Conserved class B GPCR activation by a biased intracellular agonist.

Class B G-protein-coupled receptors (GPCRs), including glucagon-like peptide 1 receptor (GLP1R) and parathyroid hormone 1 receptor (PTH1R), are important drug targets1-5. Injectable peptide drugs targeting these receptors have been developed, but orally available small-molecule drugs remain under development6,7. Here we report the high-resolution structure of human PTH1R in complex with the stimulatory G protein (Gs) and a small-molecule agonist, PCO371, which reveals an unexpected binding mode of PCO371 at the cytoplasmic interface of PTH1R with Gs. The PCO371-binding site is totally different from all binding sites previously reported for small molecules or peptide ligands in GPCRs. The residues that make up the PCO371-binding pocket are conserved in class B GPCRs, and a single alteration in PTH2R and two residue alterations in GLP1R convert these receptors to respond to PCO371. Functional assays reveal that PCO371 is a G-protein-biased agonist that is defective in promoting PTH1R-mediated arrestin signalling. Together, these results uncover a distinct binding site for designing small-molecule agonists for PTH1R and possibly other members of the class B GPCRs and define a receptor conformation that is specific only for G-protein activation but not arrestin signalling. These insights should facilitate the design of distinct types of class B GPCR small-molecule agonist for various therapeutic indications.

Au-Pd separation enhances bimetallic catalysis of alcohol oxidation.

In oxidation reactions catalysed by supported metal nanoparticles with oxygen as the terminal oxidant, the rate of the oxygen reduction can be a limiting factor. This is exemplified by the oxidative dehydrogenation of alcohols, an important class of reactions with modern commercial applications1-3. Supported gold nanoparticles are highly active for the dehydrogenation of the alcohol to an aldehyde4 but are less effective for oxygen reduction5,6. By contrast, supported palladium nanoparticles offer high efficacy for oxygen reduction5,6. This imbalance can be overcome by alloying gold with palladium, which gives enhanced activity to both reactions7,8,9; however, the electrochemical potential of the alloy is a compromise between that of the two metals, meaning that although the oxygen reduction can be improved in the alloy, the dehydrogenation activity is often limited. Here we show that by separating the gold and palladium components in bimetallic carbon-supported catalysts, we can almost double the reaction rate compared with that achieved with the corresponding alloy catalyst. We demonstrate this using physical mixtures of carbon-supported monometallic gold and palladium catalysts and a bimetallic catalyst comprising separated gold and palladium regions. Furthermore, we demonstrate electrochemically that this enhancement is attributable to the coupling of separate redox processes occurring at isolated gold and palladium sites. The discovery of this catalytic effect-a cooperative redox enhancement-offers an approach to the design of multicomponent heterogeneous catalysts.

CD147 Sparks Atherosclerosis by Driving M1 Phenotype and Impairing Efferocytosis.

BACKGROUND: Atherosclerosis is a globally prevalent chronic inflammatory disease with high morbidity and mortality. The development of atherosclerotic lesions is determined by macrophages. This study aimed to investigate the specific role of myeloid-derived CD147 (cluster of differentiation 147) in atherosclerosis and its translational significance. METHODS AND RESULTS: We generated mice with a myeloid-specific knockout of CD147 and mice with restricted CD147 overexpression, both in an apoE-deficient (ApoE-/-) background. Here, the myeloid-specific deletion of CD147 ameliorated atherosclerosis and inflammation. Consistent with our in vivo data, macrophages isolated from myeloid-specific CD147 knockout mice exhibited a phenotype shift from proinflammatory to anti-inflammatory macrophage polarization in response to lipopolysaccharide/IFN (interferon)-γ. These macrophages demonstrated a weakened proinflammatory macrophage phenotype, characterized by reduced production of NO and reactive nitrogen species derived from iNOS (inducible NO synthase). Mechanistically, the TRAF6 (tumor necrosis factor receptor-associated factor 6)-IKK (inhibitor of κB kinase)-IRF5 (IFN regulatory factor 5) signaling pathway was essential for the effect of CD147 on proinflammatory responses. Consistent with the reduced size of the necrotic core, myeloid-specific CD147 deficiency diminished the susceptibility of iNOS-mediated late apoptosis, accompanied by enhanced efferocytotic capacity mediated by increased secretion of GAS6 (growth arrest-specific 6) in proinflammatory macrophages. These findings were consistent in a mouse model with myeloid-restricted overexpression of CD147. Furthermore, we developed a new atherosclerosis model in ApoE-/- mice with humanized CD147 transgenic expression and demonstrated that the administration of an anti-human CD147 antibody effectively suppressed atherosclerosis by targeting inflammation and efferocytosis. CONCLUSIONS: Myeloid CD147 plays a crucial role in the growth of plaques by promoting inflammation in a TRAF6-IKK-IRF5-dependent manner and inhibiting efferocytosis by suppressing GAS6 during proinflammatory conditions. Consequently, the use of anti-human CD147 antibodies presents a complementary therapeutic approach to the existing lipid-lowering strategies for treating atherosclerotic diseases.

Caught in the crossfire: Fears of Chinese-American scientists.

The US global leadership in science and technology has greatly benefitted from immigrants from other countries, most notably from China in the recent decades. However, feeling the pressure of potential federal investigations since the 2018 launch of the China Initiative, scientists of Chinese descent in the United States now face higher incentives to leave the United States and lower incentives to apply for federal grants. Analyzing data pertaining to institutional affiliations of more than 200 million scientific papers, we find a steady increase in the return migration of scientists of Chinese descent from the United States to China. We also conducted a survey of scientists of Chinese descent employed by US universities in tenured or tenure-track positions (n = 1,304), with results revealing general feelings of fear and anxiety that lead them to consider leaving the United States and/or stop applying for federal grants. If the situation is not corrected, American science will likely suffer the loss of scientific talent to China and other countries.

Pathogenicity, tissue tropism and potential vertical transmission of SARSr-CoV-2 in Malayan pangolins.

Malayan pangolin SARS-CoV-2-related coronavirus (SARSr-CoV-2) is closely related to SARS-CoV-2. However, little is known about its pathogenicity in pangolins. Using CT scans we show that SARSr-CoV-2 positive Malayan pangolins are characterized by bilateral ground-glass opacities in lungs in a similar manner to COVID-19 patients. Histological examination and blood gas tests are indicative of dyspnea. SARSr-CoV-2 infected multiple organs in pangolins, with the lungs the major target, and histological expression data revealed that ACE2 and TMPRSS2 were co-expressed with viral RNA. Transcriptome analysis indicated that virus-positive pangolins were likely to have inadequate interferon responses, with relative greater cytokine and chemokine activity in the lung and spleen. Notably, both viral RNA and viral proteins were detected in three pangolin fetuses, providing initial evidence for vertical virus transmission. In sum, our study outlines the biological framework of SARSr-CoV-2 in pangolins, revealing striking similarities to COVID-19 in humans.

Methane Oxidation to Methanol.

The direct transformation of methane to methanol remains a significant challenge for operation at a larger scale. Central to this challenge is the low reactivity of methane at conditions that can facilitate product recovery. This review discusses the issue through examination of several promising routes to methanol and an evaluation of performance targets that are required to develop the process at scale. We explore the methods currently used, the emergence of active heterogeneous catalysts and their design and reaction mechanisms and provide a critical perspective on future operation. Initial experiments are discussed where identification of gas phase radical chemistry limited further development by this approach. Subsequently, a new class of catalytic materials based on natural systems such as iron or copper containing zeolites were explored at milder conditions. The key issues of these technologies are low methane conversion and often significant overoxidation of products. Despite this, interest remains high in this reaction and the wider appeal of an effective route to key products from C-H activation, particularly with the need to transition to net carbon zero with new routes from renewable methane sources is exciting.

CD160 Signaling Is Essential for CD8+ T Cell Memory Formation via Upregulation of 4-1BB.

A better understanding of the regulatory mechanisms governing the development of memory CD8+ T cells could provide instructive insights into vaccination strategies and T cell-based immunotherapies. In this article, we showed that CD160 surface protein is required for CD8+ T cell memory formation. In the response to acute lymphocytic choriomeningitis virus infection in a mouse model, CD160 ablation resulted in the failure of the development of all three memory CD8+ T cell subsets (central, effective, and tissue-resident memory), concomitant with a skewed differentiation into short-lived effector T cells. Such memory-related defect was manifested by a diminished protection from viral rechallenge. Mechanistically, CD160 deficiency led to downregulation of 4-1BB in activated CD8+ T cells, which contributes to the impaired cell survival and decreased respiratory capacity. The nexus between CD160 and 4-1BB was substantiated by the observation that ectopic introduction of 4-1BB was able to largely complement the loss of CD160 in memory CD8+ T cell development. Collectively, our studies discovered that CD160, once thought to be a coinhibitor of T cell signaling, is an essential promoter of memory CD8+ T cell development via activation of the costimulatory molecule 4-1BB.

The moral filter of patriotic prejudice: How Americans view Chinese in the COVID-19 era.

About one in six Asian Americans have fallen victim to anti-Asian racism during the COVID-19 pandemic [J. Lee, K. Ramakrishnan, aapidata.com/blog/discrimination-survey-2022/]. By examining anti-Asian racism in the United States primarily as a domestic issue, most prior studies have overlooked the connections between shifting US-China relations and Americans' prejudices against the Chinese in China and, by extension, East Asian Americans. This study investigates the patterns and perceptual bases of nationality-based prejudices against Chinese amid the COVID-19 pandemic in the United States. Our nationally representative online survey experiment reveals that Americans assess a hypothetical Chinese person in China as inferior in multiple social and psychological characteristics to an otherwise identical Japanese person in Japan or East Asian American. Furthermore, subjects who perceive China as more threatening to America's national interests assess Chinese more negatively, especially in terms of trustworthiness and morality, suggesting that perceived China threats propel Americans' negative stereotypes about Chinese. A contextual analysis further indicates that counties with a higher share of Trump voters in 2016 tend to perceive all East Asian-origin groups similarly as a racial outgroup. By contrast, residents in predominantly Democrat-voting counties tend to perceive Chinese in China more negatively relative to Asian Americans, despite broadly viewing East Asians more favorably. Overall, this study underscores the often-overlooked relationships between the prevailing anti-Asian sentiments in the United States and the US-China geopolitical tensions and America's domestic political polarization.

The Investigation of Neuromimetic Dynamics in Ferroelectrics via In Situ TEM.

The core task of neuromorphic devices is to effectively simulate the behavior of neurons and synapses. Based on the functionality of ferroelectric domains with the advantages of low power consumption and high-speed response, great progress has been made in realizing neuromimetic behaviors such as ferroelectric synaptic devices. However, the correlation between the ferroelectric domain dynamics and neuromimetic behavior remains unclear. Here, we reveal the correlation between domain/domain wall dynamics and neuromimetic behaviors from a microscopic perspective in real-time by using high temporal and spatial resolution in situ transmission electron microscopy. Furthermore, we propose utilizing ferroelectric microstructures for the simultaneous simulation of neuronal and synaptic plasticity, which is expected to improve the integration and performance of ferroelectric neuromorphic devices. We believe that this work to study neuromimetic behavior from the perspective of domain dynamics is instructive for the development of ferroelectric neuromorphic devices.

Combined Proteomic and Phosphoproteomic Characterization of the Molecular Regulators and Functional Modules During Pancreatic Progenitor Cell Development.

Differentiated multipotent pancreatic progenitors have major advantages for both modeling pancreas development and preventing or treating diabetes. Despite significant advancements in inducing the differentiation of human pluripotent stem cells into insulin-producing cells, the complete mechanism governing proliferation and differentiation remains poorly understood. This study used large-scale mass spectrometry to characterize molecular processes at various stages of human embryonic stem cell (hESC) differentiation toward pancreatic progenitors. hESCs were induced into pancreatic progenitor cells in a five-stage differentiation protocol. A high-performance liquid chromatography-mass spectrometry platform was used to undertake comprehensive proteome and phosphoproteome profiling of cells at different stages. A series of bioinformatic explorations, including coregulated modules, gene regulatory networks, and phosphosite enrichment analysis, were then conducted. A total of 27,077 unique phosphorylated sites and 8122 proteins were detected, including several cyclin-dependent kinases at the initial stage of cell differentiation. Furthermore, we discovered that ERK1, a member of the MAPK cascade, contributed to proliferation at an early stage. Finally, Western blotting confirmed that the phosphosites from SIRT1 and CHEK1 could inhibit the corresponding substrate abundance in the late stage. Thus, this study extends our understanding of the molecular mechanism during pancreatic cell development.

Cascade Dual Sites Modulate Local CO Coverage and Hydrogen-Binding Strength to Boost CO2 Electroreduction to Ethylene.

Rationally modulating the binding strength of reaction intermediates on surface sites of copper-based catalysts could facilitate C-C coupling to generate multicarbon products in an electrochemical CO2 reduction reaction. Herein, theoretical calculations reveal that cascade Ag-Cu dual sites could synergistically increase local CO coverage and lower the kinetic barrier for CO protonation, leading to enhanced asymmetric C-C coupling to generate C2H4. As a proof of concept, the Cu3N-Ag nanocubes (NCs) with Ag located in partial Cu sites and a Cu3N unit center are successfully synthesized. The Faraday efficiency and partial current density of C2H4 over Cu3N-Ag NCs are 7.8 and 9.0 times those of Cu3N NCs, respectively. In situ spectroscopies combined with theoretical calculations confirm that Ag sites produce CO and Cu sites promote asymmetric C-C coupling to *COCHO, significantly enhancing the generation of C2H4. Our work provides new insights into the cascade catalysis strategy at the atomic scale for boosting CO2 to multicarbon products.

Inhibition of transcriptional coactivator YAP Impairs the expression and function of transcription factor WT1 in diabetic podocyte injury.

Podocyte injury and loss are hallmarks of diabetic nephropathy (DN). However, the molecular mechanisms underlying these phenomena remain poorly understood. YAP (Yes-associated protein) is an important transcriptional coactivator that binds with various other transcription factors, including the TEAD family members (nuclear effectors of the Hippo pathway), that regulate cell proliferation, differentiation, and apoptosis. The present study found an increase in YAP phosphorylation at S127 of YAP and a reduction of nuclear YAP localization in podocytes of diabetic mouse and human kidneys, suggesting dysregulation of YAP may play a role in diabetic podocyte injury. Tamoxifen-inducible podocyte-specific Yap gene knockout mice (YappodKO) exhibited accelerated and worsened diabetic kidney injury. YAP inactivation decreased transcription factor WT1 expression with subsequent reduction of Tead1 and other well-known targets of WT1 in diabetic podocytes. Thus, our study not only sheds light on the pathophysiological roles of the Hippo pathway in diabetic podocyte injury but may also lead to the development of new therapeutic strategies to prevent and/or treat DN by targeting the Hippo signaling pathway.

Network pharmacology-based strategy to investigate the mechanisms of artemisinin in treating primary Sjögren's syndrome.

OBJECTIVE: The study aimed to explore the mechanism of artemisinin in treating primary Sjögren's syndrome (pSS) based on network pharmacology and experimental validation. METHODS: Relevant targets of the artemisinin and pSS-related targets were integrated by public databases online. An artemisinin-pSS network was constructed by Cytoscape. The genes of artemisinin regulating pSS were imported into STRING database to construct a protein-protein interaction (PPI) network in order to predict the key targets. The enrichment analyses were performed to predict the crucial mechanism and pathway of artemisinin against pSS. The active component of artemisinin underwent molecular docking with the key proteins. Artemisinin was administered intragastrically to SS-like NOD/Ltj mice to validate the efficacy and critical mechanisms. RESULTS: Network Pharmacology analysis revealed that artemisinin corresponded to 412 targets, and pSS related to 1495 genes. There were 40 intersection genes between artemisinin and pSS. KEGG indicated that therapeutic effects of artemisinin on pSS involves IL-17 signaling pathway, HIF-1 signaling pathway, apoptosis signaling pathway, Th17 cell differentiation, PI3K-Akt signaling pathway, and MAPK signaling pathway. Molecular docking results further showed that the artemisinin molecule had higher binding energy by combining with the key nodes in IL-17 signaling pathway. In vivo experiments suggested artemisinin can restored salivary gland secretory function and improve the level of glandular damage of NOD/Ltj mice. It contributed to the increase of regulatory T cells (Tregs) and the downregulated secretion of IL-17 in NOD/Ltj model. CONCLUSION: The treatment of pSS with artemisinin is closely related to modulating the balance of Tregs and Th17 cells via T cell differentiation.

Highly Conductive and Stable Composite Polymer Electrolyte with Boron Nitride Nanotubes for All-Solid-State Lithium Metal Batteries.

All-solid-state lithium metal batteries (ASSLMBs) have emerged as the most promising next-generation energy storage devices. However, the unsatisfactory ionic conductivity of solid electrolytes at room temperature has impeded the advancement of solid-state batteries. In this work, a multifunctional composite solid electrolyte (CSE) is developed by incorporating boron nitride nanotubes (BNNTs) into polyvinylidene fluoride-hexafluoropropylene (PVDF-HFP). BNNTs, with a high aspect ratio, trigger the dissociation of Li salts, thus generating a greater population of mobile Li+, and establishing long-distance Li+ transport pathways. PVDF-HFP/BNNT exhibits a high ionic conductivity of 8.0 × 10-4 S cm-1 at room temperature and a Li+ transference number of 0.60. Moreover, a Li//Li symmetric cell based on PVDF-HFP/BNNT demonstrates robust cyclic performance for 3400 h at a current density of 0.2 mA cm-2. The ASSLMB formed from the assembly of PVDF-HFP/BNNT with LiFePO4 and Li exhibits a capacity retention of 93.2% after 850 cycles at 0.5C and 25 °C. The high-voltage all-solid-state LiCoO2/Li cell based on PVDF-HFP/BNNT also exhibits excellent cyclic performance, maintaining a capacity retention of 96.4% after 400 cycles at 1C and 25 °C. Furthermore, the introduction of BNNTs is shown to enhance the thermal conductivity and flame retardancy of the CSE.

Experimental investigation on the internal stress of bismuth-doped fiber and its effect on the noise figure of Bismuth-doped fiber amplifier.

The noise figure (NF) of a fiber amplifier is one of the key measures of amplification performance, which characterizes the quality of the amplified signal. Residual stresses are inevitably generated during the manufacturing process of optical fibers, and this can lead to changes in the refractive index (RI) distribution of the fiber. Further, the change in RI distribution causes the mode-field characteristics of the fiber to change as well, and this ultimately has an impact on the NF performance of the amplifier. However, until now, there have been fewer studies on the effect of residual stress on the NF of the fiber amplifiers. In this work, we took a commercial single-mode bismuth-doped fiber (BDF) as an example and used a self-developed stress test device to measure its residual stress and refractive index distribution and compare it with that of a passive fiber. We also comprehensively compared the distribution of residual stress and refractive index of the fiber at different pump powers and pump wavelengths. Finally, we performed numerical simulations of the bismuth-doped fiber amplifier (BDFA) based on the BDF under the theoretical mode field area and BDF after the expansion of the mode field area due to stresses to compare the NF performance. The results demonstrate that: the entire cross-section (core and cladding) of the BDF exhibits tensile stress (>0 MPa), where the residual stress at the core of the BDF is nearly 9.8 MPa higher than that of the passive fiber; The residual stress makes the mode-field area of the BDF expand by 26.7% compared with the theoretical values, which ultimately makes the NF of the BDFA rise from 4.6 dB to 4.7 dB; The stress at the BDF core is exacerbated by pump excitation, where it is elevated by about 26% and 5% compared to vacancy at 1240 nm and 1310 nm pumps, which is most likely attributed to thermal effects. Therefore, it is necessary to consider the effect of residual stresses in the fabrication of optical fibers to better achieve the radius of the expected indicators. This work contributes to the better development of O-band BDFAs, especially for pre-simulation of the actual performance of BDFAs with a practical reference.

Survival Analysis and Immune Differences of HIV Long-Term Non-progressors in Xinjiang China: A 12-Year Prospective Cohort Observation.

This 12-year cohort study of 80 long-term non-progressors (LTNPs) observed a cumulative follow-up duration of 628.5 person-years. Among them, 60 received antiretroviral therapy (ART) for a total of 418.6 person-years. Twenty-four deaths occurred during the follow-up period, with an average age of 42.36 years and a lowest 8-year survival rate of 0.90. Cox model analysis revealed that the risk of AIDS-related death was 1.47 times higher for non-marital, non-commercial heterosexual transmission than for injection drug use. Treatment initiation at ages 31-40 was correlated with an elevated risk of mortality, while treatment for 3-10 years reduced mortality risks in untreated LTNPs. Flow cytometry observed significant differences in the proportion of NK cells. Long-term ART (> 2 years) before LTNPs developed AIDS symptoms could lower mortality risk and potentially extend lifespan, especially when it was initiated at a younger age without affecting NK cell balance. Epidemiological and immunological studies on ART-treated LTNPs are vital for advancing HIV treatment and achieving functional cures for AIDS individuals.

RESUMEN: Este estudio de cohorte de 12 años con 80 no progresores a largo plazo (LTNPs) observó un total acumulado de 628.5 personas-año. De ellos, 60 recibieron terapia antirretroviral (TAR) durante un total de 418.6 personas-año. Se produjeron veinticuatro muertes durante el período del estudio, con una edad promedio de 42.36 años y una tasa de supervivencia más baja de 0.90 a los 8 años. El análisis del modelo de Cox identificó que la transmisión heterosexual no marital ni comercial presentaba un riesgo 1.47 veces mayor de muerte relacionada con el SIDA en comparación con el uso de drogas inyectables. Comenzar el tratamiento entre los 31-40 años mostró incrementos en los riesgos de mortalidad, mientras que 3-10 años de tratamiento redujeron los riesgos de mortalidad en LTNPs no tratados. Se observaron diferencias significativas en las proporciones de células NK desde el punto de vista inmunológico. La TAR a largo plazo (> 2 años) antes de la aparición de síntomas del SIDA en LTNPs podría disminuir el riesgo de mortalidad y potencialmente prolongar la vida, especialmente si se inicia a una edad más temprana sin afectar el equilibrio de las células NK. Los estudios epidemiológicos e inmunológicos sobre LTNPs tratados con TAR son fundamentales para el progreso del tratamiento del VIH y la cura funcional del SIDA.

The predictive accuracy of machine learning for the risk of death in HIV patients: a systematic review and meta-analysis.

BACKGROUND: Early prediction of mortality in individuals with HIV (PWH) has perpetually posed a formidable challenge. With the widespread integration of machine learning into clinical practice, some researchers endeavor to formulate models predicting the mortality risk for PWH. Nevertheless, the diverse timeframes of mortality among PWH and the potential multitude of modeling variables have cast doubt on the efficacy of the current predictive model for HIV-related deaths. To address this, we undertook a systematic review and meta-analysis, aiming to comprehensively assess the utilization of machine learning in the early prediction of HIV-related deaths and furnish evidence-based support for the advancement of artificial intelligence in this domain. METHODS: We systematically combed through the PubMed, Cochrane, Embase, and Web of Science databases on November 25, 2023. To evaluate the bias risk in the original studies included, we employed the Predictive Model Bias Risk Assessment Tool (PROBAST). During the meta-analysis, we conducted subgroup analysis based on survival and non-survival models. Additionally, we utilized meta-regression to explore the influence of death time on the predictive value of the model for HIV-related deaths. RESULTS: After our comprehensive review, we analyzed a total of 24 pieces of literature, encompassing data from 401,389 individuals diagnosed with HIV. Within this dataset, 23 articles specifically delved into deaths during long-term follow-ups outside hospital settings. The machine learning models applied for predicting these deaths comprised survival models (COX regression) and other non-survival models. The outcomes of the meta-analysis unveiled that within the training set, the c-index for predicting deaths among people with HIV (PWH) using predictive models stands at 0.83 (95% CI: 0.75-0.91). In the validation set, the c-index is slightly lower at 0.81 (95% CI: 0.78-0.85). Notably, the meta-regression analysis demonstrated that neither follow-up time nor the occurrence of death events significantly impacted the performance of the machine learning models. CONCLUSIONS: The study suggests that machine learning is a viable approach for developing non-time-based predictions regarding HIV deaths. Nevertheless, the limited inclusion of original studies necessitates additional multicenter studies for thorough validation.

Hepatocyte growth factor is protective in early stage but bone-destructive in late stage of experimental periodontitis.

BACKGROUND AND OBJECTIVE: Clinical studies found high levels of hepatocyte growth factor (HGF) expression in patients with periodontitis. Studies suggest that HGF plays an important role in periodontitis, is involved in inflammation, and modulates alveolar bone integrity in periodontitis. This study aims to investigate the effects and mechanisms of HGF in the progression of experimental periodontitis. METHODS: We used silk thread ligation to induce periodontitis in HGF-overexpressing transgenic (HGF-Tg) and wild-type C57BL/6J mice. The effects of HGF overexpression on alveolar bone destruction were assessed by microcomputed tomography imaging at baseline and on days 7, 14, 21, and 28. We analyzed the cytokines (IL-6 and TNF-α) and lymphocytes in periodontitis tissues by enzyme-linked immunosorbent assay and flow cytometry. The effects of HGF on alveolar bone destruction were further tested by quantifying the systemic bone metabolism markers CTXI and PINP and by RNA sequencing for the signaling pathways involved in bone destruction. Western blotting and immunohistochemistry were performed to further elucidate the involved signaling pathways. RESULTS: We found that experimental periodontitis increased HGF production in periodontitis tissues; however, the effects of HGF overexpression were inconsistent with disease progression. In the early stage of periodontitis, periodontal inflammation and alveolar bone destruction were significantly lower in HGF-Tg mice than in wild-type mice. In the late stage, HGF-Tg mice showed higher inflammatory responses and progressively aggravated bone destruction with continued stimulation of inflammation. We identified the IL-17/RANKL/TRAF6 pathway as a signaling pathway involved in the HGF effects on the progression of periodontitis. CONCLUSION: HGF plays divergent effects in the progression of experimental periodontitis and accelerates osteoclastic activity and bone destruction in the late stage of inflammation.

Spontaneous rupture of bladder diverticulum with pseudo renal failure:A case report and literature review.

BACKGROUND: Spontaneous or non-traumatic bladder rupture is rare but can be life-threatening. Bladder rupture caused by a diverticulum is extremely rare, with only a few case reports in medical literature. CASE PRESENTATION: We report the case of a 32-year-old woman admitted to hospital complaints of abdominal pain, oliguria and ascites with no history of trauma. Laboratory tests revealed an elevated serum urea nitrogen(UN) level of 33.5 mmol/l and an elevated creatinine levels of 528 umol/l. X-ray cystography confirmed the rupture of a bladder diverticulum. Subsequent transurethral catheterization led to a prompt increase in urinary output, and serum creatinine level returned to 40 umol/l within 48 h. The patient was successfully treated with laparoscopic diverticulectomy. CONCLUSION: Clinicians should maintain a high level of suspicion for urinary bladder rupture in cases presenting with acute lower abdominal pain, urinary difficulties, and oliguria. When acute renal failure, complicated ascites, and an elevated peritoneal fluid creatinine or potassium level exceeding serum levels are observed, intraperitoneal urine leakage should be suspected without delay. This case emphasizes the importance of early diagnosis and intervention in managing this rare but serious condition.

Epigenetic mechanisms of lncRNA in response to thermal stress during embryogenesis of allotetraploid Cyprinus carpio.

Embryogenesis and epigenetic mechanisms of lncRNA may play an important role in the formation of temperature tolerance in allotetraploid Cyprinus carpio. To investigate the response of lncRNA to thermal stress during embryogenesis of C. carpio, transcriptome sequencing was performed on 81 embryo or larva samples from different early development stages and temperatures. We identified 45,097 lncRNAs and analyzed transcriptome variation during embryogenesis. Stage-specific and temperature-specific DE lncRNAs and DEGs were screened. GO and KEGG analysis identified numerous pathways involved in thermal stress. Temperature-specific regulation of cis-/trans-/antisense lncRNAs was analyzed. Interaction network analysis identified 6 hub lncRNAs and many hub genes, such as cdk1 and hsf1. Decreased expression of many essential genes regulated by lncRNAs may lead to the death of embryos at 33 °C. Our findings provide new insights into the regulation of lncRNA in thermal stress response during embryogenesis and contribute to the understanding of environmental adaptation of allotetraploid species.