YAP represses the TEAD-NF-κB complex and inhibits the growth of clear cell renal cell carcinoma.

The Hippo pathway is generally understood to inhibit tumor growth by phosphorylating the transcriptional cofactor YAP to sequester it to the cytoplasm and reduce the formation of YAP-TEAD transcriptional complexes. Aberrant activation of YAP occurs in various cancers. However, we found a tumor-suppressive function of YAP in clear cell renal cell carcinoma (ccRCC). Using cell cultures, xenografts, and patient-derived explant models, we found that the inhibition of upstream Hippo-pathway kinases MST1 and MST2 or expression of a constitutively active YAP mutant impeded ccRCC proliferation and decreased gene expression mediated by the transcription factor NF-κB. Mechanistically, the NF-κB subunit p65 bound to the transcriptional cofactor TEAD to facilitate NF-κB-target gene expression that promoted cell proliferation. However, by competing for TEAD, YAP disrupted its interaction with NF-κB and prompted the dissociation of p65 from target gene promoters, thereby inhibiting NF-κB transcriptional programs. This cross-talk between the Hippo and NF-κB pathways in ccRCC suggests that targeting the Hippo-YAP axis in an atypical manner-that is, by activating YAP-may be a strategy for slowing tumor growth in patients.

Incidence and prognosis of olfactory and gustatory dysfunctions related to SARS-CoV-2 Omicron strain infection in China: A national multicenter survey of 35,566 individuals.

Objective: This cross-sectional study aimed to determine the epidemiology of olfactory and gustatory dysfunctions related to COVID-19 in China. Methods: This study was conducted by 45 tertiary Grade-A hospitals in China. Online and offline questionnaire data were obtained from patients infected with COVID-19 between December 28, 2022, and February 21, 2023. The collected information included basic demographics, medical history, smoking and drinking history, vaccination history, changes in olfactory and gustatory functions before and after infection, and other postinfection symptoms, as well as the duration and improvement status of olfactory and gustatory disorders. Results: Complete questionnaires were obtained from 35,566 subjects. The overall incidence of olfactory and taste dysfunction was 67.75%. Being female or being a cigarette smoker increased the likelihood of developing olfactory and taste dysfunction. Having received four doses of the vaccine or having good oral health or being a alcohol drinker decreased the risk of such dysfunction. Before infection, the average olfactory and taste VAS scores were 8.41 and 8.51, respectively; after infection, they decreased to 3.69 and 4.29 and recovered to 5.83 and 6.55 by the time of the survey. The median duration of dysosmia and dysgeusia was 15 and 12 days, respectively, with 0.5% of patients having symptoms lasting for more than 28 days. The overall self-reported improvement rate was 59.16%. Recovery was higher in males, never smokers, those who received two or three vaccine doses, and those that had never experienced dental health issues, or chronic accompanying symptoms. Conclusions: The incidence of dysosmia and dysgeusia following infection with the SARS-CoV-2 virus is high in China. Incidence and prognosis are influenced by several factors, including sex, SARS-CoV-2 vaccination, history of head-facial trauma, nasal and oral health status, smoking and drinking history, and the persistence of accompanying symptoms.

[Expert consensus on the diagnosis and treatment of respiratory diseases exacerbated by nonsteroidal anti-inflammatory drugs （2024, Chengdu）].

Non-steroidal anti-inflammatory drugs-exacerbated respiratory disease （N-ERD） is a chronic respiratory disease characterized by eosinophilic inflammation, featuring chronic rhinosinusitis （CRS）, asthma, and intolerance to cyclooxygenase 1 （COX-1） inhibitors. The use of these medications can lead to an acute worsening of rhinitis and asthma symptoms. This condition has not yet received sufficient attention in China, with a high rate of misdiagnosis and a lack of related research. The Chinese Rhinology Research Group convened a group of leading young experts in otolaryngology from across the country, based on the latest domestic and international evidence-based medical practices to formulate this consensus.The consensus covers the epidemiology, pathogenesis, clinical manifestations, diagnostic methods, and treatment strategies for N-ERD, including pharmacotherapy, surgery, biologic treatments, and desensitization therapy. The goal is to improve recognition of N-ERD, reduce misdiagnosis, and enhance treatment outcomes.

Mitochondrial transfer of α-synuclein mediates carbon disulfide-induced mitochondrial dysfunction and neurotoxicity.

Exposure to carbon disulfide (CS2) is a recognized risk factor in the pathogenesis of Parkinson's disease, yet the underlying mechanisms of deleterious effects on mitochondrial integrity have remained elusive. Here, through establishing CS2 exposure models in rat and SH-SY5Y cells, we demonstrated that highly expressed α-synuclein (α-Syn) is transferred to mitochondria via membrane proteins such as Tom20 and leads to mitochondrial dysfunction and mitochondrial oxidative stress, which ultimately causes neuronal injury. We first found significant mitochondrial damage and oxidative stress in CS2-exposed rat midbrain and SH-SY5Y cells and showed that mitochondrial oxidative stress was the main factor of mitochondrial damage by Mitoquinone intervention. Further experiments revealed that CS2 exposure led to the accumulation of α-Syn in mitochondria and that α-Syn co-immunoprecipitated with mitochondrial membrane proteins. Finally, the use of an α-Syn inhibitor (ELN484228) and small interfering RNA (siRNA) effectively mitigated the accumulation of α-Syn in neurons, as well as the inhibition of mitochondrial membrane potential, caused by CS2 exposure. In conclusion, our study identifies the translocation of α-Syn to mitochondria and the impairment of mitochondrial function, which has important implications for the broader understanding and treatment of neurodegenerative diseases associated with environmental toxins.

Rational Design of a Yeast-derived 3',5'-bisphosphate Nucleotidase with Improved Substrate Specificity.

In recent years, a convenient phosphatase-coupled sulfotransferase assay method has been proven to be applicable to most sulfotransferases. The central principle of the method is that phosphatase specifically degrades 3'-phosphoadenosine-5'-phosphate (PAP) and leaves 3'-phosphoadenosine-5'-phosphosulfate (PAPS). Our group previously acquired a yeast 3',5'-bisphosphate nucleotidase (YND), which showed a higher catalytic activity for PAP than PAPS and could be a potential phosphatase for the sulfotransferase assay. Here, we obtained a beneficial mutant of YND with markedly improved substrate specificity towards PAP via rational design. Of 9 chosen mutation sites in the active site pocket, the mutation G236D showed the best specificity for PAP. After optimization of the reaction conditions, the mutant YNDG236D displayed a 4.8-fold increase in the catalytic ratio PAP/PAPS compared to the wild-type. We subsequently applied YNDG236D to the assay of human SULT1A1 and SULT1A3 with their known substrate 1-naphthol, indicating that the mutant could be used to evaluate sulfotransferase activity by colorimetry. Analysis of the MD simulation results revealed that the improved substrate specificity of the mutant towards PAP may stem from a more stable protein conformation and the changed flexibility of key residues in the entrance of the substrate tunnel. This research will provide a valuable reference for the development of efficient sulfotransferase activity assays.

The Combination of Lactoferrin and Creatine Ameliorates Muscle Decay in a Sarcopenia Murine Model.

BACKGROUND: Sarcopenia is an age-related condition characterized by progressive loss of muscle mass, strength, and function. The occurrence of sarcopenia has a huge impact on physical, psychological, and social health. Therefore, the prevention and treatment of sarcopenia is becoming an important public health issue. METHOD: 35 six-week-old male C57BL/6 mice were randomly divided into five groups, one of which served as a control group, while the rest of the groups were constructed as a model of sarcopenia by intraperitoneal injection of D-galactose. The intervention with lactoferrin, creatine, and their mixtures, respectively, was carried out through gavage for 8 weeks. Muscle function was assessed based on their endurance, hanging time, and grip strength. The muscle tissues were weighed to assess the changes in mass, and the muscle RNA was extracted for myogenic factor expression and transcriptome sequencing to speculate on the potential mechanism of action by GO and KEGG enrichment analysis. RESULT: The muscle mass (lean mass, GAS index), and muscle function (endurance, hanging time, and grip strength) decreased, and the size and structure of myofiber was smaller in the model group compared to the control group. The intervention with lactoferrin and creatine, either alone or combination, improved muscle mass and function, restored muscle tissue, and increased the expression of myogenic regulators. The combined group demonstrated the most significant improvement in these indexes. The RNA-seq results revealed enrichment in the longevity-regulated pathway, MAPK pathway, focal adhesion, and ECM-receptor interaction pathway in the intervention group. The intervention group may influence muscle function by affecting the proliferation, differentiation, senescence of skeletal muscle cell, and contraction of muscle fiber. The combined group also enriched the mTOR-S6K/4E-BPs signaling pathway, PI3K-Akt signaling pathway, and energy metabolism-related pathways, including Apelin signaling, insulin resistance pathway, and adipocytokine signaling pathway, which affect energy metabolism in muscle. CONCLUSIONS: Lactoferrin and creatine, either alone or in combination, were found to inhibit the progression of sarcopenia by influencing the number and cross-sectional area of muscle fibers and muscle protein synthesis. The combined intervention appears to exert a more significant effect on energy metabolism.

Identification of the New GmJAG1 Transcription Factor Binding Motifs Using DAP-Seq.

Interaction between transcription factors (TFs) and motifs is essential for gene regulation and the subsequent phenotype formation. Soybean (Glycine max) JAGGEED 1 (GmJAG1) is a key TF that controls leaf shape, seed number and flower size. To understand the GmJAG1 binding motifs, in this study, we performed the GmJAG1 DNA affinity purification sequencing (DAP-seq) experiment, which is a powerful tool for the de novo motif prediction method. Two new significant GmJAG1 binding motifs were predicted and the EMSA experiments further verified the ability of GmJAG1 bound to these motifs. The potential binding sites in the downstream gene promoter were identified through motif scanning and a potential regulatory network mediated by GmJAG1 was constructed. These results served as important genomic resources for further understanding the regulatory mechanism of GmJAG1.

Restoring BARX2 in OSCC reverses partial EMT and suppresses metastasis through miR-186-5p/miR-378a-3p-dependent SERPINE2 inhibition.

Tumor cells undergoing partial epithelial-mesenchymal transition (pEMT) are pivotal in local invasion and lymphatic metastasis of oral squamous cell carcinoma (OSCC), yet the mechanisms behind pEMT reversal remain poorly understood. In this study, the loss of BARX2 expression was revealed during the process of oral epithelial carcinogenesis and identified to activate the pEMT program, facilitate metastasis, and be associated with poor prognosis. Restoring BARX2 expression in OSCC cell lines effectively reversed tumor pEMT, evident in E/N-Cadherin switching, reduced cell invasion, proliferation, and stemness, and inhibited murine lung metastasis. BARX2 re-expression negatively correlated with several pEMT markers, notably SERPINE2, which was enriched in the invasive OSCC front, enhancing stemness and promoting metastasis, particularly in cervical lymph nodes. Furthermore, rescuing SERPINE2 impaired the inhibitory effect of BARX2 on the pEMT programs and reconstructed ECM through re-expression of MMP1. Mechanistically, we identified that BARX2 inhibited SERPINE2 through activating miR-186-5p and miR-378a-3p. These miRNAs, upregulated by BARX2, post-transcriptionally degraded SERPINE2 mRNA via targeting specific sequences. Blocking miR-186-5p and miR-378a-3p effectively abolished the negative regulatory effect of BARX2 on SERPINE2. Overall, our findings highlight BARX2 as a partial EMT-reverser in OSCC, providing fresh therapeutic prospects for restoring BARX2 signaling to inhibit invasion and metastasis.

Exploring the association between Frailty Index and low back pain in middle-aged and older Chinese adults: a cross-sectional analysis of data from the China Health and Retirement Longitudinal Study (CHARLS).

OBJECTIVES: This study explored the association between the Frailty Index (FI) and low back pain (LBP) in middle-aged and older Chinese adults. We hypothesised that a higher FI correlates with increased LBP prevalence. DESIGN: Cross-sectional analysis. SETTING: The study used data from the China Health and Retirement Longitudinal Study (CHARLS) across various regions of China. PARTICIPANTS: The analysis included 6375 participants aged 45 and above with complete LBP and FI data from the CHARLS for 2011, 2013 and 2015. We excluded individuals under 45, those with incomplete LBP data, participants with fewer than 30 health deficit items and those missing covariate data. OUTCOME MEASURES: We constructed an FI consisting of 35 health deficits. Logistic multivariable regression examined the relationship between FI and LBP, using threshold analysis to identify inflection points. Sensitivity analyses were performed to ensure the robustness of the findings. RESULTS: Of the participants, 27.2% reported LBP. A U-shaped association was observed between FI and LBP, with the highest quartile (Q4, FI ≥0.23) showing more than a twofold increased risk of LBP (OR=2.90, 95% CI: 2.45-3.42, p<0.001). Stratified analysis showed a significant association in participants under 60, particularly in the lowest FI quartile (OR=1.43, 95% CI: 1.14 to 1.79). Sensitivity analysis upheld the robustness of the primary results. CONCLUSIONS: The findings suggest a complex relationship between frailty and LBP, highlighting the need for early screening and tailored interventions to manage LBP in this demographic. Further research is necessary to understand the mechanisms of this association and to validate the findings through longitudinal studies.

Roles of Nuclear Orphan Receptors TR2 and TR4 during Hematopoiesis.

TR2 and TR4 (NR2C1 and NR2C2, respectively) are evolutionarily conserved nuclear orphan receptors capable of binding direct repeat sequences in a stage-specific manner. Like other nuclear receptors, TR2 and TR4 possess important roles in transcriptional activation or repression with developmental stage and tissue specificity. TR2 and TR4 bind DNA and possess the ability to complex with available cofactors mediating developmental stage-specific actions in primitive and definitive erythrocytes. In erythropoiesis, TR2 and TR4 are required for erythroid development, maturation, and key erythroid transcription factor regulation. TR2 and TR4 recruit and interact with transcriptional corepressors or coactivators to elicit developmental stage-specific gene regulation during hematopoiesis.

Characterization and quantitation of a sulfoconjugated metabolite for detection of methyltestosterone misuse and direct identification by LC-MS.

Methyltestosterone (MT) is one of the most frequently misused anabolic androgenic steroids detected in doping control analysis. The metabolism of MT in humans leads to several phase І metabolites and their corresponding phase Ⅱ conjugates. Previous studies have postulated the 3α-sulfoconjugate of 17α-methyl-5ß-androstane-3α,17ß-diol (S2) as principal sulfate metabolite of MT, with a detection window exceeding 10 days. However, a final direct and unambiguous confirmation of the structure of this metabolite is missing until now. In this study, we established an approach to detect and identify S2, using intact analysis by liquid chromatography hyphenated with tandem mass spectrometry (LC-MS/MS) without complex sample pretreatment. An in vitro study yielded the LC-MS/MS reference retention times of all 3-sulfated 17-methylandrostane-3,17-diol diastereomers, allowing for accurate structure assignment of potentially detected metabolites. In an in vivo excretion study with a single healthy male volunteer, the presence of the metabolite S2 was confirmed after a single oral dose of 10 mg MT. The reference standard was chemically synthesized, characterized by accurate mass mass spectrometry (MS) and nuclear magnetic resonance (NMR), and quantified by quantitative NMR (qNMR). Thus, this study finally provides accurate structure information on the S2 metabolite and a direct analytical method for detection of MT misuse. The availability of the reference material is expected to facilitate further evaluation and subsequent analytical method validation in anti-doping research.

A rare complex structural variant of novel intragenic inversion combined with reciprocal translocation t(X;1)(p21.2;p13.3) in Duchenne muscular dystrophy.

Structural variants (SVs) are infrequently observed in Duchenne muscular dystrophy (DMD), a condition mainly marked by deletions and point mutations in the DMD gene. SVs in DMD remain difficult to reliably detect due to the limited SV-detection capacity of conventionally used short-read sequencing technology. Herein, we present a family, a boy and his mother, with clinical signs of muscular dystrophy, elevated creatinine kinase levels, and intellectual disability. A muscle biopsy from the boy showed dystrophin deficiency. Routine molecular techniques failed to detect abnormalities in the DMD gene, however, dystrophin mRNA transcripts analysis revealed an absence of exons 59 to 79. Subsequent long-read whole-genome sequencing identified a rare complex structural variant, a 77 kb novel intragenic inversion, and a balanced translocation t(X;1)(p21.2;p13.3) rearrangement within the DMD gene, expanding the genetic spectrum of dystrophinopathy. Our findings suggested that SVs should be considered in cases where conventional molecular techniques fail to identify pathogenic variants.

Association of healthy lifestyle with self-reported sleep disordered breathing: A cross-sectional study.

Some healthy lifestyle components have been linked with sleep disordered breathing (SDB), yet little is known about the relationship between comprehensive lifestyle factors and SDB. This study aimed to examine the healthy lifestyle with SDB in community-dwelling adults. We conducted a cross-sectional analysis of the Suzhou Food Consumption and Health Survey in China between 2018 and 2020. The healthy lifestyle index (HLI) was created by combining smoking, alcohol drinking, diet, physical activity, and body mass index (BMI). Its association with SDB was assessed by multiple logistic regression analysis. Subgroup analysis and sensitivity analysis were conducted to assess the robustness of our results. The final analysis included 3788 participants (2859 without SDB and 929 with SDB). In multivariable-adjusted analyses, non-smoking (OR: 0.58, 95 % CI: 0.47-0.71), non-drinking (OR: 0.55, 95 % CI: 0.45-0.68), healthy diet (OR: 0.79, 95 % CI: 0.65-0.95), and healthy BMI (OR: 0.72, 95 % CI: 0.6-0.86) were associated with SDB. Compared with participants with HLI score of 0-1, participants with HLI score of 2, 3, 4, and 5 had OR of 0.68 (95 % CI: 0.51-0.91), 0.49 (95 % CI: 0.37-0.64), 0.29 (95 % CI: 0.21-0.38), and 0.22 (95 % CI: 0.15-0.33), respectively, after adjustment for confounding factors (P-trend<0.001). An inverse dose-response relationship between HLI and SDB was also observed. The association was similar in subgroups stratified by sex, marital status, diabetes and dyslipidemia. A higher score of HLI was associated with reduced odds of SDB in Chinese adults. Our findings suggest the potential of addressing five modifiable lifestyle factors for the prevention of SDB.

Acquired amusia after a right middle cerebral artery infarction - a case study.

A 62-year-old musician-MM-developed amusia after a right middle-cerebral-artery infarction. Initially, MM showed melodic deficits while discriminating pitch-related differences in melodies, musical memory problems, and impaired sensitivity to tonal structures, but normal pitch discrimination and spectral resolution thresholds, and normal cognitive and language abilities. His rhythmic processing was intact when pitch variations were removed. After 3 months, MM showed a large improvement in his sensitivity to tonality, but persistent melodic deficits and a decline in perceiving the metric structure of rhythmic sequences. We also found visual cues aided melodic processing, which is novel and beneficial for future rehabilitation practice.

In situ densification and heparin immobilization of bacterial cellulose vascular patch for potential vascular applications.

Nowadays, developing vascular grafts (e.g., vascular patches and tubular grafts) is challenging. Bacterial cellulose (BC) with 3D fibrous network has been widely investigated for vascular applications. In this work, different from BC vascular patch cultured with the routine culture medium, dopamine (DA)-containing culture medium is employed to in situ synthesize dense BC fibrous structure with significantly increased fiber diameter and density. Simultaneously, BC fibers are modified by DA during in situ synthesis process. Then DA on BC fibers can self-polymerize into polydopamine (PDA) accompanied with the removal of bacteria in NaOH solution, obtaining PDA-modified dense BC (PDBC) vascular patch. Heparin (Hep) is subsequently covalently immobilized on PDBC fibers to form Hep-immobilized PDBC (Hep@PDBC) vascular patch. The obtained results indicate that Hep@PDBC vascular patch exhibits remarkable tensile and burst strength due to its dense fibrous structure. More importantly, compared with BC and PDBC vascular patches, Hep@PDBC vascular patch not only displays reduced platelet adhesion and improved anticoagulation activity, but also promotes the proliferation, adhesion, spreading, and protein expression of human umbilical vein endothelial cells, contributing to the endothelialization process. The combined strategy of in situ densification and Hep immobilization provides a feasible guidance for the construction of BC-based vascular patches.

Particle size effect on surface/interfacial tension and Tolman length of nanomaterials: A simple experimental method combining with theoretical.

Surface tension and interfacial tension are crucial to the study of nanomaterials. Herein, we report a solubility method using magnesium oxide nanoparticles of different radii (1.8-105.0 nm, MgO NPs) dissolved in pure water as a targeted model; the surface tension and interfacial tension (and their temperature coefficients) were determined by measuring electrical conductivity and combined with the principle of the electrochemical equilibrium method, and the problem of particle size dependence is discussed. Encouragingly, this method can also be used to determine the ionic (atomic or molecular) radius and Tolman length of nanomaterials. This research results disclose that surface/interfacial tension and their temperature coefficients have a significant relationship with particle size. Surface/interfacial tension decreases rapidly with a radius <10 nm (while the temperature coefficients are opposite), while for a radius >10 nm, the effect is minimal. Especially, it is proven that the value of Tolman length is positive, the effect of particle size on Tolman length is consistent with the surface/interfacial tension, and the Tolman length of the bulk does not change much in the temperature range. This work initiates a new era for reliable determination of surface/interfacial tension, their temperature coefficients, ionic radius, and Tolman length of nanomaterials and provides an important theoretical basis for the development and application of various nanomaterials.

Manual Therapy in Primary Dysmenorrhea: A Systematic Review and Meta-Analysis.

Objective: This research aimed to assess the effectiveness of manual therapy in alleviating pain among women undergoing primary dysmenorrhea (PD). Methods: All randomized controlled trials (RCTs) regarding manual therapy for PD were searched from online databases, spanning from their inception to July 2023. The identified literature underwent a thorough screening process, and the data were meticulously extracted and analyzed using RevMan 5.3. Subsequently, the included studies underwent Cochrane's quality assessment and meta-analysis. The evidence obtained was then assessed using the grading of recommendations, assessment, development, and evaluation (GRADE) approach. Results: 32 RCTs, involving 2566 women were finally included for analysis. The overall quality of the concluding evidence was generally rated as low or very low. Performance bias and blind bias were found to be the main risk of bias of the included studies. In comparison to no treatment, manual therapy demonstrated a significant increase in pain relief in short-term (n=191, MD=1.30, 95% CI: 0.24~2.37). The differences in the effects of manual therapy and the placebo on pain intensity may not be statistically significant (n=255, MD=0.10, 95% CI: -0.37~0.58). In contrast to NSAIDs, manual therapy exhibited superior pain alleviation (n=507, MD=3.01, 95% CI: 1.08~4.94) and a higher effective rate (n=1029, OR=4.87, 95% CI: 3.29~7.20). Importantly, no severe adverse events were reported across all studies, indicating a relatively safe profile for manual therapy. Conclusion: Manual therapy presented promise in effectively relieving menstrual pain with minimal adverse events in short term, outperforming both no treatment and NSAIDs. However, this conclusion is tempered by the low quality of the included RCTs, highlighting the necessity for more robust trials to validate it.

Panax quinquefolius saponins and panax notoginseng saponins attenuate myocardial hypoxia-reoxygenation injury by reducing excessive mitophagy.

OBJECTIVE: Panax quinquefolius saponins (PQS) and Panax notoginseng saponins (PNS) are key bioactive compounds in Panax quinquefolius L. and Panax notoginseng, commonly used in the treatment of clinical ischemic heart disease. However, their potential in mitigating myocardial ischemia-reperfusion injury remains uncertain. This study aims to evaluate the protective effects of combined PQS and PNS administration in myocardial hypoxia/reoxygenation (H/R) injury and explore the underlying mechanisms. METHODS: To investigate the involvement of HIF-1α/BNIP3 mitophagy pathway in the myocardial protection conferred by PNS and PQS, we employed small interfering BNIP3 (siBNIP3) to silence key proteins of the pathway. H9C2 cells were categorized into four groups: control, H/R, H/R + PQS + PNS, and H/R + PQS + PNS+siBNIP3. Cell viability was assessed by Cell Counting Kit-8, apoptosis rates determined via flow cytometry, mitochondrial membrane potential assessed with the JC-1 fluorescent probes, intracellular reactive oxygen species detected with 2',7'-dichlorodihydrofluorescein diacetate, mitochondrial superoxide production quantified with MitoSOX Red, and autophagic flux monitored with mRFP-GFP-LC3 adenoviral vectors. Autophagosomes and their ultrastructure were visualized through transmission electron microscopy. Moreover, mRNA and protein levels were analyzed via real-time PCR and Western blotting. RESULTS: PQS + PNS administration significantly increased cell viability, reduced apoptosis, lowered reactive oxygen species levels and mitochondrial superoxide production, mitigated mitochondrial dysfunction, and induced autophagic flux. Notably, siBNIP3 intervention did not counteract the cardioprotective effect of PQS + PNS. The PQS + PNS group showed downregulated mRNA expression of HIF-1α and BNIP3, along with reduced HIF-1α protein expression compared to the H/R group. CONCLUSIONS: PQS + PNS protects against myocardial H/R injury, potentially by downregulating mitophagy through the HIF-1α/BNIP3 pathway.

Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.

BACKGROUND: The ubiquitin-proteasome system regulates protein degradation and the development of pulmonary arterial hypertension (PAH), but knowledge about the role of deubiquitinating enzymes in this process is limited. UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), a deubiquitinase, has been shown to reduce AKT1 (AKT serine/threonine kinase 1) degradation, resulting in higher levels. Given that AKT1 is pathological in pulmonary hypertension, we hypothesized that UCHL1 deficiency attenuates PAH development by means of reductions in AKT1. METHODS: Tissues from animal pulmonary hypertension models as well as human pulmonary artery endothelial cells from patients with PAH exhibited increased vascular UCHL1 staining and protein expression. Exposure to LDN57444, a UCHL1-specific inhibitor, reduced human pulmonary artery endothelial cell and smooth muscle cell proliferation. Across 3 preclinical PAH models, LDN57444-exposed animals, Uchl1 knockout rats (Uchl1-/-), and conditional Uchl1 knockout mice (Tie2Cre-Uchl1fl/fl) demonstrated reduced right ventricular hypertrophy, right ventricular systolic pressures, and obliterative vascular remodeling. Lungs and pulmonary artery endothelial cells isolated from Uchl1-/- animals exhibited reduced total and activated Akt with increased ubiquitinated Akt levels. UCHL1-silenced human pulmonary artery endothelial cells displayed reduced lysine(K)63-linked and increased K48-linked AKT1 levels. RESULTS: Supporting experimental data, we found that rs9321, a variant in a GC-enriched region of the UCHL1 gene, is associated with reduced methylation (n=5133), increased UCHL1 gene expression in lungs (n=815), and reduced cardiac index in patients (n=796). In addition, Gadd45α (an established demethylating gene) knockout mice (Gadd45α-/-) exhibited reduced lung vascular UCHL1 and AKT1 expression along with attenuated hypoxic pulmonary hypertension. CONCLUSIONS: Our findings suggest that UCHL1 deficiency results in PAH attenuation by means of reduced AKT1, highlighting a novel therapeutic pathway in PAH.

Antimicrobial susceptibility and genomic characterization of Vibrio parahaemolyticus isolated from aquatic foods in 15 provinces, China, 2020.

Prevalent in marine, estuarine and coastal environments, Vibrio parahaemolyticus is one of the major foodborne pathogens which can cause acute gastroenteritis through consumption of contaminated food. This study encompassed antimicrobial resistance, molecular characteristics and phylogenetic relationships of 163 V. parahaemolyticus isolated from aquatic foods across 15 provinces in China. The isolates showed high resistance rates against ampicillin (90.80 %, 148/163) and cefazolin (72.39 %, 118/163). Only 5 isolates demonstrated multi-drug resistance (MDR) phenotypes. A total of 37 different antibiotic resistance genes (ARGs) in correlation with seven antimicrobial categories were identified. tet(34) and tet(35) were present in all 163 isolates. Other most prevalent ARGs were those conferring resistance to ß-lactams, with prevalence rate around 18.40 % (30/163). The virulence genes tdh and trh were found in 17 (10.43 %) and 9 (5.52 %) isolates, respectively. Totally 121 sequence types (STs) were identified through whole genome analysis, among which 60 were novel. The most prevalent sequence type was ST3 (9.20 %, 15/163), which shared the same genotype profile of trh_, tdh+ and blaCARB-22+. Most of the tdh+V. parahaemolyticus isolates was clustered into a distinctive clade by the phylogenetic analysis. Our study showed that the antimicrobial resistance of V. parahaemolyticus in aquatic foods in China was moderate. However, the emerging of MDR isolates implicate strengthened monitoring is needed for the better treatment of human V. parahaemolyticus infections. High genetic diversity and virulence potential of the isolates analyzed in this study help better understanding and evaluating the risk of V. parahaemolyticus posed to public health.