De novo identification of mammalian ciliary motility proteins using cryo-EM.

Dynein-decorated doublet microtubules (DMTs) are critical components of the oscillatory molecular machine of cilia, the axoneme, and have luminal surfaces patterned periodically by microtubule inner proteins (MIPs). Here we present an atomic model of the 48-nm repeat of a mammalian DMT, derived from a cryoelectron microscopy (cryo-EM) map of the complex isolated from bovine respiratory cilia. The structure uncovers principles of doublet microtubule organization and features specific to vertebrate cilia, including previously unknown MIPs, a luminal bundle of tektin filaments, and a pentameric dynein-docking complex. We identify a mechanism for bridging 48- to 24-nm periodicity across the microtubule wall and show that loss of the proteins involved causes defective ciliary motility and laterality abnormalities in zebrafish and mice. Our structure identifies candidate genes for diagnosis of ciliopathies and provides a framework to understand their functions in driving ciliary motility.

ISM1 protects lung homeostasis via cell-surface GRP78-mediated alveolar macrophage apoptosis.

Alveolar macrophages (AMs) are critical for lung immune defense and homeostasis. They are orchestrators of chronic obstructive pulmonary disease (COPD), with their number significantly increased and functions altered in COPD. However, it is unclear how AM number and function are controlled in a healthy lung and if changes in AMs without environmental assault are sufficient to trigger lung inflammation and COPD. We report here that absence of isthmin 1 (ISM1) in mice (Ism1-/- ) leads to increase in both AM number and functional heterogeneity, with enduring lung inflammation, progressive emphysema, and significant lung function decline, phenotypes similar to human COPD. We reveal that ISM1 is a lung resident anti-inflammatory protein that selectively triggers the apoptosis of AMs that harbor high levels of its receptor cell-surface GRP78 (csGRP78). csGRP78 is present at a heterogeneous level in the AMs of a healthy lung, but csGRP78high AMs are expanded in Ism1-/- mice, cigarette smoke (CS)-induced COPD mice, and human COPD lung, making these cells the prime targets of ISM1-mediated apoptosis. We show that csGRP78high AMs mostly express MMP-12, hence proinflammatory. Intratracheal delivery of recombinant ISM1 (rISM1) depleted csGRP78high AMs in both Ism1-/- and CS-induced COPD mice, blocked emphysema development, and preserved lung function. Consistently, ISM1 expression in human lungs positively correlates with AM apoptosis, suggesting similar function of ISM1-csGRP78 in human lungs. Our findings reveal that AM apoptosis regulation is an important physiological mechanism for maintaining lung homeostasis and demonstrate the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD.

Revealing Metabolic Dysregulation Induced by Polypropylene Nano- and Microplastics in Nile Tilapia via Noninvasive Probing Epidermal Mucus.

A noninvasive sampling technology was conceived, employing a disposable acupuncture needle in conjunction with high-resolution mass spectrometry (termed as noninvasive direct sampling extractive electrospray ionization mass spectrometry, NIDS-EESI-MS) to scrutinize the epidermal mucus of Nile tilapia for insights into the metabolic dysregulation induced by polypropylene nano- and microplastics. This analytical method initiates with the dispensing of an extraction solvent onto the needles coated with the mucus sample, almost simultaneously applying a high voltage to generate analyte ions. This innovative strategy obliterates the necessitation for laborious sample preparation, thereby simplifying the sampling process. Employing this technique facilitated the delineation of a plethora of metabolites, encompassing, but not confined to, amino acids, peptides, carbohydrates, ketones, fatty acids, and their derivatives. Follow-up pathway enrichment analysis exposed notable alterations within key metabolic pathways, including the biosynthesis of phenylalanine, tyrosine, and tryptophan, lysine degradation, as well as the biosynthesis and metabolism of valine, leucine, and isoleucine pathways in Nile tilapia, consequent to increased concentrations of polypropylene nanoplastics. These metabolic alterations portend potential implications such as immune suppression, among other deleterious outcomes. This trailblazing application of this methodology not only spares aquatic life from sacrifice but also inaugurates an ethical paradigm for conducting longitudinal studies on the same organisms, facilitating detailed investigations into the long-term effects of environmental pollutants. This technique enhances the ability to observe and understand the subtle yet significant impacts of such contaminants over time.

Construction and validation of the nomogram predictive model for post-percutaneous nephrolithotomy urinary sepsis.

OBJECTIVE: This study aimed to construct and validate a simple and accurate clinical nomogram for predicting the occurrence of post-percutaneous nephrolithotomy sepsis, aiming to assist urologists in the early identification, warning, and early intervention of urosepsis, and to provide certain evidence-based medicine basis. METHODS: This study included patients who underwent PCNL surgery due to kidney or upper ureteral stones at the Department of Urology, Affiliated Hospital of Zunyi Medical University, from January 2019 to September 2022. This study utilized univariate and multivariate logistic regression analysis to screen and evaluate the risk factors for sepsis and construct a predictive model. An evaluation was performed using the receiver operating characteristic curve, calibration curve, and decision curve analysis curve. All statistical analyses were conducted using R version 4.2. RESULTS: A total of 946 patients who underwent post-PCNL were included in this study, among whom 69 patients (7.29%) developed post-PCNL urinary sepsis. Multiple-factor logistic regression analysis identified four independent risk factors associated with post-PCNL urinary sepsis, including positive urinary nitrite (OR = 5.9, P < 0.001), positive urine culture (OR = 7.54, P < 0.001), operative time ≥ 120 min (OR = 20.93, P = 0.0052), and stone size ≥ 30 mm (OR = 13.81, P = 0.0015). The nomogram model demonstrated good accuracy with an AUC value of 0.909, and in the validation cohort, the AUC value was 0.922. The calibration curve indicated a better consistency between the predictive line chart and the actual occurrence of post-PCNL urinary sepsis. The decision curve analysis curve showed favorable clinical utility. CONCLUSION: Preoperative positive urine culture, positive urinary nitrite, operative time ≥ 120 min, and stone size ≥ 30 mm are independent risk factors for developing post-PCNL urinary sepsis. The constructed line chart based on these factors effectively assesses the risk of urinary sepsis in patients after PCNL.

HIV Services Uptake Among People Living with HIV in Jiangsu Province, China: A Cross-Sectional Study.

Healthcare disparities are common among people living with HIV (PLWH) in China and likely impact access to HIV services. This study aimed to assess the current status of access to HIV services among PLWH and explore the correlates of service uptake using baseline data from a prospective cohort study among PLWH in Jiangsu Province. Guided by Andersen's behavioral model, univariable and multivariable logistic regressions were conducted to identify factors associated with access to HIV services. Out of 8989 eligible PLWH included in this study, 46.4% perceived difficulty in seeing a healthcare professional for HIV treatment services in 2021-2022. PLWH aged 18-34 years (adjusted odds ratio [AOR] = 1.69, 95% CI 1.32-2.15), 35-39 years (AOR = 1.33, 95% CI 1.08-1.65), identified as a bisexual/other (AOR = 1.14, 95% CI 1.01-1.29), had a college and above education (AOR = 1.32, 95% CI 1.07-1.63), and perceived moderate (AOR = 1.70, 95% CI 1.51-1.91) and severe (AOR = 2.20, 95% CI 1.94-2.49) levels of HIV stigma were more likely to perceive difficulty in seeing healthcare professionals for HIV treatment in 2021-2022. Living in northern Jiangsu was also associated with increased odds of perceiving difficulty in seeing healthcare professionals for HIV treatment (AOR = 1.12, 95% CI 1.00-1.26). These findings underscore the need for innovative solutions to eliminate the practical barriers to HIV services utilization among PLWH who are bisexual, well-educated, and effective HIV-related stigma reduction interventions.

A Mixture Fluency model using responses and response times with cognitive diagnosis model framework.

Random guessing behaviors are frequently observed in low-stakes assessments, often attributed to factors such as test-takers lacking motivation or experiencing time constraints and fatigue. Existing research suggests that responses stemming from random guessing behaviors introduce biases into the constructs and relationships of interest. This is particularly problematic when estimating the relationship between speed and ability. This study introduces a Mixture Fluency model designed to account for random guessing behaviors while utilizing valid response accuracy and response time to uncover students' latent attribute profiles. The model directly addresses a limitation present in the Fluency cognitive diagnostic model (Wang & Chen, Psychometrika, 85, 600-629, (2020), which assumes that test-takers consistently employ solution behaviors when answering questions. To investigate the effectiveness of the proposed Mixture Fluency model, we conducted a simulation study encompassing various simulation conditions. Results from this study not only confirm the model's ability to detect potential random guessing behaviors but also demonstrate its capacity to enhance the inference of targeted latent constructs within the assessment. Additionally, we showcase the practical utility of the proposed model through an application to real data.

N-acetylgalactosaminyltransferase-4 protects against hepatic ischemia/reperfusion injury by blocking apoptosis signal-regulating kinase 1 N-terminal dimerization.

BACKGROUND AND AIMS: Ischemia-reperfusion (I/R) injury is an inevitable complication of liver transplantation (LT) and compromises its prognosis. Glycosyltransferases have been recognized as promising targets for disease therapy, but their roles remain open for study in hepatic I/R (HIR) injury. Here, we aim to demonstrate the exact function and molecular mechanism of a glycosyltransferase, N-acetylgalactosaminyltransferase-4 (GALNT4), in HIR injury. APPROACH AND RESULTS: By an RNA-sequencing data-based correlation analysis, we found a close correlation between GALNT4 expression and HIR-related molecular events in a murine model. mRNA and protein expression of GALNT4 were markedly up-regulated upon reperfusion surgery in both clinical samples from subjects who underwent LT and in a mouse model. We found that GALNT4 deficiency significantly exacerbated I/R-induced liver damage, inflammation, and cell death, whereas GALNT4 overexpression led to the opposite phenotypes. Our in-depth mechanistic exploration clarified that GALNT4 directly binds to apoptosis signal-regulating kinase 1 (ASK1) to inhibit its N-terminal dimerization and subsequent phosphorylation, leading to a robust inactivation of downstream c-Jun N-terminal kinase (JNK)/p38 and NF-κB signaling. Intriguingly, the inhibitory capacity of GALNT4 on ASK1 activation is independent of its glycosyltransferase activity. CONCLUSIONS: GALNT4 represents a promising therapeutic target for liver I/R injury and improves liver surgery prognosis by inactivating the ASK1-JNK/p38 signaling pathway.

Mechanism of ASK1 involvement in liver diseases and related potential therapeutic targets: A critical pathway molecule worth investigating.

Since the discovery of apoptosis signal-regulated kinase 1 (ASK1), the signal transduction mechanism and pathophysiological process involved in its regulation have been continuously revealed. Many previous studies have identified that ASK1 is involved and plays a critical role in the development of diseases affecting the nervous, cardiac, renal, and other systems. As a mitogen-activated protein kinase (MAPK) kinase kinase, ASK1 mediates apoptosis, necrosis, inflammation, and other pathological processes by activating its downstream c-Jun N-terminal kinase (JNK)/p38 MAPK. Owing to the important role of ASK1, an increasing number of studies in recent years have focused on its status in liver-related diseases. In this paper, we review the mechanisms and targets of ASK1 in liver-related diseases to emphasize its important role in the development of liver disease.

NCOA7 Regulates Growth and Metastasis of Clear Cell Renal Cell Carcinoma via MAPK/ERK Signaling Pathway.

NCOA7 is a nuclear receptor coactivator that is downregulated in a variety of cancers. However, the expression and prognostic significance of NCOA7 in clear cell renal cell carcinoma (ccRCC) remain unknown. The expression of NCOA7 in ccRCC tissues was analyzed using bioinformatics analysis, Western blotting, and immunohistochemistry. Kaplan-Meier analysis, the receiver operating characteristic (ROC) curve, and clinicopathological correlation analysis were used to assess the predictive power of NCOA7. Overexpression function tests were conducted in cells and mouse models to clarify the function and mechanism of NCOA7 in inhibiting the progression of ccRCC. NCOA7 expression was downregulated in all three subtypes of renal cell carcinoma, and only had significant prognostic value for patients with ccRCC. NCOA7 overexpression inhibited the proliferation, invasion, and metastasis of ccRCC cells in vivo and in vitro. Mechanistically, NCOA7 inhibited the MAPK/ERK pathway to regulate epithelial-mesenchymal transformation (EMT) and apoptosis, thereby inhibiting the progression of ccRCC. NCOA7 inhibits tumor growth and metastasis of ccRCC through the MAPK/ERK pathway, thus indicating its potential as a prognostic marker and therapeutic target for ccRCC.

SS-31 alleviated nociceptive responses and restored mitochondrial function in a headache mouse model via Sirt3/Pgc-1α positive feedback loop.

Migraine is the second highest cause of disability worldwide, bringing a huge socioeconomic burden. Improving mitochondrial function has promise as an effective treatment strategy for migraine. Szeto-Schiller peptide (SS-31) is a new mitochondria-targeted tetrapeptide molecule that has been shown to suppress the progression of diseases by restoring mitochondrial function, including renal disease, cardiac disease, and neurodegenerative disease. However, whether SS-31 has a therapeutic effect on migraine remains unclear. The aim of this study is to clarify the treatment of SS-31 for headache and its potential mechanisms. Here we used a mouse model induced by repeated dural infusion of inflammatory soup (IS), and examined roles of Sirt3/Pgc-1α positive feedback loop in headache pathogenesis and mitochondrial function. Our results showed that repeated IS infusion impaired mitochondrial function, mitochondrial ultrastructure and mitochondrial homeostasis in the trigeminal nucleus caudalis (TNC). These IS-induced damages in TNC were reversed by SS-31. In addition, IS-induced nociceptive responses were simultaneously alleviated. The effects of SS-31 on mitochondrial function and mitochondrial homeostasis (mainly mitochondrial biogenesis) were attenuated partially by the inhibitor of Sirt3/Pgc-1α. Overexpression of Sirt3/Pgc-1α increased the protein level of each other. These results indicated that SS-31 alleviated nociceptive responses and restored mitochondrial function in an IS-induced headache mouse model via Sirt3/Pgc-1α positive feedback loop. SS-31 has the potential to be an effective drug candidate for headache treatment.

Ciliary dynein arms: Cytoplasmic preassembly, intraflagellar transport, and axonemal docking.

The microtubular scaffold of motile cilia-the axoneme, is decorated with dynein arms, which are large multiprotein complexes essential for ciliary motility. Dynein arms are arranged along the length of the axoneme in a precise repeating pattern, converting chemical energy from ATP hydrolysis into ciliary mechanical movement. How these complicated molecular machines are assembled coordinately and accurately, starting from mere polypeptide chains in the cytoplasm, remains a fascinating yet perplexing question. Rapidly emerging evidence, from multiple studies carried out with different model organisms and with various methodologies, has highlighted the existence of a dedicated assembly pathway. Here, we summarize recent progress made in clarifying the axonemal dynein arm assembly process, focusing on individual assembly steps, including cytoplasmic preassembly, intraflagellar transport, and axonemal docking.

A prospective study on the application of HINTS in distinguishing the localization of acute vestibular syndrome.

BACKGROUND: Acute vestibular syndrome (AVS) is a common clinical syndrome in neurology clinics and emergency department. Canonical standard for AVS diagnosis requires the presence of persistent vertigo for more than 24 h. HINTS (head impulse-nystagmus-test of skew) is an emerging scheme in the diagnosis of AVS. In this prospective study, we evaluated the specificity and sensitivity of HINTS in distinguishing between central and peripheral AVS. METHODS: A cohort of 239 cases with complete clinical record was recruited in the study. All patients completed emergency brain CT examination to exclude hemorrhagic stroke. HINTS examination was conducted to distinguish between central AVS and peripheral AVS, and all patients completed head MRI, BAEP and vestibular function examinations within one week. Patients diagnosed as central AVS were subject to angiography (CTA/MRA/DSA), and patients with peripheral AVS were considered for a 3-month follow-up to correct the initial diagnosis. RESULTS: Patients with central AVS were associated with an elder age, higher incidences of hypertension, atrial fibrillation, family history of stroke and previous history of stroke. Posterior circulation cerebral infarction, vestibular migraine and cerebellitis were the dominant diseases associated with central AVS. The sensitivities of HIT, GE, and TS in the diagnosis of central AVS were 73.5%, 61.2%, and 26.5%, and the specificities were 97.9%, 92.6%, and 93.2% respectively. CONCLUSIONS: The sensitivity of HINTS for central AVS diagnosis is 89.8% and the specificity is 84.2%. HINTS is an easy-to-operate, low-cost, high-sensitivity and specific examination technique, which is practical in neurology outpatient clinics and emergency departments.

Dexamethasone reduces the formation of thoracic aortic aneurysm and dissection in a murine model.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease with no effective pharmaceutical therapies currently available. Inflammation plays a key role in the progression of aneurysms. Dexamethasone (DEX), a synthetic glucocorticoid, has showed alleviating effects on cells in vitro from TAAD patients. Here we performed a study aiming at investigating the protective role of DEX in a ß-aminopropionitrile monofumarate (BAPN)-induced TAAD mouse model. DEX (dose: 0.04 mg/kg/day) treatment significantly reduced the aortic diameter and inhibited TAAD formation. DEX reduced infiltration of macrophages and neutrophils, apoptosis of vascular smooth muscle cells (VSMCs), expression of metalloproteinase 2/9, and extracellular matrix degradation in BAPN-treated TAAD mice. Furthermore, DEX therapy downregulated the expression of p-p65 in macrophages and VSMCs, which suggested that DEX might ameliorate BAPN-induced TAAD by suppressing NF-κB signaling. Therefore, DEX therapy attenuates the progression of BAPN-induced TAAD murine model and could be used as an effective adjuvant therapy for treating TAAD.

NOx Emission Removal from a Parallel Diesel Engine Group by SCR System Based on Distributed Control Technology.

In industrial application, an engine group with several engines running in parallel produces emissions, and because of its variable operation conditions and the number of engines being run, it produces great pollution. This study proposes a distributed control system (DCS) method to deal with NOx emissions from a diesel engine group. This DCS method contains several diesel engine test benches in parallel, and each engine is connected to an independent DCS unit with a selective catalytic reduction (SCR) device, and the central processing unit (CPU) distributes controlling quantities to each DCS unit. A dimensionless parameter, coefficient of difficulty K, is introduced to evaluate the NOx conversion efficiency of each unit. A control algorithm adopting the minimum K as the optimization control object to distribute the real-time NOx conversion efficiency for each unit is presented. This DCS deNOx technology has been applied in 10-engine test benches in parallel, and the results show that the DCS method not only controls NOx emissions of the engine group within the emission standard limit but also exhibits a good economic performance for suitable NOx conversion efficiency distribution and economical urea injection dose. This DCS emission control method is suitable for multiple diesel engines running in parallel under conditions of varied speeds and loads.

The impact of COVID-19 pandemic on HIV care continuum in Jiangsu, China.

BACKGROUND: The COVID-19 pandemic seriously threatens general public health services globally. This study aimed to evaluate the impact of the COVID-19 pandemic on the HIV care continuum in Jiangsu province, China. METHODS: Data on newly diagnosed HIV persons for analysis were retrieved from Chinas' web-based Comprehensive Response Information Management System (CRIMS) for HIV/AIDS from 2016 to 2020. We recorded data for the first 3 months (January to March, 2020) of strictly implementing COVID-19 measures from publicly available disease databases of the Jiangsu provincial Health Committee. We used seasonal autoregressive integrated moving average (SARIMA) and exponential smoothing in forecasting the parameters. Subgroup differences were accessed using Chi-square tests. RESULTS: Compared to the estimated proportions, the HIV testing rates decreased by 49.0% (919,938) in the first three months of implementing COVID-19 measures. Of an estimated 1555 new HIV diagnosis expected in the same period, only 63.0% (980) new diagnoses were recorded. According to actual data recorded during the said period, 980 positively tested persons received confirmatory tests, of which 71.4% (700) were reportedly linked to care. And only 49.5% (235) out of the expected 475 newly diagnosed HIV persons received CD4 cell count testing. Meanwhile 91.6% (208) of newly diagnosed HIV persons who received CD4 count tests reportedly initiated antiretroviral therapy (ART) compared to the 227 expected. Compared to the same period from 2016 to 2019, PLWH less than 30 years old and migrants were more likely to be affected by the COVID-19 policies. CONCLUSIONS: The COVID-19 pandemic negatively impacted HIV healthcare systems in Jiangsu, China. Further measures that can counter the impact of the pandemic are needed to maintain the HIV care continuum.

HIV/AIDS late presentation and its associated factors in China from 2010 to 2020: a systematic review and meta-analysis.

BACKGROUND: Late presentation to HIV/AIDS care presents serious health concerns, like increased transmission and high healthcare costs, increased mortality, early development of opportunistic infection, increased risk of antiretroviral therapy drug resistance. Despite the effort to contain the HIV/AIDS epidemic, LP has remained an impediment to individual immune reconstitution and public health. OBJECTIVE: This review aimed to estimate the prevalence and determine the factors associated with late presentation to HIV/AIDS care. METHODS: We searched PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Wanfang, and Weipu database for articles published from 2010 to 2020. We utilized I2 statistics and Q-test to estimate heterogeneity between studies. Random-effects meta-analysis models were used to calculate the aggregate odds ratio of late presentation to HIV/AIDS care. RESULTS: Of 9563 titles and abstracts retrieved, 189 were identified as potentially eligible and 39 fulfilled the inclusion criteria. The pooled prevalence of late presentation to HIV/AIDS care was 43.26%. The major risk factors were patients ≥ 50 years old (OR = 2.19, 95% CI: 1.85-2.58; I2 = 97.44%), married (OR = 1.50, 95% CI: 1.35-1.68; I2 = 96.58%), with heterosexual contact as risk factor for infection (OR = 1.91, 95% CI: 1.73-2.11; I2 = 90.74%) and diagnosed in medical institutions (OR = 2.35,95% CI: 2.11-2.62; I2 = 96.05%). In middle or low HIV prevalence areas, patients ≥ 50 years old (P = 0.01), married (P < 0.01) and diagnosed in medical institutions (P = 0.01) were more likely to be presented late than in high prevalence areas. From 2016-2020, the OR of patients who were married and diagnosed in medical facilities were significantly lower than before (P < 0.01). CONCLUSION: Patients ≥ 50 years old, married, with heterosexual contact as risk factor for infection, and diagnosed in medical institutions were risk factors of LP. Gender had no significant relationship with LP. In middle or low prevalence areas, patients who were ≥ 50 years old, married, and diagnosed in medical institutions were more likely to be presented late than in other areas. Married patients and those diagnosed in medical institutions after 2015 have a lower risk of LP than before.

Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus Endovascular Treatment on Functional Independence in Patients With Acute Ischemic Stroke: The DEVT Randomized Clinical Trial.

Importance: For patients with large vessel occlusion strokes, it is unknown whether endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment (standard treatment) can achieve similar functional outcomes. Objective: To investigate whether endovascular thrombectomy alone is noninferior to intravenous alteplase followed by endovascular thrombectomy for achieving functional independence at 90 days among patients with large vessel occlusion stroke. Design, Setting, and Participants: Multicenter, randomized, noninferiority trial conducted at 33 stroke centers in China. Patients (n = 234) were 18 years or older with proximal anterior circulation intracranial occlusion strokes within 4.5 hours from symptoms onset and eligible for intravenous thrombolysis. Enrollment took place from May 20, 2018, to May 2, 2020. Patients were enrolled and followed up for 90 days (final follow-up was July 22, 2020). Interventions: A total of 116 patients were randomized to the endovascular thrombectomy alone group and 118 patients to combined intravenous thrombolysis and endovascular thrombectomy group. Main Outcomes and Measures: The primary end point was the proportion of patients achieving functional independence at 90 days (defined as score 0-2 on the modified Rankin Scale; range, 0 [no symptoms] to 6 [death]). The noninferiority margin was -10%. Safety outcomes included the incidence of symptomatic intracerebral hemorrhage within 48 hours and 90-day mortality. Results: The trial was stopped early because of efficacy when 234 of a planned 970 patients had undergone randomization. All 234 patients who were randomized (mean age, 68 years; 102 women [43.6%]) completed the trial. At the 90-day follow-up, 63 patients (54.3%) in the endovascular thrombectomy alone group vs 55 (46.6%) in the combined treatment group achieved functional independence at the 90-day follow-up (difference, 7.7%, 1-sided 97.5% CI, -5.1% to ∞)P for noninferiority = .003). No significant between-group differences were detected in symptomatic intracerebral hemorrhage (6.1% vs 6.8%; difference, -0.8%; 95% CI, -7.1% to 5.6%) and 90-day mortality (17.2% vs 17.8%; difference, -0.5%; 95% CI, -10.3% to 9.2%). Conclusions and Relevance: Among patients with ischemic stroke due to proximal anterior circulation occlusion within 4.5 hours from onset, endovascular treatment alone, compared with intravenous alteplase plus endovascular treatment, met the prespecified statistical threshold for noninferiority for the outcome of 90-day functional independence. These findings should be interpreted in the context of the clinical acceptability of the selected noninferiority threshold. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IOR-17013568.

The application of Temporary Ark Hospitals in controlling COVID-19 spread: The experiences of one Temporary Ark Hospital, Wuhan, China.

Coronavirus disease 2019 (COVID-19) had its evolution in Wuhan, Hubei Province, China, and now it has spread around the world, resulting in a large number of deaths. Temporary Ark hospitals (TAHs) have played an important role in controlling the spread of the epidemic in the city of Wuhan. Taking one TAH with 800 beds as an example, we summarized details of the layout, setting, working mode of medical staff, patient management, admission standards, discharge standards, and standards for transferring to another hospital, hospital operation, and so on. Over the period of operation, a total of 1124 patients were admitted for treatment. Of these, 833 patients were cured and discharged from the hospital and 291 patients were transferred to other designated hospitals, owing to aggravation of their condition. The achievement was to have zero infection for medical staff, zero in-hospital deaths among admitted patients, and zero readmission for discharged patients. The rapid deployment of TAH provided a suitable place for treating mild/moderate or no asymptomatic COVID-19 patients, which successfully helped to control the infection in Wuhan. The successful model of TAH would rapidly and effectively control the spread of COVID-19 in other cities.

Ubiquitin-specific protease-44 inhibits the proliferation and migration of cells via inhibition of JNK pathway in clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer. Ubiquitin-specific protease (USP)44 has been reported to be involved in various cancers. We investigated the function, role and molecular mechanism of USP44 in ccRCC. METHODS: Data obtained from the Cancer Genome Atlas Data Portal and Gene Expression Omnibus database were analyzed to uncover the clinical relevance of USP44 expression and tumor development. USP44 function in the proliferation and migration of tumor cells was assessed by cellular and molecular analyses using ccRCC lines (786-O cells and Caki-1 cells). RESULTS: USP44 showed low expression in ccRCC cancer tissues compared with that in normal tissue. USP44 expression was negatively correlated with tumor stage, tumor grade, and patient survival. USP44 overexpression inhibited the proliferation and migration of 786-O cells and Caki-1 cells significantly. USP44 overexpression also prohibited cell proliferation by upregulating expression of P21, downregulating cyclin-D1 expression, and inhibiting cell migration by downregulating expression of matrix metalloproteinase (MMP)2 and MMP9. USP44 knockdown enhanced the proliferation and migration of 786-O cells and Caki-1 cells. USP44 function in inhibiting the proliferation and migration of 786-O cells and Caki-1 cells was associated with phosphorylation of Jun N-terminal kinase (JNK). CONCLUSION: USP44 may be a marker in predicting ccRCC progression. Inhibition by USP44 of the proliferation and migration of 786-O cells and Caki-1 cells is dependent upon the JNK pathway.

DUSP12 protects against hepatic ischemia-reperfusion injury dependent on ASK1-JNK/p38 pathway in vitro and in vivo.

Hepatic ischemia-reperfusion (I/R) injury is an important risk factor resulting in liver failure during liver surgery. However, there is still lack of effective therapeutic methods to treat hepatic I/R injury. DUSP12 is a member of the dual specific phosphatase (DUSP) family. Some DUSPs have been identified as being involved in the regulation of hepatic I/R injury. However, the role of DUSP12 during hepatic I/R injury is still unclear. In the present study, we observed a significant decrease in DUSP12 expression in a hepatic I/R injury mouse model in vivo and in hypoxia/reoxygenation (H/R) model in vitro. Using hepatocyte-specific DUSP12 knockout mice and DUSP12 transgenic mice, we demonstrated that DUSP12 apparently relieved I/R-induced liver injury. Moreover, DUSP12 inhibited hepatic inflammatory responses and alleviated apoptosis both in vitro and in vivo. Furthermore, we demonstrated that JNK and p38 activity, but not ERK1/2, was increased in the DUSP12-deficient mice and decreased in the DUSP12 transgenic mice under I/R condition. ASK1 was required for DUSP12 function in hepatic I/R injury and inhibition of ASK1 prevented inflammation and apoptosis in DUSP12-deficient hepatocytes and mice. In conclusion, DUSP12 protects against hepatic I/R injury and related inflammation and apoptosis. This regulatory role of DUSP12 is primarily through ASK1-JNK/p38 signaling pathway. Taken together, DUSP12 could be a potential therapeutic target for hepatic I/R injury.