs under hypoxia. Treatment with LBH+ exosomes promoted cellular proliferation, differentiation, and epithelial-mesenchymal transition-like processes in CFs. Additionally, in primary LBHKO CFs, western blotting showed that LBH knockout partially inhibited TGF-ß1-induced CF activation, while LBH-CRYAB signaling affected TGF-ß1 expression and secretion through a positive feedback loop. The administration of a Smad3 phosphorylation inhibitor to LBHKO CFs under TGF-ß1 stimulation indicated that Smad3 phosphorylation partially accounted for TGF-ß1-induced LBH upregulation. In conclusion, LBH upregulation in CMs in post-MI peri-infarct areas correlated with a hypoxic cardiac microenvironment and led to elevated exosomal LBH levels, promoting the activation of recipient CFs, which brings new insights into the studies and therapeutic strategies of post-MI cardiac repair.

Immune disguise: the mechanisms of Neu5Gc inducing autoimmune and transplant rejection.

Organ (stem cell) transplantation is the most effective treatment for advanced organ failure. Neu5Gc (N-hydroxyacetylneuraminic acid) is a pathogenic non-human sialic acid, which is very similar to the molecular structure of Neu5Ac (N-acetylneuraminic acid) in human body. Neu5Gc has the function of "immune disguise", which is the main obstacle to transplantation. Gene knockout such as cytidine monophosphate-N-acetylneuraminidase (CMAH) reduces donor antigenicity, making xenotransplantation from fiction to reality. Exploring the immune disguise event in this emerging field has become a hot topic in the research of transplantation immune tolerance mechanism.

Effect of Late Testing and Antiretroviral Treatment on Mortality Among People Living With HIV in the Era of Treat-All in Guangdong Province, China, 1992-2018: A Cohort Study.

Late testing and antiretroviral therapy (ART) prevailed among people living with HIV (PLHIV) and impacted the benefit of immediate ART. This study aimed to identify the benefit of the test-and-immediate-treat policy in China, the effect of immediate ART, and the influence of late testing and ART on the whole PLHIV in Guangdong Province, China. We designed two tendency analyses in aggregative form and two cohorts (surveillance and ART cohort) in individuals' perspectives based on the HIV/AIDS Comprehensive Response Information Management System. Two interrupted time series models were conducted for tendency analysis from 2009 to 2018 to explore the all-cause and short-term mortality decrease after the test-and-immediate-treat policy. A time-dependent Cox model was performed for the surveillance cohort from 1992 to 2018 and a joint model was utilized for the ART cohort to identify the effect of immediate ART and the influence of late testing and ART on death. The tendency analysis included 324,914 and 68,679 person-year for all-cause/short-term mortality. A total of 49,289 and 26,287 PLHIV were recruited in the surveillance and ART cohort with 5,557 and 459 deaths, respectively. The short-term mortality dropped from 4.69 cases/100 person-year in January 2009 to 0.35 cases/100 person-year in December 2018 (standardized rate). The all-cause mortality saw a decreasing trend from 1.46 cases/100 person-year in January 2009 to 0.14 cases/100 person-year in December 2018 (standardized rate). The tendency analysis showed a significant short-term mortality slope decrease after the test-and-immediate-treat policy (P = 0.024). From the surveillance cohort, late testing, in general, was a risk factor for all-cause mortality [hazard ratio (HR) = 1.330, 95% CI, 1.250, 1.416]. ART cohort showed higher hazards of all-cause mortality among PLHIV with no late testing, but late ART (HR = 1.690, 95% CI, 1.166, 2.451) and both the late testing and late ART (HR = 1.335, 95% CI, 1.042, 1.710). Immediate ART might decrease the hazard of all-cause death though it is insignificant (HR = 0.923, 95% CI: 0.755, 1.129) in the ART cohort. The test-and-immediate-test policy brought benefit to PLHIV. We should enlarge HIV testing using comprehensive approaches to decrease late testing and ART and increase the benefit of immediate ART.