Co-stimulators CD40-CD40L, a potential immune-therapy target for atherosclerosis: A review.

The interaction between CD40 and CD40 ligand (CD40L) a crucial co-stimulatory signal for activating adaptive immune cells, has a noteworthy role in atherosclerosis. It is well-known that atherosclerosis is linked to immune inflammation in blood vessels. In atherosclerotic lesions, there is a multitude of proinflammatory cytokines, adhesion molecules, and collagen, as well as smooth muscle cells, macrophages, and T lymphocytes, particularly the binding of CD40 and CD40L. Therefore, research on inhibiting the CD40-CD40L system to prevent atherosclerosis has been ongoing for more than 30 years. However, it's essential to note that long-term direct suppression of CD40 or CD40L could potentially result in immunosuppression, emphasizing the critical role of the CD40-CD40L system in atherosclerosis. Thus, specifically targeting the CD40-CD40L interaction on particular cell types or their downstream signaling pathways may be a robust strategy for mitigating atherosclerosis, reducing potential side effects. This review aims to summarize the potential utility of the CD40-CD40L system as a viable therapeutic target for atherosclerosis.

Bariatric Surgery Improves Serum CD40L Levels as a Predictor of Cardiovascular Risk: Systematic Review and Meta-analysis.

CD40 and its ligand have been recently implicated in the pathogenesis of cardiovascular disease (CVD). This meta-analysis examined the effect of bariatric surgery in reducing circulating CD40L levels. A systematic review was performed using Embase, Google Scholar, PubMed, Scopus, and Web of Science. The meta-analysis was provided by Comprehensive Meta-Analysis (CMA) V4 software. The overall effect size was detected by a random-effects meta-analysis and the leave-one-out approach. Random-effects meta-analysis of 7 studies including 191 subjects showed a significant reduction in CD40L after bariatric surgery (standardized mean difference (SMD), - 0.531; 95% CI, - 0.981, - 0.082; p = 0.021; I2, 87.00). Circulating levels of CD40L are decreased after bariatric surgery which may represent a mechanism for improvement of metabolic profile.

Modelling Annihilation Properties of Positronium Confined in Nanoporous Materials: A Review.

Positronium (Ps) is a valuable probe to investigate nanometric or sub-nanometric cavities in non-metallic materials, where Ps can be confined. Accessible experimental measurements concern the lifetime of trapped Ps, which is largely influenced by pick-off processes, depending on the size of the cavity as well as on the density of the electrons belonging to the surface of the host trap. Another relevant physical quantity is the contact density, that is the electron density at the positron position, which is usually found to be well below the vacuum value. Here, we review the principal models that have been formulated to account and explain for these physical properties of confined Ps. Starting with models, treating Ps as a single particle formulated essentially to study pick-off, we go on to describe more refined two-particle models because a two-body model is the simplest approach able to describe any change in the contact density, observed in many materials. Finally, we consider a theory of Ps annihilation in nanometric voids in which the exchange correlations between the electron of Ps and the outer electrons play a fundamental role. This theory is not usually taken into account in the literature, but it has to be considered for a correct theory of pick-off annihilation processes.

Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs.

Xenotransplantation represents a possible solution to the organ shortage crisis and is an imminent clinical reality with long-term xenograft survival in pig-to-nonhuman primate (NHP) heart and kidney large animal models, and short-term success in recent human decedent and clinical studies. However, concerns remain about safe clinical translation of these results, given the inconsistency in published survival as well as key differences between preclinical procurement and immunosuppression and clinical standards-of-care. Notably, no studies of solid organ pig-to-NHP transplantation have achieved xenograft survival longer than one month without CD40/CD154 costimulatory blockade, which is not currently an FDA-approved immunosuppression strategy. We now present consistent survival in consecutive cases of pig-to-NHP kidney xenotransplantation, including long-term survival after >3 hours of xenograft cold preservation time as well as long-term survival using FDA-approved immunosuppression. These data provide critical supporting evidence for the safety and feasibility of clinical kidney xenotransplantation. Moreover, long-term survival without CD40/CD154 costimulatory blockade may provide important insights for immunosuppression regimens to be considered for first-in-human clinical trials.

Engineering surface state density of monolayer CVD grown 2D MoS2 for enhanced photodetector performance.

This study demonstrates the effect of nitrogen doping on the surface state densities (Nss) of monolayer MoS2 and its effect on the responsivity and the response time of the photodetector. Our experimental results shows that by doping monolayer MoS2 by nitrogen, the surface state (Nss) increases thereby increasing responsivity. The mathematical model included in the paper supports the relation of photocurrent gain and its dependency on trap level which states that the increasing the trap density increases the photocurrent gain and the same is observed experimentally. The experimental results at room temperature revealed that nitrogen doped MoS2 have a high NSS of 1.63 X 1013 states/m2/eV compared to undoped MoS2 of 4.2 x 1012 states/m2/eV. The increase in Nss in turn is the cause for rise in trap states which eventually increases the value of photo responsivity from 65.12 A/W (undoped MoS2) to 606.3 A/W (nitrogen doped MoS2). The response time calculated for undoped MoS2 was 0.85 sec and for doped MoS2 was 0.35 sec. Finally, to verify the dependence of surface states on the responsivity, the surface states were varied by varying temperature and it was observed that upon increment in temperature, the surface states decreases which causes the responsivity values also to decrease.

CD40 stimulation via CD40 ligand enhances adenovirus-mediated tumour immunogenicity including 'find-me', 'eat-me', and 'kill-me' signalling.

Immunostimulatory gene therapy using oncolytic viruses is currently evaluated as a promising therapy for cancer aiming to induce anti-tumour immunity. Here, we investigate the capacity of oncolytic adenoviruses (LOAd) and their transgenes to induce immunogenicity in the infected tumour cells. Oncolysis and death-related markers were assessed after infection of eight human solid cancer cell lines with different LOAd viruses expressing a trimerized, membrane-bound (TMZ)-CD40L, TMZ-CD40L and 41BBL, or no transgenes. The viruses induced transgene expression post infection before they were killed by oncolysis. Death receptors TRAIL-R1, TRAIL-R2 and Fas as well as immunogenic cell death marker calreticulin were upregulated in cell lines post infection. Similarly, caspase 3/7 activity was increased in most cell lines. Interestingly, in CD40+ cell lines there was a significant effect of the TMZ-CD40L-encoding viruses indicating activation of the CD40-mediated apoptosis pathway. Further, these cell lines showed a significant increase of calreticulin, and TRAIL receptor 1 and 2 post infection. However, LOAd viruses induced PD-L1 upregulation which may hamper anti-tumour immune responses. In conclusion, LOAd infection increased the immunogenicity of infected tumour cells and this was potentiated by CD40 stimulation. Due to the simultaneous PD-L1 increase, LOAd viruses may benefit from combination with antibodies blocking PD1/PD-L1.

Perioperative Treatment with Rivaroxaban and Dabigatran on Changes of Coagulation and Platelet Activation Biomarkers following Left Atrial Appendage Closure.

Insufficient data exist regarding the investigation of the impact of novel oral anticoagulants (NOACs) on coagulation activation biomarkers in the context of left atrial appendage closure (LAAC) and device-related thrombosis (DRT). The study was designed to investigate the changes and presence of coagulation activation biomarkers between different antithrombotic strategies following LAAC. A total of 120 nonvalvular atrial fibrillation patients intolerant of long-term anticoagulants, who underwent successful WATCHMAN closure implantation, were enrolled (rivaroxaban, n = 82; dabigatran, n = 38). Blood samples were obtained from left atrium (LA) and left atrial appendage (LAA) during the operation and fasting blood samples on the same day of LAAC and 45 days after discharge. The biochemical indicators, thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), von Willebrand factor (vWF), and CD40 ligand (CD40L), were measured by enzyme-linked immunosorbent assay. The primary endpoints of this study were the efficacy and safety characteristics of different antithrombotic strategies, including DRT incidence, stroke or transient ischemic attack, systemic embolism, and clinical major and nonmajor bleeding complications during the follow-up of 180 days. The results revealed that TAT, vWF, sP-selectin, and CD40L levels in vein were significantly reduced by 2.4% (p = 0.043), 5.0% (p < 0.001), 8.7% (p < 0.001), and 2.5% (p = 0.043) from their baseline levels after rivaroxaban treatment. Conversely, no significant changes were detected in the dabigatran group. Furthermore, the plasma levels of platelet activation biomarkers (CD40L and sP-selectin) in both LA and LAA groups were significantly lower after anticoagulation with rivaroxaban, as compared to dabigatran treatment (CD40L: 554.62 ± 155.54 vs. 445.02 ± 130.04 for LA p = 0.0013, 578.51 ± 156.28 vs. 480.13 ± 164.37 for LAA p = 0.0052; sP-selectin: 2849.07 ± 846.69 vs. 2225.54 ± 799.96 for LA p = 0.0105, 2915.52 ± 1402.40 vs. 2203.41 ± 1061.67 for LAA p = 0.0022). Notably, the present study suggests that rivaroxaban may be more effective in the prevention of DRT for patients undergoing LAAC.

Advanced Glycation End Products Upregulate CD40 in Human Retinal Endothelial and Müller Cells: Relevance to Diabetic Retinopathy.

CD40 induces pro-inflammatory responses in endothelial and Müller cells and is required for the development of diabetic retinopathy (DR). CD40 is upregulated in these cells in patients with DR. CD40 upregulation is a central feature of CD40-driven inflammatory disorders. What drives CD40 upregulation in the diabetic retina remains unknown. We examined the role of advanced glycation end products (AGEs) in CD40 upregulation in endothelial cells and Müller cells. Human endothelial cells and Müller cells were incubated with unmodified or methylglyoxal (MGO)-modified fibronectin. CD40 expression was assessed by flow cytometry. The expression of ICAM-1 and CCL2 was examined by flow cytometry or ELISA after stimulation with CD154 (CD40 ligand). The expression of carboxymethyl lysine (CML), fibronectin, and laminin as well as CD40 in endothelial and Müller cells from patients with DR was examined by confocal microscopy. Fibronectin modified by MGO upregulated CD40 in endothelial and Müller cells. CD40 upregulation was functionally relevant. MGO-modified fibronectin enhanced CD154-driven upregulation of ICAM-1 and CCL2 in endothelial and Müller cells. Increased CD40 expression in endothelial and Müller cells from patients with DR was associated with increased CML expression in fibronectin and laminin. These findings identify AGEs as inducers of CD40 upregulation in endothelial and Müller cells and enhancers of CD40-dependent pro-inflammatory responses. CD40 upregulation in these cells is associated with higher CML expression in fibronectin and laminin in patients with DR. This study revealed that CD40 and AGEs, two important drivers of DR, are interconnected.

Immunoprecipitation and FRET-FLIM to Determine Metabolons on the Plant ER.

Metabolons are protein complexes that contain all the enzymes necessary for a metabolic pathway but also scaffolding proteins. Such a structure allows efficient channeling of intermediate metabolites form one active site to the next and is highly advantageous for labile or toxic intermediates. Here we describe two methods currently used to identify metabolons via protein-protein interaction methodology: immunoprecipitations using GFP-Trap®_A beads to find novel interaction partners and potential metabolon components and FRET-FLIM to test for and quantify protein-protein interactions in planta.

Safety, Tolerability, Pharmacokinetics, and pharmacodynamics of YH35324, a novel Long-Acting High-Affinity IgETrap-Fc protein in subjects with Atopy: Results from the First-in-Human study.

BACKGROUND: YH35324, a long-acting IgETrap-Fc fusion protein, is a novel therapeutic agent for immunoglobulin E (IgE)-mediated allergic diseases. This randomized, double-blind, placebo/active-controlled, single ascending dose Phase 1 study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of YH35324 in subjects with atopy. METHODS: Eligible subjects were healthy subjects or atopic adults with mild allergic rhinitis, atopic dermatitis, food allergy, or urticaria, and a serum total IgE level of 30-700 IU/mL (Part A) or > 700 IU/mL (Part B). In Part A, 35 subjects in 5 cohorts received YH35324 (0.3, 1, 3, 6, and 9 mg/kg), 8 received omalizumab (300 mg), and 9 received placebo. In Part B, 8 subjects received YH35324 and 8 received omalizumab. RESULTS: Twenty subjects (38.5 %) in Part A (YH35324: 37.1 %, omalizumab: 50.0 %, placebo: 33.3 %) and 10 subjects (62.5 %) in Part B (YH35324: 100 %; omalizumab: 25.0 %) experienced treatment-emergent adverse events (TEAEs). TEAEs were mostly grade 1/2; no serious AEs, AE-related treatment discontinuation, or anaphylaxis were reported. YH35324 exhibited dose-proportional increase in Cmax and AUClast over the dose range of 0.3-9 mg/kg. YH35324 rapidly suppressed serum-free IgE levels to a significant extent (< 25 and < 82.8 ng/mL, both P < 0.05) and with longer duration than omalizumab. CONCLUSION: This study showed that YH35324 has a favorable safety profile and is effective in reducing serum-free IgE levels in subjects with atopic conditions.

Coronary artery bypass grafting (CABG) induces pro-inflammatory and immunomodulatory phenotype of platelets in the absence of a pro-aggregatory state.

BACKGROUND: Coronary artery bypass grafting (CABG) is considered the choice treatment for patients suffering from coronary artery disease (CAD). In the inflammatory milieu of cardiopulmonary bypass (CPB), systemic inflammatory response syndrome (SIRS) can induce a platelet pro-inflammatory state which could exacerbate post-CABG inflammatory status while affecting hemostatic function in patients. Therefore, focusing on platelets, the study presented here attempted to evaluate the pro-inflammatory and immunomodulatory profile of platelets as well as pro-aggregatory status during CABG. METHODS: Platelets from patients undergoing CABG were subjected to flowcytometry analysis to evaluate P-selectin and CD40L expressions and PAC-1 binding in five intervals of 24 h before surgery, immediately, 2 h, 24 h, and one week after surgery. Moreover, intra-platelet TGF-ß1 was also examined with western blotting. RESULTS: Data showed increases of P-selectin and CD40L expressions in patients, with the meaningful loss of platelet contents of TGF-ß1 after CABG (p < 0.001), where the changes tended to recover by day 7 of surgery while remaining above baseline (p < 0.001). Meanwhile, no significant change in PAC-1 binding capacity was shown. CONCLUSION: The study presented here suggests that although the release of pro-inflammatory substances from platelets during CABG supports the post-operative inflammatory state, platelets are not pro-aggregatory enough to enhance thrombotic events after surgery. Whilst these observations could be due to successful medical interventions to optimize hemostasis during and after surgery, post-CABG reversal of anticoagulant by protamine is considered as another factor that may also have contributed to preventing pro-aggregatory but not pro-inflammatory and immunomodulatory functions of platelets.

Evaluation of the DN-Mini (miniaturized double net) trap for sampling host-seeking Anopheles mosquitoes in malaria-endemic villages of southern Tanzania.

BACKGROUND: Surveillance of malaria vectors is crucial for assessing the transmission risk and impact of control measures. Human landing catches (HLC) directly estimate the biting rates but raise ethical concerns due to the exposure of volunteers to mosquito-borne pathogens. A common alternative is the CDC-light trap, which is effective for catching host-seeking mosquitoes indoors but not outdoors. New, exposure-free methods are needed for sampling mosquitoes indoors and outdoors in ways that reflect their natural risk profiles. The aim of this study was therefore to evaluate the efficacy of the miniaturized double net trap (DN-Mini) for sampling host-seeking mosquitoes in south-eastern Tanzania, where malaria transmission is dominated by Anopheles funestus. METHODS: Adult mosquitoes were collected from 222 randomly selected houses across three villages (74 per village) in Ulanga district, south-eastern Tanzania, using the DN-Mini traps, CDC-Light traps, and Prokopack aspirators. First, we compared CDC-light and DN-Mini traps for collecting indoor host-seeking mosquitoes, while Prokopack aspirators were used for indoor-resting mosquitoes. Second, we deployed the DN-Mini and Prokopack aspirators to collect host-seeking and resting mosquitoes indoors and outdoors. Generalized linear mixed models (GLMM) with a negative binomial distribution were used to compare the effectiveness of the traps for catching different mosquito species. RESULTS: The DN-Mini was 1.53 times more efficient in collecting An. funestus indoors (RR = 1.53, 95% CI: 1.190-1.98) compared to the CDC-Light trap. However, for Anopheles arabiensis, the DN-Mini caught only 0.32 times as many mosquitoes indoors as the CDC-Light traps (RR = 0.32, 95% CI: 0.183-0.567). Both An. funestus and An. arabiensis were found to be more abundant indoors than outdoors when collected using the DN-Mini trap. Similarly, the Prokopack aspirator was greater indoors than outdoors for both An. funestus and An. arabiensis. CONCLUSION: The DN-Mini outperformed the CDC-light trap in sampling the dominant malaria vector, An. funestus species, but was less effective in capturing An. arabiensis, and for both vector species, the biting risk was greater indoors than outdoors when measured using the DN-Mini trap. These findings highlight the importance of selecting appropriate trapping methods based on mosquito species and behaviors.

Inhibition of CD40L with Frexalimab in Multiple Sclerosis.

BACKGROUND: The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis. METHODS: In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab. RESULTS: Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches. CONCLUSIONS: In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

Aedes albopictus in a recently invaded area in Spain: effects of trap type, locality, and season on mosquito captures.

Mosquitoes are primary vectors of pathogens impacting humans, wildlife, and livestock. Among them, the Asian tiger mosquito, Aedes albopictus, stands out as an invasive species with a global distribution, having established populations on every continent except Antarctica. Recent findings incriminate Ae. albopictus in the local transmission of several pathogens causing human diseases, including dengue, chikungunya, and Zika viruses and worm parasites as Dirofilaria. In Spain, the establishment of Ae. albopictus occurred in 2004 and it rapidly expanded, currently reaching southern provinces and creating novel epidemiological scenarios in recently invaded areas. In this study, we conducted captures of Ae. albopictus from May to November 2022 in two provinces, Granada and Malaga, situated near the current edge of the species' expanding range in Spain. The objective was to identify the primary factors influencing their captures in these regions. Mosquitoes were captured using BG-Sentinel traps baited with CO2 and BG-Lure, and miniature CDC-UV traps in five different localities. Our findings underscore the influence of both extrinsic factors, such as locality, and intrinsic factors, including mosquito sex, on the abundance of captured Ae. albopictus. A higher abundance of Ae. albopictus was observed in the Malaga province compared to localities in the Granada province. Furthermore, similar numbers of Ae. albopictus mosquitoes were captured in more urbanized areas of Granada, while the lowest counts were recorded in the less urbanized area. These results were compared to captures of another common species in the area, specifically Culex pipiens. Overall, these results represent the first monitoring of invasive Ae. albopictus in the area and are discussed in the light of the potential importance of the species as a nuisance for humans and vectors of pathogens of public health relevance.

Investigation of T cell-related hub genes in diabetic nephropathy by bioinformatics analysis and experiment validation.

Diabetic nephropathy(DN) remains a significant risk factor for cardiovascular and all-cause mortality, and end-stage renal disease (ESRD) associated with it is growing in prevalence.However, there is absolutely no curative strategy for DN. We subjected db/db and control mouse kidneys to transcriptional sequencing analysis to obtain transcriptome expression profile data in the diabetic nephropathy.We next performed differential analysis of db/db and control mice kidney sequencing data to obtain differentially expressed genes. The differential expressed genes were intersected with the oxidative stress and inflammatory response related genes derived from the MGI/MsiDB gene set to yield oxidative stress inflammatory response related differential 122 genes (OIRDEGs). To further clarify the biological functions of DEGs, we conducted GOKEGG analysis and obtained the top 20 genes by five computational algorithms of the cytohubba plugin via cytoscape, respectively. The genes obtained by the five algorithms were intersected and the intersection genes were considered as key genes,including Cd40lg, Il2rb, Lck, Il2rg, Zap70, Serpinb1a. Also,we used GSEA and immune infiltration analysis to clarify the biological signaling pathways and immune cell infiltration that are substantial in the diabetic nephropathy.Correlation studies of key genes with immune cell infiltration revealed that they were correlated with the majority types of T cells while only with two types of B cells.Then, we predicted miRNA and TF for the key genes and constructed the interaction network. Finally, the expression differences of key genes were examined by validation dataset and RT-PCR experiment.In conclusion,we have identified key genes associated with T cell immune response in a diabetic nephropathy model, which bear significance in the etiopathogenesis of immunological injury in diabetic nephropathy and provide an innovative proposal for the recognition and management of DN.

Genetically engineered IgG1 and nanobody oligomers acquire strong intrinsic CD40 agonism.

Most anti-CD40 antibodies show robust agonism only upon binding to FcγR+ cells, such as B cells, macrophages, or DCs, but a few anti-CD40 antibodies display also strong intrinsic agonism dependent on the recognized epitope and/or isotype. It is worth mentioning, however, that also the anti-CD40 antibodies with intrinsic agonism can show a further increase in agonistic activity when bound by FcγR-expressing cells. Thus, conventional antibodies appear not to be sufficient to trigger the maximum possible CD40 activation independent from FcγR-binding. We proved here the hypothesis that oligomeric and oligovalent anti-CD40 antibody variants generated by genetic engineering display high intrinsic, thus FcγR-independent, agonistic activity. We generated tetra-, hexa- and dodecavalent variants of six anti-CD40 antibodies and a CD40-specific nanobody. All these oligovalent variants, even when derived of bivalent antagonistic anti-CD40 antibodies, showed strongly enhanced CD40 agonism compared to their conventional counterparts. In most cases, the CD40 agonism reached the maximum response induced by FcγR-bound anti-CD40 antibodies or membrane CD40L, the natural engager of CD40. In sum, our data show that increasing the valency of anti-CD40 antibody constructs by genetic engineering regularly results in molecules with high intrinsic agonism and level out the specific limitations of the parental antibodies.

Predictive value of soluble CD40L combined with APACHE II score in elderly patients with sepsis in the emergency department.

BACKGROUND: The prognostic performance of soluble CD40L (sCD40L) for illness severity in infectious diseases is rarely reported. We investigated the ability of sCD40L combined with Acute Physiology and Chronic Health Evaluation II (APACHE II) score to evaluate mortality in septic patients in the emergency department(ED). METHODS: We enrolled 222 septic patients in the ED of Beijing Chao-Yang Hospital from October 2020 to April 2021. Their serum sCD40L, PCT, lactate (Lac), Sequential Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation II (APACHE II) score were used to predict the prognosis of septic patients in terms of 28-day mortality. Serum sCD40L was detected by Human XL Cytokine Luminex. Logistic regression analysis and receiver operating characteristic (ROC) curves were used to assess the prognostic value of the variables. RESULTS: One hundred ninety-five patients met the inclusion criteria, divided into survival group (55 cases) and non-survival group (140 cases). sCD40L, PCT, Lac, SOFA and APACHE II score were found to independently predict 28-day mortality (P < 0.05). The AUC values of sCD40L, PCT, Lac, SOFA and APACHE II score were 0.662,0.727,0.704, 0.719 and 0.716, respectively. There was no difference in the diagnostic value of sCD40L compared with the PCT, Lac, SOFA score or APACHE II score (Z1 = 1.19, P = 0.234; Z2 = 0.77, P = 0.441; Z3 = 1.05, P = 0.294; Z4 = 0.97, P = 0.332). However, the combined evaluation of sCD40L + APACHE II (AUC:0.772, Z = 2.10, P = 0.036) was much better than sCD40L alone in predicting 28-day mortality. CONCLUSION: The predictive value of sCD40L + APACHE II is better than sCD40L alone for 28-day mortality. sCD40L combined with APACHE II score is valuable for predicting 28-day mortality in elderly patients with sepsis.

Environmental and geographical factors influence the occurrence and abundance of the southern house mosquito, Culex quinquefasciatus, in Hawai'i.

Hawaiian honeycreepers, a group of endemic Hawaiian forest birds, are being threatened by avian malaria, a non-native disease that is driving honeycreepers populations to extinction. Avian malaria is caused by the parasite Plasmodium relictum, which is transmitted by the invasive mosquito Culex quinquefasciatus. Environmental and geographical factors play an important role in shaping mosquito-borne disease transmission dynamics through their influence on the distribution and abundance of mosquitoes. We assessed the effects of environmental (temperature, precipitation), geographic (site, elevation, distance to anthropogenic features), and trap type (CDC light trap, CDC gravid trap) factors on mosquito occurrence and abundance. Occurrence was analyzed using classification and regression tree models (CART) and generalized linear models (GLM); abundance (count data) was analyzed using generalized linear mixed models (GLMMs). Models predicted highest mosquito occurrence at mid-elevation sites and between July and November. Occurrence increased with temperature and precipitation up to 580 mm. For abundance, the best model was a zero-inflated negative-binomial model that indicated higher abundance of mosquitoes at mid-elevation sites and peak abundance between August and October. Estimation of occurrence and abundance as well as understanding the factors that influence them are key for mosquito control, which may reduce the risk of forest bird extinction.

Role of Skewed X-Chromosome Inactivation in Common Variable Immunodeficiency.

The term common variable immunodeficiency (CVID) encompasses a clinically diverse group of disorders, mainly characterized by hypogammaglobulinemia, insufficient specific antibody production, and recurrent infections. The genetics of CVID is complex, and monogenic defects account for only a portion of cases, typically <30%. Other proposed mechanisms include digenic, oligogenic, or polygenic inheritance and epigenetic dysregulation. In this study, we aimed to assess the role of skewed X-chromosome inactivation (XCI) in CVID. Within our cohort of 131 genetically analyzed CVID patients, we selected female patients with rare variants in CVID-associated genes located on the X-chromosome. Four patients harboring heterozygous variants in BTK (n = 2), CD40LG (n = 1), and IKBKG (n = 1) were included in the study. We assessed XCI status using the HUMARA assay and an NGS-based method to quantify the expression of the 2 alleles in mRNA. Three of the 4 patients (75%) exhibited skewed XCI, and the mutated allele was predominantly expressed in all cases. Patient 1 harbored a hypomorphic variant in BTK (p.Tyr418His), patient 3 had a pathogenic variant in CD40LG (c.288+1G>A), and patient 4 had a hypomorphic variant in IKBKG (p.Glu57Lys) and a heterozygous splice variant in TNFRSF13B (TACI) (c.61+2T>A). Overall, the analysis of our cohort suggests that CVID in a small proportion of females (1.6% in our cohort) is caused by skewed XCI and highly penetrant gene variants on the X-chromosome. Additionally, skewed XCI may contribute to polygenic effects (3.3% in our cohort). These results indicate that skewed XCI may represent another piece in the complex puzzle of CVID genetics.

Fringe-fields-modulated double-gate tunnel-FET biosensor.

This paper aims to evaluate a groundbreaking bio-TFET that utilizes the fringe fields capacitance concept to detect neutral and charged biomolecules. While facilitating fabrication process and scalability, this innovative bio-TFET is able to rival the conventional bio-TFET which relies on carving cavities in the gate oxide. The cavities of the proposed device are carved in the spacers over the source region and in the vicinity of the gate metal. Inserting biomolecules in the cavities of our bio-TFET modifies the fringe fields arising out of the gate metal. As a result, these spacers modulate tunneling barrier width at the source-channel tunneling junction. We have assessed our proposed device's DC/RF performance using the calibrated Silvaco ATLAS device simulator. For further evaluation of the reliability of our bio-TFET, non-idealities, such as trap-assisted tunneling and temperature, are also studied. The device we propose is highly suitable for biosensing applications, as evidenced by the parameters of [Formula: see text] = 1.21 × 103, SSS = 0.365, and [Formula: see text] = 1.63 × 103 at VGS = 1 V.