Chirality-driven strong thioredoxin reductase inhibition.

Overexpression of thioredoxin reductase (TXNRD) plays crucial role in tumorigenesis. Therefore, designing TXNRD inhibitors is a promising strategy for targeted anticancer drug development. However, poor selectivity has always been a challenge, resulting in unavoidable toxicity in clinic. Herein we demonstrate a strategy to develop highly selective chiral metal complexes-based TXNRD inhibitors. By manipulating the conformation of two distinct weakly interacting groups, we optimize the compatibility between the drug and the electrophilic group within the active site of TXNRD to enhance their non-covalent interaction, thus effectively avoids the poor selectivity deriving from covalent drug interaction, on the basis of ensuring the strong inhibition. Detailed experimental and computational results demonstrate that the chiral isomeric drugs bind to the active site of TXNRD, and the interaction strength is well modulated by chirality. Especially, the meso-configuration, in which the two large sterically hindered active groups are positioned on opposite sides of the drug, exhibits the highest number of non-covalent interactions and most effective inhibition on TXNRD. Taken together, this work not only provides a novel approach for developing highly selective proteinase inhibitors, but also sheds light on possible underlying mechanisms for future application.

Visual and refractive outcomes of opposite clear corneal incision combined with rotationally asymmetric multifocal intraocular lens implantation.

Purpose: To evaluate the visual and refractive outcomes of astigmatic cataract patients following opposite clear corneal incision (OCCI) combined with rotationally asymmetric multifocal intraocular lens (IOL) implantation. Setting: Department of Ophthalmology, Zhongshan Hospital (Xiamen), Fudan University, People's Republic of China. Design: Retrospective cohort study. Methods: This study comprised 58 cataract eyes of 54 patients with corneal astigmatism who underwent phacoemulsification and rotationally asymmetric multifocal IOL implantation which received either OCCI (OCCI group) or a single clear corneal incision (SCCI group). The follow-up period was 3 months after surgery. Distance, intermediate and near visual acuity, refractive outcomes, and corneal anterior keratometry were compared between the two groups. Vector analysis was used to evaluate astigmatism correction. Results: Three months after surgery, the distance, intermediate and near visual acuity, and sphere remained comparable between the two groups, but a significant difference was detected in residual astigmatism and anterior corneal keratometric astigmatism. In the OCCI group, the residual astigmatism and keratometric astigmatism were -0.60 ± 0.29 D and 0.59 ± 0.28 D, respectively, which were lower than those in SCCI groups (-1.18 ± 0.47 D and 1.15 ± 0.45 D, both p < 0.05). In vector analysis, the difference vector (DV), angle of error (AoE), absolute AoE, index of success (IoS) and correction index (CI) were statistically significantly different between the two groups (p < 0.05). Conclusion: OCCI combined with rotationally asymmetric multifocal intraocular lens implantation showed predictable and desirable efficacy in treating cataract patients with astigmatism.

EPSTI1 promotes osteoclast differentiation and bone resorption by PKR/NF-κB signaling.

BACKGROUND: Epithelial stromal interaction 1 (EPSTI1) plays an important role in M1 macrophages, which induce osteoclastogenesis. One recent genome-wide association study (GWAS) involving 426,824 individuals has shown that EPSTI1 is strongly associated with osteoporosis (P < 5E-8). Therefore, we speculate that EPSTI1 participates in the modulation of osteoporosis through osteoclastogenesis. The roles of EPSTI1 in osteoclastogenesis and bone resorption remain unclear. METHODS: Femur specimens were collected from osteoporotic patients and control patients. Immunofluorescence staining was used to detect the expression of EPSTI1 and signaling pathways. The osteoclastic potential of RAW264.7 cells with Sh-EPSTI1 lentivirus infection was tested using tartrate-resistant acid phosphatase (TRAP) staining, western blotting, and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Western blotting was also used to examine signaling pathways. RESULTS: In this study, EPSTI1 was found to be significantly increased in tartrate-resistant acid phosphatase positive (ACP5+) osteoclasts of bone sections from osteoporotic patients. Next, we identified EPSTI1 as a positive regulator of osteoclastogenesis and osteoclast differentiation capability. Diminished EPSTI1 expression resulted in reduced osteoclastic resorption. Mechanistically, EPSTI1-driven osteoclastogenesis was regulated by NF-κB pathway, which was mediated by the phosphorylation of protein kinase R (p-PKR). Furthermore, EPSTI1 participating in the modulation of osteoporosis via PKR/NF-κB pathway was also verified in the bone samples of osteoporotic patients. CONCLUSIONS: Collectively, our findings suggest that EPSTI1 may regulate osteoclast differentiation and bone resorption through PKR/NF-κB pathway and in vivo experiments are needed to further verify EPSTI1 as the therapy target for osteoporosis.

Global nitrous oxide emissions from livestock manure during 1890-2020: An IPCC tier 2 inventory.

Nitrous oxide (N2O) emissions from livestock manure contribute significantly to the growth of atmospheric N2O, a powerful greenhouse gas and dominant ozone-depleting substance. Here, we estimate global N2O emissions from livestock manure during 1890-2020 using the tier 2 approach of the 2019 Refinement to the 2006 IPCC Guidelines. Global N2O emissions from livestock manure increased by ~350% from 451 [368-556] Gg N year-1 in 1890 to 2042 [1677-2514] Gg N year-1 in 2020. These emissions contributed ~30% to the global anthropogenic N2O emissions in the decade 2010-2019. Cattle contributed the most (60%) to the increase, followed by poultry (19%), pigs (15%), and sheep and goats (6%). Regionally, South Asia, Africa, and Latin America dominated the growth in global emissions since the 1990s. Nationally, the largest emissions were found in India (329 Gg N year-1), followed by China (267 Gg N year-1), the United States (163 Gg N year-1), Brazil (129 Gg N year-1) and Pakistan (102 Gg N year-1) in the 2010s. We found a substantial impact of livestock productivity, specifically animal body weight and milk yield, on the emission trends. Furthermore, a large spread existed among different methodologies in estimates of global N2O emission from livestock manure, with our results 20%-25% lower than those based on the 2006 IPCC Guidelines. This study highlights the need for robust time-variant model parameterization and continuous improvement of emissions factors to enhance the precision of emission inventories. Additionally, urgent mitigation is required, as all available inventories indicate a rapid increase in global N2O emissions from livestock manure in recent decades.

Efficacy of borneol-gypsum in skin regeneration and pain control in toxic epidermal necrolysis: A case report.

BACKGROUND: Toxic epidermal necrolysis (TEN) is a life-threatening dermatological emergency mainly induced by drug hypersensitivity reactions. Standard management includes discontinuation of culprit drug and application of immunomodulatory therapy. However, mortality remains high due to complications like septic shock and multiorgan failures. Innovative approaches for skin care are crucial. This report introduces borneol-gypsum, a traditional Chinese drug but a novel dressing serving as an adjuvant of TEN therapy, might significantly improve skin conditions and patient outcomes in TEN. CASE SUMMARY: A 38-year-old woman diagnosed with eosinophilic granulomatosis with polyangiitis experienced gangrenous complications and motor nerve involvement. After initial treatment of high-dose corticosteroids and cyclophosphamide, symptom of foot drop improved, absolute eosinophil counts decreased, while limb pain sustained. Duloxetine was added to alleviate her symptom. Subsequently, TEN developed. Additional topical application of borneol-gypsum dressing not only protected the skin lesions from infection but also significantly eased localized pain. This approach demonstrated its merit in TEN management by promoting skin healing and potentially reducing infection risks. CONCLUSION: Borneol-gypsum dressing is a promising adjuvant that could significantly improve TEN management, skin regeneration, and patient comfort.

Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents.

The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC50 values at the nanomolar level. Impressively, the compound (S)-2a (10 µM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery.

miR-541 is associated with the prognosis of liver cirrhosis and directly targets JAG2 to inhibit the activation of hepatic stellate cells.

BACKGROUND: The activation of hepatic stellate cells (HSCs) has been emphasized as a leading event of the pathogenesis of liver cirrhosis, while the exact mechanism of its activation is largely unknown. Furthermore, the novel non-invasive predictors of prognosis in cirrhotic patients warrant more exploration. miR-541 has been identified as a tumor suppressor in hepatocellular carcinoma and a regulator of fibrotic disease, such as lung fibrosis and renal fibrosis. However, its role in liver cirrhosis has not been reported. METHODS: Real-time PCR was used to detect miR-541 expression in the liver tissues and sera of liver cirrhosis patients and in the human LX-2. Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the activation of LX-2. Bioinformatics analysis and a luciferase reporter assay were conducted to investigate the target gene of miR-541. RESULTS: miR-541 was downregulated in the tissues and sera of patients with liver cirrhosis, which was exacerbated by deteriorating disease severity. Importantly, the lower expression of miR-541 was associated with more episodes of complications including ascites and hepatic encephalopathy, a shorter overall lifespan, and decompensation-free survival. Moreover, multivariate Cox's regression analysis verified lower serum miR-541 as an independent risk factor for liver-related death in cirrhotic patients (HR = 0.394; 95% CI: 0.164-0.947; P = 0.037). miR-541 was also decreased in LX-2 cells activated by TGF-ß and the overexpression of miR-541 inhibited the proliferation, activation and hydroxyproline secretion of LX-2 cells. JAG2 is an important ligand of Notch signaling and was identified as a direct target gene of miR-541. The expression of JAG2 was upregulated in the liver tissues of cirrhotic patients and was inversely correlated with miR-541 levels. A rescue assay further confirmed that JAG2 was involved in the function of miR-541 when regulating LX-2 activation and Notch signaling. CONCLUSIONS: Dysregulation of miR-541/JAG2 axis might be a as a new mechanism of liver fibrosis, and miR-541 could serve as a novel non-invasive biomarker and therapeutic targets for liver cirrhosis.

Reproducible and High-Performance WOLEDs Based on Independent High-Efficiency Triplet Harvesting of Yellow Hot-Exciton ESIPT and Blue TADF Emitters.

Hot exciton organic light-emitting diode (OLED) emitters can balance the high performance of a device and reduce efficiency roll-off by fast reverse intersystem crossing from high-lying triplets (hRISC). In this study, an excited-state intramolecular proton transfer (ESIPT) fluorophore of 2-(benzo[d]thiazol-2-yl)-4-(pyren-1-yl)phenol (PyHBT) with the typical characteristic properties of a hot exciton is developed. With high efficiency of utilization of the exciton (91%), its yellow OLED exhibited high external quantum efficiency (EQE) of 5.6%, current efficiency (CE) of 16.8 cd A-1 , and power efficiency (PE) of 17.3 lm W-1 . The performance of the yellow emissive "hot exciton" ESIPT fluorophores is among the highest recorded. Due to the large Stokes shift of the ESIPT emitter, non-energy-transferred high-performance white OLEDs (WOLEDs) are developed, which are reproducible and highly efficient. This is possible because of the independent harvesting of most of the triplets in both complementary-color emitters without the interference of energy transfer. The PyHBT-based WOLEDs exhibit a maximum EQE of 14.3% and CE of 41.1 cd A-1 , which facilitates the high-yield mass production of inexpensive WOLEDs.

Comparative analysis of alternative splicing events in skeletal muscle of different sheep.

This paper aims to investigate the relationship between genes with alternative splicing (AS) events and breed-specific differences in muscle development in two breeds of sheep. RNA-seq was utilized to identify genes with AS between Small-tailed Han sheep and Dorset sheep. The gene lists of differentially spliced genes were identified, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted on these genes. In this study, 299 genes with 356 AS indicated significant differences between two diffrerent breeds. There are differences in 31 genes with 35 AS. Cassette, alt5' and alt3' exhibited the highest levels of enrichment across various significant levels. GO and KEGG enrichment analysis demonstrated a significant correlation between Wnt, TGF-beta, Notch and MAPK signaling pathways and the development of muscle in sheep. These findings indicate that genes with AS are linked to variations in muscle development in sheep. These results offer significant scientific and practical implications for improving the quality of sheep meat.

Investigation of novel 5'-amino adenosine derivatives with potential anti-Zika virus activity.

The Zika virus (ZIKV) infections remains a global health threat. However, no approved drug for treating ZIKV infection. We previously found TZY12-9, a 5'-amino NI analog, that showed anti-ZIKV activity without chemical phosphorylation. Here, a series of 5'-amino NI analogs were synthesized and evaluated. The compound XSJ2-46 exhibited potent in vitro activity without requiring chemical phosphorylation, favorable pharmacokinetic and acute toxicity profiles. Preliminary mechanisms of anti-ZIKV activity of XSJ2-46 were investigated via a series of ZIKV non-structural protein inhibition assays and host cell RNA-seq. XSJ2-46 acted at the replication stage of viral infection cycle, and exhibited reasonable inhibition of RNA-dependent RNA polymerases (RdRp) with an IC50 value of 8.78 µM, while not affecting MTase. RNA-seq analysis also revealed differential expression genes involved in cytokine and cytokine receptor pathway in ZIKV-infected U87 cells treated with XSJ2-46. Importantly, treatment with XSJ2-46 (10 mg/kg/day) significantly enhanced survival protection (70% survival) in ZIKV-infected ICR mice. Additionally, XSJ2-46 administration resulted in a significant decrease in serum levels of ZIKV viral RNA in the IFNα/ß receptor-deficient (Ifnar-/-) A129 mouse model. Therefore, the remarkable in vitro and in vivo anti-ZIKV activity of compound XSJ2-46 highlights the promising research direction of utilizing the 5'-amino NI structure skeleton for developing antiviral NIs.

Ciprofol versus propofol for sedation in gastrointestinal endoscopy: protocol for a systematic review and meta-analysis.

INTRODUCTION: Painless gastrointestinal endoscopy is being increasingly practised in the clinical field. The management and choice of sedation are important during the endoscopy procedure to reduce patient discomfort and facilitate high disease detection rates. Ciprofol is principally an agonist of the γ-aminobutyric acid type A receptor; it comprises the active ingredient HSK3486, which is similar to the currently used intravenous anaesthetic propofol in clinical practice. A systematic review and meta-analysis comparing ciprofol and propofol will be conducted to assess their efficacy and safety during endoscopy. Before starting the study, we describe the specific protocol of this systematic review. METHODS AND ANALYSIS: This protocol was prepared in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols 2015. The following databases will be searched: Embase, Cochrane Library, PubMed, Web of Science, Chinese Biomedical Literature Service System, China National Knowledge Infrastructure, Wanfang Database, China Science and Technology Journal Database and a clinical trial registry. The database search strategy will adopt a combination of subject words and free words. Randomised controlled trials related to ciprofol use for sedation during gastrointestinal endoscopy will also be included. Based on the inclusion and exclusion criteria, two researchers will independently screen the articles and extracted data. Following the qualitative evaluation of each study, analysis will be conducted using Review Manager software. ETHICS AND DISSEMINATION: The protocol for this systematic review and meta-analysis involves no individual patient data; thus, ethical approval is not required. This will be the first meta-analysis to assess the sedation efficacy of ciprofol and provide evidence to clinicians for decision-making. The results will be disseminated through conference presentations and publications in peer-review journals related to this field. PROSPERO REGISTRATION NUMBER: CRD42022370047.

Comparison of alternative splicing (AS) events in adipose tissue of polled dorset versus small tail han sheep.

Background: During the alternative splicing (AS), the exons of primary transcripts are spliced in various arrangements, resulting in structurally and functionally distinct mRNAs and proteins. This study aimed to examine genes with AS events from Small Tail Han sheep and Dorset sheep to explore the mechanism of adipose developments. Methods: This study identified the genes with AS events in adipose tissues of two different sheep with next-generation sequencing. In this paper, genes with significantly different AS events were performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Results: 364 genes with 411 A S events showed significant differences in adipose tissues between the two breeds; 108 genes with 120 A S events were extremely significant differences between the two breeds. We identified several novel genes that are related with adipose growth and development. The results of KEGG and GO analysis indicated that oocyte meiosis, mitogen-activated protein kinase (Wnt), mitogen-activated protein kinase (MAPK) signaling pathway, etc. Were closely related to the adipose tissue developments. Conclusions: This paper revealed that the genes with AS events are important for adipose tissues in sheep, exploring the mechanisms of AS events associated with adipose tissue developments in sheep of different breeds.

Research on the association of China-US virtual water trade based on hypothesis extraction method.

Based on the EORA input-output tables from 2006 to 2016, this paper divided 189 countries in the world into three economies (China, the USA, and other countries) and used the hypothetical extraction method to calculate the virtual water trade volume of the three economies in the Sino-US bilateral trade. Combining with the analysis of the global value chain, the following conclusions were drawn: (1) the virtual water trade volume exported by China and the USA showed an overall increasing trend. The virtual water trade volume exported by the USA was far less than that of China, but more virtual water was transferred through trade. (2) Compared with intermediate products, China's virtual water exports of final products were larger, but the USA was the opposite. (3) Among the three major industrial sectors, the secondary sector was the largest virtual water export sector in China, but it was the primary sector in the USA that had the largest volume of. (4) Bilateral trade had brought environmental disadvantages to China, but this situation was gradually improving.

High-plex protein and whole transcriptome co-mapping at cellular resolution with spatial CITE-seq.

In this study, we extended co-indexing of transcriptomes and epitopes (CITE) to the spatial dimension and demonstrated high-plex protein and whole transcriptome co-mapping. We profiled 189 proteins and whole transcriptome in multiple mouse tissue types with spatial CITE sequencing and then further applied the method to measure 273 proteins and transcriptome in human tissues, revealing spatially distinct germinal center reactions in tonsil and early immune activation in skin at the Coronavirus Disease 2019 mRNA vaccine injection site.

Impact of FecB Mutation on Ovarian DNA Methylome in Small-Tail Han Sheep.

Booroola fecundity (FecB) gene, a mutant of bone morphogenetic protein 1B (BMPR-1B) that was discovered in Booroola Merino, was the first prolificacy gene identified in sheep related to increased ovulation rate and litter size. The mechanism of FecB impact on reproduction is unclear. METHODS: In this study, adult Han ewes with homozygous FecB(B)/FecB(B) mutations (Han BB group) and ewes with FecB(+)/FecB(+) wildtype (Han ++ group) were selected. Methylated DNA immunoprecipitation and high-throughput sequencing (MeDIP-seq) was used to identify differences in methylated genes in ovary tissue. RESULTS: We examined differences in DNA methylation patterns between HanBB and Han ++ sheep. In both sheep, methylated reads were mainly distributed at the gene body regions, CpG islands and introns. The differentially methylated genes were enriched in neurotrophy in signaling pathway, Gonadotropin Releasing Hormone (GnRH) signaling pathway, Wnt signaling pathway, oocyte meiosis, vascular endothelial growth factor (VEGF) signaling pathway, etc. Differentially-methylated genes were co-analyzed with differentially-expressed mRNAs. Several genes which could be associated with female reproduction were identified, such as FOXP3 (forkhead box P3), TMEFF2 (Transmembrane Protein with EGF Like and Two Follistatin Like Domains 2) and ADAT2 (Adenosine Deaminase TRNA Specific 2). CONCLUSIONS: We constructed a MeDIP-seq based methylomic study to investigate the ovarian DNA methylation differences between Small-Tail Han sheep with homozygous FecB mutant and wildtype, and successfully identified FecB gene-associated differentially-methylated genes. This study has provided information with which to understand the mechanisms of FecB gene-induced hyperprolificacy in sheep.

Study on the technology of brewing red raspberry wine by using new immobilized yeast technology.

The aim of the present study was to establish a new process for brewing red raspberry wine with immobilized yeast and improve the value of red raspberry. Using the spore filaments of P. chrysogenum as a carrier to co-culture with yeast to obtain immobilized yeast. And the preparation method of immobilized yeast was optimized by single-factor experiment and orthogonal experiments. And the red raspberry wine was brewed in these conditions. The result shows that the optimal preparation conditions for the immobilized yeast of P. chrysogenum were 5 g/L gluconic acid, 5 g/L yeast extract, and the addition amount of P. chrysogenum spores 1 × 105 cfu/ml. Compared with free yeast, the immobilized yeast of P. chrysogenum has better fermenting ability, can better keep the anthocyanins and polyphenols and other active ingredients of red raspberry. The quality of the wine was improved due to increase in aroma components such as alcohols and esters. The immobilized yeast of P. chrysogenum maintained good fermentation performance after three consecutive fermentations.

The Roles of the Two-Component System, MtrAB, in Response to Diverse Cell Envelope Stresses in Dietzia sp. DQ12-45-1b.

Two-component systems (TCSs) act as common regulatory systems allowing bacteria to detect and respond to multiple environmental stimuli, including cell envelope stress. The MtrAB TCS of Actinobacteria is critical for cell wall homeostasis, cell proliferation, osmoprotection, and antibiotic resistance, and thus is found to be highly conserved across this phylum. However, how precisely the MtrAB TCS regulates cellular homeostasis in response to environmental stress remains unclear. Here, we show that the MtrAB TCS plays an important role in the tolerance to different types of cell envelope stresses, including environmental stresses (i.e., oxidative stress, lysozyme, SDS, osmotic pressure, and alkaline pH stresses) and envelope-targeting antibiotics (i.e., isoniazid, ethambutol, glycopeptide, and ß-lactam antibiotics) in Dietzia sp. DQ12-45-1b. An mtrAB mutant strain exhibited slower growth compared to the wild-type strain and was characterized by abnormal cell shapes when exposed to various environmental stresses. Moreover, deletion of mtrAB resulted in decreased resistance to isoniazid, ethambutol, and ß-lactam antibiotics. Further, Cleavage under targets and tagmentation sequencing (CUT&Tag-seq) and electrophoretic mobility shift assays (EMSAs) revealed that MtrA binds the promoters of genes involved in peptidoglycan biosynthesis (ldtB, ldtA, murJ), hydrolysis (GJR88_03483, GJR88_4713), and cell division (ftsE). Together, our findings demonstrated that the MtrAB TCS is essential for the survival of Dietzia sp. DQ12-45-1b under various cell envelope stresses, primarily by controlling multiple downstream cellular pathways. Our work suggests that TCSs act as global sensors and regulators in maintaining cellular homeostasis, such as during episodes of various environmental stresses. The present study should shed light on the understanding of mechanisms for bacterial adaptivity to extreme environments. IMPORTANCE The multilayered cell envelope is the first line of bacterial defense against various extreme environments. Bacteria utilize a large number of sensing and regulatory systems to maintain cell envelope homeostasis under multiple stress conditions. The two-component system (TCS) is the main sensing and responding apparatus for environmental adaptation. The MtrAB TCS highly conserved in Actinobacteria is critical for cell wall homeostasis, cell proliferation, osmoprotection, and antibiotic resistance. However, how MtrAB works with regard to signals impacting changes to the cell envelope is not fully understood. Here, we found that in the Actinobacterium Dietzia sp. DQ12-45-1b, a TCS named MtrAB is pivotal for ensuring normal cell growth as well as maintaining proper cell morphology in response to various cell envelope stresses, namely, by regulating the expression of cell envelope-related genes. Our findings should greatly advance our understanding of the adaptive mechanisms responsible for maintaining cell integrity in times of sustained environmental shocks.