Whether 10-day short-course vonoprazan-amoxicillin dual therapy (VA-dual) is noninferior to the standard 14-day bismuth-based quadruple therapy (B-quadruple) against Helicobacter pylori eradication ...has not been determined. This trial aimed to compare the eradication rate, adverse events, and compliance of 10-day VA-dual regimen with standard 14-day B-quadruple regimen as first-line H. pylori treatment.
This prospective randomized clinical trial was performed at 3 institutions in eastern China. A total of 314 treatment-naive, H. pylori -infected patients were randomly assigned in a 1:1 ratio to either 10-day VA-dual group or 14-day B-quadruple group. Eradication success was determined by 13 C-urea breath test at least 4 weeks after treatment. Eradication rates, adverse events, and compliance were compared between groups.
Eradication rates of VA-dual and B-quadruple groups were 86.0% and 89.2% ( P = 0.389), respectively, by intention-to-treat (ITT) analysis; 88.2% and 91.5% ( P = 0.338), respectively, by modified ITT analysis; and 90.8% and 91.3% ( P = 0.884), respectively, by per-protocol (PP) analysis. The efficacy of the VA-dual remained noninferior to B-quadruple therapy in all ITT, modified ITT, and PP analyses. The incidence of adverse events in the VA-dual group was significantly lower compared with that in the B-quadruple group ( P < 0.001). Poor compliance contributed to eradication failure in the VA-dual group ( P < 0.001), while not in the B-quadruple group ( P = 0.110).
The 10-day VA-dual therapy provided satisfactory eradication rates of >90% (PP analysis) and lower rates of adverse events compared with standard 14-day B-quadruple therapy as first-line H. pylori therapy.
ChiCTR2300070100.
Abstract Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy, characterized by excess proliferation, apoptosis resistance, inflammation, fibrosis, and vasoconstriction. ...Although PAH therapies target some of these vascular abnormalities (primarily vasoconstriction), most do not directly benefit the right ventricle (RV). This is suboptimal because a patient's functional state and prognosis are largely determined by the success of the adaptation of the RV to the increased afterload. The RV initially hypertrophies but might ultimately decompensate, becoming dilated, hypokinetic, and fibrotic. A number of pathophysiologic abnormalities have been identified in the PAH RV, including: ischemia and hibernation (partially reflecting RV capillary rarefaction), autonomic activation (due to G protein receptor kinase 2-mediated downregulation and desensitization of β-adrenergic receptors), mitochondrial-metabolic abnormalities (notably increased uncoupled glycolysis and glutaminolysis), and fibrosis. Many RV abnormalities are detectable using molecular imaging and might serve as biomarkers. Some molecular pathways, such as those regulating angiogenesis, metabolism, and mitochondrial dynamics, are similarly deranged in the RV and pulmonary vasculature, offering the possibility of therapies that treat the RV and pulmonary circulation. An important paradigm in PAH is that the RV and pulmonary circulation constitute a unified cardiopulmonary unit. Clinical trials of PAH pharmacotherapies should assess both components of the cardiopulmonary unit.
Pulmonary arterial hypertension (PAH) is an obstructive vasculopathy characterized by excessive pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis resistance. This ...cancer-like phenotype is promoted by increased cytosolic calcium (Ca
), aerobic glycolysis, and mitochondrial fission.
To determine how changes in mitochondrial calcium uniporter (MCU) complex (MCUC) function influence mitochondrial dynamics and contribute to PAH's cancer-like phenotype.
PASMCs were isolated from patients with PAH and healthy control subjects and assessed for expression of MCUC subunits. Manipulation of the pore-forming subunit, MCU, in PASMCs was achieved through small interfering RNA knockdown or MCU plasmid-mediated up-regulation, as well as through modulation of the upstream microRNAs (miRs) miR-138 and miR-25. In vivo, nebulized anti-miRs were administered to rats with monocrotaline-induced PAH.
Impaired MCUC function, resulting from down-regulation of MCU and up-regulation of an inhibitory subunit, mitochondrial calcium uptake protein 1, is central to PAH's pathogenesis. MCUC dysfunction decreases intramitochondrial calcium (Ca
), inhibiting pyruvate dehydrogenase activity and glucose oxidation, while increasing Ca
, promoting proliferation, migration, and fission. In PAH PASMCs, increasing MCU decreases cell migration, proliferation, and apoptosis resistance by lowering Ca
, raising Ca
, and inhibiting fission. In normal PASMCs, MCUC inhibition recapitulates the PAH phenotype. In PAH, elevated miRs (notably miR-138) down-regulate MCU directly and also by decreasing MCU's transcriptional regulator cAMP response element-binding protein 1. Nebulized anti-miRs against miR-25 and miR-138 restore MCU expression, reduce cell proliferation, and regress established PAH in the monocrotaline model.
These results highlight miR-mediated MCUC dysfunction as a unifying mechanism in PAH that can be therapeutically targeted.
Two-dimensional (2D) nanochannel arrays are constructed by bottom-up reassembly of montmorillonite monolayers that are obtained by liquid-phase exfoliation of its layered crystals, and the ...as-constructed interstitial space between these monolayers is uniform and provides ions with nanoscale transport channels. Surface-charge-controlled ion transport behavior is observed through these nanochannels as the electrolyte concentration reduces to 10–4 M at room temperature. Furthermore, the nanochannel structure remains even after 400 °C heat treatment, and nanofluidic devices based on the annealed nanochannel arrays still exhibit surface-charge-governed ion transport at low electrolyte concentrations. In addition, a drift–diffusion experiment is conducted to investigate the mobility ratio of cations/anions through the nanochannels with asymmetric bulk electrolyte concentrations, and the results show that the mobility of cations is about eight to nine times that of anions, which is consistent with the fact that the montmorillonite monolayers are negatively charged and the nanochannels are permselective. Last, ionic current rectification is observed in the nanofluidic system of asymmetric geometric shape, and rectification factors of ∼2.6 and ∼3.5 can be obtained in KCl and HCl electrolytes, respectively, at a bias between −1 and +1 V because of the asymmetric electrostatic potential through the nanochannels.
High-porosity, melt-focusing channel systems (comprising reactive dunite and its surrounding harzburgite) reflect an essential type of melt extraction within the mantle under mid-ocean ridges, ...proposed mainly by investigations of ophiolites produced in fast-spreading centers. However, relevant melt-migration processes from mantle wall rocks into dunitic channels under slow-ultraslow spreading centers and their effects are less well understood. We present systematic petrographic observations and whole-rock/mineral compositional analyses of a dunite-harzburgite channel system (∼250 m in width) within the Dazhuka mantle section (∼3–4 km thick) of the Xigaze ophiolite (South Tibet), produced in a Neo-Tethyan slow-ultraslow spreading center. The harzburgites, closely surrounding a dunite-rich zone, show large variations in pyroxene/olivine ratios (0.1–0.6), whole-rock MgO (41.2–45.9 wt%), Al2O3 (0.23–1.87 wt%) and CaO (0.38–2.80 wt%), as well as spinel Cr# (molar Cr3+/(Cr3++Al3+), 0.20–0.73) and pyroxene major and trace elements, almost covering the whole ranges of the Xigaze ophiolitic mantle. The harzburgites closer to the dunite-rich zone are gradually more depleted than those further ones, and finally replaced by the most depleted dunites. Modeling of decompressional melting from a depleted-MORB-mantle (DMM) source shows that the harzburgitic compositions correspond to melt depletion degrees of ∼6.9–19.2%, requiring a ∼30-km solely decompressional distance that is much greater than the sampling size of the channel system. It suggests that the wall-rock harzburgites can be produced by the reaction between high-fluxing, silica-undersaturated melts and the least-depleted harzburgites during the formation of reactive dunite-harzburgite channels. In addition, clinopyroxenes in dunites and some harzburgites show metasomatic enrichments, reflected in higher Na2O (up to 0.32 wt%), TiO2 (up to 0.17 wt%) and concentrations of Zr, Hf, light rare earth elements (LREE) and fluid-mobile elements relative to those in other harzburgites. These distinct signatures suggest the later localized metasomatism by batches of basaltic melts (some are volatile-rich) flowing through the harzburgitic wall rocks into the dunite-rich zone. We therefore propose that the dunite-harzburgite channel system archives at least the formation of reactive channels in deep upwelling asthenosphere during the high-melt-flux stage, and the subsequent metasomatic enrichments by basaltic melts reusing the channels in the shallow asthenosphere. The multistage and diverse melt-mantle interaction styles may characterize the melt extraction processes under oceanic slow-ultraslow spreading centers.
•A dunite-harzburgite channel system was identified in the Xigaze ophiolite (Tibet).•It records diverse melt-mantle interaction under slow-ultraslow spreading centers.•The melt extraction processes are distinct from those under fast-spreading centers.
Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the ...lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and β3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway.
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•Cold exposure increases 12-LOX activity in brown adipose tissue•12-LOX activity in BAT contributes to cold adaptation•12-HEPE is a cold-induced and BAT-secreted oxylipin•12-HEPE promotes glucose uptake in vivo and in vitro
Leiria et al. uncover a cold-induced response involving the activation of the enzyme 12-lipoxygenase in brown adipose tissue, which subsequently produces an omega-3 oxylipin 12-HEPE to promote glucose uptake into tissue via an insulin-like intracellular signaling pathway.
Forward osmosis (FO) is a promising membrane-based technology for water treatment and desalination. But, internal concentration polarization (ICP), a unique phenomenon in FO, generally leads to the ...sharp performance decline. In this study, a novel polyacrylonitrile (PAN) substrate with low polymer concentration (4 wt%) of the thin-film composite (TFC) membrane with a low membrane structural parameter (S) is developed with sodium chloride (NaCl) aqueous solution as the coagulation bath, and exhibits high performance for FO applications. The existence of NaCl in the coagulation bath not only affects the phase inversion process significantly, resulting in the formation of a thin substrate with finely tuned morphology structure, but also benefits the formation of a uniform and defect-free top polyamide (PA) layer. Effects of NaCl content in the coagulation bath on the morphology and intrinsic properties of resulting PAN substrates, the formed PA layer, as well as the morphology and FO performance of resulting TFC membranes, are investigated systematically. Moreover, an extended study on cellulose acetate (CA) substrate is also conducted to study the universality of this salt induction method to fabricate high-performance TFC membranes. Compared to the control TFC membrane, modified TFC membranes show much lower S parameters and superior separation performance with the higher water flux (324% increment) and lower reverse salt flux (58% reduction).
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•Substrates with low ICP were fabricated using salt-containing coagulation bath.•Modified substrates exhibit higher porosity, smaller thickness and large pore size.•TFC membranes with a modified substrate have rougher and thicker PA layers.•Modified TFC membrane possesses much higher water flux and lower reverse salt flux.•Modified TFC membrane has significantly lower structural parameter.
Brown fat is specialized for energy expenditure and has therefore been proposed to function as a defense against obesity. Despite recent advances in delineating the transcriptional regulation of ...brown adipocyte differentiation, cellular lineage specification and developmental cues specifying brown-fat cell fate remain poorly understood. In this study, we identify and isolate a subpopulation of adipogenic progenitors (Sca-1⁺/CD45⁻/Mac1⁻; referred to as Sca-1⁺ progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, although the ScaPCs from interscapular brown adipose tissue (BAT) are constitutively committed brown-fat progenitors, Sca-1⁺ cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with bone morphogenetic protein 7 (BMP7). Consistent with these findings, human preadipocytes isolated from subcutaneous white fat also exhibit the greatest inducible capacity to become brown adipocytes compared with cells isolated from mesenteric or omental white fat. When muscle-resident ScaPCs are re-engrafted into skeletal muscle of syngeneic mice, BMP7-treated ScaPCs efficiently develop into adipose tissue with brown fat-specific characteristics. Importantly, ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared with cells isolated from obesity-prone mice. These data establish the molecular characteristics of tissue-resident adipose progenitors and demonstrate a dynamic interplay between these progenitors and inductive signals that act in concert to specify brown adipocyte development.
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