Clayey silt reservoirs bearing natural gas hydrates (NGH) are considered to be the hydrate-bearing reservoirs that boast the highest reserves but tend to be the most difficult to exploit. They are ...proved to be exploitable by the first NGH production test conducted in the South China Sea in 2017. Based on the understanding of the first production test, the China Geological Survey determined the optimal target NGH reservoirs for production test and conducted a detailed assessment, numerical and experimental simulation, and onshore testing of the reservoirs. After that, it conducted the second offshore NGH production test in 1225 m deep Shenhu Area, South China Sea (also referred to as the second production test) from October 2019 to April 2020. During the second production test, a series of technical challenges of drilling horizontal wells in shallow soft strata in deep sea were met, including wellhead stability, directional drilling of a horizontal well, reservoir stimulation and sand control, and accurate depressurization. As a result, 30 days of continuous gas production was achieved, with a cumulative gas production of 86.14 ×104 m3. Thus, the average daily gas production is 2.87 ×104 m3, which is 5.57 times as much as that obtained in the first production test. Therefore, both the cumulative gas production and the daily gas production were highly improved compared to the first production test. As indicated by the monitoring results of the second production test, there was no anomaly in methane content in the seafloor, seawater, and atmosphere throughout the whole production test. This successful production test further indicates that safe and effective NGH exploitation is feasible in clayey silt NGH reservoirs. The industrialization of hydrates consists of five stages in general, namely theoretical research and simulation experiments, exploratory production test, experimental production test, productive production test, and commercial production. The second production test serves as an important step from the exploratory production test to experimental production test.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Organometallic halide perovskite films with good surface morphology and large grain size are desirable for obtaining high‐performance photovoltaic devices. However, defects and related trap sites are ...generated inevitably at grain boundaries and on surfaces of solution‐processed polycrystalline perovskite films. Seeking facial and efficient methods to passivate the perovskite film for minimizing defect density is necessary for further improving the photovoltaic performance. Here, a convenient strategy is developed to improve perovskite crystallization by incorporating a 2D polymeric material of graphitic carbon nitride (g‐C3N4) into the perovskite layer. The addition of g‐C3N4 results in improved crystalline quality of perovskite film with large grain size by retarding the crystallization rate, and reduced intrinsic defect density by passivating charge recombination centers around the grain boundaries. In addition, g‐C3N4 doping increases the film conductivity of perovskite layer, which is beneficial for charge transport in perovskite light‐absorption layer. Consequently, a champion device with a maximum power conversion efficiency of 19.49% is approached owing to a remarkable improvement in fill factor from 0.65 to 0.74. This finding demonstrates a simple method to passivate the perovskite film by controlling the crystallization and reducing the defect density.
Graphitic carbon nitride (g‐C3N4) is incorporated into the perovskite precursor solution to modify the perovskite film by controlling the perovskite crystallization, reducing the intrinsic defect density, and improving the film conductivity. As a result, a champion device with a maximum power conversion efficiency of 19.49% is approached.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, ...China)
; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced CD4
and CD8
T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) plays a critical role in cancer metabolism by coordinating glycolysis and biosynthesis. A well-validated PGAM1 inhibitor, however, has not been ...reported for treating pancreatic ductal adenocarcinoma (PDAC), which is one of the deadliest malignancies worldwide. By uncovering the elevated PGAM1 expressions were statistically related to worse prognosis of PDAC in a cohort of 50 patients, we developed a series of allosteric PGAM1 inhibitors by structureguided optimization. The compound KH3 significantly suppressed proliferation of various PDAC cells by down-regulating the levels of glycolysis and mitochondrial respiration in correlation with PGAM1 expression. Similar to PGAM1 depletion, KH3 dramatically hampered the canonic pathways highly involved in cancer metabolism and development. Additionally, we observed the shared expression profiles of several signature pathways at 12 h after treatment in multiple PDAC primary cells of which the matched patient-derived xenograft (PDX) models responded similarly to KH3 in the 2 wk treatment. The better responses to KH3 in PDXs were associated with higher expression of PGAM1 and longer/stronger suppressions of cancer metabolic pathways. Taken together, our findings demonstrate a strategy of targeting cancer metabolism by PGAM1 inhibition in PDAC. Also, this work provided “proof of concept” for the potential application of metabolic treatment in clinical practice.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of ...hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value.
The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays.
NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model.
NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for ...COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC
between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.
The rapid outbreak of coronavirus disease 2019 (COVID-19) has been a matter of international concern as the disease is spreading fast 1, 2. Considering that the contagious disease has led to an ...enormous impact globally, there is an urgent need to identify the risk populations with poor prognosis. Ageing is associated with certain changes in pulmonary physiology, pathology and function, during the period of lung infection. Therefore, age-related differences in responsiveness and tolerance become obvious and lead to worse clinical outcomes in elderly individuals 3. Previous studies have mentioned that older COVID-19 patients are at an increased risk of death 4–7. However, the age-related clinical characteristics, disease courses and outcomes other than death in COVID-19 patients remain unclear.
Age significantly determined the clinical features and prognosis of COVID-19. The prognosis was worse in patients older than 60 years, calling for clinicians to pay more attention to patients of this age.
https://bit.ly/34DTI05
To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses.
A retrospective observational ...study was conducted in 121 patients (2016-2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B).
Among cohort A (male:female=79:42; median age: 42 (14-78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00-5352.00) vs 700.00 (76.70-2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.500.13-0.94 vs 0.600.26-1.23,
=0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0-6) vs 0 (0-3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031).
Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.
Abstract
In this paper, we model the dynamics and radiation physics of the rarity event GRB 221009A afterglow in detail. By introducing a top-hat jet that propagates in an environment dominated by ...stellar winds, we explain the publicly available observations of afterglow associated with GRB 221009A over the first week. It is predicted that GRB 221009A emits a luminous very high energy afterglow based on the synchrotron self-Compton (SSC) process in our model. We show the broadband spectral energy distribution (SED) analysis results of GRB 221009A and find that the SSC radiation component of GRB 221009A is very bright in the 0.1–10 TeV band. The integrated SED shows that the SSC emission in the TeV band has detection sensitivity significantly higher than that of LHASSO, MAGIC, and CTA. However, since the release of further observations, deviations from the standard wind environment model have gradually shown up in data. For example, the late-time multiband afterglow cannot be consistently explained under the standard wind environment scenario. It may be necessary to consider modeling with a structured jet with complex geometry or a partial revision of the standard model. Furthermore, we find that the inclusion of GeV observations could break the degeneracy between model parameters, highlighting the significance of high-energy observations in determining accurate parameters for GRB afterglows.
Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like α-smooth muscle actin (ACTA2). ...Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization. HKB99 acted to allosterically block conformational change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99 suppressed tumor growth and metastasis and overcame erlotinib resistance in non-small-cell lung cancer (NSCLC). Mechanistically, HKB99 enhanced the oxidative stress and altered multiple signaling pathways including the activation of JNK/c-Jun and suppression of AKT and ERK. Collectively, the study highlights the potential of PGAM1 as a therapeutic target in NSCLC and reveals a distinct mechanism by which HKB99 inhibits both metabolic activity and nonmetabolic function of PGAM1 by allosteric regulation.
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•A PGAM1 allosteric inhibitor HKB99 is developed via structure-based optimization•HKB99 modulates PGAM1 both in its catalytic process and ACTA2 interaction•HKB99 suppresses NSCLC growth and metastasis through allosteric PGAM1 regulation•PGAM1 is a potential therapeutic target in NSCLC
PGAM1 plays a critical role in cancer cell metabolism. Huang et al. discovered a novel PGAM1 inhibitor HKB99, which allosterically blocks the structure of PGAM1, impacting both its catalytic activity and ACTA2 interaction. HKB99 significantly inhibits NSCLC tumor growth and metastasis in vivo by impacting both PGAM1’s metabolic activity and nonmetabolic function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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