Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity.

The enzyme cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA in infected and malignant cells and catalyzes the formation of 2'3'cGMP-AMP (cGAMP), which in turn triggers interferon (IFN) production via the STING pathway. Here, we examined the contribution of anion channels to cGAMP transfer and anti-viral defense. A candidate screen revealed that inhibition of volume-regulated anion channels (VRACs) increased propagation of the DNA virus HSV-1 but not the RNA virus VSV. Chemical blockade or genetic ablation of LRRC8A/SWELL1, a VRAC subunit, resulted in defective IFN responses to HSV-1. Biochemical and electrophysiological analyses revealed that LRRC8A/LRRC8E-containing VRACs transport cGAMP and cyclic dinucleotides across the plasma membrane. Enhancing VRAC activity by hypotonic cell swelling, cisplatin, GTPγS, or the cytokines TNF or interleukin-1 increased STING-dependent IFN response to extracellular but not intracellular cGAMP. Lrrc8e-/- mice exhibited impaired IFN responses and compromised immunity to HSV-1. Our findings suggest that cell-to-cell transmission of cGAMP via LRRC8/VRAC channels is central to effective anti-viral immunity.

Mechano-regulation of Peptide-MHC Class I Conformations Determines TCR Antigen Recognition.

TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.

Rtt105 stimulates Rad51-ssDNA assembly and orchestrates Rad51 and RPA actions to promote homologous recombination repair.

Homologous recombination (HR) is essential for the maintenance of genome stability. During HR, Replication Protein A (RPA) rapidly coats the 3'-tailed single-strand DNA (ssDNA) generated by end resection. Then, the ssDNA-bound RPA must be timely replaced by Rad51 recombinase to form Rad51 nucleoprotein filaments that drive homology search and HR repair. How cells regulate Rad51 assembly dynamics and coordinate RPA and Rad51 actions to ensure proper HR remains poorly understood. Here, we identified that Rtt105, a Ty1 transposon regulator, acts to stimulate Rad51 assembly and orchestrate RPA and Rad51 actions during HR. We found that Rtt105 interacts with Rad51 in vitro and in vivo and restrains the adenosine 5' triphosphate (ATP) hydrolysis activity of Rad51. We showed that Rtt105 directly stimulates dynamic Rad51-ssDNA assembly, strand exchange, and D-loop formation in vitro. Notably, we found that Rtt105 physically regulates the binding of Rad51 and RPA to ssDNA via different motifs and that both regulations are necessary and epistatic in promoting Rad51 nucleation, strand exchange, and HR repair. Consequently, disrupting either of the interactions impaired HR and conferred DNA damage sensitivity, underscoring the importance of Rtt105 in orchestrating the actions of Rad51 and RPA. Our work reveals additional layers of mechanisms regulating Rad51 filament dynamics and the coordination of HR.

An inhibitory mechanism of AasS, an exogenous fatty acid scavenger: Implications for re-sensitization of FAS II antimicrobials.

Antimicrobial resistance is an ongoing "one health" challenge of global concern. The acyl-ACP synthetase (termed AasS) of the zoonotic pathogen Vibrio harveyi recycles exogenous fatty acid (eFA), bypassing the requirement of type II fatty acid synthesis (FAS II), a druggable pathway. A growing body of bacterial AasS-type isoenzymes compromises the clinical efficacy of FAS II-directed antimicrobials, like cerulenin. Very recently, an acyl adenylate mimic, C10-AMS, was proposed as a lead compound against AasS activity. However, the underlying mechanism remains poorly understood. Here we present two high-resolution cryo-EM structures of AasS liganded with C10-AMS inhibitor (2.33 Å) and C10-AMP intermediate (2.19 Å) in addition to its apo form (2.53 Å). Apart from our measurements for C10-AMS' Ki value of around 0.6 µM, structural and functional analyses explained how this inhibitor interacts with AasS enzyme. Unlike an open state of AasS, ready for C10-AMP formation, a closed conformation is trapped by the C10-AMS inhibitor. Tight binding of C10-AMS blocks fatty acyl substrate entry, and therefore inhibits AasS action. Additionally, this intermediate analog C10-AMS appears to be a mixed-type AasS inhibitor. In summary, our results provide the proof of principle that inhibiting salvage of eFA by AasS reverses the FAS II bypass. This facilitates the development of next-generation anti-bacterial therapeutics, esp. the dual therapy consisting of C10-AMS scaffold derivatives combined with certain FAS II inhibitors.

Mechanism of strand exchange from RecA-DNA synaptic and D-loop structures.

The strand-exchange reaction is central to homologous recombination. It is catalysed by the RecA family of ATPases, which form a helical filament with single-stranded DNA (ssDNA) and ATP. This filament binds to a donor double-stranded DNA (dsDNA) to form synaptic filaments, which search for homology and then catalyse the exchange of the complementary strand, forming either a new heteroduplex or-if homology is limited-a D-loop1,2. How synaptic filaments form, search for homology and catalyse strand exchange is poorly understood. Here we report the cryo-electron microscopy analysis of synaptic mini-filaments with both non-complementary and partially complementary dsDNA, and structures of RecA-D-loop complexes containing a 10- or a 12-base-pair heteroduplex. The C-terminal domain of RecA binds to dsDNA and directs it to the RecA L2 loop, which inserts into and opens up the duplex. The opening propagates through RecA sequestering the homologous strand at a secondary DNA-binding site, which frees the complementary strand to sample pairing with the ssDNA. At each RecA step, there is a roughly 20% probability that duplex opening will terminate and the as-yet-unopened dsDNA portion will bind to another C-terminal domain. Homology suppresses this process, through the cooperation of heteroduplex pairing with the binding of ssDNA to the secondary site, to extend dsDNA opening. This mechanism locally limits the length of ssDNA sampled for pairing if homology is not encountered, and could allow for the formation of multiple, widely separated synapses on the donor dsDNA, which would increase the likelihood of encountering homology. These findings provide key mechanistic insights into homologous recombination.

Structural basis for regulation of SOS response in bacteria.

In response to DNA damage, bacterial RecA protein forms filaments with the assistance of DinI protein. The RecA filaments stimulate the autocleavage of LexA, the repressor of more than 50 SOS genes, and activate the SOS response. During the late phase of SOS response, the RecA filaments stimulate the autocleavage of UmuD and λ repressor CI, leading to mutagenic repair and lytic cycle, respectively. Here, we determined the cryo-electron microscopy structures of Escherichia coli RecA filaments in complex with DinI, LexA, UmuD, and λCI by helical reconstruction. The structures reveal that LexA and UmuD dimers bind in the filament groove and cleave in an intramolecular and an intermolecular manner, respectively, while λCI binds deeply in the filament groove as a monomer. Despite their distinct folds and oligomeric states, all RecA filament binders recognize the same conserved protein features in the filament groove. The SOS response in bacteria can lead to mutagenesis and antimicrobial resistance, and our study paves the way for rational drug design targeting the bacterial SOS response.

Structural insights into Ras regulation by SIN1.

Over the years it has been established that SIN1, a key component of mTORC2, could interact with Ras family small GTPases through its Ras-binding domain (RBD). The physical association of Ras and SIN1/mTORC2 could potentially affect both mTORC2 and Ras-ERK pathways. To decipher the precise molecular mechanism of this interaction, we determined the high-resolution structures of HRas/KRas-SIN1 RBD complexes, showing the detailed interaction interface. Mutation of critical interface residues abolished Ras-SIN1 interaction and in SIN1 knockout cells we demonstrated that Ras-SIN1 association promotes SGK1 activity but inhibits insulin-induced ERK activation. With structural comparison and competition fluorescence resonance energy transfer (FRET) assays we showed that HRas-SIN1 RBD association is much weaker than HRas-Raf1 RBD but is slightly stronger than HRas-PI3K RBD interaction, providing a possible explanation for the different outcome of insulin or EGF stimulation. We also found that SIN1 isoform lacking the PH domain binds stronger to Ras than other longer isoforms and the PH domain appears to have an inhibitory effect on Ras-SIN1 binding. In addition, we uncovered a Ras dimerization interface that could be critical for Ras oligomerization. Our results advance our understanding of Ras-SIN1 association and crosstalk between growth factor-stimulated pathways.

Transcription factor EB coordinates environmental cues to regulate T regulatory cells' mitochondrial fitness and function.

T regulatory (Treg) cells are essential for self-tolerance whereas they are detrimental for dampening the host anti-tumor immunity. How Treg cells adapt to environmental signals to orchestrate their homeostasis and functions remains poorly understood. Here, we identified that transcription factor EB (TFEB) is induced by host nutrition deprivation or interleukin (IL)-2 in CD4+ T cells. The loss of TFEB in Treg cells leads to reduced Treg accumulation and impaired Treg function in mouse models of cancer and autoimmune disease. TFEB intrinsically regulates genes involved in Treg cell differentiation and mitochondria function while it suppresses expression of proinflammatory cytokines independently of its established roles in autophagy. This coordinated action is required for mitochondria integrity and appropriate lipid metabolism in Treg cells. These findings identify TFEB as a critical regulator for orchestrating Treg generation and function, which may contribute to the adaptive responses of T cells to local environmental cues.

Novel Hemodynamic, Vascular Lesion, and Cytokine/Chemokine Differences Regarding Sex in a Pulmonary Arterial Hypertension Model.

Sex differences are recognized in pulmonary hypertension. However, the progression of disease with regard to vascular lesion formation and circulating cytokines/chemokines is unknown. To determine whether vascular lesion formation, changes in hemodynamics, and alterations in circulating chemokines/cytokines differ between males and females, we used a progressive model of pulmonary arterial hypertension (PAH), Sugen/hypoxia, and analyzed cohorts of male and female rats at time points suggested to indicate worsening disease. Our analysis included echocardiography for hemodynamics, morphometry, immunofluoresecence, and chemokine/cytokine analysis of plasma at each time point in both sexes. We found that male rats had significantly increased Fulton index, compared with those for females at each time point, as well as increased medial artery thickening at 8 weeks of PAH. Furthermore, females exhibited fewer obliterative vascular lesions than males at our latest time point. Our data also show increased IL-4, granulocyte-macrophage colony-stimulating factor, IL-10, and macrophage interacting protein-1α that were not observed in females, whereas females were observed to have increased RANTES (whose name derives from Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted) and CXCL-10 that were not found in males. Males also have increased infiltrating macrophages in vascular lesions, compared with females. We found that development of progressive PAH in hemodynamics, morphology, and chemokine/cytokine circulation differs significantly between males and females. These data suggest a macrophage-driven pathology in males, whereas there may be T cell protection from vascular damage in females with PAH.

Asperosaponin VI facilitates the regeneration of skeletal muscle injury by suppressing GSK-3ß-mediated cell apoptosis.

Asperosaponin VI (ASA VI) is a bioactive triterpenoid saponin extracted from Diptychus roots, of Diptyl, and has previously shown protective functions in rheumatoid arthritis and sepsis. This study investigates the effects and molecular mechanisms of ASA VI on skeletal muscle regeneration in a cardiotoxin (CTX)-induced skeletal muscle injury mouse model. Mice were subjected to CTX-induced injury in the tibialis anterior and C2C12 myotubes were treated with CTX. Muscle fiber histology was analyzed at 7 and 14 days postinjury. Apoptosis and autophagy-related protein expression were evaluated t s by Western blot, and muscle regeneration markers were quantified by quantitative polymerase chain reaction. Docking studies, cell viability assessments, and glycogen synthase kinase-3ß (GSK-3ß) activation analyses were performed to elucidate the mechanism. ASA VI was observed to improve muscle interstitial fibrosis, remodeling, and performance in CTX-treated mice, thereby increased skeletal muscle size, weight, and locomotion. Furthermore, ASA VI modulated the expression of apoptosis and autophagy-related proteins through GSK-3ß inhibition and activated the transcription of regeneration genes. Our results suggest that ASA VI mitigates skeletal muscle injury by modulating apoptosis and autophagy via GSK-3ß signaling and promotes regeneration, thus presenting a probable therapeutic agent for skeletal muscle injury.

cUMP elicits interendothelial gap formation during Pseudomonas aeruginosa infection.

Pseudomonas aeruginosa utilizes a type 3 secretion system to intoxicate host cells with the nucleotidyl cyclase ExoY. After activation by its host cell cofactor, filamentous actin, ExoY produces purine and pyrimidine cyclic nucleotides, including cAMP, cGMP, and cUMP. ExoY-generated cyclic nucleotides promote interendothelial gap formation, impair motility, and arrest cell growth. The disruptive activities of cAMP and cGMP during the P. aeruginosa infection are established; however, little is known about the function of cUMP. Here, we tested the hypothesis that cUMP contributes to endothelial cell barrier disruption during P. aeruginosa infection. Using a membrane permeable cUMP analog, cUMP-AM, we revealed that during infection with catalytically inactive ExoY, cUMP promotes interendothelial gap formation in cultured pulmonary microvascular endothelial cells (PMVECs) and contributes to increased filtration coefficient in the isolated perfused lung. These findings indicate that cUMP contributes to endothelial permeability during P. aeruginosa lung infection.NEW & NOTEWORTHY During pneumonia, bacteria utilize a virulence arsenal to communicate with host cells. The Pseudomonas aeruginosa T3SS directly introduces virulence molecules into the host cell cytoplasm. These molecules are enzymes that trigger interkingdom communication. One of the exoenzymes is a nucleotidyl cyclase that produces noncanonical cyclic nucleotides like cUMP. Little is known about how cUMP acts in the cell. Here we found that cUMP instigates pulmonary edema during Pseudomonas aeruginosa infection of the lung.

Performance of large language models on benign prostatic hyperplasia frequently asked questions.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common condition, yet it is challenging for the average BPH patient to find credible and accurate information about BPH. Our goal is to evaluate and compare the accuracy and reproducibility of large language models (LLMs), including ChatGPT-3.5, ChatGPT-4, and the New Bing Chat in responding to a BPH frequently asked questions (FAQs) questionnaire. METHODS: A total of 45 questions related to BPH were categorized into basic and professional knowledge. Three LLM-ChatGPT-3.5, ChatGPT-4, and New Bing Chat-were utilized to generate responses to these questions. Responses were graded as comprehensive, correct but inadequate, mixed with incorrect/outdated data, or completely incorrect. Reproducibility was assessed by generating two responses for each question. All responses were reviewed and judged by experienced urologists. RESULTS: All three LLMs exhibited high accuracy in generating responses to questions, with accuracy rates ranging from 86.7% to 100%. However, there was no statistically significant difference in response accuracy among the three (p > 0.017 for all comparisons). Additionally, the accuracy of the LLMs' responses to the basic knowledge questions was roughly equivalent to that of the specialized knowledge questions, showing a difference of less than 3.5% (GPT-3.5: 90% vs. 86.7%; GPT-4: 96.7% vs. 95.6%; New Bing: 96.7% vs. 93.3%). Furthermore, all three LLMs demonstrated high reproducibility, with rates ranging from 93.3% to 97.8%. CONCLUSIONS: ChatGPT-3.5, ChatGPT-4, and New Bing Chat offer accurate and reproducible responses to BPH-related questions, establishing them as valuable resources for enhancing health literacy and supporting BPH patients in conjunction with healthcare professionals.

Accelerometer-derived moderate-to-vigorous physical activity and incident nonalcoholic fatty liver disease.

BACKGROUND: The liver effects of concentrated vs. more evenly distributed moderate-to-vigorous physical activity (MVPA) patterns remain unclear. We aimed to examine the association of accelerometer-measured MVPA and different MVPA patterns with liver outcomes. METHODS: Eighty-eight thousand six hundred fifty-six participants without prior liver diseases from UK Biobank were included. MVPA was measured by a wrist-worn accelerometer. Based on the guideline-based threshold (≥ 150 min/week), MVPA patterns were defined as inactive (< 150 min/week), active weekend warrior (WW; ≥ 150 min/week with ≥ 50% of total MVPA achieved within 1-2 days), and regularly active (≥ 150 min/week but not active WW) patterns. The primary outcome was incident nonalcoholic fatty liver disease (NAFLD). RESULTS: During a median follow-up of 6.8 years, 562 participants developed NAFLD. Overall, there was a nonlinear inverse association of total MVPA with incident NAFLD (P for nonlinearity = 0.009): the risk of NAFLD rapidly decreased with the increment of MVPA (per 100 min/week increment: HR = 0.68; 95%CI, 0.57-0.81) when MVPA < 208 min/week, while moderately declined (HR = 0.91; 95%CI, 0.84-0.99) when MVPA ≥ 208 min/week. For MVPA patterns, compared with inactive group, both active WW (HR = 0.55, 95%CI, 0.44-0.67) and active regular (HR = 0.49, 95%CI, 0.38-0.63) group were associated with a similar lower risk of NAFLD. Similar results were observed for each secondary outcome, including incident severe liver diseases, incident liver cirrhosis, and liver magnetic resonance imaging-based liver steatosis and fibrosis. CONCLUSIONS: Regardless of whether MVPA was concentrated within 1 to 2 days or spread over most days of the week, more MVPA was associated with a lower risk of incident liver outcomes, including NAFLD, liver cirrhosis, liver steatosis, and fibrosis, to MVPA more evenly distributed.

Relationship of serum 25-hydroxyvitamin D, obesity with new-onset obstructive sleep apnea.

OBJECTIVE: The prospective association between vitamin D and obstructive sleep apnea (OSA) remains uncertain. We aimed to assess the association between serum 25-hydroxyvitamin D (25(OH)D), a major circulating form of vitamin D, and new-onset OSA, and examine the modifying effect of obesity. MATERIALS AND METHODS: This prospective cohort study included 444,975 participants from UK Biobank without prior OSA. The primary outcome was new-onset OSA. RESULTS: During a median follow-up duration of 12.0 years, 6051 (1.4%) participants occurred new-onset OSA. Overall, there was an inverse relation of serum 25(OH)D concentrations with the risk of new-onset OSA (per SD increment, HR, 0.92; 95%CI: 0.89-0.95). In the analysis of the interactions of serum 25(OH)D with the combination of BMI (<25, 25- < 30, and ≥30 kg/m2) and waist circumference (WC) (<90 and ≥90 cm) categories on new-onset OSA, the significantly inverse association of serum 25(OH)D and new-onset OSA was mainly found in participants with both BMI ≥ 25 kg/m2 and WC ≥ 90 cm (BMI 25-30 kg/m2 and WC ≥ 90 cm: per SD increment, HR, 0.90; 95%CI: 0.84-0.95; BMI ≥ 30 kg/m2 and WC ≥ 90 cm: per SD increment, HR, 0.85; 95%CI: 0.81-0.88), but not in other four groups with BMI < 25 kg/m2 or WC < 90 cm (P -interaction = 0.004). CONCLUSIONS: There was an inverse relation of serum 25(OH)D with the risk of new-onset OSA in participants with both BMI ≥ 25 kg/m2 and WC ≥ 90 cm. Our findings suggest the importance of maintaining a higher serum 25(OH)D concentration for primary prevention of OSA in a population with obesity.

Longitudinal Patterns of Ankle-Brachial Index and Their Association With Progression of CKD in Patients With Type 2 Diabetes and Elevated Body Mass Index.

RATIONALE & OBJECTIVE: Ankle-brachial index (ABI) is used to screen for vascular complications in the setting of diabetes. This study sought to examine the relationship of longitudinal ABI data and chronic kidney disease (CKD) progression in patients with type 2 diabetes (T2D) and elevated body mass index (BMI). STUDY DESIGN: A post-hoc analysis of the Look AHEAD trial. SETTING & PARTICIPANTS: This study included 3,631 participants in the Look AHEAD trial with a baseline glomerular filtration rate (eGFR) >60 ml/min/1.73 m2. EXPOSURES: Average ABI and average annual change in ABI were calculated based on annual ABI measurements during the first 4 years of the study. OUTCOME: CKD progression, defined as kidney failure requiring maintenance dialysis or the occurrence of eGFR<60 ml/min/1.73 m2 with a drop of ≥30% at a follow-up visit relative to the first eGFR measurement. ANALYTICAL APPROACH: Restricted cubic spline and Cox proportional hazards models were fit to estimate associations and to explore non-linearity. RESULTS: Over a median follow-up of 10.1 years, 1,051 participants developed CKD progression. There was a reversed J-shaped relationship of CKD progression with average ABI (when ABI <1.17: HR (per SD decrement), 1.23; 95%CI, 1.06-1.42; when ABI ≥ 1.17: HR (per SD increment), 1.10; 95%CI, 1.00-1.22) and average annual change in ABI (when change in ABI <-0.007: HR (per SD decrement), 1.37; 95%CI, 1.12-1.66; when change in ABI ≥-0.007: HR (per SD increment), 1.13; 95%CI, 1.03-1.24). LIMITATIONS: Observational study, potential unmeasured confounding. CONCLUSIONS: Low and high average ABI, even at clinically normal values, as well as decreasing and increasing average annual ABI, were associated a higher risk of CKD progression in patients with T2D and elevated BMI. Monitoring ABI and its changes over time may facilitate CKD risk stratification in patients with T2D.

Infection promotes Ser-214 phosphorylation important for generation of cytotoxic tau variants.

Patients who recover from hospital-acquired pneumonia exhibit a high incidence of end-organ dysfunction following hospital discharge, including cognitive deficits. We have previously demonstrated that pneumonia induces the production and release of cytotoxic oligomeric tau from pulmonary endothelial cells, and these tau oligomers can enter the circulation and may be a cause of long-term morbidities. Endothelial-derived oligomeric tau is hyperphosphorylated during infection. The purpose of these studies was to determine whether Ser-214 phosphorylation of tau is a necessary stimulus for generation of cytotoxic tau variants. The results of these studies demonstrate that Ser-214 phosphorylation is critical for the cytotoxic properties of infection-induced oligomeric tau. In the lung, Ser-214 phosphorylated tau contributes to disruption of the alveolar-capillary barrier, resulting in increased permeability. However, in the brain, both the Ser-214 phosphorylated tau and the mutant Ser-214-Ala tau, which cannot be phosphorylated, disrupted hippocampal long-term potentiation suggesting that inhibition of long-term potentiation was relatively insensitive to the phosphorylation status of Ser-214. Nonetheless, phosphorylation of tau is essential to its cytotoxicity since global dephosphorylation of the infection-induced cytotoxic tau variants rescued long-term potentiation. Collectively, these data demonstrate that multiple forms of oligomeric tau are generated during infectious pneumonia, with different forms of oligomeric tau being responsible for dysfunction of distinct end-organs during pneumonia.

Identification of amino acids metabolomic profiling in human plasma distinguishes lupus nephritis from systemic lupus erythematosus.

Lupus nephritis (LN) is an immunoinflammatory glomerulonephritis associated with renal involvement in systemic lupus erythematosus (SLE). Given the close relationship between plasma amino acids (AAs) and renal function, this study aimed to elucidate the plasma AA profiles in LN patients and identify key AAs and diagnostic patterns that distinguish LN patients from those with SLE and healthy controls. Participants were categorized into three groups: normal controls (NC), SLE, and LN. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to quantify AA levels in human plasma. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were utilized to identify key AAs. The diagnostic capacity of the models was assessed using receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) values. Significant alterations in plasma AA profiles were observed in LN patients compared to the SLE and NC groups. The OPLS-DA model effectively separated LN patients from the SLE and NC groups. A joint model using histidine (His), lysine (Lys), and tryptophan (Trp) demonstrated exceptional diagnostic performance, achieving an AUC of 1.0 with 100% sensitivity, specificity, and accuracy in predicting LN. Another joint model comprising arginine (Arg), valine (Val), and Trp also exhibited robust predictive performance, with an AUC of 0.998, sensitivity of 93.80%, specificity of 100%, and accuracy of 95.78% in distinguishing between SLE and LN. The joint forecasting models showed excellent predictive capabilities in identifying LN and categorizing lupus disease status. This approach provides a novel perspective for the early identification, prevention, treatment, and management of LN based on variations in plasma AA levels.

Tunable Colloidal Properties of Lauramidopropyl Betaine and Li Co-modified Montmorillonite in Ethanol/Water.

Montmorillonite (Mt) is a hydrophilic clay mineral with a generally high cationic exchange capacity and a remarkable swellability in water. Yet the application of Mt in cosmetics, paints, polymer nanocomposites, drug delivery systems, and tissue engineering are limited due to its unfavorable swelling and dispersion in alcohol/water mixtures. Improving the swellability and dispersibility of Mt in mixtures of ethanol and water remains challenging. Here, we showed that the swellability and dispersibility of Mt in ethanol/water could be significantly enhanced when lithium-Mt (Li-Mt) was intercalated by zwitterionic surfactant lauramidopropyl betaine (LPB). The binding mechanism of the LPB intercalate to Li-Mt originated from a combination of van der Waals forces, ion-dipole interaction, and electrostatic attraction. Due to the synergistic effect of Li+ and LPB, the comodified Mt (LPB-Li-Mt) exhibited excellent swellability, dispersibility, and rheological properties. The structure, morphology, zeta potential, dispersibility, and gel-forming performance of LPB-Li-Mt can be modulated by the concentrations of ethanol in ethanol/water mixtures. When the ethanol concentration increased to 75% v/v ethanol solution, the free swelling of LPB-Li-Mt remained above 80%. The results from X-ray diffraction, thermogravimetric analysis, Fourier transform infrared spectroscopy, X-ray photoemission spectrometry, and small-angle X-ray scattering confirmed the full exfoliation of LPB-Li-Mt at 75% (v/v) ethanol solution. The formation of a stable colloidal LPB-Li-Mt dispersion in a mixture of ethanol/water might be derived from the association between water molecules and the Li+, the hydrophobic interaction, and the ion-dipole of ethanol with the LPB molecules. The findings provide a guide for improving dispersion and swelling of Mt and modified ones in water-miscible organic solvents.

Saliva-based detection of SARS-CoV-2: a bibliometric analysis of global research.

Saliva has emerged as a promising noninvasive biofluid for the diagnosis of oral and systemic diseases, including viral infections. During the coronavirus disease 2019 (COVID-19) pandemic, a growing number of studies focused on saliva-based detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Taking advantage of the WoS core collection (WoSCC) and CiteSpace, we retrieved 1021 articles related to saliva-based detection of SARS-CoV-2 and conducted a comprehensive bibliometric analysis. We analyzed countries, institutions, authors, cited authors, and cited journals to summarize their contribution and influence and analyzed keywords to explore research hotspots and trends. From 2020 to 2021, research focused on viral transmission via saliva and verification of saliva as a reliable specimen, whereas from 2021 to the present, the focus of research has switched to saliva-based biosensors for SARS-CoV-2 detection. By far, saliva has been verified as a reliable specimen for SARS-CoV-2 detection, although a standardized procedure for saliva sampling and processing is needed. Studies on saliva-based detection of SARS-CoV-2 will promote the development of saliva-based diagnostics and biosensors for viral detection. Collectively, our findings could provide valuable information to help scientists perceive the basic knowledge landscapes on saliva-based detection of SARS-CoV-2, the past and current research hotspots, and future opportunities.

Association between longitudinal changes in body composition and the risk of kidney outcomes in participants with overweight/obesity and type 2 diabetes mellitus.

AIMS: To assess the relationship of longitudinal changes in fat mass (FM), lean mass (LM) and waist circumference (WC) with incident kidney outcomes in people with overweight/obesity and type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A total of 3927 participants with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 from the Look AHEAD (Action for Health in Diabetes) trial were included. The primary outcome was kidney outcomes, defined as a decrease in eGFR of at least 40% from baseline at follow-up visit, or end-stage kidney disease. RESULTS: During a median follow-up of 8.0 years, 450 kidney outcomes were documented after the first 1 year. In the intensive lifestyle intervention (ILI) group, reductions in FM (per 10% decrease, adjusted hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69-0.94) and WC (per 10% decrease, adjusted HR 0.72, 95% CI 0.59-0.88) from baseline to 1-year follow-up were significantly associated with a lower risk of kidney outcomes. The change in LM was not significantly associated with risk of kidney outcomes (per 10% decrease, adjusted HR 0.78, 95% CI 0.58-1.06). In the diabetes support and education group (control group), no significant association was found between changes in body composition and kidney outcomes. Similar results were observed for the 4-year changes in body composition. CONCLUSIONS: In this post hoc analysis of the Look AHEAD trial, longitudinal declines in FM and WC were associated with a lower risk of kidney outcomes in the ILI group in participants with overweight/obesity and T2DM.