Chronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks ...that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, including cholesterol and glucose metabolism in the liver, resolution of endoplasmic reticulum stress, intestinal glucocorticoid production, pancreatic development and acinar differentiation. In genome-wide association studies, single nucleotide polymorphisms in the vicinity of NR5A2 have previously been associated with the risk of pancreatic adenocarcinoma. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration and cooperates with mutant Kras in tumour progression. Here, using a global transcriptomic analysis, we describe an epithelial-cell-autonomous basal pre-inflammatory state in the pancreas of Nr5a2
mice that is reminiscent of the early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreases with reduced expression of NR5A2 mRNA. In Nr5a2
mice, NR5A2 undergoes a marked transcriptional switch, relocating from differentiation-specific to inflammatory genes and thereby promoting gene transcription that is dependent on the AP-1 transcription factor. Pancreatic deletion of Jun rescues the pre-inflammatory phenotype, as well as binding of NR5A2 to inflammatory gene promoters and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programmes. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.
Cutaneous sclerosis is one of the most common clinical manifestations of chronic graft-versus-host disease (cGVHD). Donor CD4+ T and B cells play important roles in cGVHD pathogenesis, but the role ...of antibodies from donor B cells remains unclear. In the current studies, we generated immunoglobulin (Ig)Hµγ1 DBA/2 mice whose B cells have normal antigen-presentation and regulatory functions but cannot secrete antibodies. With a murine cGVHD model using DBA/2 donors and BALB/c recipients, we have shown that wild-type (WT) grafts induce persistent cGVHD with damage in the thymus, peripheral lymphoid organs, and skin, as well as cutaneous T helper 17 cell (Th17) infiltration. In contrast, IgHµγ1 grafts induced only transient cGVHD with little damage in the thymus or peripheral lymph organs or with little cutaneous Th17 infiltration. Injections of IgG-containing sera from cGVHD recipients given WT grafts but not IgG-deficient sera from recipients given IgHµγ1 grafts led to deposition of IgG in the thymus and skin, with resulting damage in the thymus and peripheral lymph organs, cutaneous Th17 infiltration, and perpetuation of cGVHD in recipients given IgHµγ1 grafts. These results indicate that donor B-cell antibodies augment cutaneous cGVHD in part by damaging the thymus and increasing tissue infiltration of pathogenic Th17 cells.
•Antibodies produced by donor B cells are required for thymic and lymphoid damage in mice with chronic GVHD.•Antibody-producing donor B cells associate with infiltration of Th17 cells in the skin and perpetuation of cutaneous chronic GVHD in mice.
Closed and semi-closed pyrolysis of a lacustrine shale sample was conducted using the same instrument characterized by lithostatic pressure and limited reactive space in order to unravel the impacts ...of the system sealing capacity on organic matter occurrence and nanopore development in shales under conditions analogous to natural processes. The solid residues were subjected to organic geochemical measurements, low-pressure gas (N2 and CO2) adsorption tests, and field emission-scatter electrical microscope analysis. The results revealed that solvent extraction played positive and negative roles in the pore development of solid residues from both systems at different thermal maturities. Inorganic and organic pores were primarily filled or shielded by soluble bitumen at low and high temperatures, respectively. The occurrences of organic matter in solid residues from the two systems were different at lower temperatures but gradually evolved similarly at higher temperatures and were dominated by nanoscale interparticle organic matter. Organic pore occurrence in solid residues from the two systems was approximately comparable. However, differences in pore volume and specific surface area of solid residues from the closed and semi-closed systems increased measurably below 550 °C. At 550 °C, a strong mechanical compaction and overpressure environment caused deformation and closure of pores surrounding rigid minerals and pores associated with ductile minerals surrounding organic matter in solid residue from the closed system, while only a few pores surrounding rigid minerals from the semi-closed system deformed. Consequently, similar pore parameters of solid residues from the two systems were obtained at this temperature. Additionally, the variation in organic porosity of solid residues from the two systems has obvious stages based on mass balance calculation. The organic porosity evolution is collectively affected by system sealing capacity and thermal maturity at lower matured stages. In contrast, organic porosity evolution in solid residues is independent of system sealing capacity at high- and overmatured stages. Although the depositional environment is different, this study provides direct evidence that the difference in system sealing capacity is not the predominant factor leading to different organic pore developments in the Silurian and Cambrian shales in South China.
•Closed and semi-closed pyrolysis were conducted under conditions analogous to geology.•Pore development in solid residues before and after solvent extraction were compared.•Pore developments in solid residues were affected by system sealing capacity as temperatures < 550 °C.•The system sealing capacity and thermal maturity controlled the evolution of organic porosity at different stages.
Closed and semi-closed pyrolysis of a lacustrine shale sample were conducted using the same instrument characterized by lithostatic pressure and limited reactive space in order to unravel the impacts ...of system sealing capacity on organic matter evolution and hydrocarbon generation in shales under conditions analogous to natural processes. The products and solid residues were subjected to chemical composition determination, gaseous carbon isotopic composition analysis, solvent extraction, and Rock-Eval pyrolysis. Higher organic matter transformation and oil retention contents were obtained at 300–500 °C in the closed pyrolysis system compared to those in the semi-closed system at the same temperature ranges. However, lower yields of hydrocarbons except for methane were obtained in the closed system at this temperature range, while the iso-/n-C4,5 as well as C1/C1-5 values were significantly higher in this system. Stronger recombined reactions between kerogen and hydrocarbons were proposed to occur at 300–500 °C during the closed pyrolysis process, leading to the consumption of oil and hydrocarbon gases. Ultimately, positive deviations of initially more negative δ13C2∼3 values were occurred in the closed system, resulting in similar δ13C2∼3 values from the two systems before secondary cracking of hydrocarbon gases commences, but the δ13C1 value from the closed system was overall more negative. Different water retention ratios and hydrocarbon expulsion efficiencies induced by system sealing capacity are the predominant factor controlling organic matter evolution and petroleum generation during the pyrolysis processes. This highlights that the different gas contents of the Cambrian and Silurian shales in South China may be associated with the differences in the system sealing capacities of shales, although the sedimentary environment of the studied sample is lacustrine, and the lower methane content of the Cambrian shale gas is probably ascribed to semi-closed system. Finally, a higher ratio of oil cracking gas may be an important signal for natural gas systems that have better exploration potential.
•Closed and semi-closed pyrolysis were conducted under conditions analogous to geology.•Organic matter transformation and petroleum generation were different in the two systems.•Ratio of oil cracking gas was associated with potential and prospect of natural gas exploration.
The novel coronavirus disease 2019 (COVID-19) pandemic has become a challenge for nursing homes in China. Nursing homes are particularly dangerous places in terms of the spread of COVID-19 given that ...they house vulnerable, high-risk populations. As such, several useful guidelines for coping with COVID-19 in nursing homes have been provided. However, the actual implementation rates of such guidelines are unknown. This study aims to document the adherence of nursing homes to the Ministry of Civil Affairs guidelines for COVID-19 prevention and control in nursing homes.
A cross-sectional study was conducted among 484 nursing homes in 136 cities of 28 provinces in China. A self-report questionnaire was created based on the Ministry of Civil Affairs guidelines for COVID-19 prevention and control in nursing homes (first edition). The questionnaire and the Transformational Leadership in the Public Sector Scale were sent to nursing home managers via the Wenjuanxing app online from February 7 to 29, 2020. Ultimately, 461 of 960 nursing homes participated, for a response rate of 48.0%.
The average overall implementation rate of COVID-19 prevention and control measures was 80.0% (143.97/180). The average implementation rates for hygienic behaviour management and access management were lower, at 75.3 and 78.7%, respectively. Number of medical staff and transformational leadership score of nursing home's manager were associated with total implementation score (p < 0.05). A total of 69.8% (322/461) of the nursing home managers had serious resource problems, and inadequate protective supplies (72.0%) and staff shortages (47.7%) were the two primary problems. The nursing homes that located in urban, with large nursing home size, had hospital-nursing home cooperation and the transformational leadership score of manager> 60, had a lower risk of having serious resource problems.
Overall, the implementation of prevention and control measures by nursing homes are insufficient during the epidemic in China. More medical staff, adequate resource, cooperation with hospitals, and higher transformational leadership of manager are required to improve the implementation rate. It is urgent for nursing homes to maintain the safety of residents and staff.
Abstract
Magnesium is an essential ion for numerous physiological processes. MgtE is a Mg
2+
selective channel involved in the maintenance of intracellular Mg
2+
homeostasis, whose gating is ...regulated by intracellular Mg
2+
levels. Here, we report that ATP binds to MgtE, regulating its Mg
2+
-dependent gating. Crystal structures of MgtE–ATP complex show that ATP binds to the intracellular CBS domain of MgtE. Functional studies support that ATP binding to MgtE enhances the intracellular domain affinity for Mg
2+
within physiological concentrations of this divalent cation, enabling MgtE to function as an in vivo Mg
2+
sensor. ATP dissociation from MgtE upregulates Mg
2+
influx at both high and low intracellular Mg
2+
concentrations. Using site-directed mutagenesis and structure based-electrophysiological and biochemical analyses, we identify key residues and main structural changes involved in the process. This work provides the molecular basis of ATP-dependent modulation of MgtE in Mg
2+
homeostasis.
To study the sedimentary environment of the Lower Cambrian organic-rich shales and isotopic geochemical characteristics of the residual shale gas, 20 black shale samples from the Niutitang Formation ...were collected from the Youyang section, located in southeastern Chongqing, China. A combination of geochemical, mineralogical, and trace element studies has been performed on the shale samples from the Lower Cambrian Niutitang Formation, and the results were used to determine the paleoceanic sedimentary environment of this organic-rich shale. The relationships between total organic carbon (TOC) and total sulfur (TS) content, carbon isotope value (δ13Corg), trace element enrichment, and mineral composition suggest that the high-TOC Niutitang shale was deposited in an anoxic environment and that the organic matter was well preserved after burial. Stable carbon isotopes and biomarkers both indicate that the organic matter in the Niutitang black shales was mainly derived from both lower aquatic organisms and algaes and belong to type I kerogen. The oil-prone Niutitang black shales have limited residual hydrocarbons, with low values of S2, IH, and bitumen A. The carbon isotopic distribution of the residual gas indicate that the shale gas stored in the Niutitang black shale was mostly generated from the cracking of residual bitumen and wet gas during a stage of significantly high maturity. One of the more significant observations in this work involves the carbon isotope compositions of the residual gas (C1, C2, and C3) released by rock crushing. A conventional δ13C1–δ13C2 trend was observed, and most δ13C2 values of the residual gases are heavier than those of the organic matter (OM) in the corresponding samples, indicating the splitting of ethane bonds and the release of smaller molecules, leading to 13C enrichment in the residual ethane.
•Niutitang black shales was mainly derived from both lower aquatic organisms and algaes and belong to type I kerogen.•Organic rich Niutitang shale was deposited in an anoxic environment.•Oil-prone Niutitang shale with high TOC abundance but very low residual hydrocarbon.•The retained gas show a conventional δ13C1–δ13C2 trend and most δ13C2 values are heavier than those of organic matter (OM).
The paleoceanic redox conditions and the vertical and spatial distribution of organic-matter-rich lower Cambrian Niutitang shales are varied in the Upper Yangtze region, China. An integrated ...approach, including organic geochemistry, major and trace elemental geochemistry, and X-ray diffraction (XRD) mineralogy, was used to characterize changes in redox conditions and to determine key controls on organic-matter accumulation during deposition of the lower Cambrian Niutitang shales. A 202-m-long cored well located in Kaiyang County in northern Guizhou, China, was thoroughly characterized by the integrated approach in this study. Vertically, total organic carbon (TOC-) rich siliceous and argillaceous black shales were developed in the Lower and Middle Niutitang Formation, and TOC-lean silty shales were found in the Upper Niutitang Formation. The TOC content in the Lower and Middle Niutitang shales ranges from 0.27% to 6.7%, with an average value of 2.1%, and it decreases from 0.30% to 0.11% in the Upper Niutitang Formation shales. The TOC-rich siliceous shales in the Lower Niutitang Formation were characterized by high total sulfur content, enrichment in redox-sensitive trace elements, high Corg:P ratios, and high authigenic MoU covariation, indicating they were deposited under persistent anoxic conditions. Most organic-rich shales from the Middle Niutitang Formation were deposited under anoxic conditions, whereas a few intervals having low TOC contents were deposited in a predominantly oxic depositional environment. In contrast, the Upper Niutitang Formation were deposited under fully oxic conditions. A combination of high primary productivity and enhanced organic preservation under euxinic water column conditions is the key control on organic-matter accumulation in the Lower Niutitang Formation shales. However, a coupling of redox depositional environment and terrestrial mineral dilution plays an important role in organic-matter accumulation and preservation in the Middle Niutitang Formation. Similar organic-matter abundance distribution and carbon isotope excursion of organic matter in the sediments deposited at different depositional facies on the Yangtze Platform suggest regional isotopically homogenous organic carbon input due to the widespread transgressive event with deep basinal waters being transported into the shallow shelf environments at the base of the lower Cambrian. As a result, δ13Corg distribution patterns can be used as a stratigraphic correlation marker in the Upper Yangtze region.
•Similar δ13Corg patterns as stratigraphic correlation marker in the Yangtze region.•Lower and Middle Niutitang TOC-rich shales were deposited under anoxic conditions.•MoU covariation indicates an unrestricted marine environment in the early Cambrian.•The controls on organic-matter richness in the Niutitang shales are different.
Normal early human B-cell development from lymphoid progenitors in the bone marrow depends on instructions from elements in that microenvironment that include stromal cells and factors secreted by ...these cells including the extracellular matrix. Glycosylation is thought to play a key role in such interactions. The sialyltransferase ST6Gal1, with high expression in specific hematopoietic cell types, is the only enzyme thought to catalyze the terminal addition of sialic acids in an α2-6-linkage to galactose on N-glycans in such cells. Expression of ST6Gal1 increases as B cells undergo normal B-lineage differentiation. B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) with differentiation arrest at various stages of early B-cell development have widely different expression levels of
at diagnosis, with high
in some but not in other relapses. We analyzed the consequences of increasing ST6Gal1 expression in a diagnosis sample using lentiviral transduction. NSG mice transplanted with these BCP-ALL cells were monitored for survival. Compared to mice transplanted with leukemia cells expressing original ST6Gal1 levels, increased ST6Gal1 expression was associated with significantly reduced survival. A cohort of mice was also treated for 7 weeks with vincristine chemotherapy to induce remission and then allowed to relapse. Upon vincristine discontinuation, relapse was detected in both groups, but mice transplanted with ST6Gal1 overexpressing BCP-ALL cells had an increased leukemia burden and shorter survival than controls. The BCP-ALL cells with higher ST6Gal1 were more resistant to long-term vincristine treatment in an
tissue co-culture model with OP9 bone marrow stromal cells. Gene expression analysis using RNA-seq showed a surprisingly large number of genes with significantly differential expression, of which approximately 60% increased mRNAs, in the ST6Gal1 overexpressing BCP-ALL cells. Pathways significantly downregulated included those involved in immune cell migration. However, ST6Gal1 knockdown cells also showed increased insensitivity to chemotherapy. Our combined results point to a context-dependent effect of ST6Gal1 expression on BCP-ALL cells, which is discussed within the framework of its activity as an enzyme with many N-linked glycoprotein substrates.
The prokaryotic mechanosensitive channel of large conductance (MscL) is a pressure-relief valve protecting the cell from lysing during acute osmotic downshock. When the membrane is stretched, MscL ...responds to the increase of membrane tension and opens a non-selective pore to about 30 Å wide, exhibiting a large unitary conductance of ∼3 nS. A fundamental step toward understanding the gating mechanism of MscL is to decipher the molecular details of the conformational changes accompanying channel opening. By applying fusion-protein strategy and controlling detergent composition, we have solved the structures of an archaeal MscL homolog fromMethanosarcina acetivoranstrapped in the closed and expanded intermediate states. The comparative analysis of these two new structures reveals significant conformational rearrangements in the different domains of MscL. The large changes observed in the tilt angles of the two transmembrane helices (TM1 and TM2) fit well with the helix-pivoting model derived from the earlier geometric analyses based on the previous structures. Meanwhile, the periplasmic loop region transforms from a folded structure, containing an ω-shaped loop and a short β-hairpin, to an extended and partly disordered conformation during channel expansion. Moreover, a significant rotating and sliding of the N-terminal helix (N-helix) is coupled to the tilting movements of TM1 and TM2. The dynamic relationships between the N-helix and TM1/TM2 suggest that the N-helix serves as a membrane-anchored stopper that limits the tilts of TM1 and TM2 in the gating process. These results provide direct mechanistic insights into the highly coordinated movement of the different domains of the MscL channel when it expands.
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