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Background and purposeHalofuginone is a febrifugine derivative originally isolated from Chinese traditional herb Chang Shan that exhibits anti-hypertrophic, anti-fibrotic and anti-proliferative effects. We sought to investigate whether halofuginone induced pulmonary vasodilation and attenuates chronic hypoxia-induced pulmonary hypertension (HPH).Experimental approachPatch-clamp experiments were conducted to examine the activity of voltage-dependent Ca2+ channels (VDCCs) in pulmonary artery smooth muscle cells (PASMCs). Digital fluorescence microscopy was used to measure intracellular Ca2+ concentration in PASMCs. Isolated perfused and ventilated mouse lungs were used to measure pulmonary artery pressure (PAP). Mice exposed to hypoxia (10% O2 ) for 4 weeks were used as model of HPH for in vivo experiments.Key resultsHalofuginone increased voltage-gated K+ (Kv ) currents in PASMCs and K+ currents through KCNA5 channels in HEK cells transfected with KCNA5 gene. HF (0.03-1 μM) inhibited receptor-operated Ca2+ entry in HEK cells transfected with calcium-sensing receptor gene and attenuated store-operated Ca2+ entry in PASMCs. Acute (3-5 min) intrapulmonary application of halofuginone significantly and reversibly inhibited alveolar hypoxia-induced pulmonary vasoconstriction dose-dependently (0.1-10 μM). Intraperitoneal administration of halofuginone (0.3 mg·kg-1 , for 2 weeks) partly reversed established PH in mice.Conclusion and implicationsHalofuginone is a potent pulmonary vasodilator by activating Kv channels and blocking VDCC and receptor-operated and store-operated Ca2+ channels in PASMCs. The therapeutic effect of halofuginone on experimental PH is probably due to combination of its vasodilator effects, via inhibition of excitation-contraction coupling and anti-proliferative effects, via inhibition of the PI3K/Akt/mTOR signalling pathway.

Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS), a refractory lung disease with an unacceptable high mortality rate. Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The specific mechanisms involved in VILI-induced pulmonary capillary leakage, a key pathologic feature of VILI are still far from resolved. The mechanoreceptor, transient receptor potential cation channel subfamily V member 4, TRPV4 plays a key role in the development of VILI through unresolved mechanism. Endothelial nitric oxide synthase (eNOS) uncoupling plays an important role in sepsis-mediated ARDS so in this study we investigated whether there is a role for eNOS uncoupling in the barrier disruption associated with TRPV4 activation during VILI. Our data indicate that the TRPV4 agonist, 4α-Phorbol 12,13-didecanoate (4αPDD) induces pulmonary arterial endothelial cell (EC) barrier disruption through the disruption of mitochondrial bioenergetics. Mechanistically, this occurs via the mitochondrial redistribution of uncoupled eNOS secondary to a PKC-dependent phosphorylation of eNOS at Threonine 495 (T495). A specific decoy peptide to prevent T495 phosphorylation reduced eNOS uncoupling and mitochondrial redistribution and preserved PAEC barrier function under 4αPDD challenge. Further, our eNOS decoy peptide was able to preserve lung vascular integrity in a mouse model of VILI. Thus, we have revealed a functional link between TRPV4 activation, PKC-dependent eNOS phosphorylation at T495, and EC barrier permeability. Reducing pT495-eNOS could be a new therapeutic approach for the prevention of VILI.

[Purpose/Significance] With the rapid development of information technology and the arrival of the era of big data, big data has become a key production factor and a strategic fundamentally resource for a country. Big data governance has become an important way to fully release data value and realize the modernization of national governance system and governance capacity. This study reviews the related research on big data governance, in order to better play its positive role as a new production factor and a means of social governance. [Method/Process] On the basis of bibliometrics and content analysis, this study systematically reviews the relevant research on big data governance in China, and finds that the research on big data governance has been rising in recent years. The relevant research topics have also displayed characteristics such as wide diversity and multidisciplinary integration. The core topics involved in the research include big data governance, social governance, government governance, big data technology, data resources, network public opinion, risk governance, and data security. The research on the big data governance system of the whole process is the most critical part. [Results/Conclusions] This study classified the relevant research topics into three aspects: theoretical system, implementation evaluation and practical challenges. The big data governance system is a complex, multi-level and multi-dimensional systematic project, which consists of governance goals, governance subjects, governance objects and governance tools. Big data governance implementation and evaluation includes three stages: organizational planning, specific implementation, evaluation and optimization. The organizational planning stage includes formulating implementation guidelines and constructing governance organizations; the specific implementation stage includes metadata management, master data management, data quality and data security; the evaluation optimization phase includes big data governance maturity evaluation and big data governance audit. The practice of big data governance focuses on three aspects: the Chinese government actively uses big data to improve scientific decision-making ability, social management level and public service construction. The practical challenges are mainly reflected in the management and technical challenges faced by data-centered fields. As an open topic and dynamic process, big data governance is still mostly based on conceptual and descriptive qualitative analysis, and focuses on theoretical discussion and experience summary. There is still a lack of relevant case support and technology application research, and the design and implementation evaluation of the big data governance system still needs to be improved and optimized.

Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure.

Background: In clinical practice guidelines, there is no consensus about the medications that should be initially offered to patients with brucellosis. To provide informative evidence, we compared and ranked brucellosis medications based on their efficacy and safety. Methods: For this systematic review and network meta-analysis, we searched 4 English databases and 3 Chinese databases, from the date of database inception to December 13, 2023. We included randomized controlled trials (RCTs) involving children and adolescents with brucellosis, comparing different antibiotic regimens. We excluded studies explicitly targeting patients with spondylitis brucellosis, endocarditis brucellosis, and neuro-brucellosis. The primary outcomes were overall failure (efficacy) and side effects (safety). Secondary outcomes were relapse and therapeutic failure. Pairwise meta-analysis was first examined. Data were analyzed using random effects network meta-analysis, with subgroup and sensitivity analyses performed. The Confidence in Network Meta-Analysis (CINeMA) framework was used to assess the certainty of evidence. The protocol was preregistered in PROSPERO (CRD42023491331). Results: Of the 11,747 records identified through the database search, 43 RCTs were included in the network meta-analysis. Compared with standard therapy (Doxycycline + Rifampicin), Rifampicin + Tetracyclines (RR 4.96; 95% CI 1.47 to 16.70; very low certainty of evidence), Doxycycline + TMP/SMX (RR 0.18; 95% CI 0.06 to 0.52; low certainty of evidence), Doxycycline + Quinolones (RR 0.27; 95% CI 0.11 to 0.71; low certainty of evidence), Streptomycin + Tetracyclines (RR 0.04; 95% CI 0.01 to 0.16; low certainty of evidence), and Single (RR 0.05; 95% CI 0.02 to 0.16; moderate certainty of evidence) were less efficacious. Doxycycline + Gentamicin ranked the best in efficacy (SUCRA values: 0.94), the second is Triple (SUCRA values: 0.87), and the third is Doxycycline + Streptomycin (SUCRA values: 0.78). Conclusions: Brucellosis medications differ in efficacy and safety. Doxycycline + Gentamicin, Triple, and Doxycycline + Streptomycin have superior efficacy and safety. Treatment of brucellosis should strike a balance between efficacy, safety, and cost. Author summary: Brucellosis, with nearly 500,000 new cases outbreak in more than 170 countries or regions worldwide each year, is a zoonotic infectious disease caused by Brucella. Due to the lack of an effective human vaccine and the impracticality of eradicating brucellosis in animals globally, treatment remains the primary strategy for addressing human brucellosis. However, there is no consensus in clinical practice guidelines regarding the initial medications for brucellosis treatment. Therefore, we compared and ranked brucellosis medications based on their efficacy and safety to aid clinicians in matching risk/benefits of drugs to brucellosis treatment. In this systematic review and network meta-analysis of 43 randomized clinical trials with 4,283 patients, 6 weeks of doxycycline plus 1 to 2 weeks of gentamicin or plus 2 to 3 weeks of streptomycin is the best therapy for human brucellosis. Six weeks of rifampicin plus quinolones treatment is considered as an alternative therapy. If finances allow, consider triple therapy. Single, Streptomycin + Tetracyclines, Streptomycin + TMP/SMX, and Rifampicin + TMP/SMX therapies cannot currently be recommended. [ABSTRACT FROM AUTHOR]

Polymer composite materials are increasingly used in civil aircraft structures. The failure mode and energy-absorption characteristics of polymer composite structures have garnered significant attention from academia and industry. For thin-walled polymer composite C-channels with layups of [0/90]3s, [45/-45]3s, and [45/90/-45/0]3, low-speed axial compression tests were performed to investigate the failure modes, failure mechanisms, and energy-absorbing characteristics. After parametric studies using [0] and [90] single-element models, stacked shell models of thin-walled composite C-channels were established using the Lavadèze single-layer damage constitutive model, Puck 2000, and Yamada Sun failure criteria. The results show that these thin-walled composite C-channels exhibit a stable progressive crushing process with a local buckling failure mode, encompassing local buckling, fiber break-age, matrix cracks, delamination, and corner cracking. The stacked shell model demonstrates reasonable agreement with the progressive crushing process of thin-walled composites, accurately capturing interlayer matrix failure and interface delamination cracking behavior. A comparison of the specific energy absorption (SEA) and mean crushing force (Fmean) between the simulation and test results yields a difference of less than 6%, indicating a strong correlation between the simulation results and the experimental energy-absorbing characteristics. It also shows that a deep understanding of the parameters is helpful for accurate numerical modeling. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits often associated with the development of neurodegenerative diseases. Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice. We observed a significant elevation of Na+/H+ exchanger protein (NHE1) expression in GFAP+ reactive astrocytes, IBA1+ microglia, and OLIG2+ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function. [ABSTRACT FROM AUTHOR]

Using single-shot velocity map imaging technique, explosion imaging of different ion species ejected from 50 nm SiO2 nanoparticles are obtained excitedly by strong near-infrared and ultraviolet femtosecond laser fields. Characteristic momentum distributions showing forward emission of the ions at low excitation intensities and shock wave behaviors at high intensities are observed. When the excitation intensity is close to the dissociative ionization threshold of the surface molecules, the resulting ion products can be used to image the instant near-field distributions. The underlying dynamics of shock formation are simulated by using a Coulomb explosion model. Our results allow one to distinguish the ultrafast strong-field response of various molecular species in nanosystems and will open a new way for further exploration of the underlying dynamics of laser-and-nanoparticle interactions.