Machine learning based on biological context facilitates the identification of microvascular invasion in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is a rare disease associated with a poor prognosis, primarily due to early recurrence and metastasis. An important feature of this condition is microvascular invasion (MVI). However, current predictive models based on imaging have limited efficacy in this regard. This study employed a random forest model to construct a predictive model for MVI identification and uncover its biological basis. Single-cell transcriptome sequencing, whole exome sequencing, and proteome sequencing were performed. The area under the curve of the prediction model in the validation set was 0.93. Further analysis indicated that MVI-associated tumor cells exhibited functional changes related to epithelial-mesenchymal transition and lipid metabolism due to alterations in the NF-kappa B and MAPK signaling pathways. Tumor cells were also differentially enriched for the IL-17 signaling pathway. There was less infiltration of SLC30A1+ CD8+ T cells expressing cytotoxic genes in MVI-associated ICC, whereas there was more infiltration of myeloid cells with attenuated expression of the MHC II pathway. Additionally, MVI-associated intercellular communication was closely related to the SPP1-CD44 and ANXA1-FPR1 pathways. These findings resulted in a brilliant predictive model and fresh insights into MVI.

Stress granules in cancer: Adaptive dynamics and therapeutic implications.

Stress granules (SGs), membrane-less cellular organelles formed via liquid-liquid phase separation, are central to how cells adapt to various stress conditions, including endoplasmic reticulum stress, nutrient scarcity, and hypoxia. Recent studies have underscored a significant link between SGs and the process of tumorigenesis, highlighting that proteins, associated components, and signaling pathways that facilitate SG formation are often upregulated in cancer. SGs play a key role in enhancing tumor cell proliferation, invasion, and migration, while also inhibiting apoptosis, facilitating immune evasion, and driving metabolic reprogramming through multiple mechanisms. Furthermore, SGs have been identified as crucial elements in the development of resistance against chemotherapy, immunotherapy, and radiotherapy across a variety of cancer types. This review delves into the complex role of SGs in cancer development and resistance, bringing together the latest progress in the field and exploring new avenues for therapeutic intervention.

Multiexcitation Peaks and Multicolor Emission Nanoassemblies for Transmembrane Cell Imaging and Photoresponsivity Antibacterial.

Nanomaterials with photoresponsivity have garnered attention due to their fluorescence imaging, photodynamic, and photothermal therapeutic properties. In this study, a photoresponsivity nanoassembly was developed by using photosensitizers and carbon dots (CDs). Due to their multiple excitation peaks and multicolor fluorescence emission, especially their membrane-permeating properties, these nanoassemblies can label cells with multiple colors and track cell imaging in real time. Additionally, the incorporation of photosensitizers and CDs provides the nanoassemblies with the potential for photodynamic therapy (PDT) and photothermal therapy (PTT). The nanoassemblies effectively suppressed the activity of Escherichia coli and Staphylococcus aureus through PDT and PTT. Moreover, the nanoassemblies exhibited a high affinity for E. coli and S. aureus. These distinct features confer broad-spectrum antibacterial properties to the nanoassemblies. As a photoresponsivity nanoplatform, these nanoassemblies have demonstrated potential applications in the fields of bioimaging and antimicrobial.

Carbapenem-resistant Enterobacterales sepsis following endoscopic retrograde cholangiopancreatography: risk factors for 30-day all-cause mortality and the development of a nomogram based on a retrospective cohort.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has become a routine endoscopic procedure that is essential for diagnosing and managing various conditions, including gallstone extraction and the treatment of bile duct and pancreatic tumors. Despite its efficacy, post-ERCP infections - particularly those caused by carbapenem-resistant Enterobacterales (CRE) - present significant risks. These risks highlight the need for accurate predictive models to enhance postprocedural care, reduce the mortality risk associated with post-ERCP CRE sepsis, and improve patient outcomes in the context of increasing antibiotic resistance. OBJECTIVE: This study aimed to examine the risk factors for 30-day mortality in patients with CRE sepsis following ERCP and to develop a nomogram for accurately predicting 30-day mortality risk. METHODS: Data from 195 patients who experienced post-ERCP CRE sepsis between January 2010 and December 2022 were analyzed. Variable selection was optimized via the least absolute shrinkage and selection operator (LASSO) regression model. Multivariate logistic regression analysis was then employed to develop a predictive model, which was evaluated in terms of discrimination, calibration, and clinical utility. Internal validation was achieved through bootstrapping. RESULTS: The nomogram included the following predictors: age > 80 years (hazard ratio [HR] 2.61), intensive care unit (ICU) admission within 90 days prior to ERCP (HR 2.64), hypoproteinemia (HR 4.55), quick Pitt bacteremia score ≥ 2 (HR 2.61), post-ERCP pancreatitis (HR 2.52), inappropriate empirical therapy (HR 3.48), delayed definitive therapy (HR 2.64), and short treatment duration (< 10 days) (HR 5.03). The model demonstrated strong discrimination and calibration. CONCLUSIONS: This study identified significant risk factors associated with 30-day mortality in patients with post-ERCP CRE sepsis and developed a nomogram to accurately predict this risk. This tool enables healthcare practitioners to provide personalized risk assessments and promptly administer appropriate therapies against CRE, thereby reducing mortality rates.

Preliminary investigation on the effect of Vibrio splendidus stimulation on the intestinal flora of Strongylocentrotus intermedius.

To better understand the effect of Vibrio splendidus infection on Strongylocentrotus intermedius, 16S rRNA sequencing was carried out to investigate the intestinal flora of S. intermedius stimulated by 0 CFU/mL (Con), 1.5 × 107 CFU/mL (Vib1) and 1.5 × 108 CFU/mL (Vib2) concentrations of V. splendidus. The results showed that there was significant difference in intestinal flora diversity between Con group and Vib1 group, but no significant difference between Con group and Vib2 group. However, there were significant differences in the composition of intestinal flora among all groups. Bacteroidota, Proteobacteria and Firmicutes were the dominant phylum in the Con group. The abundance of Bacteroidota and Firmicutes decreased and Proteobacteria increased in Vib1 and Vib2 groups. The relative abundance of the potential probiotic bacteria Muribaculaceae and Alloprevotella was significantly lower in the Vib1 and Vib2 groups. In addition, the opportunistic pathogen Desulfovibrio was found in Vib1 and Vib2 groups. It is evident that V. splendidus infection not only alters the composition of the microbial community in the intestinal tract of S. intermedius, but may also lead to the production of opportunistic pathogens, which could be potentially harmful to the health of S. intermedius. The results of this study provide a foundation for exploring the diseases caused by V. splendidus stimulation leading to an imbalance in the intestinal flora of S. intermedius, and contribute to our further understanding of the role of Vibrio on the health of S. intermedius.

Order-in-disordered ultrathin carbon nanostructure with nitrogen-rich defects bridged by pseudographitic domains for high-performance ion capture.

Carbon materials with defect-rich structure are highly demanded for various electrochemical scenes, but encountering a conflict with the deteriorative intrinsic conductivity. Herein, we build a highway-mediated nanoarchitecture that consists of the ordered pseudographitic nanodomains among disordered highly nitrogen-doped segments through a supramolecular self-assembly strategy. The "order-in-disorder" nanosheet-like carbon obtained at 800 °C (O/D NSLC-800) achieves a tradeoff with high defect degree (21.9 at% of doped nitrogen) and compensated electrical conductivity simultaneously. As expected, symmetrical O/D NSLC-800 electrodes exhibit superior capacitive deionization (CDI) performance, including brackish water desalination (≈82 mgNaCl g-1 at a cell voltage of 1.6 V in a 1000 mg L-1 NaCl solution) and reusage of actual refining circulating cooling water, outperforming most of the reported state-of-the-art CDI electrodes. The implanted pseudographitic nanodomains lower the resistance and activation energy of charge transfer, which motivates the synergy of hosting sites of multiple nitrogen configurations. Our findings shed light on electrically conductive nanoarchitecture design of defect-rich materials for advanced electrochemical applications based on molecular-level modulation.

Development and validation of a nomogram for predicting anorexia of aging in older people.

BACKGROUND: Anorexia of aging (AA) is a common geriatric syndrome that seriously endangers the health of older adults. Early identification of populations at risk of AAand the implementation of appropriate intervention measures hold significant public health importance. This study aimed to develop a nomogram for predicting the risk of AA among older people. METHODS: We conducted a cross-sectional study involving 2144 community-dwelling older adults to evaluate the AA using the Simplified Nutritional Appetite Questionnaire. We utilized the Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis to select variables and develop a nomogram prediction model. The predictive performance of the nomogram was evaluated using the Receiver Operating Characteristic (ROC) curves, calibration curves, Decision Curve Analysis (DCA), and internal validation. RESULTS: The prevalence of AA among Chinese older adults was 21.7% (95%CI: 20.0%-23.5%). Age, sex, family economic level, smoking status, dysphagia, loneliness, depressive symptoms, living alone, health literacy, life satisfaction, and body mass index have been identified as predictive factors for AA among older people. The nomogram constructed based on these predictive factors showed an area under the curve (AUC) of 0.766 (95%CI: 0.742-0.791), indicating good calibration and discrimination ability. Additionally, the results obtained from the 10-fold cross-validation process confirmed the nomogram's good predictive capabilities. Furthermore, the DCA results showed that the nomogram has clinical utility. CONCLUSION: The nomogram constructed in this study serves as an effective tool for predicting anorexia of aging among community-dwelling older adults. Its implementation can help community healthcare workers evaluate the risk of AA in this population and identify high-risk groups.

Long-lifetime aqueous Si-air batteries prepared by growing multi-dimensionally tunable ZIF-8 crystals on Si anodes.

Si-air batteries have a high energy density, high theoretical voltage, and long lifetime, but they present a low anode utilization rate in a potassium hydroxide electrolyte. In this work, a ZIF-8 protective layer was prepared and modulated by a secondary growth method and then applied to protect the Si flat and Si nanowire (NW) anodes of a Si-air battery. By adjusting the conversion ratio, particle size, and crystallinity of ZIF-8 on the Si surface, the contact mode of the Si anode with water and OH- was controlled, thus achieving long-term corrosion and passivation resistance. Si NWs@ZIF-8 exhibited the highest average discharge voltage of 1.16 V, and the Si flat@ZIF-8 anode achieved the longest discharge time of 420 h. This work confirms that ZIF-8 acts as an anode protective layer to improve the properties of Si-air batteries and also provides valuable insights into the protection of Si anodes by MOFs.

Cobalt-copper bimetallic selenides embedded in nitrogen-doped porous carbon nanocubes for diclofenac electrochemical sensing.

Diclofenac (DCF) is a non-steroidal anti-inflammatory drug (NSAID), and its overuse poses a potential threat to human health and the aquatic environment, designing high-efficiency electrocatalysts for DCF detection is urgent. Herein, cobalt-copper bimetallic selenides embedded in nitrogen-doped porous carbon nanocubes (CoCuSe@NC) were elaborately designed via one-step in situ selenization of bimetallic CoCu-MOF. The chemical constituents and micromorphology of CoCuSe@NC composites can be further optimized by precisely regulating the selenization process and the doping ratio of bimetal in MOF precursor. As an electrocatalyst, CoCuSe@NC was proved to be highly efficient in electrochemical sensing of DCF with a broad linear range of 0.1-400 µmol/L and a detection limit of 0.024 µmol/L. This was attributed to the synergistic advantages between the heterogeneous structures, which produced more electrochemically active sites, effectively shortened the electron transport path, and improved electrocatalytic performance. Consequently, the constructed sensor exhibits high sensitivity, remarkable stability and applicability, and in particular can selectively detect DCF from other structurally similar coexisting analogs, resulting from the unique metal chelation ability. This work paves the way for designing effective bimetallic selenide electrocatalysts and exploring their applications in DCF electrochemical sensing.

An ultrasound-based nomogram for predicting central lymph node metastasis in papillary thyroid microcarcinoma.

AIMS: Performing prophylactic central lymph node dissection for papillary thyroid microcarcinoma (PTMC) patients with clinically negative lymph node metastasis remains controversial - not all patients with PTMC are suitable for active surveillance. Therefore, we aimed to establish a nomogram based on ultrasound features for predicting CLNM in PTMC. MATERIAL AND METHODS: This retrospective study included 636 patients with PTMC, in which the CLNM status was pathologically confirmed. Univariate and multivariate regression analyses were conducted to screen for risk factors associated with CLNM. Then, a CLNM prediction model was established, receiver operating characteristic, calibration, and decision curve analyses were used to assess the model's performance. RESULTS: Five variables, including age, sex, combined CLNM status, tumor size, and capsule invasion, were included in the nomogram. The values of the area under the receiver operating characteristic curve in the training and validation datasets were 0.720 (95% confidence interval [CI], 0.649-0.791) and 0.704 (95% CI, 0.622-0.786), respectively. CONCLUSIONS: An ultrasound-based nomogram was successfully established, of which the predictive model shows excellent predictive performance and can be used to evaluate the status of CLNM in PTMC. Thus, patients with high nomogram scores should be considered for prophylactic central neck dissection.

Comparative transcriptome analysis reveals disruption of Plutella xylostella immune system by fungal peptide cyclosporin C.

The diamondback moth (Plutella xylostella), a major threat to crucifers across the globe, has developed resistance against the majority of insecticides enhancing the need for alternate control measures against this pest. Recently cyclosporin C, a secondary metabolite produced by the insect pathogenic fungus Purpeocillium lilacinum, has been reported to induce lethal and sub-lethal effects against P. xylostella. To date, little is known about the molecular mechanisms of interaction between cyclosporin C and P. xylostella immune systems. This study reports the transcriptome-based immune response of P. xylostella to cyclosprin C treatment. Our results showed differential expression of 322, 97, and 504 differentially expressed genes (DEGS) in P. xylostella treated with cyclosporin C compared to control 24, 48, and 72 h post-treatment, respectively. Thirteen DEGs were commonly expressed at different time intervals in P. xylostella larvae treated with cyclosporin C compared to control. Cyclosporin C treatment induced the down-regulated expression of majority of immune-related genes related to pattern recognition responses, signal modulation, Toll and IMD pathways, antimicrobial peptides and antioxidant responses confirming the ability to suppress immune response of P. xylostella. These results will further improve our knowledge of the infection mechanism and complex biochemical processes involved in interaction between cyclosporin C and insect immune systems.

Differential isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 mutation-related landscape in intrahepatic cholangiocarcinoma.

BACKGROUND: Patients with intrahepatic cholangiocarcinoma (ICC) are prone to recurrence and poor survival. Targeted therapy related to isocitrate dehydrogenase (IDH) is an extremely important treatment. IDH1 and IDH2 mutations are generally thought to have similar effects on the tumor landscape. However, it is doubtful whether these 2 mutations have exactly the same effects on tumor cells and the tumor microenvironment. METHODS: All collected tumor samples were subjected to simultaneous whole-exon sequencing and proteome sequencing. RESULTS: IDH1 mutations accounted for 12.2%, and IDH2 mutations accounted for 5.5%, all missense mutations. Tumors with IDH mutations had lower proportions of KRAS and TP53 mutations. Mutated genes were obviously enriched in the kinase pathway in the tumors with IDH2 mutations. The signaling pathways were mainly enriched in the activation of cellular metabolic activities and an increase of inhibitory immune cells in the tumors with IDH mutations. Moreover, tumors had unique enrichment in DNA repair in IDH1 mutants and secretion of biological molecules in IDH2 mutants. Inhibitory immune cells might be more prominent in IDH2 mutants, and the expression of immune checkpoints PVR and HLA-DQB1 was more prominent in IDH1 mutants. IDH mutants were more related to metabolism-related and inflammation-immune response clusters, and some belonged to the DNA replication and repair cluster. CONCLUSIONS: These results revealed the differential IDH1 and IDH2 mutation-related landscapes, and we have provided an important reference database to guide ICC treatment.

Abnormal amygdala volume moderates parenting and anxiety symptoms in children and adolescents with anxiety disorder.

Anxiety disorders (AD) usually onset in childhood or adolescence and are related to brain development and early experiences during this period. As the hub of the fear circuit, the amygdala plays a crucial role in the development of emotional processing, and abnormalities in its structure and function are associated with anxiety disorders. We aim to uncover the amygdala volume's moderation between parenting and anxiety severity in children and adolescents with AD. 129 children and adolescents with anxiety and 135 age- and sex-matched Health controls (HC) using the publicly available Healthy Brain Network (HBN) dataset were included. Anxiety severity was measured using the Screen for Child Anxiety Related Disorders Self-report (SCARED-SR) and parenting was measured using the Alabama Parenting Questionnaire Self-Report (APQ-SR). We investigated age-related differences in amygdala volume in children and adolescents with anxiety disorders. Further, we examined the role of amygdala volume in moderating the association between parental involvement, particularly the maternal involvement, and anxiety symptoms in this population. We found larger bilateral amygdala in the AD group compared with the HC among the age range of 7-12. And increases in amygdala volume tended to negatively moderate the linear relationships between maternal involvement and anxiety symptoms in the AD group. These findings provide new evidence of abnormal brain alteration in children and adolescents with anxiety and may reflect proactive adaptations of adolescent brain development.

Anti-inflammatory Effects of Bacteroidota Strains Derived From Outstanding Donors of Fecal Microbiota Transplantation for the Treatment of Ulcerative Colitis.

BACKGROUND: The proportion of certain Bacteroidota species decreased in patients with ulcerative colitis, and the recovery of Bacteroidota is associated with the efficacy of fecal microbiota transplantation therapy. We hypothesized that certain Bacteroidota may advance ulcerative colitis treatment. Accordingly, we aimed to evaluate the anti-inflammatory effects of Bacteroidota strains isolated from donors. METHODS: Donors with proven efficacy of fecal microbiota transplantation for ulcerative colitis were selected, and Bacteroidota strains were isolated from their stools. The immune function of Bacteroidota isolates was evaluated through in vitro and in vivo studies. RESULTS: Twenty-four Bacteroidota strains were isolated and identified. Using an in vitro interleukin (IL)-10 induction assay, we identified 4 Bacteroidota strains with remarkable IL-10-induction activity. Of these, an Alistipes putredinis strain exhibited anti-inflammatory effects in a mouse model of colitis induced by sodium dextran sulfate and oxazolone. However, 16S rRNA gene-based sequencing analysis of A. putredinis cultures in the in vivo study revealed unexpected Veillonella strain contamination. A second in vitro study confirmed that the coculture exhibited an even more potent IL-10-inducing activity. Furthermore, the production of A. putredinis-induced IL-10 was likely mediated via toll-like receptor 2 signaling. CONCLUSIONS: This study demonstrated that A. putredinis, a representative Bacteroidota species, exhibits anti-inflammatory effects in vivo and in vitro; however, the effects of other Bacteroidota species remain unexplored. Our fecal microbiota transplantation-based reverse translation approach using promising bacterial species may represent a breakthrough in microbiome drug development for controlling dysbiosis during ulcerative colitis.

We isolated Bacteroidota species from the feces of donors who were effectively cured of UC with fecal microbiota transplantation and proved the anti-inflammatory effects of Bacteroidota species, especially Alistipes putredinis, through cell experiments and in vivo experiments.

Characteristics and adsorption behavior of typical microplastics in long-term accelerated weathering simulation.

Microplastics can function as carriers in the environment, absorbing various toxins and spreading to diverse ecosystems. Toxins accumulated in microplastics have the potential to be re-released, posing a threat. In this study, two typical plastics, namely polyethylene (PE) and polystyrene (PS), along with the degradable plastic poly(butylene adipate-co-terephthalate) (PBAT), were subjected to a long-term ultraviolet alternating weathering experiment. The study investigated the variations in the weathering process and pollutant adsorption of microplastics of different particle sizes. Furthermore, the adsorption capacity of microplastics for various pollutants was assessed. The findings indicate that particle size significantly influences weathering, leading to variations in adsorption capacity. The weathered PE displays a higher adsorption capacity for azo dyes. Additionally, the adsorption capacity of PBAT for neutral red is double that of antibiotics. Importantly, the maximum adsorption capacity of PBAT for pollutants after aging is approximately 10 times greater than that of PE. Consequently, degradable plastics undergoing weathering in the natural environment may pose a higher ecological risk than traditional plastics.

No Effect of High Eating Frequency Compared with Low Eating Frequency on Appetite and Inflammation Biomarkers: Results from a Randomized Crossover Clinical Trial.

BACKGROUND: Eating frequency (EF) focuses on the total number of eating occasions per day and may influence metabolic health. OBJECTIVES: We sought to examine the effect of high compared with low EF on appetite regulation and inflammatory biomarkers among healthy adults. METHODS: Data are from a randomized, crossover trial (the Frequency of Eating and Satiety Hormones study). Participants (n = 50) completed 2 isocaloric 21-d study periods of low EF (3 eating occasions/d) and high EF (6 eating occasions/d) in random order with a 14-d washout period in between. Participants were free-living and consumed their own food, using study-directed, structured meal plans with identical foods and total energy in both study periods. On days 1 and 21 of each EF period, fasting blood was collected during in-person clinic visits to assess plasma concentrations of ghrelin, leptin, adiponectin, and high-sensitivity C-reactive protein (hs-CRP). Linear mixed models with EF, diet sequence, and period as fixed effects and participant as random effect were used to estimate the intervention effect. Interaction effects between EF and body fat percentage were examined. RESULTS: Among the 50 participants who completed the trial, 39 (78%) were women, 30 (60%) were Non-Hispanic White, and 40 (80%) had a body mass index of <25 kg/m2, and the mean age was 32.1 y. The differences between high and low EF in fasting ghrelin (geometric mean difference: 17.76 ng/mL; P = 0.60), leptin (geometric mean difference: 2.09 ng/mL; P = 0.14), adiponectin (geometric mean difference: 381.7 ng/mL; P = 0.32), and hs-CRP (geometric mean difference: -0.018 mg/dL; P = 0.08) were not statistically significant. No significant interaction was observed between EF and body fat percentage on appetite regulation and inflammatory biomarkers. CONCLUSIONS: No differences was observed in fasting ghrelin, leptin, adiponectin, and hs-CRP comparing high and low EF. Future studies are needed to understand the physiology of EF and appetite as they relate to metabolic health. This trial was registered at clinicaltrials.gov as NCT02392897.

Analysis of spatial and temporal changes in vegetation cover and its drivers in the Aksu River Basin, China.

Exploring vegetation dynamics in arid areas and their responses to different natural and anthropogenic factors is critical for understanding ecosystems. Based on the monthly MOD13Q1 (250 m) remote sensing data from 2000 to 2019, this study analyzed spatio-temporal changes in vegetation cover in the Aksu River Basin and predicted future change trends using one-dimensional linear regression, the Mann-Kendall test, and the Hurst index. Quantitative assessment of the magnitude of anthropogenic and natural drivers was performed using the Geodetector model. Eleven natural and anthropogenic factors were quantified and analyzed within five time periods. The influence of the driving factors on the changes in the normalized difference vegetation index (NDVI) in each period was calculated and analyzed. Four main results were found. (1) The overall vegetation cover in the region significantly grew from 2000 to 2019. The vegetation cover changes were dominated by expected future improvements, with a Hurst index average of 0.45. (2) Land use type, soil moisture, surface temperature, and potential vapor dispersion were the main drivers of NDVI changes, with annual average q-values above 0.2. (3) The driving effect of two-factor interactions was significantly greater than that of single factors, especially land use type interacts with other factors to a greater extent on vegetation cover. (4) The magnitude of the interaction between soil moisture and potential vapor dispersion and the magnitude of the interaction between anthropogenic factors and other factors showed an obvious increasing trend. Current soil moisture and human activities had a positive influence on the growth of vegetation in the area. The findings of this study are important for ecological monitoring and security as well as land desertification control.

Association between sociodemographics and change in alcohol or tobacco use behaviors during the COVID-19 pandemic.

OBJECTIVE: To examine the association between various sociodemographic factors with alcohol and tobacco use behaviors during the COVID-19 pandemic. METHODS: Participants from Ohio and Indiana were asked to participate in the 'Impact of COVID-19 on the Cancer Continuum Consortium' study (N = 32,989) from June-November 2020. Those who completed the survey and responded to key study questions were included (n = 5,374). Participants were asked about the frequency and type of alcohol and tobacco product used. Multivariable logistic regression was conducted to determine factors associated with the impact of COVID-19 on change in alcohol and/or tobacco use. RESULTS: Mean age was 57 years old, 68% were female, 90% non-Hispanic white, 75% married, and 31% lived in rural counties. Out of 5,374 participants, 53% used alcohol-only (n = 2,833), 5% used tobacco-only (n = 255), 7% used both alcohol and tobacco (n = 395), and 35% used neither alcohol nor tobacco (n = 1,891). Urban county of residence (vs. rural) was associated with an increase in alcohol-use (p = 0.0001), change in alcohol products (p = 0.023), and an increase in tobacco use (p = 0.05). Among alcohol-only users, those who were younger (OR = 0.97), female (OR = 1.58), married (OR = 1.69), of high socioeconomic status (OR = 1.99), residing in urban counties (OR = 1.65), and had elevated financial (OR = 1.06) and employment concerns (OR = 1.28) were significantly more likely to report increased alcohol-use. Similarly, among tobacco users, those who were younger (OR = 0.97), female (OR = 2.79), married (OR = 2.16) or divorced (OR = 2.83), and had higher levels of neighborhood disadvantage (OR = 2.19) were significantly more likely to report increased tobacco-use. CONCLUSIONS: Findings suggest targeted intervention and prevention strategies for young, female participants with elevated financial and employment concerns during the COVID-19 pandemic are necessary to mitigate risks associated with higher odds of alcohol and tobacco use. Our findings on alcohol and tobacco use may be a result of the unique social and economic influence of the pandemic on women.

Deficiency of CBL and CBLB ubiquitin ligases leads to hyper T follicular helper cell responses and lupus by reducing BCL6 degradation.

Recent evidence reveals hyper T follicular helper (Tfh) cell responses in systemic lupus erythematosus (SLE); however, molecular mechanisms responsible for hyper Tfh cell responses and whether they cause SLE are unclear. We found that SLE patients downregulated both ubiquitin ligases, casitas B-lineage lymphoma (CBL) and CBLB (CBLs), in CD4+ T cells. T cell-specific CBLs-deficient mice developed hyper Tfh cell responses and SLE, whereas blockade of Tfh cell development in the mutant mice was sufficient to prevent SLE. ICOS was upregulated in SLE Tfh cells, whose signaling increased BCL6 by attenuating BCL6 degradation via chaperone-mediated autophagy (CMA). Conversely, CBLs restrained BCL6 expression by ubiquitinating ICOS. Blockade of BCL6 degradation was sufficient to enhance Tfh cell responses. Thus, the compromised expression of CBLs is a prevalent risk trait shared by SLE patients and causative to hyper Tfh cell responses and SLE. The ICOS-CBLs axis may be a target to treat SLE.