Fragile Guts Make Fragile Brains: Intestinal Epithelial Nrf2 Deficiency Exacerbates Neurotoxicity Induced by Polystyrene Nanoplastics.

Oral ingestion is the primary route for human exposure to nanoplastics, making the gastrointestinal tract one of the first and most impacted organs. Given the presence of the gut-brain axis, a crucial concern arises regarding the potential impact of intestinal damage on the neurotoxic effects of nanoplastics (NPs). The intricate mechanisms underlying NP-induced neurotoxicity through the microbiome-gut-brain axis necessitate further investigation. To address this, we used mice specifically engineered with nuclear factor erythroid-derived 2-related factor 2 (Nrf2) deficiency in their intestines, a strain whose intestines are particularly susceptible to polystyrene NPs (PS-NPs). We conducted a 28-day repeated-dose oral toxicity study with 2.5 and 250 mg/kg of 50 nm PS-NPs in these mice. Our study delineated how PS-NP exposure caused gut microbiota dysbiosis, characterized by Mycoplasma and Coriobacteriaceae proliferation, resulting in increased levels of interleukin 17C (IL-17C) production in the intestines. The surplus IL-17C permeated the brain via the bloodstream, triggering inflammation and brain damage. Our investigation elucidated a direct correlation between intestinal health and neurological outcomes in the context of PS-NP exposure. Susceptible mice with fragile guts exhibited heightened neurotoxicity induced by PS-NPs. This phenomenon was attributed to the elevated abundance of microbiota associated with IL-17C production in the intestines of these mice, such as Mesorhizobium and Lwoffii, provoked by PS-NPs. Neurotoxicity was alleviated by in vivo treatment with anti-IL-17C-neutralizing antibodies or antibiotics. These findings advanced our comprehension of the regulatory mechanisms governing the gut-brain axis in PS-NP-induced neurotoxicity and underscored the critical importance of maintaining intestinal health to mitigate the neurotoxic effects of PS-NPs.

Population genomics uncovers global distribution, antimicrobial resistance, and virulence genes of the opportunistic pathogen Klebsiella aerogenes.

Klebsiella aerogenes is an understudied and clinically important pathogen. We therefore investigate its population structure by genome analysis aligned with metadata. We sequence 130 non-duplicated K. aerogenes clinical isolates and identify two inter-patient transmission events. We then retrieve all publicly available K. aerogenes genomes (n = 1,026, accessed by January 1, 2023) and analyze them with our 130 genomes. We develop a core-genome multi-locus sequence-typing scheme. We find that K. aerogenes is a species complex comprising four phylogroups undergoing evolutionary divergence, likely forming three species. We delineate remarkable clonal diversity and identify three worldwide-distributed carbapenemase-encoding clonal clusters, representing high-risk lineages. We uncover that K. aerogenes has an open genome equipped by a large arsenal of antimicrobial resistance genes. We identify two genetic regions specific for K. aerogenes, encoding a type VI secretion system and flagella/chemotaxis for motility, respectively, both contributing to the virulence. These results provide much-needed insights into the population structure and pan-genomes of K. aerogenes.

Magnetically attracting hydrogel reshapes iron metabolism for tissue repair.

Ferroptosis, caused by disorders of iron metabolism, plays a critical role in various diseases, making the regulation of iron metabolism essential for tissue repair. In our analysis of degenerated intervertebral disc tissue, we observe a positive correlation between the concentration of extracellular iron ions (ex-iron) and the severity of ferroptosis in intervertebral disc degeneration (IVDD). Hence, inspired by magnets attracting metals, we combine polyether F127 diacrylate (FDA) with tannin (TA) to construct a magnetically attracting hydrogel (FDA-TA). This hydrogel demonstrates the capability to adsorb ex-iron and remodel the iron metabolism of cells. Furthermore, it exhibits good toughness and self-healing properties. Notably, it can activate the PI3K-AKT pathway to inhibit nuclear receptor coactivator 4-mediated ferritinophagy under ex-iron enrichment conditions. The curative effect and related mechanism are further confirmed in vivo. Consequently, on the basis of the pathological mechanism, a targeted hydrogel is designed to reshape iron metabolism, offering insights for tissue repair.

Identification of programmed cell death-related genes and diagnostic biomarkers in endometriosis using a machine learning and Mendelian randomization approach.

Background: Endometriosis (EM) is a prevalent gynecological disorder frequently associated with irregular menstruation and infertility. Programmed cell death (PCD) is pivotal in the pathophysiological mechanisms underlying EM. Despite this, the precise pathogenesis of EM remains poorly understood, leading to diagnostic delays. Consequently, identifying biomarkers associated with PCD is critical for advancing the diagnosis and treatment of EM. Methods: This study used datasets from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs) following preprocessing. By cross-referencing these DEGs with genes associated with PCD, differentially expressed PCD-related genes (DPGs) were identified. Enrichment analyses for KEGG and GO pathways were conducted on these DPGs. Additionally, Mendelian randomization and machine learning techniques were applied to identify biomarkers strongly associated with EM. Results: The study identified three pivotal biomarkers: TNFSF12, AP3M1, and PDK2, and established a diagnostic model for EM based on these genes. The results revealed a marked upregulation of TNFSF12 and PDK2 in EM samples, coupled with a significant downregulation of AP3M1. Single-cell analysis further underscored the potential of TNFSF12, AP3M1, and PDK2 as biomarkers for EM. Additionally, molecular docking studies demonstrated that these genes exhibit significant binding affinities with drugs currently utilized in clinical practice. Conclusion: This study systematically elucidated the molecular characteristics of PCD in EM and identified TNFSF12, AP3M1, and PDK2 as key biomarkers. These findings provide new directions for the early diagnosis and personalized treatment of EM.

An 8-(Diazomethyl) Quinoline Derivatized Acyl-CoA in Silico Mass Spectral Library Reveals the Landscape of Acyl-CoA in Aging Mouse Organs.

Acyl-Coenzyme As (acyl-CoAs) are essential intermediates to incorporate carboxylic acids into the bioactive metabolic network across all species, which play important roles in lipid remodeling, fatty acids, and xenobiotic carboxylic metabolism. However, due to the poor liquid chromatographic behavior, the relatively low mass spectrometry (MS) sensitivity, and lack of authentic standards for annotation, the in-depth untargeted profiling of acyl-CoAs is challenging. We developed a chemical derivatization strategy of acyl-CoAs by employing 8-(diazomethyl) quinoline (8-DMQ) as the labeling reagent, which increased the detection sensitivity by 625-fold with good peak shapes. By applying the MS/MS fragmentation rules learned from the MS/MS spectra of 8-DMQ-acyl-CoA authentic standards, an 8-DMQ-acyl-CoA in silico mass spectral library containing 33,344 high-resolution tandem mass spectra of 8,336 acyl-CoA species was created. The in silico library facilitated the high-throughput and automatic annotation of acyl-CoA using multiple metabolomic data processing tools, such as NIST MS Search and MSDIAL. The feasibility of the in silico library in a complex sample was demonstrated by profiling endogenous acyl-CoAs in multiple organs of an aging mouse. 53 acyl-CoA species were annotated, including 12 oxidized fatty acyl-CoAs and 3 novel nonfatty acyl-CoAs. False positive annotations were further screened by developing an eXtreme Gradient Boosting (XGBoost) based retention time prediction model. The organ distribution and the aging dynamics of acyl-CoAs in a mouse model were discussed for the first time, which helped to elucidate the organ-specific function of acyl-CoAs and the role of different acyl-CoA species during aging.

Endoscopic polidocanol foam sclerobanding for the treatment of grade II-III internal hemorrhoids: A prospective, multi-center, randomized study.

BACKGROUND: Endoscopic rubber band ligation (ERBL) is a nonsurgical technique for the treatment of symptomatic internal hemorrhoids but is limited by recurrence and post-procedural pain. AIM: To evaluate satisfaction, long-term recurrence, and post-procedural pain in managing internal hemorrhoids using a combination of polidocanol foam sclerotherapy and ERBL. METHODS: This was a prospective, multicenter, randomized study. A total of 195 consecutive patients diagnosed with grade II-III internal hemorrhoids were enrolled from four tertiary hospitals and randomly divided into a cap-assisted endoscopic polidocanol foam sclerobanding (EFSB) or an ERBL group. All patients were followed-up for 12 months. Symptom-based severity and post-procedural pain were assessed using a hemorrhoid severity score (HSS) and a visual analog scale (VAS). Continuous variables were reported as medians and interquartile range. RESULTS: One hundred and ninety-five patients were enrolled, with 98 in the EFSB group. HSS was lower in the EFSB group than in the ERBL group at 8 weeks [4.0 (3.0-5.0) vs 5.0 (4.0-6.0), P = 0.003] and 12-month [2.0 (1.0-3.0) vs 3.0 (2.0-3.0), P < 0.001] of follow-up. The prolapse recurrence rate was lower in the EFSB group at 12 months (11.2% vs 21.6%, P = 0.038). Multiple linear regression analysis demonstrated that EFSB treatment [B = -0.915, 95% confidence interval (CI): -1.301 to -0.530, P = 0.001] and rubber band number (B = 0.843, 95%CI: 0.595-1.092, P < 0.001) were negatively and independently associated with the VAS score 24 hours post-procedure. The median VAS was lower in the EFSB group than in the ERBL [2.0 (1.0-3.0) vs 3.0 (2.0-4.0), P < 0.001]. CONCLUSION: Cap-assisted EFSB provided long-term satisfaction and effective relief from the recurrence of prolapse and pain 24 hours post-procedure.

The INMSG Survey on the Loss of Signal Management on the First Side During Planned Bilateral Thyroid Surgery.

BACKGROUND: The aim of this study is to describe the management and associated follow-up strategies adopted by thyroid surgeons with different surgical volumes when loss of signal (LOS) occurred on the first side of planned bilateral thyroid surgery, and to further define the consensus on intraoperative neuromonitoring (IONM) applications. METHODS: The International Neural Monitoring Study Group (INMSG) web-based survey was sent to 950 thyroid surgeons worldwide. The survey included information on the participants, IONM team/equipment/procedure, intraoperative/postoperative management of LOS, and management of LOS on the first side of thyroidectomy for benign and malignant disease. RESULTS: Out of 950, 318 (33.5%) respondents completed the survey. Subgroup analyses were performed based on thyroid surgery volume: <50 cases/year (n = 108, 34%); 50 to 100 cases/year (n = 69, 22%); and >100 cases/year (n = 141, 44.3%). High-volume surgeons were significantly (P < .05) more likely to perform the standard procedures (L1-V1-R1-S1-S2-R2-V2-L2), to differentiate true/false LOS, and to verify the LOS lesion/injury type. When LOS occurs, most surgeons arrange otolaryngologists or speech consultation. When first-side LOS occurs, not all respondents decided to perform stage contralateral surgery, especially for malignant patients with severe disease (eg, extrathyroid invasion and poorly differentiated thyroid cancer). CONCLUSIONS: Respondents felt that IONM was optimized when conducted under a collaborative team-based approach, and completed IONM standard procedures and management algorithm for LOS, especially those with high volume. In cases of first-site LOS, surgeons can determine the optimal management of disease-related, patient-related, and surgical factors. Surgeons need additional education on LOS management standards and guidelines to master their decision-making process involving the application of IONM.

Synergistically activating nucleophile strategy enabled organocatalytic asymmetric P-addition of cyclic imines.

Herein, we present an attractive organocatalytic asymmetric addition of P-nucleophiles to five-membered cyclic N-sulfonyl imines facilitated by phosphonium salt catalysis, enabling the highly enantioselective synthesis of tri- and tetra-substituted cyclic phosphorus-containing benzosultams. With this protocol, various cyclic α-aminophosphonates were efficiently synthesized with high yields and exceptional enantioselectivities (up to >99% ee) under mild reaction conditions. The utility and practicality of this method were demonstrated through gram-scale reactions and straightforward elaborations. Notably, the success of this approach relies on the deliberate selection of a synergistic organocatalytic system, which helps circumvent foreseeable side effects while handling secondary phosphine oxides (SPOs). Systematic mechanistic studies, incorporating experiments and DFT calculations, have revealed the critical importance of judiciously selecting bifunctional phosphonium salt catalysts for effectively activating P-nucleophiles while stereoselectively controlling the P-attack process.

Structural insights into transcription activation of the Streptomyces antibiotic regulatory protein, AfsR.

The Streptomyces antibiotic regulatory proteins (SARPs) are ubiquitously distributed transcription activators in Streptomyces and control antibiotics biosynthesis and morphological differentiation. However, the molecular mechanism behind SARP-dependent transcription initiation remains elusive. We here solve the cryo-EM structure of an AfsR-loading RNA polymerase (RNAP)-promoter intermediate complex (AfsR-RPi) including the Streptomyces coelicolor RNAP, a large SARP member AfsR, and its target promoter DNA that retains the upstream portion straight. The structure reveals that one dimeric N-terminal AfsR-SARP domain (AfsR-SARP) specifically engages with the same face of the AfsR-binding sites by the conserved DNA-binding domains (DBDs), replacing σHrdBR4 to bind the suboptimal -35 element, and shortens the spacer between the -10 and -35 elements. Notably, the AfsR-SARPs also recruit RNAP through extensively interacting with its conserved domains (ß flap, σHrdBR4, and αCTD). Thus, these macromolecular snapshots support a general model and provide valuable clues for SARP-dependent transcription activation in Streptomyces.

Age-related changes in mitral annular disjunction: A retrospective analysis using enhanced cardiac CT.

AIMS: The current recognition of mitral annular disjunction (MAD) as an anatomical abnormality potentially associated with ventricular arrhythmias has sparked controversy regarding its prevalence and clinical implications. This study aimed to investigate the prevalence and extent of MAD in individuals with no significant structural abnormalities involving the left heart using enhanced cardiac CT, while also exploring potential factors, such as age, that may be associated with MAD. METHODS: Systolic datasets of cardiac CT from 742 subjects were retrospectively included. MAD was determined by rotating orthogonal multiplanar reconstruction images around the central axis of the mitral annulus. The maximal distance of disjunction (DMAD) and segments involved (SI, 0 to 5 basal segments at left ventricular wall) was quantified to evaluate the extent of separation. RESULTS: In total, 449 (60.5%) had MAD. Subjects with MAD were significantly older (51.3 ± 19.9 years vs. 29.6 ± 20.3 years, P < 0.001). Age was found to be an independent relevant factor for MAD (OR = 1.059; 95%CI: 1.033, 1.085; P < 0.001). Subjects with MAD were then divided into 4 subgroups (G1: ≤20 years, G2: 21-40 years, G3: 41-60 years, G4: ≥61 years). DMAD and SI of each age subgroup were 1.9 ± 0.2 mm, 2.0 ± 1.2 (G1, n = 36), 2.7 ± 0.8 mm, 2.9 ± 1.3 (G2, n = 51), 3.0 ± 0.8 mm, 3.0 ± 1.3 (G3, n = 183), and 3.0 ± 1.0 mm, 3.7 ± 1.1 (G4, n = 179). Age was an independent relevant factor associated with DMAD (R2 = 0.132; ß = 0.014; 95%CI: 0.004, 0.024; P = 0.007) and SI (OR = 1.030; 95%CI: 1.005, 1.055; P = 0.016). CONCLUSIONS: MAD is a common finding on cardiac CT. Its prevalence and extent increase with age.

Vasorin (VASN) overexpression promotes pulmonary metastasis and resistance to adjuvant chemotherapy in patients with locally advanced rectal cancer.

BACKGROUND: LARC patients commonly receive adjuvant therapy, however, hidden micrometastases still limit the improvement of OS. This study aims to investigate the impact of VASN in rectal cancer with pulmonary metastasis and understand the underlying molecular mechanisms to guide adjuvant chemotherapy selection. METHODS: Sequencing data from rectal cancer patients with pulmonary metastasis from Sun Yat-sen University Cancer Center (SYSUCC) and publicly available data were meticulously analyzed. The functional role of VASN in pulmonary metastasis was validated in vivo and in vitro. Coimmunoprecipitation (co-IP), immunofluorescence, and rescue experiments were conducted to unravel potential molecular mechanisms of VASN. Moreover, VASN expression levels in tumor samples were examined and analyzed for their correlations with pulmonary metastasis status, tumor stage, adjuvant chemotherapy benefit, and survival outcome. RESULTS: Our study revealed a significant association between high VASN expression and pulmonary metastasis in LARC patients. Experiments in vitro and in vivo demonstrated that VASN could promote the cell proliferation, metastasis, and drug resistance of colorectal cancer. Mechanistically, VASN interacts with the NOTCH1 protein, leading to concurrent activation of the NOTCH and MAPK pathways. Clinically, pulmonary metastasis and advanced tumor stage were observed in 90% of VASN-positive patients and 53.5% of VASN-high patients, respectively, and VASN-high patients had a lower five-year survival rate than VASN-low patients (26.7% vs. 83.7%). Moreover, the Cox analysis and OS analysis indicated that VASN was an independent prognostic factor for OS (HR = 7.4, P value < 0.001) and a predictor of adjuvant therapy efficacy in rectal cancer. CONCLUSIONS: Our study highlights the role of VASN in decreasing drug sensitivity and activating the NOTCH and MAPK pathways, which leads to tumorigenesis and pulmonary metastasis. Both experimental and clinical data support that rectal cancer patients with VASN overexpression detected in biopsies have a higher risk of pulmonary metastasis and adjuvant chemotherapy resistance.

Assessing Stroke Recurrence Risk by Using a Lipoprotein-Associated Phospholipase A2 and Platelet Count-Based Nomogram.

Stroke recurrence remains a critical challenge in clinical neurology, necessitating the identification of reliable predictive markers for better management and treatment strategies. This study investigates the interaction between lipoprotein-associated phospholipase A2 (Lp-PLA2) and platelets as a potential predictor for stroke recurrence, aiming to refine risk assessment and therapeutic approaches. In a retrospective cohort of 580 ischemic stroke patients, we analyzed clinical data with a focus on Lp-PLA2 and platelet levels. By using multivariable logistic regression, we identified independent predictors of stroke recurrence. These predictors were then used to develop a comprehensive nomogram. The study established diabetes mellitus, hypertension, low-density lipoprotein (LDL), Lp-PLA2 levels, and platelet counts as independent predictors of stroke recurrence. Crucially, the interaction parameter Lp-PLA2 * platelet (multiplication of Lp-PLA2 and platelet count) exhibited superior predictive power over each factor considered separately. Our nomogram incorporated diabetes mellitus, cerebral infarction causes, hypertension, LDL, and the Lp-PLA2 * platelet count interaction and demonstrated enhanced accuracy in predicting stroke recurrence compared to traditional risk models. The interaction between Lp-PLA2 and platelets emerged as a significant predictor for stroke recurrence when integrated with traditional risk factors. The developed nomogram offers a novel and practical tool in molecular neurobiology for assessing individual risks, facilitating personalized treatment strategies. This approach underscores the importance of multifactorial assessment in stroke management and opens avenues for targeted interventions to mitigate recurrence risks.

Study the local metabolic changes of aneurysms through microcatheter sampling.

Intracranial aneurysm is the primary cause of nontraumatic subarachnoid hemorrhage. To assess aneurysm metabolism, we present a method of intra-operatively collecting blood samples from the aneurysm neck, as well as the proximal and distal responsible vessels, using microcatheters. Through these paired comparisons, we can eliminate the interpatient variation usually observed in plasma samples taken from the peripheral vein. We utilized 39 plasma samples from 13 intracranial patients to characterize the metabolite profiles using untargeted liquid chromatography-mass spectrometry. Our findings revealed that L-tyrosine is upregulated at relatively high levels at the aneurysm neck than the proximal and distal aneurysm, whereas phenylpyruvic acid, L-cystine, and L-ornithine are downregulated. Based on this, there was also a significant decrease in arginine within small aneurysm of the internal carotid artery. The 6-month follow-up indicated that patients who experienced good recovery had lower levels of biliverdin, bilirubin, and metabolites of coenzyme Q within the aneurysm. In conclusion, our investigation provides a comprehensive overview of plasma metabolites in patients with intracranial aneurysms, shedding light on potential pathogenetic mechanisms in unruptured intracranial aneurysms. Moreover, the study proposes innovative ideas for establishing postoperative follow-up timelines for flow diverter devices.

Predicting intraoperative major blood loss in microsurgery for brain arteriovenous malformations.

Objective: Intraoperative blood loss poses a great challenge for brain arteriovenous malformation (AVM) microsurgery, although systematic researches are still lacking. This study aimed to identify factors predicting intraoperative major blood loss in brain AVM microsurgery and to investigate its impact on patient outcome. To deal with the fierce bleeding, we introduced a modified hemostatic method, bone-wax (BW) coated bipolar electrocoagulation. Methods: The authors retrospectively analyzed the clinical data of 131 patients (50/81 in intraoperative major/non-major blood loss cohort) with brain AVMs who underwent microsurgery in our center during the period between January 2018 and April 2023. According to previous studies, major blood loss was defined as blood loss of at least 1,000 mL. The accuracy and objectivity of our grouping methodology were validated by comparing the hemoglobin mass loss, hematocrit loss and factors associated with intraoperative bleeding. Potential clinical and radiological predictors for intraoperative major blood loss were evaluated using a multivariate stepwise logistic regression. And outcomes of patients in the two cohorts were also compared. At last, the performance of BW coated bipolar electrocoagulation in brain AVM microsurgery was illustrated by the case presentation, histological staining and transmission electron microscopy of the coagulated nidus vessels. Results: Hemoglobin mass loss, hematocrit loss and factors associated with intraoperative bleeding were significant different between the two cohorts. five independent factors predicting intraoperative major blood loss were identified: (1) clinical manifestations; (2,3) location and size of the nidus; (4) deep venous drainage; and (5) the number of draining veins. And the intraoperative major blood loss can not only adversely affect the surgical progression, but also predict poor perioperative outcomes for patients. Regarding the application of BW coated bipolar electrocoagulation, we found the novel hemostatic method exerted efficient hemostatic effect and reduced the damage to the vascular structure in brain AVM microsurgery. Conclusion: This study proposed a nomogram for neurosurgeons to predict intraoperative major blood loss in brain AVM microsurgery preoperatively. And intraoperative major blood loss is associated with poor patient outcomes. In addition, BW coated bipolar electrocoagulation, can be applied to control ferocious bleeding during brain AVM microsurgery, which still remains further researches.

PFN1 Knockdown Aggravates Mitophagy to Retard Lung Adenocarcinoma Initiation and M2 Macrophage Polarization.

Tumor-associated macrophages (TAM) are considered as crucial influencing factors of lung adenocarcinoma (LUAD) carcinogenesis and metastasis. Profilin 1 (PFN1) has been proposed as a potent driver of migration and drug resistance in LUAD. The focus of this work was to figure out the functional mechanism of PFN1 in macrophage polarization in LUAD. PFN1 expression and its significance in patients' survival were detected by ENCORI and Kaplan-Meier Plotter. RT-qPCR and western blotting examined PFN1 expression in LUAD cells. CCK-8 assay and colony formation assay detected cell proliferation. Flow cytometry detected cell apoptosis. Relevant assay kit tested caspase3 concentration. Western blotting analyzed the expression of proliferation- and apoptosis-related proteins. RT-qPCR and immunofluorescence staining measured M1 and M2 macrophages markers. Mitophagy was assessed by MitoTracker Red staining, immunofluorescence staining, and western blotting. PFN1 expression was increased in LUAD tissues and cells and correlated with the poor survival rate of LUAD patients. Deficiency of PFN1 hindered the proliferation, whereas facilitated the apoptosis of LUAD cells. Additionally, PFN1 interference impaired M2 macrophage polarization. Moreover, PFN1 knockdown exacerbated the mitophagy in LUAD cells and mitophagy inhibitor mitochondrial division inhibitor 1 (Mdivi-1) notably reversed the effects of PFN1 down-regulation on the proliferation, apoptosis as well as macrophage polarization in LUAD cells. To sum up, activation of mitophagy initiated by PFN1 depletion might obstruct the occurrence and M2 macrophage polarization in LUAD.

mRNA lipid nanoparticles expressing cell-surface cleavage independent HIV Env trimers elicit autologous tier-2 neutralizing antibodies.

The HIV-1 envelope glycoprotein (Env) is the sole neutralizing determinant on the surface of the virus. The Env gp120 and gp41 subunits mediate receptor binding and membrane fusion and are generated from the gp160 precursor by cellular furins. This cleavage event is required for viral entry. One approach to generate HIV-1 neutralizing antibodies following immunization is to express membrane-bound Env anchored on the cell-surface by genetic means using the natural HIV gp41 transmembrane (TM) spanning domain. To simplify the process of Env trimer membrane expression we sought to remove the need for Env precursor cleavage while maintaining native-like conformation following genetic expression. To accomplish these objectives, we selected our previously developed 'native flexibly linked' (NFL) stabilized soluble trimers that are both near-native in conformation and cleavage-independent. We genetically fused the NFL construct to the HIV TM domain by using a short linker or by restoring the native membrane external proximal region, absent in soluble trimers, to express the full HIV Env ectodomain on the plasma membrane. Both forms of cell-surface NFL trimers, without and with the MPER, displayed favorable antigenic profiles by flow cytometry when expressed from plasmid DNA or mRNA. These results were consistent with the presence of well-ordered cell surface native-like trimeric Env, a necessary requirement to generate neutralizing antibodies by vaccination. Inoculation of rabbits with mRNA lipid nanoparticles (LNP) expressing membrane-bound stabilized HIV Env NFL trimers generated tier 2 neutralizing antibody serum titers in immunized animals. Multiple inoculations of mRNA LNPs generated similar neutralizing antibody titers compared to immunizations of matched NFL soluble proteins in adjuvant. Given the recent success of mRNA vaccines to prevent severe COVID, these are important developments for genetic expression of native-like HIV Env trimers in animals and potentially in humans.

Relationship between intraoperative hypothermia and hyperthermia with postoperative pulmonary infection and surgical site infection in major non-cardiac surgery.

Background: Surgical patients often experience intraoperative hypothermia or hyperthermia. However, the relationship of intraoperative hypothermia and hyperthermia with postoperative pulmonary infection (PPI) and surgical site infection (SSI) is unclear. Here, we conducted a retrospective cohort study to address these issues. Methods: Adult patients who underwent major non-cardiac surgery under general anesthesia were eligible for the study and were recruited. Three indices of core body temperature under hypothermia (<36°C) and hyperthermia (>37.3°C) were calculated as mentioned in the following: absolute value (0C), duration of exposure (min), and area under the curve (AUC,°C× min). The outcomes were in-hospital PPI and SSI. The risk-adjusted association of intraoperative hypothermia and hyperthermia with PPI and SSI was determined. Results: The absolute value (the nadir value of hypothermia and the peak value of hyperthermia) was not associated with PPI and SSI. PPI was associated with (1) duration: hypothermia >90 min [adjusted odds ratio (aOR): 1.425, 95% confidence interval (CI): 1.131-1.796] and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208-1.612) and (2) AUC: hypothermia >3,198 (aOR: 1.390, 95%CI: 1.128-1.731) and hyperthermia >7,945 (aOR: 2.045, 95%CI: 1.138-3.676). SSI was associated with (1) duration: hypothermia > 195 min (aOR: 2.900, 95%CI: 1.703-4.937) and hyperthermia >75 min (aOR: 1.395, 95%CI: 1.208-1.612) and (2) AUC: hypothermia >6,946 (aOR: 2.665, 95%CI: 1.618-4.390), hyperthermia >7,945 (aOR: 2.619, 95%CI: 1.625-4.220). Interactions were not observed between hyperthermia and hypothermia on the outcomes. Conclusions: It was observed that intraoperative hypothermia and hyperthermia are associated with postoperative pulmonary infection and surgical site infection in major non-cardiac surgery.

SOS! Hydrogen Sulfide Enhances the Flavonoid Early Warning System in Rice Plants to Cope with Thiocyanate Pollution.

The presence of thiocyanate (SCN-) in irrigation water has adverse effects on both plant growth and crop output. Hydrogen sulfide (H2S) is an important gaseous signaling molecule that can alleviate SCN- stress. Flavonoids are secondary compounds produced by plants and are ubiquitous in the plant kingdom. They play important roles in several physiological and biochemical processes. To investigate the effect of exogenous H2S on the growth of early rice plants under SCN- stress, we carried out a hydroponic experiment focusing on the interaction of exogenous H2S with flavonoids. In this study, a hydroponic experiment was performed to investigate the behavior of SCN- when subjected to varying effective doses (EC20: 24.0 mg/L; EC50: 96.0 mg/L; and EC75: 300.0 mg/L). The findings indicated that the relative growth rate (RGR) of the plants treated with H2S + SCN- was greater than that of the plants treated with SCN- alone. Higher amounts of flavonoids were detected in the shoots than in the roots, with more variability in the shoots. The early warning level results showed that most of the flavonoids were present at levels I and II, while quercetin was present at level IV. Genetic expression variation factor (GEVF) analyses revealed an increase in the quantity of "promoter genes" with increasing SCN- concentration in both rice tissues. Furthermore, administering external H2S while exposing rice tissues to SCN- resulted in a considerable decrease in the levels of reactive oxygen species. This study provides novel insights into the regulation of flavonoid levels in rice plants by exogenous H2S, facilitating enhanced resistance to SCN- stress and promoting sustainable agriculture.

Effects of table based air curtains on respiratory aerosol exposure risk mitigation at face-to-face meeting setups.

Face-to-face meetings on a conference table are a frequent form of communication. The short-range exposure risk of aerosol disease transmission is high in the scenario of susceptible facing the infectious person over the table. We propose a mitigation methodology using the air curtain to reduce direct exposure to virus-laden aerosols. A numerical model was validated with experimental data to simulate the dispersion of aerosols. A dynamic mesh was adopted to consider the head movement of a 3D thermal manikin model. Results show that nodding head increase the potential risk by 74 % compared to motionless. Subsequently, for a single air curtain, placing it in the middle of the table is more effective in preventing risks than on the sides. For double air curtains, increasing the distance between them has a greater risk reduction effect than a shorter distance. Increasing the air velocity or width is more effective than increasing the number of air curtains. A moderate velocity (1 m s-1) works well to reduce the risk of nasal breathing. A higher velocity (2 m s-1) is needed for the coughing scenario. For similar indoor environments, the air curtains on the table can offer active precautions without changing the current ventilation system.

Dihydrolipoamide dehydrogenase (DLD) is a novel molecular target of bortezomib.

Proteasome inhibitors (PIs), such as bortezomib and calfizomib, were backbone agents in the treatment of multiple myeloma (MM). In this study, we investigated bortezomib interactors in MM cells and identified dihydrolipoamide dehydrogenase (DLD) as a molecular target of bortezomib. DLD catalyzes the oxidation of dihydrolipoamide to form lipoamide, a reaction that also generates NADH. Our data showed that bortezomib bound to DLD and inhibited DLD's enzymatic function in MM cells. DLD knocked down MM cells (DLD-KD) had decreased levels of NADH. Reduced NADH suppressed assembly of proteasome complex in cells. As a result, DLD-KD MM cells had decreased basal-level proteasome activity and were more sensitive to bortezomib. Since PIs were used in many anti-MM regimens in clinics, we found that high expression of DLD correlated with inferior prognosis of MM. Considering the regulatory role of DLD in proteasome assembly, we evaluated DLD targeting therapy in MM cells. DLD inhibitor CPI-613 showed a synergistic anti-MM effect with bortezomib in vitro and in vivo. Overall, our findings elucidated DLD as an alternative molecular target of bortezomib in MM. DLD-targeting might increase MM sensitivity to PIs.