The spatiotemporal control of ER membrane fragmentation during reticulophagy.

Reticulophagy is an evolutionarily conserved mechanism essential to maintain the endoplasmic reticulum (ER) homeostasis. A series of studies identified a panel of reticulophagy receptors. However, it remains unclear how these receptors sense upstream signals for spatiotemporal control of reticulophagy and how ER is fragmented into small pieces for sequestration into phagophores. Recently, we and others showed that the oligomerization of RETREG1/FAM134B (reticulophagy regulator 1), an reticulophagy receptor, triggers the scission of ER membrane to facilitate reticulophagy. Furthermore, we demonstrated that upstream signals are transduced by sequential phosphorylation and acetylation of RETREG1, which stimulate its oligomerization, ER fragmentation and reticulophagy. Our work provides further mechanistic insights into how reticulophagy receptor conveys cellular signals to fine-tune of ER homeostasis.Abbreviations: ER, endoplasmic reticulum; MAP1LC3, microtubule-associated protein light chain 3; RETREG1, reticulophagy regulator 1; RHD, reticulon-homology domain.

The immunogenicity of Alum+CpG adjuvant SARS-CoV-2 inactivated vaccine in mice.

The ongoing evolution and emergence of SARS-CoV-2 variants have raised concerns regarding the efficacy of existing vaccines and therapeutic agents. This study aimed to investigate the immunogenicity of an aluminum hydroxide (Alum) and CpG adjuvanted inactivated vaccine (IAV) candidate against SARS-CoV-2 in mice. A comparison was made between the immune response of mice vaccinated with the Alum+CpG adjuvant IAV and those vaccinated with the Alum adjuvant IAV. Mice immunized with Alum+CpG adjuvant IAV demonstrated high antibody titers and a durable humoral immune response, as well as a Th1-type cellular immune response. Notably, compared to Alum alone vaccine, the Alum+CpG adjuvant IAV induced significantly higher proportions of GC B cells in the splenocytes of immunized mice. Importantly, the changes in inflammatory cytokine levels in the sera of mice vaccinated with the Alum+CpG adjuvant IAV followed a similar trend to that of the Alum adjuvant IAV, which had been proven safe in clinical trials. Overall, our results demonstrate that Alum+CpG adjuvant has the potential to serve as a novel adjuvant, thereby providing valuable insights into the development of vaccine formulations.

A Variant of the Sulfoglycolytic Transketolase Pathway for the Degradation of Sulfoquinovose into Sulfoacetate.

Sulfoquinovose (SQ, 6-deoxy-6-sulfo-glucose) constitutes the polar head group of plant sulfolipids and is one of the most abundantly produced organosulfur compounds in nature. Degradation of SQ by bacterial communities contributes to sulfur recycling in many environments. Bacteria have evolved at least four mechanisms for glycolytic degradation of SQ, termed sulfoglycolysis, producing C3 sulfonate (dihydroxypropanesulfonate and sulfolactate) and C2 sulfonate (isethionate) by-products. These sulfonates are further degraded by other bacteria, leading to the mineralization of the sulfonate sulfur. The C2 sulfonate sulfoacetate is widespread in the environment and is also thought to be a product of sulfoglycolysis, although the mechanistic details are yet unknown. Here, we describe a gene cluster in an Acholeplasma sp., from a metagenome derived from deeply circulating subsurface aquifer fluids (GenBank accession no. QZKD01000037), encoding a variant of the recently discovered sulfoglycolytic transketolase (sulfo-TK) pathway that produces sulfoacetate instead of isethionate as a by-product. We report the biochemical characterization of a coenzyme A (CoA)-acylating sulfoacetaldehyde dehydrogenase (SqwD) and an ADP-forming sulfoacetate-CoA ligase (SqwKL), which collectively catalyze the oxidation of the transketolase product sulfoacetaldehyde into sulfoacetate, coupled with ATP formation. A bioinformatics study revealed the presence of this sulfo-TK variant in phylogenetically diverse bacteria, adding to the variety of mechanisms by which bacteria metabolize this ubiquitous sulfo-sugar. IMPORTANCE Many bacteria utilize environmentally widespread C2 sulfonate sulfoacetate as a sulfur source, and the disease-linked human gut sulfate- and sulfite-reducing bacteria can use it as a terminal electron receptor for anaerobic respiration generating toxic H2S. However, the mechanism of sulfoacetate formation is unknown, although it has been proposed that sulfoacetate originates from bacterial degradation of sulfoquinovose (SQ), the polar head group of sulfolipids present in all green plants. Here, we describe a variant of the recently discovered sulfoglycolytic transketolase (sulfo-TK) pathway. Unlike the regular sulfo-TK pathway that produces isethionate, our biochemical assays with recombinant proteins demonstrated that a CoA-acylating sulfoacetaldehyde dehydrogenase (SqwD) and an ADP-forming sulfoacetate-CoA ligase (SqwKL) in this variant pathway collectively catalyze the oxidation of the transketolase product sulfoacetaldehyde into sulfoacetate, coupled with ATP formation. A bioinformatics study revealed the presence of this sulfo-TK variant in phylogenetically diverse bacteria and interpreted the widespread existence of sulfoacetate.

The Scap-SREBP1-S1P/S2P lipogenesis signal orchestrates the homeostasis and spatiotemporal activation of NF-κB.

The nuclear factor κB (NF-κB) pathway plays essential roles in innate and adaptive immunity, but little is known how NF-κB signaling is compartmentalized and spatiotemporally activated in the cytoplasm. Here, we show that the lipogenesis signal cascade Scap-SREBP1-S1P/S2P orchestrates the homeostasis and spatiotemporal activation of NF-κB. SREBP cleavage-activating protein (Scap) and sterol regulatory element-binding protein 1 (SREBP1) form a super complex with inhibitors of NF-κB α (IκBα) to associate NF-κB close to the endoplasmic reticulum (ER). Upon lipopolysaccharide (LPS) stimulation, Scap transports the complex to the Golgi apparatus, where SREBP1 is cleaved by site-1 protease (S1P)/S2P, liberating IκBα for IκB kinase (Ikk)-mediated phosphorylation and subsequent activation of NF-κB. Loss of Scap or inhibition of S1P or S2P diminishes, while SREBP1 deficiency augments, LPS-induced NF-κB activation and subsequent inflammatory responses. Our results reveal the Scap-SREBP1 complex as an additional cytoplasmic checkpoint for NF-κB homeostasis and unveil the Golgi apparatus as the optimal cellular platform for NF-κB activation, providing insights into the crosstalk between lipogenesis signaling and immunity.

Meg8-DMR as the Secondary Regulatory Region Regulates the Expression of MicroRNAs While It Does Not Affect Embryonic Development in Mice.

Meg8-DMR is the first maternal methylated DMR to be discovered in the imprinted Dlk1-Dio3 domain. The deletion of Meg8-DMR enhances the migration and invasion of MLTC-1 depending on the CTCF binding sites. However, the biological function of Meg8-DMR during mouse development remains unknown. In this study, a CRISPR/Cas9 system was used to generate 434 bp genomic deletions of Meg8-DMR in mice. High-throughput and bioinformatics profiling revealed that Meg8-DMR is involved in the regulation of microRNA: when the deletion was inherited from the mother (Mat-KO), the expression of microRNA was unchanged. However, when the deletion occurred from the father (Pat-KO) and homozygous (Homo-KO), the expression was upregulated. Then, differentially expressed microRNAs (DEGs) were identified between WT with Pat-KO, Mat-KO, and Homo-KO, respectively. Subsequently, these DEGs were subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) term enrichment analysis to explore the functional roles of these genes. In total, 502, 128, and 165 DEGs were determined. GO analysis showed that these DEGs were mainly enriched in axonogenesis in Pat-KO and Home-KO, while forebrain development was enriched in Mat-KO. Finally, the methylation levels of IG-DMR, Gtl2-DMR, and Meg8-DMR, and the imprinting status of Dlk1, Gtl2, and Rian were not affected. These findings suggest that Meg8-DMR, as a secondary regulatory region, could regulate the expression of microRNAs while not affecting the normal embryonic development of mice.

A regulatory circuit comprising the CBP and SIRT7 regulates FAM134B-mediated ER-phagy.

Macroautophagy (autophagy) utilizes a serial of receptors to specifically recognize and degrade autophagy cargoes, including damaged organelles, to maintain cellular homeostasis. Upstream signals spatiotemporally regulate the biological functions of selective autophagy receptors through protein post-translational modifications (PTM) such as phosphorylation. However, it is unclear how acetylation directly controls autophagy receptors in selective autophagy. Here, we report that an ER-phagy receptor FAM134B is acetylated by CBP acetyltransferase, eliciting intense ER-phagy. Furthermore, FAM134B acetylation promoted CAMKII-mediated phosphorylation to sustain a mode of milder ER-phagy. Conversely, SIRT7 deacetylated FAM134B to temper its activities in ER-phagy to avoid excessive ER degradation. Together, this work provides further mechanistic insights into how ER-phagy receptor perceives environmental signals for fine-tuning of ER homeostasis and demonstrates how nucleus-derived factors are programmed to control ER stress by modulating ER-phagy.

Construction of Development Momentum Index of Financial Technology by Principal Component Analysis in the Era of Digital Economy.

The purpose is to study applying mathematical analysis in financial technology (FinTech) development in the era of digital economy. An Evaluation Index System (EIS) for the current situation of Chinese FinTech enterprises is established by considering the impact of the era of the digital economy on the development of FinTech. Specifically, the Principal Component Analysis (PCA) is introduced to construct the principal component prediction model based on functional data. Then, six Chinese State-owned Enterprises (SOEs) are selected. Their stock prices are predicted using the proposed model through an empirical study. The results show that selecting three principal components to evaluate the financial situations of six SOEs is reasonable. The accumulated variance values of the first three principal components of the stock's closing price and opening price are all greater than 85%. Thus, the selected three principal components can obtain the potential information of the original data. The gap between the actual value and the proposed model-predicted value of the stocks of the six SOEs is relatively small. The Root Mean Square Error (RMSE) of China National Petroleum Corporation (CNPC) is 0.105, more than 10%. The predicted values of Huadian Energy and China Shenhua are 9.4% and 8.5%, respectively, second only to CNPC. Therefore, the proposed principal component prediction model based on functional data can predict the closing price of stocks well. The accuracy is relatively high and matches well with financial data analysis. This research has important implications for the development of FinTech.

Myocarditis in children after COVID-19 vaccine.

Three healthy adolescents presented with myocarditis confirmed on cardiac magnetic resonance imaging after receiving Pfizer-BioNTech COVID-19 vaccine. All patients were hemodynamically stable and had good short-term outcomes. Long-term outcomes are yet to be determined. Larger studies are needed to determine whether an association between Pfizer-BioNTech COVID-19 vaccine and myocarditis exists.

Investigation on a Zr-based metal-organic framework (MOF-801) for the high-performance separation of light alkanes.

A Zr-based metal-organic framework (MOF-801) with high thermal and chemical stability was prepared by the solvothermal synthesis method. Notably, MOF-801 exhibits a high separation selectivity for C3H8/CH4 and C2H6/CH4, making it a practical material for the storage and purification of light alkanes.

The Critical Role of Additive Sulfate for Stable Alkaline Seawater Oxidation on Nickel-Based Electrodes.

Seawater electrolysis to produce hydrogen is a critical technology in marine energy projects; however, the severe anode corrosion caused by the highly concentrated chloride is a key issue should be addressed. In this work, we discover that the addition of sulfate in electrolyte can effectively retard the corrosion of chloride ions to the anode. We take nickel foam as the example and observe that the addition of sulfate can greatly improve the corrosion resistance, resulting in prolonged operating stability. Theoretical simulations and in situ experiments both demonstrate that sulfate anions can be preferentially adsorbed on anode surface to form a negative charge layer, which repulses the chloride ions away from the anode by electrostatic repulsion. The repulsive effect of the adsorbed sulfate is also applicable in highly-active catalyst (nickel iron layered double hydroxide) on nickel foam, which shows ca. 5 times stability of that in traditional electrolyte.

MRD abnormal expression predict poor outcomes for refractory or relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation.

We retrospectively analyzed data from 197 patients with refractory or relapsed acute myeloid leukemia (r/rAML) who underwent allo-HCT between January 2013 and February 2020 in our center (patients with promyelocytic leukemia were excluded). Of all patients, 86 achieved a complete morphological remission (CR) before transplant, while 111 failed to do so (NR). In the CR group, 32 patients displayed minimal residual disease (MRD-positive). According to their immunophenotype pre-HCT, we divided the MRD-positive group and NR group into three subgroups: MRD 0+ group (without any antigen abnormal expression of CD7+, CD56+, CD38-, or HLA-DR-) 28 patients, MRD 1+ group (with one abnormal antigen expression of CD7+, CD56+, CD38-, or HLA-DR-) 63 patients, MRD 2+ group (with two or more abnormal antigens expression of CD7+, CD56+, CD38-, or HLA-DR-) 52 patients. 3-year estimates of disease-free survival (DFS) for MRD 0+, MRD 1+ and MRD 2+ patients were 59.5 ± 9.5%, 29.9 ± 6.1%, and 9.4 ± 5.1%, and 3-year estimates of overall survival (OS) were 59.5 ± 9.5%, 34.5 ± 6.3%, and 14.5 ± 10.8%, respectively. Multivariate analysis adjusted for genetic risk, blast cell level, secondary disease, age, sex, and donor relationship pre-HCT, the hazard ratios of abnormal expression of CD7+, CD56+, HLA-DR-, and CD38- were 6.69 (range 2.08-21.52; p = 0.001) for DFS, 2.24 (range 1.21-4.14; p = 0.010) for OS, and 7.18 (range 2.23-23.10; p = 0.001) for relapse compared with CD7-, CD56-, HLA-DR+, and CD38+ patients. Our finding suggested that abnormal expression of CD7+, CD56+, HLA-DR-, and CD38- is associated with poor outcomes, and the more number of abnormal antigens expression predict worse outcomes.

Influence of three different anesthesia protocols on aged rat brain: a resting-state functional magnetic resonance imaging study.

BACKGROUND: Resting-state functional magnetic resonance imaging (rs-fMRI) is a promising method for the study of brain function. Typically, rs-fMRI is performed on anesthetized animals. Although different functional connectivity (FC) in various anesthetics on whole brain have been studied, few studies have focused on different FC in the aged brain. Here, we measured FC under three commonly used anesthesia methods and analyzed data to determine if the FC in whole brain analysis were similar among groups. METHODS: Twenty-four male aged Wistar rats were randomly divided into three groups (n = 8 in each group). Anesthesia was performed under either isoflurane (ISO), combined ISO + dexmedetomidine (DEX) or α-chloralose (AC) according to the groups. Data of rs-fMRI was analyzed by FC in a voxel-wise way. Differences in the FC maps between the groups were analyzed by one-way analysis of variance and post hoc two-sample t tests. RESULTS: Compared with ISO + DEX anesthesia, ISO anesthesia caused increased FC in posterior brain and decreased FC in the middle brain of the aged rat. AC anesthesia caused global suppression as no increase in FC was observed. CONCLUSION: ISO could be used as a substitute for ISO + DEX in rat default mode network studies if the left temporal association cortex is not considered important.

Ammonia Thermal Treatment toward Topological Defects in Porous Carbon for Enhanced Carbon Dioxide Electroreduction.

Topological defects, with an asymmetric local electronic redistribution, are expected to locally tune the intrinsic catalytic activity of carbon materials. However, it is still challenging to deliberately create high-density homogeneous topological defects in carbon networks due to the high formation energy. Toward this end, an efficient NH3 thermal-treatment strategy is presented for thoroughly removing pyrrolic-N and pyridinic-N dopants from N-enriched porous carbon particles, to create high-density topological defects. The resultant topological defects are systematically investigated by near-edge X-ray absorption fine structure measurements and local density of states analysis, and the defect formation mechanism is revealed by reactive molecular dynamics simulations. Notably, the as-prepared porous carbon materials possess an enhanced electrocatalytic CO2 reduction performance, yielding a current density of 2.84 mA cm-2 with Faradaic efficiency of 95.2% for CO generation. Such a result is among the best performances reported for metal-free CO2 reduction electrocatalysts. Density functional theory calculations suggest that the edge pentagonal sites are the dominating active centers with the lowest free energy (ΔG) for CO2 reduction. This work not only presents deep insights for the defect engineering of carbon-based materials but also improves the understanding of electrocatalytic CO2 reduction on carbon defects.

FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy.

Degradation of endoplasmic reticulum (ER) by selective autophagy (ER-phagy) is crucial for ER homeostasis. However, it remains unclear how ER scission is regulated for subsequent autophagosomal sequestration and lysosomal degradation. Here, we show that oligomerization of ER-phagy receptor FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its reticulon-homology domain is required for membrane fragmentation in vitro and ER-phagy in vivo. Under ER-stress conditions, activated CAMK2B phosphorylates the reticulon-homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER-phagy. Unexpectedly, FAM134B G216R, a variant derived from a type II hereditary sensory and autonomic neuropathy (HSAN) patient, exhibits gain-of-function defects, such as hyperactive self-association and membrane scission, which results in excessive ER-phagy and sensory neuron death. Therefore, this study reveals a mechanism of ER membrane fragmentation in ER-phagy, along with a signaling pathway in regulating ER turnover, and suggests a potential implication of excessive selective autophagy in human diseases.

[A new napthalenone from roots of Rumex nepalensis].

A new napthalenone, rumexone A (1), was isolated from the roots of Rumex nepalensis. The structure of 1 was elucidated by extensive spectroscopic analyses, including 1D and 2D NMR spectra and MS data. Its cytotoxic effect was evaluated using four clinically relevant human cancer cell lines, gastric carcinoma SGC7901, breast carcinoma MDA-MB-231, lung carcinoma A549, and hepatocellular carcinoma HepG2.

[Investigation of original materials under traditonal Chinese medicine names of "Jinchai" and "Jinchai Shihu"].

To clear from botanical view the original materials under the traditional Chinese medicine names of "Jinchai", "Jinchai Shihu" within the genus Dendrobium of the family Orchidaceae. Combined of different methods including study of historical records from the local chronicles and historical accounts of past event in Hubei, Sichuan, Chongqing, Henan and Shaanxi provinces, interviewing face to face with the old traditional Chinese workers and folk doctors in 20 downtowns and countrysides, such as, Laohekou, Lichuan, Fangxian, Xixia, Neixiang, and Ankang, and collecting a few plants of "Jinchai" for taxonomic identification. The traditional Chinese medicine names of "Jinchai", "Jinchai Shihu" were widely used by the local people from the eastern Chongqing, western Hubei, northeasten Sichuan, southeastern Shaanxi, western Henan. Those two names were frequently found in the local Chronicles and historical accounts of past event, even in the local daily life such as folk songs and stories. The botanical identification results showed that a endemic species of D. flexicaule is the original materials of the traditional Chinese medicine names "Jinchai" and "Jinchai Shihu", and this species are also called "Longtoujin", "Renzijin", "Huanzijin" and "Longtoufengweijin" by the local people. The dried artifactitious specimens of D. flexicaule are traditionally named as "Jinerhuan". The botanic resource plants of the traditional Chinese medicine names of "Jinchai", "Jinchai Shihu" are the endemic species of D. flexicaule that is distributed mainly in central areas of China including eastern Chongqing, western Hubei, northeasten Sichuan, southeastern Shaanxi, and western Henan, rather than D. nobile as referring in both Chinese and English version of Flora of China, and in official recorded serious versions of The Chinese Pharmacopoeia since 1977. In order to avoid confusion in the traditional Chinese medicine dendrobiums industry, the Chinese name of D. nobile is suggested as "Biancao Shihu", which characterized one stem feature of this species, and the traditional Chinese medicine names "Jinchai" or "JinchaiShihu" is suggested to refer to the species D. flexicaule.

Depletion of DSS1 protein disables homologous recombinational repair in human cells.

DSS1 is a small, highly acidic protein widely conserved among eukaryotes as a component of the 19S proteasome and implicated in ubiquitin-mediated proteolysis. The BRCA2 tumor suppressor protein functions in homologous recombinational repair (HRR) of DNA double-strand breaks, and does so in part through the actions of a carboxy-proximal region that binds DNA and several other proteins, including DSS1. In the unicellular eukaryote Ustilago maydis, Dss1 interacts with Brh2, a BRCA2-like protein, and regulates its function in mediating HRR. We used RNA interference to deplete DSS1 in human cells, and assayed the effects on double-strand break repair by homologous recombination. Partial depletion of DSS1 protein in human cells reduced the efficiency of HRR to small fractions of normal levels. Residual HRR activity correlated roughly with the residual level of DSS1 expression. The results imply that mammalian DSS1 makes a critical contribution to the function of BRCA2 in mediating HRR, and hence to genomic stability. Activity of the ubiquitin-proteasome system can influence HRR. However, treatment with proteasome inhibitors only partially reproduced the effects of DSS1 depletion on HRR, suggesting that the function of DSS1 in HRR involves more than proteolysis per se.