Ischemic-Preconditioning Induced Serum Exosomal miR-133a-3p Improved Post-Myocardial Infarction Repair via Targeting LTBP1 and PPP2CA.

Background: Ischemic preconditioning-induced serum exosomes (IPC-exo) protected rat heart against myocardial ischemia/reperfusion injury. However, whether IPC-exo regulate replacement fibrosis after myocardial infarction (MI) and the underlying mechanisms remain unclear. MicroRNAs (miRs) are important cargos of exosomes and play an essential role in cardioprotection. We aim to investigate whether IPC-exo regulate post-MI replacement fibrosis by transferring cardioprotective miRs and its action mechanism. Methods: Exosomes obtained from serum of adult rats in control (Con-exo) and IPC groups were identified and analyzed, subsequently intracardially injected into MI rats following ligation. Their miRs profiles were identified using high-throughput miR sequencing to identify target miRs for bioinformatics analysis. Luciferase reporter assays confirmed target genes of selected miRs. IPC-exo transfected with selected miRs antagomir or NC were intracardially administered to MI rats post-ligation. Cardiac function and degree of replacement fibrosis were detected 4 weeks post-MI. Results: IPC-exo exerted cardioprotective effects against excessive replacement fibrosis. MiR sequencing and RT-qPCR identified miR-133a-3p as most significantly different between IPC-exo and Con-exo. MiR-133a-3p directly targeted latent transforming growth factor beta binding protein 1 (LTBP1) and protein phosphatase 2, catalytic subunit, alpha isozyme (PPP2CA). KEGG analysis showed that transforming growth factor-ß (TGF-ß) was one of the most enriched signaling pathways with miR-133a-3p. Comparing to injection of IPC-exo transfected with miR-133a-3p antagomir NC, injecting IPC-exo transfected with miR-133a-3p antagomir abolished protective effects of IPC-exo on declining excessive replacement fibrosis and cardiac function enhancement, while increasing the messenger RNA and protein expression of LTBP1, PPP2CA, and TGF-ß1in MI rats. Conclusion: IPC-exo inhibit excessive replacement fibrosis and improve cardiac function post-MI by transferring miR-133a-3p, the mechanism is associated with directly targeting LTBP1 and PPP2CA, and indirectly regulating TGF-ß pathway in rats. Our finding provides potential therapeutic effect of IPC-induced exosomal miR-133a-3p for cardiac repair.

JAK2 inhibitor protects the septic heart through enhancing mitophagy in cardiomyocytes.

Sepsis-induced myocardial dysfunction (SIMD) is a severe complication in sepsis, manifested as myocardial systolic dysfunction, which is associated with poor prognosis and higher mortality. Mitophagy, a self-protective mechanism maintaining cellular homeostasis, plays an indispensable role in cardioprotection. This study aimed to unveil the cardioprotective effects of Baricitinib on LPS-induced myocardial dysfunction and its effect on mitophagy. Herein, we demonstrated that LPS induced severe myocardial dysfunction and initiated mitophagy in septic mice hearts. Despite the initiation of mitophagy, a significant number of apoptotic cells and damaged mitochondria persisted in the myocardium, and myocardial energy metabolism remained impaired, indicating that the limited mitophagy was insufficient to mitigate LPS-induced damage. The JAK2-AKT-mTOR signaling pathway is activated in LPS-induced cardiomyocytes and in the hearts of septic mice. Baricitinib administration remarkably improved cardiac function, suppressed systemic inflammatory response, attenuated histopathological changes, inhibited cardiac cell apoptosis and alleviated myocardial damage in septic mice. Furthermore, Baricitinib treatment significantly enhanced PINK1-Parkin-mediated mitophagy, increased autophagosomes, decreased impaired mitochondria, and restored myocardial energy metabolism. Mechanically, the limited mitophagy in septic myocardium was associated with increased p-ULK1 (Ser757), which was regulated by p-mTOR. Baricitinib reduced p-ULK1 (Ser757) and enhanced mitophagy by inhibiting the JAK2-AKT-mTOR signaling pathway. Inhibition of mitophagy with Mdivi-1 reversed the cardiac protective and anti-inflammatory effects of Baricitinib in septic mice. These findings suggest that Baricitinib attenuates SIMD by enhancing mitophagy in cardiomyocytes via the JAK2-AKT-mTOR signaling pathway, providing a novel mechanistic and therapeutic insight into the SIMD.

Improvement in the 95-95-95 Targets Is Accompanied by a Reduction in Both the Human Immunodeficiency Virus Transmission Rate and Incidence in China.

BACKGROUND: In 2016, China has implemented the World Health Organization's "treat all" policy. We aimed to assess the impact of significant improvements in the 95-95-95 targets on population-level human immunodeficiency virus (HIV) transmission dynamics and incidence. METHODS: We focused on 3 steps of the HIV care continuum: diagnosed, on antiretroviral therapy, and achieving viral suppression. The molecular transmission clusters were inferred using HIV-TRACE. New HIV infections were estimated using the incidence method in the European Centre for Disease Prevention and Control HIV Modelling Tool. RESULTS: Between 2004 and 2023, the national HIV epidemiology database recorded 2.99 billion person-times of HIV tests and identified 1 976 878 new diagnoses. We noted a roughly "inverted-V" curve in the clustering frequency, with the peak recorded in 2014 (67.1% [95% confidence interval, 63.7%-70.5%]), concurrent with a significant improvement in the 95-95-95 targets from 10-13-<71 in 2005 to 84-93-97 in 2022. Furthermore, we observed a parabolic curve for a new infection with the vertex occurring in 2010. CONCLUSIONS: In general, it was suggested that the improvements in the 95-95-95 targets were accompanied by a reduction in both the population-level HIV transmission rate and incidence. Thus, China should allocate more effort to the first "95" target to achieve a balanced 95-95-95 target.

LINC02454-CCT complex interaction is essential for telomerase activity and cell proliferation in head and neck squamous cell carcinoma.

Telomerase activity is upregulated in head and neck squamous cell carcinoma (HNSCC), yet its regulatory mechanisms remain unclear. Here, we identified a cancer-specific lncRNA (LINC02454) associated with poor prognosis by using LncRNA chip of our HNSCC cohorts and external datasets. Through employing negative-stain transmission electron microscopy (NS-TEM), we discovered an interaction between LINC02454 and CCT complex which would augment telomerase activity for maintaining telomere homeostasis. Supporting this, in the telomerase repeat amplification protocol (TRAP) assay and quantitative fluorescence in situ hybridization (Q-FISH) analysis, LINC02454 depletion significantly reduced telomerase activity and shortened telomere length. Consistently, pathways related to telomerase, mitosis, and apoptosis were significantly impacted upon LINC02454 knockdown in RNAseq analysis. Functionally, LINC02454-deficient cells exhibited a more significant senescence phenotype in ß-galactosidase staining, cell cycle, and apoptosis assays. We further confirmed the role of LINC02454 in HNSCC proliferation through a combination of in vitro and in vivo experiments. The therapeutic potential of targeting LINC02454 was verified by adenovirus-shRNA approach in HNSCC patient-derived xenograft (PDX) models. In summary, our findings provided valuable insights into the molecular mechanisms of HNSCC tumorigenesis and potential targets for future treatment modalities.

Lysophosphatidic acid contributes to myocardial ischemia/reperfusion injury by activating TRPV1 in spinal cord.

Lysophosphatidic acid (LPA) is a bioactive phospholipid that plays a crucial role in cardiovascular diseases. Here, we question whether LPA contributes to myocardial ischemia/reperfusion (I/R) injury by acting on transient receptor potential vanilloid 1 (TRPV1) in spinal cord. By ligating the left coronary artery to establish an in vivo I/R mouse model, we observed a 1.57-fold increase in LPA level in the cerebrospinal fluid (CSF). The I/R-elevated CSF LPA levels were reduced by HA130, an LPA synthesis inhibitor, compared to vehicle treatment (4.74 ± 0.34 vs. 6.46 ± 0.94 µg/mL, p = 0.0014). Myocardial infarct size was reduced by HA130 treatment compared to the vehicle group (26 ± 8% vs. 46 ± 8%, p = 0.0001). To block the interaction of LPA with TRPV1 at the K710 site, we generated a K710N knock-in mouse model. The TRPV1K710N mice were resistant to LPA-induced myocardial injury, showing a smaller infarct size relative to TRPV1WT mice (28 ± 4% vs. 60 ± 7%, p < 0.0001). Additionally, a sequence-specific TRPV1 peptide targeting the K710 region produced similar protective effects against LPA-induced myocardial injury. Blocking the K710 region through K710N mutation or TRPV1 peptide resulted in reduced neuropeptides release and decreased activity of cardiac sensory neurons, leading to a decrease in cardiac norepinephrine concentration and the restoration of intramyocardial pro-survival signaling, namely protein kinase B/extracellular regulated kinase/glycogen synthase kinase-3ß pathway. These findings suggest that the elevation of CSF LPA is strongly associated with myocardial I/R injury. Moreover, inhibiting the interaction of LPA with TRPV1 by blocking the K710 region uncovers a novel strategy for preventing myocardial ischemic injury.

Piezo1-Mediated Neurogenic Inflammatory Cascade Exacerbates Ventricular Remodeling After Myocardial Infarction.

BACKGROUND: Heart failure is associated with a high rate of mortality and morbidity, and ventricular remodeling invariably precedes heart failure. Ventricular remodeling is fundamentally driven by mechanotransduction that is regulated by both the nervous system and the immune system. However, it remains unknown which key molecular factors govern the neuro/immune/cardio axis that underlies mechanotransduction during ventricular remodeling. Here, we investigated whether the mechanosensitive Piezo cation channel-mediated neurogenic inflammatory cascade underlies ventricular remodeling-related mechanotransduction. METHODS: By ligating the left coronary artery of rats to establish an in vivo model of chronic myocardial infarction (MI), lentivirus-mediated thoracic dorsal root ganglion (TDRG)-specific Piezo1 knockdown rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific Piezo1 knockout mice were used to investigate whether Piezo1 in the TDRG plays a functional role during ventricular remodeling. Subsequently, neutralizing antibody-mediated TDRG IL-6 (interleukin-6) inhibition rats and adeno-associated virus-PHP.S-mediated TDRG neuron-specific IL-6 knockdown mice were used to determine the mechanism underlying neurogenic inflammation. Primary TDRG neurons were used to evaluate Piezo1 function in vitro. RESULTS: Expression of Piezo1 and IL-6 was increased, and these factors were functionally activated in TDRG neurons at 4 weeks after MI. Both knockdown of TDRG-specific Piezo1 and deletion of TDRG neuron-specific Piezo1 lessened the severity of ventricular remodeling at 4 weeks after MI and decreased the level of IL-6 in the TDRG or heart. Furthermore, inhibition of TDRG IL-6 or knockdown of TDRG neuron-specific IL-6 also ameliorated ventricular remodeling and suppressed the IL-6 cascade in the heart, whereas the Piezo1 level in the TDRG was not affected. In addition, enhanced Piezo1 function, as reflected by abundant calcium influx induced by Yoda1 (a selective agonist of Piezo1), led to increased release of IL-6 from TDRG neurons in mice 4 weeks after MI. CONCLUSIONS: Our findings point to a critical role for Piezo1 in ventricular remodeling at 4 weeks after MI and reveal a neurogenic inflammatory cascade as a previously unknown facet of the neuronal immune signaling axis underlying mechanotransduction.

Distribution pattern, molecular transmission networks, and phylodynamic of hepatitis C virus in China.

In China, few molecular epidemiological data on hepatitis C virus (HCV) are available and all previous studies were limited by small sample sizes or specific population characteristics. Here, we report characterization of the epidemic history and transmission dynamics of HCV strains in China. We included HCV sequences of individuals belonging to three HCV surveillance programs: 1) patients diagnosed with HIV infection at the Beijing HIV laboratory network, most of whom were people who inject drugs and former paid blood donors, 2) men who have sex with men, and 3) the general population. We also used publicly available HCV sequences sampled in China in our study. In total, we obtained 1,603 Ns5b and 865 C/E2 sequences from 1,811 individuals. The most common HCV strains were subtypes 1b (29.1%), 3b (25.5%) and 3a (15.1%). In transmission network analysis, factors independently associated with clustering included the region (OR: 0.37, 95% CI: 0.19-0.71), infection subtype (OR: 0.23, 95% CI: 0.1-0.52), and sampling period (OR: 0.43, 95% CI: 0.27-0.68). The history of the major HCV subtypes was complex, which coincided with some important sociomedical events in China. Of note, five of eight HCV subtype (1a, 1b, 2a, 3a, and 3b), which constituted 81.8% HCV strains genotyped in our study, showed a tendency towards decline in the effective population size during the past decade until present, which is a good omen for the goal of eliminating HCV by 2030 in China.

Plasma exosomes generated by ischaemic preconditioning are cardioprotective in a rat heart failure model.

BACKGROUND: Exosomes released into the plasma after brief cardiac ischaemia mediate subsequent cardioprotection. Whether donor exosomes can provide cardioprotection to recipients with chronic heart failure, which confers the highest perioperative risk, is unknown. We examined whether ischaemic preconditioning (IPC)-induced plasma exosomes exerted cardioprotection after their transfer from normal donors to post-infarcted failing hearts. METHODS: Plasma exosomes were obtained from adult rats after IPC or sham. An exosome inhibitor GW4869 was administrated before IPC in an in vivo model of ischaemia/reperfusion (I/R) injury in normal rats. The IPC exosomes or control exosomes from normal donor rats were perfused to the normal or post-infarcted failing rat hearts before ischaemia in Langendorff perfusion experiments. Infarct size, cardiac enzymes, cardiac function, and pro-survival kinases were quantified. RESULTS: The IPC stimulus increased the release of exosomes, whereas GW4869 inhibited the rise of plasma exosomes. Pre-treatment with GW4869 reversed IPC-mediated cardioprotection against in vivo I/R injury. In the Langendorff perfusion experiments, IPC exosomes from normal donor rats reduced mean infarct size from 41.05 (1.87)% to 31.43 (1.81)% and decreased lactate dehydrogenase activity in the post-infarcted failing rat hearts. IPC exosomes but not control exosomes activated pro-survival kinases in the heart tissues. CONCLUSIONS: Ischaemic preconditioning-induced exosomes from normal rats can restore cardioprotection in heart failure after myocardial infarction, which is associated with activation of pro-survival protein kinases. These results suggest a potential perioperative therapeutic role for ischaemic preconditioning-induced exosomes.

A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents.

Pain signals are relayed to the brain via a nociceptive system, and in rare cases, this nociceptive system contains genetic variants that can limit the pain response. Here, we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and, further, whether we could target this region with a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N-knockin mouse using CRISPR/Cas9, we discovered that the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral responses to noxious chemical stimuli and less hypersensitivity to nerve injury, while their response to noxious heat remained intact. Furthermore, blocking this K710 region in WT rodents using a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and returned pain hypersensitivity induced by nerve injury to baseline levels. These findings identify K710 TRPV1 as a discrete site that is crucial for the control of nociception and provide insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

V1-Cal hydrogelation enhances its effects on ventricular remodeling reduction and cardiac function improvement post myocardial infarction.

Myocardial infarction (MI) is a major cause of disability and mortality worldwide. A cell permeable peptide V1-Cal has shown remarkable therapeutic effects on ML However, using V1-Cal to improve long-term cardiac function after MI is presently limited by its short half-life. Herein, we co-assembled V1-Cal with a well-known hydrogelator Nap-Phe-Phe-Tyr (NapFFY) to obtain a new supramolecular hydrogel V1-Cal/NapFFY. We found that the hydrogel could significantly enhance the therapeutic effects of V1-Cal on ventricular remodeling reduction and cardiac function improvement in a myocardial infarction rat model. In vitro experiments indicated that co-assembly of V1-Cal with NapFFY significantly increased mechanic strength of the hydrogel, enabling a sustained release of V1-Cal for more than two weeks. In vivo experiments supported that sustained release of V1-Cal from V1-Cal/NapFFY hydrogel could effectively decrease the expression and activation of TRPV1, reduce apoptosis and the release of inflammatory factors in a MI rat model. In particular, V1-Cal/NapFFY hydrogel significantly decreased infarct size and fibrosis, while improved cardiac function 28 days post MI. We anticipate that V1-Cal/NapFFY hydrogel could be used clinically to treat MI in the near future.

MMP 9-instructed assembly of bFGF nanofibers in ischemic myocardium to promote heart repair.

Background: The only effective treatment for myocardial infarction (MI) is the timely restoration of coronary blood flow in the infarcted area, but further reperfusion exacerbates myocardial injury and leads to distal coronary no-reflow, which affects patient prognosis. Angiogenesis could be an important therapeutic strategy for re-establishing the blood supply to save the ischemic myocardium after MI. Basic fibroblast growth factor (bFGF) has been shown to promote angiogenesis. However, direct intravenous administration of bFGF is not a viable option given its poor half-life in vivo. Methods: Herein, we developed a peptide Lys-Lys-Pro-Leu-Gly-Leu-Ala-Gly-Phe-Phe (K2) to encapsulate bFGF to form bFGF@K2 micelle and proposed an enzyme-instructed self-assembly (EISA) strategy to deliver and slowly release bFGF in the ischemic myocardium. Results: The bFGF@K2 micelle exerted a stronger cardioprotective effect than free bFGF in a rat model of myocardial ischemia-reperfusion (MI/R). In vitro results revealed that the bFGF@K2 micelle could be cleaved by matrix metallopeptidase 9 (MMP-9) to yield bFGF@Nanofiber through amphipathic changes. In vivo experiments indicated that intravenous administration of bFGF@K2 micelle could lead to their restructuring into bFGF@Nanofiber and long term retention of bFGF in the ischemic myocardium of rat due to high expression of MMP-9 and assembly-induced retention (AIR) effect, respectively. Twenty-eight days after MI/R model establishment, bFGF@K2 micelle treatment significantly reduced fibrosis and improved cardiac function of the rats. Conclusion: We predict that our strategy could be applied in clinic for MI treatment in the future.

Spinal cord astrocytes regulate myocardial ischemia-reperfusion injury.

Astrocytes play a key role in the response to injury and noxious stimuli, but its role in myocardial ischemia-reperfusion (I/R) injury remains largely unknown. Here we determined whether manipulation of spinal astrocyte activity affected myocardial I/R injury and the underlying mechanisms. By ligating the left coronary artery to establish an in vivo I/R rat model, we observed a 1.7-fold rise in glial fibrillary acidic protein (GFAP) protein level in spinal cord following myocardial I/R injury. Inhibition of spinal astrocytes by intrathecal injection of fluoro-citrate, an astrocyte inhibitor, decreased GFAP immunostaining and reduced infarct size by 29% relative to the I/R group. Using a Designer Receptor Exclusively Activated by Designer Drugs (DREADD) chemogenetic approach, we bi-directionally manipulated astrocyte activity employing GFAP promoter-driven Gq- or Gi-coupled signaling. The Gq-DREADD-mediated activation of spinal astrocytes caused transient receptor potential vanilloid 1 (TRPV1) activation and neuropeptide release leading to a 1.3-fold increase in infarct size, 1.2-fold rise in serum norepinephrine level and higher arrhythmia score relative to I/R group. In contrast, Gi-DREADD-mediated inhibition of spinal astrocytes suppressed TRPV1-mediated nociceptive signaling, resulting in 35% reduction of infarct size and 51% reduction of arrhythmia score from I/R group, as well as lowering serum norepinephrine level from 3158 ± 108 to 2047 ± 95 pg/mL. Further, intrathecal administration of TRPV1 or neuropeptide antagonists reduced infarct size and serum norepinephrine level. These findings demonstrate a functional role of spinal astrocytes in myocardial I/R injury and provide a novel potential therapeutic approach targeting spinal cord astrocytes for the prevention of cardiac injury.

Interleukin-6 trans-signalling in hippocampal CA1 neurones mediates perioperative neurocognitive disorders in mice.

BACKGROUND: Interleukin-6 (IL-6), a pleiotropic cytokine with both degenerative and regenerative properties, is necessary and sufficient to provoke perioperative neurocognitive disorders after aseptic trauma in mice. IL-6 initiates its actions after binding to either membrane-bound IL-6 receptor α (mIL-6Rα) through classical signalling, or soluble IL-6 receptor (IL-6R) through trans-signalling; both signalling pathways require the transducer gp130. We investigated the site and type of IL-6 signalling that pertains in a tibial fracture aseptic trauma model of perioperative neurocognitive disorder. METHODS: Wild-type or genetically altered adult mice that lacked molecules unique to either classical or trans-IL-6 signalling underwent tibial fracture under isoflurane anaesthesia. In separate cohorts, we assessed postoperative memory using a trace fear conditioning paradigm (72 h postoperatively), and post-receptor IL-6 signalling (24 h postoperatively) using phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) in CA1 hippocampal neurones. Fracture healing was assessed at postoperative day 15 after inhibiting either both forms of IL-6 signalling with BE0047 or only trans-signalling with sgp130Fc. RESULTS: The surgical phenotype of memory decline (decrease in freezing in trace fear conditioning) and upregulated IL-6 signalling (pSTAT3) did not occur after pretreatment before surgery with either BE0047 or sgp130Fc, or after depleting gp130 from CA1 neurones. The surgical phenotype still occurred when IL-6Rα was depleted in either CA1 hippocampal neurones (freezing time, 38.9% [11.5%] vs 58.4% [12.3%]; pSTAT+ CA1 neurones, 31.7 [4.9] vs 7.0 [3.1]) or microglia (freezing time, 40.1% [13.9%] vs 65.2% [12.6%]; pSTAT+ CA1 neurones, 30.1 [5.5] vs 7.9 [3.2]). In global IL-6Rα-/- mice, hyper-IL-6, the trans-signalling agonist, produced the surgical phenotype when administered i.c.v. (freezing time, 42.4% [8.8%] vs 59.7% [10.4%]; pSTAT+ cells, 29.3 [4.3] vs 10.0 [4.4]). Bone-fracture healing (% of fracture callus comprised of new collagen) was significantly greater with sgp130Fc than with BE0047 (52.2% [8.3%] vs 39.7% [7.9%]). CONCLUSIONS: After orthopaedic trauma, IL-6 produces perioperative neurocognitive disorders through IL-6 trans-signalling in mouse CA1 neurones. Druggable targets of the trans-signalling pathway should be sought to reduce perioperative neurocognitive disorders while allowing the healing properties of classical IL-6 signalling.

p53-Dependent Mitochondrial Compensation in Heart Failure With Preserved Ejection Fraction.

Background Heart failure with preserved ejection fraction (HFpEF) accounts for 50% of patients with heart failure. Clinically, HFpEF prevalence shows age and gender biases. Although the majority of patients with HFpEF are elderly, there is an emergence of young patients with HFpEF. A better understanding of the underlying pathogenic mechanism is urgently needed. Here, we aimed to determine the role of aging in the pathogenesis of HFpEF. Methods and Results HFpEF dietary regimen (high-fat diet + Nω-Nitro-L-arginine methyl ester hydrochloride) was used to induce HFpEF in wild type and telomerase RNA knockout mice (second-generation and third-generation telomerase RNA component knockout), an aging murine model. First, both male and female animals develop HFpEF equally. Second, cardiac wall thickening preceded diastolic dysfunction in all HFpEF animals. Third, accelerated HFpEF onset was observed in second-generation telomerase RNA component knockout (at 6 weeks) and third-generation telomerase RNA component knockout (at 4 weeks) compared with wild type (8 weeks). Fourth, we demonstrate that mitochondrial respiration transitioned from compensatory state (normal basal yet loss of maximal respiratory capacity) to dysfunction (loss of both basal and maximal respiratory capacity) in a p53 dosage dependent manner. Last, using myocardial-specific p53 knockout animals, we demonstrate that loss of p53 activation delays the development of HFpEF. Conclusions Here we demonstrate that p53 activation plays a role in the pathogenesis of HFpEF. We show that short telomere animals exhibit a basal level of p53 activation, mitochondria upregulate mtDNA encoded genes as a mean to compensate for blocked mitochondrial biogenesis, and loss of myocardial p53 delays HFpEF onset in high fat diet + Nω-Nitro-L-arginine methyl ester hydrochloride challenged murine model.

CRF07_BC is associated with slow HIV disease progression in Chinese patients.

HIV subtypes convey important epidemiological information and possibly influence the rate of disease progression. In this study, HIV disease progression in patients infected with CRF01_AE, CRF07_BC, and subtype B was compared in the largest HIV molecular epidemiology study ever done in China. A national data set of HIV pol sequences was assembled by pooling sequences from public databases and the Beijing HIV laboratory network. Logistic regression was used to assess factors associated with the risk of AIDS at diagnosis ([AIDSAD], defined as a CD4 count < 200 cells/µL) in patients with HIV subtype B, CRF01_AE, and CRF07_BC. Of the 20,663 sequences, 9,156 (44.3%) were CRF01_AE. CRF07_BC was responsible for 28.3% of infections, followed by B (13.9%). In multivariable analysis, the risk of AIDSAD differed significantly according to HIV subtype (OR for CRF07_BC vs. B: 0.46, 95% CI 0.39─0.53), age (OR for ≥ 65 years vs. < 18 years: 4.3 95% CI 1.81─11.8), and transmission risk groups (OR for men who have sex with men vs. heterosexuals: 0.67 95% CI 0.6─0.75). These findings suggest that HIV diversity in China is constantly evolving and gaining in complexity. CRF07_BC is less pathogenic than subtype B, while CRF01_AE is as pathogenic as B.

Tumour-derived extracellular vesicle membrane hybrid lipid nanovesicles enhance siRNA delivery by tumour-homing and intracellular freeway transportation.

Extracellular vesicles (EVs) have been proved a promising small interfering RNA (siRNA) delivery vehicle to mediate gene-silencing. Tumour-derived extracellular vesicles (TDEVs) as genetic exchange vectors in the tumour microenvironment, enable intercellular communication for a wide range of endogenous cargo molecules, such as RNAs and proteins. However, the oncogenic cargo of TDEVs limits their application in siRNA delivery for cancer therapy. Herein, we isolated TDEVs from hepatocellular carcinoma (HCC) cells and derived TDEV membranes by abandoning their content. Innovative TDEV membrane hybrid lipid nanovesicles (LEVs) were then fabricated by fusion of TDEV membranes and phospholipids to realize precise delivery to tumours and highly efficient transfection of siRNA. The TDEV membranes endow LEVs with 'homing' targeting ability, facilitating specific internalisation into parent HCC cells primarily through heparan sulfate proteoglycan-mediated pathways. Unlike conventional lipid-based nanovesicles, LEVs can bypass the endosomal degradation pathway, boost the delivery of siRNA through the Golgi and endoplasmic reticulum (ER) intracellular 'freeway' transportation, achieving a 1.7-fold improvement in siRNA transfection efficiency compared with liposomes. Additionally, siRNA loaded LEVs were demonstrated to enhance the antitumour efficacy in HCC bearing mice through effective gene silencing in the tumour sites. Our results highlight the potential application of the TDEV membrane-derived nanovesicles as an advanced siRNA delivery strategy for cancer therapy.

Sexual orientation and characteristics of sexual behaviors among 200 HIV positive male college students in Beijing / 中国学校卫生

Objective@#To understand sexual orientation and characteristics of sexual behaviors related with HIV infection among HIV positive male college students in Beijing and to provide suggestions for development of sexual health education and HIV prevention strategy for student population.@*Methods@#HIV positive male college students diagnosed from 2016 to June 30, 2019 in Beijing were recruited. Questionnaire was used to retrospectively investigate sexual orientation and characteristics of sexual behaviors before HIV infection. Behaviors related to HIV infection were compared between absolutely homosexual and others sexual orientation.@*Results@#The average age of male students firstly identified to be HIV positive was (22.18±2.70) years old, 61.5%(123) of them were undergraduate, 69.5%(139) were not registered permanent residency in Beijing, 38.5%(77) of their interviewed sexual partners were from online chat and 83.0%(166) had homosexual behaviors. Sexual orientation score analysis showed that 50.0% of the participants self identified as exclusively homosexual. Compared with other sexual oriental group, exclusively homosexual group had lower mean age of their HIV infection firstly identified（ t =2.77， P =0.01）, higher rate of Rush use, firstly insertive sexual behavior with male, firstly insertive sexual behavior before 18 years old, sexual partners more than three persons, having regular partners, nonpersistent use of condom, being diagnosed of sexual transmitted disease and the frequency of homosexual behaviors more than 1 time per month （ χ 2=5.15,28.06,4.16,5.34,5.89,7.39,6.68, P <0.05）. Rush users had higher rate of STD diagnosis than non users in exclusively homosexual group ( χ 2=6.26， P =0.01).@*Conclusion@#Risky sexual behaviors associated with HIV infection were higher in exclusively homosexual group then other sexual orientation groups among HIV positive male college students. Family and school should concern with sexual health education byreinforcing health education via network media to improve college students’ awarenees on HIV/AIDS.

A human TRPV1 genetic variant within the channel gating domain regulates pain sensitivity in rodents

Pain signals are relayed to the brain via a nociceptive system, and in rare situations, this nociceptive system contains genetic variants that can limit pain response. Here we questioned whether a human transient receptor potential vanilloid 1 (TRPV1) missense variant causes a resistance to noxious stimuli and further if we can target this region by a cell-permeable peptide as a pain therapeutic. Initially using a computational approach, we identified a human K710N TRPV1 missense variant in an otherwise highly conserved region of mammalian TRPV1. After generating a TRPV1K710N knock-in mouse using CRISPR/Cas9, we discovered the K710N variant reduced capsaicin-induced calcium influx in dorsal root ganglion neurons. The TRPV1K710N rodents also had less acute behavioral response to chemical noxious stimuli and less hypersensitivity to nerve injury-induced pain, while leaving the response to noxious heat intact. Furthermore, blocking this K710 region in wild-type rodents by a cell-penetrating peptide limited acute behavioral responses to noxious stimuli and rescued pain hypersensitivity induced by nerve injury back to baseline. These findings identify K710 TRPV1 as a discrete site crucial for the control of nociception and provides new insights into how to leverage rare genetic variants in humans to uncover fresh strategies for developing pain therapeutics.

Approximation of a melting plateau of large area HTFP cells used for spectral irradiance realization.

This paper adopted an approximation of a melting plateau to solve the problem that temperature data cannot be monitored continuously when measuring the spectral irradiance of a large area tungsten carbide-carbon high-temperature fixed-point blackbody at each measured wavelength. Tests with fully measured curves showed that the method has a rather small deviation from the measured data of 0.017 K maximum, which corresponds to the spectral irradiance deviation of 0.005% at 500 nm. The maximum relative deviation between the Akima fitting method and the measured temperature in terms of spectral irradiance was 0.002%, which was better than -0.067% of a single temperature of 3020.11 K method and 0.026% of a linear interpolation method.

Rush use and related factors among HIV positive young male students in Beijing / 中国学校卫生

Objective@#This study investigated the use of rush and related factors among HIV positive male students in Beijing, and provided suggestions for education and intervention.@*Methods@#Data on HIV positive male students was collected from 2017 to June 30, 2020 in Beijing and analyzed in SPSS 20.0.@*Results@#A total of 200 valid questionnaires were collected. The mean age at HIV diagnosis was (22.18±2.70) years. The rate of using rush was 46.00%. The proportion with homosexual behavior before infection was 92.00%. The results of multivariate analysis showed that meeting sexual partners through the Internet( OR=3.84, 95%CI =1.65-8.96), drinking alcohol( OR=3.26, 95%CI =1.51-7.02), group homosexual behavior( OR=4.84, 95%CI =1.71-13.71), and STD diagnosis ( OR=0.23, 95%CI =1.02-4.87) were associated with the use of rush before infection.@*Conclusion@#The rate of rush use was higher among male students infected with HIV. Government regulation could be strengthened and drug abuse could be prevented through better health education for students.