[Effects of Straw and Fertilizer Managements on Nitrogen Loss in Rice Cultivation in Taihu Lake Basin].

Nitrogen loss from rice systems is an important source of agricultural non-point source pollution. Many studies revolve around reducing the rate of nitrogen fertilizer application. However, studies examining the characteristics of nitrogen loss in multiple loss paths （runoff, leaching, and lateral seepage） under different straw and fertilizer managements are lacking. Therefore, a study was carried out based on a rice field planted for more than 20 years with straw continuously returned to the field for more than 5 years in Taihu lake basin. The effects of straw and fertilizer managements on nitrogen loss in different paths during the whole growth period of rice were studied. Moreover, straw and fertilizer managements were evaluated by their production suitability and environmental friendliness based on crop yield, nitrogen use efficiency, and nitrogen loss. The results showed that straw removal from the field increased the response sensitivity of nitrogen accumulation in plant tissue to nitrogen application. The nitrogen loss in the rice season was 9-17 kg·hm-2, accounting for 5%-7% of the nitrogen application rate. Straw removal increased the risk of nitrogen loss when soaking water discharged. Straw returning could decrease the nitrogen loss by more than 15%, though the effect of straw on nitrogen loss via lateral seepage was not clear. Furthermore, the suitable substitution of organic fertilizer （30% in this study） could respectively reduce the amount of nitrogen loss via runoff, leaching, and lateral seepage by 16%, 26%, and 37% compared with the fertilizer application under the same nitrogen gradient. In conclusion, the implementation of straw returning and fertilizer type optimization measures effectively reduced the nitrogen loss for unit weight of rice production and realized the balance between agricultural production and environmental protection.

Amplification editing enables efficient and precise duplication of DNA from short sequence to megabase and chromosomal scale.

Duplication is a foundation of molecular evolution and a driver of genomic and complex diseases. Here, we develop a genome editing tool named Amplification Editing (AE) that enables programmable DNA duplication with precision at chromosomal scale. AE can duplicate human genomes ranging from 20 bp to 100 Mb, a size comparable to human chromosomes. AE exhibits activity across various cell types, encompassing diploid, haploid, and primary cells. AE exhibited up to 73.0% efficiency for 1 Mb and 3.4% for 100 Mb duplications, respectively. Whole-genome sequencing and deep sequencing of the junctions of edited sequences confirm the precision of duplication. AE can create chromosomal microduplications within disease-relevant regions in embryonic stem cells, indicating its potential for generating cellular and animal models. AE is a precise and efficient tool for chromosomal engineering and DNA duplication, broadening the landscape of precision genome editing from an individual genetic locus to the chromosomal scale.

Disulfidptosis: A new type of cell death.

Disulfidptosis is a novel form of cell death that is distinguishable from established programmed cell death pathways such as apoptosis, pyroptosis, autophagy, ferroptosis, and oxeiptosis. This process is characterized by the rapid depletion of nicotinamide adenine dinucleotide phosphate (NADPH) in cells and high expression of solute carrier family 7 member 11 (SLC7A11) during glucose starvation, resulting in abnormal cystine accumulation, which subsequently induces andabnormal disulfide bond formation in actin cytoskeleton proteins, culminating in actin network collapse and disulfidptosis. This review aimed to summarize the underlying mechanisms, influencing factors, comparisons with traditional cell death pathways, associations with related diseases, application prospects, and future research directions related to disulfidptosis.

Exploring the therapeutic potential of "Xiaochaihu Decoction": a systematic review and meta-analysis on the clinical effectiveness and safety in managing cancer-related fever.

Objective: This study aimed to conduct the first meta-analysis to comprehensively evaluate the clinical effectiveness and safety of Xiaochaihu Decoction in treating Cancer-related Fever (CRF). Methods: Eight databases were systematically searched in September 2023. The risk of bias (ROB) 2.0 tool recommended by Cochrane Handbook was applied to evaluate the ROB of the included randomized controlled trials (RCTs). Additionally, the quality of evidence was assessed using the Grading of recommendations assessment, development and evaluation (GRADE) tool. Results: We included 18 RCTs involving 1,424 patients. Compared to Western medicine or Xinhuang Tablets, Xiaochaihu Decoction significantly improved clinical effectiveness in CRF patients (risk ratio [RR] = 1.24, 95% confidence interval [CI]: 1.17, 1.32) and expedited the normalization of body temperature (mean difference [MD] = -5.29, 95%CI: -5.59, -4.99). It also demonstrated a reduction in tumor necrosis factor-α (TNF-α) levels (MD = -0.63, 95%CI: -0.84, -0.41) and an increase in IL-2 levels (MD = 1.42, 95%CI: -1.09, 1.74). Analysis of Karnofsky Performance Status (KPS) scores showed that the use of Xiaochaihu Decoction improved the quality of life in CRF patients (RR = 1.57, 95%CI: 1.11, 2.22) and reduced the incidence of adverse events. However, it is important to note that the majority of included studies showed "some concerns" in risk of bias based on ROB 2.0, and the evidence quality assessed by GRADE method was rated as "low". Conclusion: While this study suggests the clinical effectiveness and safety of Xiaochaihu Decoction in treating patients with CRF, confirming these findings will necessitate additional high-quality, large-scale RCTs in future research. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023484068.

Exploring the association between acute pancreatitis and biliary tract cancer: A large-scale population-based matched cohort study.

BACKGROUND: Biliary tract cancer (BTC) often goes undetected until its advanced stages, resulting in a poor prognosis. Given the anatomical closeness of the gallbladder and bile ducts to the pancreas, the inflammatory processes triggered by acute pancreatitis might increase the risk of BTC. OBJECTIVE: To assess the association between acute pancreatitis and the risk of BTC. METHODS: Using the Swedish Pancreatitis Cohort (SwePan), we compared the BTC risk in patients with a first-time episode of acute pancreatitis during 1990-2018 to a 1:10 matched pancreatitis-free control group. Multivariable Cox regression models, stratified by follow-up duration, were used to calculate hazard ratios (HRs), adjusting for socioeconomic factors, alcohol use, and comorbidities. RESULTS: BTC developed in 0.94% of 85,027 acute pancreatitis patients and in 0.23% of 814,993 controls. The BTC risk notably increased within 3 months of hospital discharge (HR 82.63; 95% CI: 63.07-108.26) and remained elevated beyond 10 years of follow-up (HR 1.82; 95% CI: 1.35-2.47). However, the long-term risk of BTC subtypes did not increase with anatomical proximity to the pancreas, with a null association for gallbladder and extrahepatic tumors. Importantly, patients with acute pancreatitis had a higher occurrence of early-stage BTC within 2 years of hospital discharge than controls (13.0 vs. 3.6%; p-value <0.01). CONCLUSION: Our nationwide study found an elevated BTC risk in acute pancreatitis patients; however, the risk estimates for BTC subtypes were inconsistent, thereby questioning the causality of the association. Importantly, the amplified detection of early-stage BTC within 2 years after a diagnosis of acute pancreatitis underscores the necessity for proactive BTC surveillance in these patients.

Constructing network structures to enhance stability and target deposition of selenium nanoparticles via amphiphilic sodium alginate and alkyl glycosides.

Dietary selenium (Se) supplementation has recently received increasing attention; however, Selenium nanoparticles (SeNPs) exhibit poor stability and tend to aggregate in aqueous solution. Therefore, enhancing the stability of SeNPs and their effective delivery to plants remain challenging. In this study, sodium alginate (SA) and lysozyme (LZ) were reacted via the wet-heat Maillard reaction (MR) to obtain amphiphilic alginate-based polymers (SA-LZ). Alkyl glycosides (APG) were introduced into SA-LZ to enhance the deposition of SeNPs in leaves. Thus, a renewable and degradable polysaccharide-based material (SA-LZ/APG) loaded with Se formed an amphiphilic alginate-based-based shell with a Se core. Notably, the encapsulation of SeNPs into a polysaccharide base (SA-LZ/APG) increased the stabilization of SeNPs and resulted in orange-red, zero-valent, monoclinic and spherical SeNPs with a mean diameter of approximately 43.0 nm. In addition, SA-LZ/APG-SeNPs reduced the interfacial tension of plant leaves and increased the Se content of plants compared to the blank group. In vitro studies have reported that SA-LZ/APG-SeNPs and SA-LZ-SeNPs have significantly better clearance of DDPH and ABTS than that of APG-SeNPs. Thus, we believe that SA-LZ/APG is a promising smart delivery system that can synergistically enhance the stability of SeNPs in aqueous solutions and improve the bioavailability of Se nutrient solutions.

Microwave Ablation versus Surgical Resection for US-detected Multifocal T1N0M0 Papillary Thyroid Carcinoma: A 10-Center Study.

Background Microwave ablation (MWA) is currently under preliminary investigation for the treatment of multifocal papillary thyroid carcinoma (PTC) and has shown promising treatment efficacy. Compared with surgical resection (SR), MWA is minimally invasive and could preserve thyroid function. However, a comparative analysis between MWA and SR is warranted to draw definitive conclusions. Purpose To compare MWA and SR for preoperative US-detected T1N0M0 multifocal PTC in terms of overall and 1-, 3-, and 5-year progression-free survival rates and complication rates. Materials and Methods In this retrospective study, 775 patients with preoperative US-detected T1N0M0 multifocal PTC treated with MWA or SR across 10 centers between May 2015 and December 2021 were included. Propensity score matching (PSM) was performed for patients in the MWA and SR groups, followed by comparisons between the two groups. The primary outcomes were overall and 1-, 3-, and 5-year progression-free survival (PFS) rates and complication rates. Results After PSM, 229 patients (median age, 44 years [IQR 36.5-50.5 years]; 179 female) in the MWA group and 453 patients (median age, 45 years [IQR 37-53 years]; 367 female) in the SR group were observed for a median of 20 months (range, 12-74 months) and 26 months (range, 12-64 months), respectively. MWA resulted in less blood loss, shorter incision length, and shorter procedure and hospitalization durations (all P < .001). There was no evidence of differences in overall and 1-, 3-, or 5-year PFS rates (all P > .05) between MWA and SR (5-year rate, 77.2% vs 83.1%; P = .36) groups. Permanent hoarseness (2.2%, P = .05) and hypoparathyroidism (4.0%, P = .005) were encountered only in the SR group. Conclusion There was no evidence of a significant difference in PFS rates between MWA and SR for US-detected multifocal T1N0M0 PTC, and MWA resulted in fewer complications. Therefore, MWA is a feasible option for selected patients with multifocal T1N0M0 PTC. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Georgiades in this issue.

Transcatheter arterial chemoembolization of apatinib and camrelizumab (SHR1210) against liver metastasis from hepatic neuroendocrine tumor: a case report.

In this case report, we present the case of a 46-year-old woman with a hepatic neuroendocrine tumor (NET G2)-induced liver metastases. Initially, the left lateral lobectomy of the liver was performed. The post-operative pathological examination revealed NET G2, leading to the post-operative recovery with a general review. Further, the re-examination of liver magnetic resonance imaging (MRI) showed post-operative changes in the tumor of the left lateral lobe, with multiple liver masses and possible metastasis. Thus, the liver interventional therapy and apatinib-based targeted therapy based on the "camrelizumab + apatinib" regimen were performed, respectively. The 20-month follow-up indicated a slightly increased hepatic hilum and retroperitoneal lymph nodes, accompanied by hand-foot syndrome. Eventually, the overall condition continued to relieve, indicating that the combined treatment could substantially improve the NET G2 conditions-associated liver metastasis.

CAF-derived exosomal lncRNA FAL1 promotes chemoresistance to oxaliplatin by regulating autophagy in colorectal cancer.

Oxaliplatin is a widely applied anti-cancer drug in clinics for colorectal cancer (CRC) treatment. Nonetheless, the treatment efficacy is always limited by the acquisition of chemoresistance in cancer cells. The deregulation of long non-coding RNA (lncRNA) FAL1 has been implicated in the tumorigenesis and progression of different malignancies. Nevertheless, the possible contribution of lnc-FAL1 in drug resistance development of CRC has not been investigated. Here, we reported the overexpression of lnc-FAL1 in CRC samples, and elevated lnc-FAL1 levels seemed to be associated with the poor survival in CRC patients. We further demonstrated that lnc-FAL1 promoted oxaliplatin chemoresistance in both cell and animal model. Additionally, lnc-FAL1 was mainly derived from exosomes secreted by cancer associated fibroblasts (CAFs), and lnc-FAL1-containing exosomes or lnc-FAL1 overexpression significantly inhibited oxaliplatin-induced autophagy in CRC cells. Mechanistically, lnc-FAL1 acted as a scaffold for the interaction between Beclin1 and TRIM3 to promote TRIM3-dependent Beclin1 polyubiquitination and degradation, thereby suppressing oxaliplatin-induced autophagic cell death. In summary, these data imply a molecular mechanism through which CAF-derived exosomal lnc-FAL1 contributes to the acquisition of oxaliplatin resistance in CRC.

Association between transition patterns of sleep problems and suicidal ideation in Chinese female nurses: A prospective study.

OBJECTIVE: Suicidal ideation and sleep problems are both common in nurses. However, few longitudinal studies are available to examine the temporal association between sleep and suicidal ideation in nurses. METHOD: Data from the Health Longitudinal Survey of Nurses in Shandong Province was analyzed, involving 623 female nurses who had completed data of concern in 2018 (T1) and 2019 (T2). Sleep problem was assessed by the Pittsburgh Sleep Quality Index, in which the transition patterns for global and specific sleep component and the cumulative number of sleep component problems were defined. Suicidal ideation was measured by the ninth item of the Patient Health Questionnaire. Binary logistic regression was used to explore the association between sleep and suicidal ideation. RESULTS: Chronic and deteriorated global sleep problems is associated with a greater risk of suicidal ideation. For the specific component of sleep, sleep disturbance and short sleep duration are associated with a higher risk of suicidal ideation. The higher number of cumulative sleep component problems is associated with a higher risk of suicidal ideation. CONCLUSION: Findings indicate sleep disturbance and short sleep duration may be pathways to suicidal ideation. Initiatives that target at sleep problems may be important to reduce suicidal ideation in nurses.

Visualization of conformational transition of GRP94 in solution.

GRP94, an ER paralog of the heat-shock protein 90 family, binds and hydrolyses ATP to chaperone the folding and maturation of its selected clients. Compared with other hsp90 proteins, the in-solution conformational dynamics of GRP94 along the ATP hydrolysis cycle are less understood, hindering our understanding of its chaperoning mechanism. Leveraging small-angle X-ray scattering, negative-staining EM, and hydrogen-deuterium exchange coupled mass-spec, here we show that in its apo form, ∼60% of mouse GRP94 (mGRP94) populates an "extended" conformation, whereas the rest exist in either "close V" or "twist V" like "compact" conformations. Different from other hsp90 proteins, the presence of AMPPNP only impacts the relative abundance of the two compact conformations, rather than shifting the equilibrium between the "extended" and "compact" conformations of mGRP94. HDX-MS study of apo, AMPPNP-bound, and ADP-bound mGRP94 suggests a conformational transition from "twist V" to "close V" upon ATP binding and a back transition from "close V" to "twist V" upon ATP hydrolysis. These results illustrate the dissimilarities of GRP94 in conformation transition during ATP hydrolysis from other hsp90 paralogs.

Icariin improves cardiac function and remodeling via the TGF-ß1/Smad signaling pathway in rats following myocardial infarction.

BACKGROUND: Postinfarction cardiac remodeling presents a compensatory mechanism aimed at mitigating congestive heart failure. It is distinguished by progressive dilatation and hypertrophy of the ventricular chambers, fibrotic alterations, and prolonged apoptosis of cardiomyocytes. The primary objective of this study was to assess the effects of icariin on myocardial fibrosis and ventricular remodeling in rats subjected to myocardial infarction (MI). METHODS: Male Sprague‒Dawley (SD) rats were subjected to randomization and subsequently divided into distinct groups: the control group, the sham group (undergoing sham operation), the MI group (experiencing ligation of the left anterior descending artery), and the icariin group. Within the icariin group, rats were further categorized into three different dose groups based on the administered icariin dosage: the MI30 group (30 mg/kg/day), the MI60 group (60 mg/kg/day), and the MI120 group (120 mg/kg/day). Cardiac function evaluation was carried out using echocardiography. Histological examinations, including hematoxylin and eosin (HE) staining, Masson staining, and immunohistochemistry studies, were conducted 90 days after the occurrence of MI. Additionally, Western blotting was employed to assess TGF-ß1, p-Smad2, and p-Smad3 levels. RESULTS: The administration of icariin revealed a noteworthy enhancement in cardiac function among rats afflicted with left anterior descending coronary artery (LAD) ligation. In comparison to the icariin groups, the MI group exhibited reduced EF and FS, along with elevated LVEDD and LVESD. Furthermore, the cardiac fibrosis levels in the MI group rats exhibited a considerable increase compared to those in the icariin group. Notably, the levels of Collagen I, Collagen III, MMP2, and MMP9 were significantly higher in the MI group than in the icariin group, with evident distinctions. Moreover, the expression levels of TGF-ß, IL-13, p-Smad2, and p-Smad3 were notably upregulated in the MI group compared to the icariin group. CONCLUSIONS: In an experimental rat model of MI, the administration of icariin resulted in the amelioration of both cardiac function and remodeling processes, operating through the intricate TGF-ß1/Smad signaling pathway.

Priming of macrophage by glycosphingolipids from extracellular vesicles facilitates immune tolerance for embryo-maternal crosstalk.

Glycosphingolipids (GSLs) display diverse functions during embryonic development. Here, we examined the GSL profiles of extracellular vesicles (EVs) secreted from human embryonic stem cells (hESCs) and investigated their functions in priming macrophages to enhance immune tolerance of embryo implantation. When peripheral blood mononuclear cells were incubated with ESC-secreted EVs, globo-series GSLs (GHCer, SSEA3Cer, and SSEA4Cer) were transferred via EVs into monocytes/macrophages. Incubation of monocytes during their differentiation into macrophages with either EVs or synthetic globo-series GSLs induced macrophages to exhibit phenotypic features that imitate immune receptivity, i.e., macrophage polarization, augmented phagocytic activity, suppression of T cell proliferation, and the increased trophoblast invasion. It was also demonstrated that decidual macrophages in first-trimester tissues expressed globo-series GSLs. These findings highlight the role of globo-series GSLs via transfer from EVs in priming macrophages to display decidual macrophage phenotypes, which may facilitate healthy pregnancy.

Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs.

Reactivating silenced γ-globin expression through the disruption of repressive regulatory domains offers a therapeutic strategy for treating ß-hemoglobinopathies. Here, we used transformer base editor (tBE), a recently developed cytosine base editor with no detectable off-target mutations, to disrupt transcription-factor-binding motifs in hematopoietic stem cells. By performing functional screening of six motifs with tBE, we found that directly disrupting the BCL11A-binding motif in HBG1/2 promoters triggered the highest γ-globin expression. Via a side-by-side comparison with other clinical and preclinical strategies using Cas9 nuclease or conventional BEs (ABE8e and hA3A-BE3), we found that tBE-mediated disruption of the BCL11A-binding motif at the HBG1/2 promoters triggered the highest fetal hemoglobin in healthy and ß-thalassemia patient hematopoietic stem/progenitor cells while exhibiting no detectable DNA or RNA off-target mutations. Durable therapeutic editing by tBE persisted in repopulating hematopoietic stem cells, demonstrating that tBE-mediated editing in HBG1/2 promoters is a safe and effective strategy for treating ß-hemoglobinopathies.

Bacterial community assembly driven by temporal succession rather than spatial heterogeneity in Lake Bosten: a large lake suffering from eutrophication and salinization.

Oligosaline lakes in arid and semi-arid regions play a crucial role in providing essential water resources for local populations. However, limited research exists on the impact of the environment on bacterial community structure in these lakes, co-occurrence patterns and the mechanisms governing bacterial community assembly. This study aims to address this knowledge gap by examining samples collected from five areas of Lake Bosten over four seasons. Using the 16S rRNA gene sequencing method, we identified a total of 510 to 1,005 operational taxonomic units (OTUs) belonging to 37 phyla and 359 genera in Lake Bosten. The major bacterial phyla were Proteobacteria (46.5%), Actinobacteria (25.9%), Bacteroidetes (13.2%), and Cyanobacteria (5.7%), while the major genera were hgcI_clade (12.9%), Limnohabitans (6.2%), and Polynucleobacter (4.7%). Water temperature emerged as the primary driver of these community structure variations on global level. However, when considering only seasonal variations, pH and nitrate were identified as key factors influencing bacterial community structures. Summer differed from other seasons in aspects of seasonal symbiotic patterns of bacterial communities, community assembly and function are different from other seasons. There were notable variations in bacterial community structures between winter and summer. Deterministic processes dominated community assembly, but there was an increase in the proportion of stochastic processes during summer. In summer, the functions related to photosynthesis, nitrogen fixation, and decomposition of organic matter showed higher abundance. Our findings shed light on the response of bacterial communities to environmental changes and the underlying mechanisms of community assembly in oligosaline lakes in arid regions.

Prime editor-mediated functional reshaping of ACE2 prevents the entry of multiple human coronaviruses, including SARS-CoV-2 variants.

The spike protein of SARS-CoV-2 hijacks the host angiotensin converting enzyme 2 (ACE2) to meditate its entry and is the primary target for vaccine development. Nevertheless, SARS-CoV-2 keeps evolving and the latest Omicron subvariants BQ.1 and XBB have gained exceptional immune evasion potential through mutations in their spike proteins, leading to sharply reduced efficacy of current spike-focused vaccines and therapeutics. Compared with the fast-evolving spike protein, targeting host ACE2 offers an alternative antiviral strategy that is more resistant to viral evolution and can even provide broad prevention against SARS-CoV and HCoV-NL63. Here, we use prime editor (PE) to precisely edit ACE2 at structurally selected sites. We demonstrated that residue changes at Q24/D30/K31 and/or K353 of ACE2 could completely ablate the binding of tested viruses while maintaining its physiological role in host angiotensin II conversion. PE-mediated ACE2 editing at these sites suppressed the entry of pseudotyped SARS-CoV-2 major variants of concern and even SARS-CoV or HCoV-NL63. Moreover, it significantly inhibited the replication of the Delta variant live virus. Our work investigated the unexplored application potential of prime editing in high-risk infectious disease control and demonstrated that such gene editing-based host factor reshaping strategy can provide broad-spectrum antiviral activity and a high barrier to viral escape or resistance.

Exploring the relationship between depression and multimorbidity in Chinese middle-aged and older people based on propensity score matching.

BACKGROUND: This study aimed to explore the relationship between depression and multimorbidity among middle-aged and older people in China. METHODS: The cross-sectional study used the 2018 China Longitudinal Study of Health and Retirement and included a sample of 19,761 middle-aged and older adults aged 45 years and above. Propensity score matching was used to match samples of individuals with and without depression symptoms. The association between depression symptoms and multimorbidity and dose-response relationships were analyzed using logistic regression and restricted cubic spline (RCS) models for matched samples. RESULTS: Logistic regression analysis showed that the prevalence of multimorbidity was 1.49 times higher among middle-aged and older adults in the depression symptom group compared to the non-depression group (95% CI:1.24, 1.80). The RCS curves for the relationship between depression and multimorbidity showed an overall increasing trend (P = 0.028). And prevalence of arthritis and digestive disease in the depressed and non-depressed groups is 3.6% and 3.9%, respectively. LIMITATIONS: It was difficult to draw conclusions about causation since the study was cross-sectional, and CESD-10 scores do not represent the population study finally diagnosed with depression, the conclusions should be promoted with caution. CONCLUSIONS: Middle-aged and older people with depressive symptoms are more likely to have multimorbidity than non-depressed individuals. Furthermore, the likelihood of multimorbidity increases with higher depression scores, and the binary combinations were similarly distributed. Therefore, attention should be paid to the management of mental health in the middle-aged and older adult population to alleviate and prevent any mental health issues they might face.

Single-nucleus RNA-sequencing reveals NRF1/NFE2L1 as a key factor determining the thermogenesis and cellular heterogeneity and dynamics of brown adipose tissues in mice.

Brown adipose tissue (BAT) is a major site of non-shivering thermogenesis in mammals and plays an important role in energy homeostasis. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a master regulator of cellular metabolic homeostasis and numerous stress responses, has been found to function as a critical driver in BAT thermogenic adaption to cold or obesity by providing proteometabolic quality control. Our recent studies using adipocyte-specific Nfe2l1 knockout [Nfe2l1(f)-KO] mice demonstrated that NFE2L1-dependent transcription of lipolytic genes is crucial for white adipose tissue (WAT) homeostasis and plasticity. In the present study, we found that Nfe2l1(f)-KO mice develop an age-dependent whitening and shrinking of BAT, with signatures of down-regulation of proteasome, impaired mitochondrial function, reduced thermogenesis, pro-inflammation, and elevated regulatory cell death (RCD). Mechanistic studies revealed that deficiency of Nfe2l1 in brown adipocytes (BAC) primarily results in down-regulation of lipolytic genes, which decelerates lipolysis, making BAC unable to fuel thermogenesis. These changes lead to BAC hypertrophy, inflammation-associated RCD, and consequently cold intolerance. Single-nucleus RNA-sequencing of BAT reveals that deficiency of Nfe2l1 induces significant transcriptomic changes leading to aberrant expression of a variety of genes involved in lipid metabolism, proteasome, mitochondrial stress, inflammatory responses, and inflammation-related RCD in distinct subpopulations of BAC. Taken together, our study demonstrated that NFE2L1 serves as a vital transcriptional regulator that controls the lipid metabolic homeostasis in BAC, which in turn determines the metabolic dynamics, cellular heterogeneity and subsequently cell fates in BAT.

Discovery, Optimization, and Evaluation of Novel N-(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment.

Signal transducer and activator of transcription 3 (STAT3) is an attractive target for cancer therapy. However, identifying potent and selective STAT3 small-molecule inhibitors with drug-like properties remains challenging. Based on a scaffold combination strategy, compounds with a novel N-(benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine scaffold were designed and their inhibition of the interleukin-6 (IL-6)/JAK/STAT3 pathway was tested in HEK-Blue IL-6 reporter cells. After optimization of lead compound 12, compound 40 was identified as a selective STAT3 inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound 40 exhibited antiproliferative activities against STAT3-overactivated DU145 (IC50 value = 2.97 µM) and MDA-MB-231 (IC50 value = 3.26 µM) cancer cells and induced cell cycle arrest and apoptosis. In the DU145 xenograft model, compound 40 showed in vivo antitumor efficacy following intraperitoneal administration, with a tumor growth inhibition rate of 65.3% at 50 mg/kg, indicating promise for further development.