Water deficit and aphid resilience on wheat: examining Sitobion avenae F. and their bacterial symbionts interplay under controlled laboratory conditions.

BACKGROUND: Climate change has far-reaching effects on food security and agriculture, affecting crop yields and food distribution. Agriculture relies heavily on water for irrigation and production, making it vulnerable to water scarcity. Additionally, climate change can affect crop pest insects, leading to increased global crop losses, particularly in cereals, an important component of the human diet. Aphids are major crop pests and have a symbiotic relationship with bacterial endosymbionts that can contribute to their success as pests under a climate change scenario. To test the effect of drought on aphids, we examined varying levels of water deficit and endosymbiont composition on the grain aphid (Sitobion avenae) performance on wheat under controlled laboratory conditions. We measured the intrinsic rate of population increase (rm), the body weight of adult aphids, and the pre-reproductive period for different genotypes of the grain aphid (including Chilean superclones) under different irrigation regimes. We also analyzed the relative abundance of their endosymbionts under the different water treatments. RESULTS: Our findings revealed that water deficit affects each aphid genotype differently, impacting various traits. For instance, the body weight of adult aphids was notably affected by different water treatments, with aphids grown under intermediate water deficit (IW) being significantly bigger. The relative abundance of endosymbionts also varied among genotypes and water treatments-specifically Regiella insecticola had a noticeably higher abundance under IW (P < 0.05). CONCLUSION: This study provides valuable insights into the impact of water deficit on aphid performance and the role of endosymbionts in mitigating the effects of water deficit. © 2024 Society of Chemical Industry.

Microbiome contributions to pain: a review of the preclinical literature.

ABSTRACT: Over the past 2 decades, the microbiome has received increasing attention for the role that it plays in health and disease. Historically, the gut microbiome was of particular interest to pain scientists studying nociplastic visceral pain conditions given the anatomical juxtaposition of these microorganisms and the neuroimmune networks that drive pain in such diseases. More recently, microbiomes both inside and across the surface of the body have been recognized for driving sensory symptoms in a broader set of diseases. Microbiomes have never been a more popular topic in pain research, but to date, there has not been a systematic review of the preclinical microbiome pain literature. In this article, we identified all animal studies in which both the microbiome was manipulated and pain behaviors were measured. Our analysis included 303 unique experiments across 97 articles. Microbiome manipulation methods and behavioral outcomes were recorded for each experiment so that field-wide trends could be quantified and reported. This review specifically details the animal species, injury models, behavior measures, and microbiome manipulations used in preclinical pain research. From this analysis, we were also able to conclude how manipulations of the microbiome alter pain thresholds in naïve animals and persistent pain intensity and duration in cutaneous and visceral pain models. This review summarizes by identifying existing gaps in the literature and providing recommendations for how to best plan, implement, and interpret data collected in preclinical microbiome pain experiments.

Preclinical evaluation of a fully human, quadrivalent-hantavirus polyclonal antibody derived from a non-human source.

Hantaviruses are rodent-borne viruses that cause severe disease in infected humans. In the New World, major hantaviruses include Andes virus (ANDV) and Sin Nombre virus (SNV) causing hantavirus pulmonary syndrome. In the Old World, major hantaviruses include Hantaan virus (HTNV) and Puumala virus (PUUV) causing hemorrhagic fever with renal syndrome. Here, we produced a pan-hantavirus therapeutic (SAB-163) comprised of fully human immunoglobulin purified from the plasma of transchromosomic bovines (TcB) vaccinated with hantavirus DNA plasmids coding for the major glycoproteins of ANDV, SNV, HTNV, and PUUV. SAB-163 has potent neutralizing antibodies (PRNT50 > 200,000) against the four targeted hantavirus and cross-neutralization against several other heterotypic hantaviruses. At a dosage of 10 mg/kg, SAB-163 is bioavailable in Syrian hamsters out to 70 days post-treatment with a half-life of 10-15 days. At this same dosage, SAB-163 administered 1 day before, or 5 days after exposure, protected all hamsters from lethal disease caused by ANDV. At a higher dose, partial but significant protection was achieved as late as day 6. SAB-163 also protected hamsters in the HTNV, PUUV, and SNV infection models when administered 1 day before or up to 3 days after challenge. This pan-hantavirus therapeutic is attractive because it is fully human, multi-targeted, safe, stable at 4°C, and effective in animal models. SAB-163 was evaluated for safety in GLP human tissue binding studies and a GLP rabbit toxicity study at 365 and 730 mg/kg and is investigational new drug enabled for phase 1 clinical trial(s). IMPORTANCE: This candidate polyclonal human IgG product was produced using synthetic gene-based vaccines and transgenic cows. Having now gone through cGMP production, GLP safety testing, and efficacy testing in animals, SAB-163 is the world's most advanced anti-hantavirus antibody-based medical countermeasure, aside from convalescent human plasma. Importantly, SAB-163 targets the most prevalent hantaviruses on four continents.

Nsp1 stalls DNA Polymerase α at DNA hairpins.

The human primosome, a four-subunit complex of DNA primase and DNA polymerase alpha (Polα), plays a critical role in DNA replication by initiating RNA and DNA synthesis on both chromosome strands. A recent study has shown that a major virulence factor in the SARS-CoV-2 infection, Nsp1 (non-structural protein 1), forms a stable complex with Polα but does not affect the primosome activity. Here we show that Nsp1 inhibits DNA synthesis across inverted repeats prone to hairpin formation. Analysis of current structural data revealed the overlapping binding sites for Nsp1 and the winged helix-turn-helix domain of RPA (wHTH) on Polα, indicating a competition between them. Comparison of the inhibitory effect of Nsp1 and wHTH on DNA hairpin bypass by Polα showed an 8-fold lower IC50 value for Nsp1 (1 µM). This study provides a valuable insight into the mechanism of inhibition of human DNA replication by Nsp1 during a SARS-CoV-2 infection.

Experiences with home monitoring technology in older adults with traumatic brain injury: a qualitative study.

BACKGROUND: Home monitoring systems utilising artificial intelligence hold promise for digitally enhanced healthcare in older adults. Their real-world use will depend on acceptability to the end user i.e. older adults and caregivers. We explored the experiences of adults over the age of 60 and their social and care networks with a home monitoring system installed on hospital discharge after sustaining a moderate/severe Traumatic Brain Injury (TBI), a growing public health concern. METHODS: A qualitative descriptive approach was taken to explore experiential data from older adults and their caregivers as part of a feasibility study. Semi-structured interviews were conducted with 6 patients and 6 caregivers (N = 12) at 6-month study exit. Data were analysed using Framework analysis. Potential factors affecting acceptability and barriers and facilitators to the use of home monitoring in clinical care and research were examined. RESULTS: Home monitoring was acceptable to older adults with TBI and their caregivers. Facilitators to the use of home monitoring were perceived need for greater support after hospital discharge, the absence of sound and video recording, and the peace of mind provided to care providers. Potential barriers to adoption were reliability, lack of confidence in technology and uncertainty at how data would be acted upon to improve safety at home. CONCLUSIONS: Remote monitoring approaches are likely to be acceptable, especially if patients and caregivers see direct benefit to their care. We identified key barriers and facilitators to the use of home monitoring in older adults who had sustained TBI, which can inform the development of home monitoring for research and clinical use. For sustained use in this demographic the technology should be developed in conjunction with older adults and their social and care networks.

PARAFAC under non-negativity constraint is adapted to recover the underlying Beer-Lambert law of the excitation-emission fluorescence matrix measurements acquired from analyte-triggered semiconductor QDs photoluminescence modulation. When and why?

BACKGROUND: Analyte-triggered semiconductor quantum dots (QDs) modulation in the presence of non-consistently responsive fluorescent species represents a challenging analytical issue in concrete multi-way data handling. QDs with heterogeneous sizes and/or uneven distribution of functional moieties on their surfaces exhibit significant fluctuations in the fluorescent response components, known as chemical rank, across different excitation/emission modes. This phenomenon may lead to a substantial deviation from the proportionality prescribed by Beer-Lambert law. Nonetheless, even in the presence of such deviation, a multi-way model may be successfully selected after determining a proper chemical rank in a QDs system. RESULTS: We show that in a valid PARAllel FACtor (PARAFAC) model under properly determined chemical rank, meaningfully resolved pure spectral profiles can be reached for each fluorescent responsive constituent in the original excitation-emission fluorescence matrix (EEFM) measurements. This was thoroughly illustrated by applying PARAFAC trilinear decomposition of a three-way data array of two distinct datasets acquired from semiconductor QDs sensing systems with low-rank trilinear assumption. The first dataset, presented here for the first time, comprises EEFM measurements of the ligand-driven quenching of thiomalic acid (TMA)-capped AgInS2 (AIS) QDs by vomitoxin. The second dataset, employed for illustrative purposes, comprises EEFM measurements of the quenching, via cation bridging, of glutathione (GSH)-capped CdTe QDs by Pb(II). The results of this study enabled the determination of vomitoxin at a ppb level in real samples of fish feeds, showcasing the efficacy of the PARAFAC model in resolving spectral signatures (loadings) and pure concentration profiles (scores). SIGNIFICANCE: PARAFAC under a properly examined chemical rank can be easily adapted for retrieval the underlying Beer-Lambert law of the original EEFM measurements with a low-rank trilinear structure through the chemically meaningful information either when (i) no deviation of Beer-Lambert law was observed as deeply discussed in connection with the dataset acquired from vomitoxin-driven molecular sensing through TMA-capped AIS QDs, or when (ii) substantial deviations of the Beer-Lambert law are evident, as discussed in connection with the dataset collected from sensing ionic species through Pb(II) bridging of GSH-capped CdTe QDs.

High-dimensional proteomic analysis for pathophysiological classification of traumatic brain injury.

Pathophysiology and outcomes after Traumatic Brain Injury (TBI) are complex and heterogenous. Current classifications are uninformative about pathophysiology. Proteomic approaches with fluid-based biomarkers are ideal for exploring complex disease mechanisms, as they enable sensitive assessment of an expansive range of processes potentially relevant to TBI pathophysiology. We used novel high-dimensional, multiplex proteomic assays to assess altered plasma protein expression in acute TBI. We analysed samples from 88 participants from the BIO-AX-TBI cohort (n=38 moderate-severe TBI [Mayo Criteria], n=22 non-TBI trauma, n=28 non-injured controls) on two platforms: Alamar NULISA™ CNS Diseases and OLINK® Target 96 Inflammation. Patient participants were enrolled after hospital admission, and samples taken at a single timepoint up to 10 days post-injury. Participants also had neurofilament light, GFAP, total tau, UCH-L1 (all Simoa®) and S100B (Millipore) data. The Alamar panel assesses 120 proteins, most of which were previously unexplored in TBI, plus proteins with known TBI-specificity, such as GFAP. A subset (n=29 TBI, n=24 non-injured controls) also had subacute (10 days to 6 weeks post-injury) 3T MRI measures of lesion volume and white matter injury (fractional anisotropy). Differential Expression analysis identified 16 proteins with TBI-specific significantly different plasma expression. These were neuronal markers (calbindin2, UCH-L1, visinin-like protein1), astroglial markers (S100B, GFAP), neurodegenerative disease proteins (total tau, pTau231, PSEN1, amyloid-beta-42, 14-3-3γ), inflammatory cytokines (IL16, CCL2, ficolin2), cell signalling (SFRP1), cell metabolism (MDH1) and autophagy related (sequestome1) proteins. Acute plasma levels of UCH-L1, PSEN1, total tau and pTau231 correlated with subacute lesion volume. Sequestome1 was positively correlated, whilst CLL2 was inversely correlated, with white matter fractional anisotropy. Neuronal, astroglial, tau and neurodegenerative proteins correlated with each other, IL16, MDH1 and sequestome1. Exploratory clustering (k means) by acute protein expression identified 3 TBI subgroups that differed in injury patterns, but not age or outcome. One TBI cluster had significantly lower white matter fractional anisotropy than control-predominant clusters, but had significantly lower lesion subacute lesions volumes than another TBI cluster. Proteins that overlapped on two platforms had excellent (r>0.8) correlations between values. We identified TBI-specific changes in acute plasma levels of proteins involved in neurodegenerative disease, inflammatory and cellular processes. These changes were related to patterns of injury, thus demonstrating that processes previously only studied in animal models are also relevant in human TBI pathophysiology. Our study highlights how proteomic approaches might improve classification and understanding of TBI pathophysiology, with implications for prognostication and treatment development.

A comprehensive framework for managing metabolic dysfunction-associated steatotic liver disease: analyzing novel risk factors and advances in nanotechnology-based treatments and diagnosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing global health challenge requiring innovative approaches for effective management. This comprehensive review examines novel risk factors, including environmental pollutants like heavy metals, and underscores the complexity of personalized medicine tailored to individual patient profiles, influenced by gender and sex differences. Traditional treatments for MASLD, such as glucose- and lipid-lowering agents, show mixed results, highlighting the necessity for larger, long-term studies to establish safety and efficacy. Alternative therapies, including antioxidants, stem cells, and antiplatelets, although promising, demand extensive clinical trials for validation. This review highlights the importance of personalized medicine, considering individual variations and specific factors such as gender and sex, to optimize treatment responses. The shift from metabolic-associated fatty liver disease (MAFLD) to MASLD terminology underscores the metabolic components of the disease, aligning with the multiple-hit theory and highlighting the necessity for comprehensive risk factor management. Our vision advocates for an integrated approach to MASLD, encompassing extensive risk factor analysis and the development of safer, more effective treatments. Primary prevention and awareness initiatives are crucial in addressing the rising prevalence of MASLD. Future research must prioritize larger, long-term studies and personalized medicine principles to ensure the effective use of emerging therapies and technologies. The review underscores the need for continuous exploration and innovation, balancing the benefits and challenges of nanotechnology, to combat MASLD and improve patient outcomes comprehensively.

Change in prostate tissue gene expression following finasteride or doxazosin administration in the medical therapy for prostatic symptoms (MTOPS) study.

Benign prostatic hyperplasia (BPH) may decrease patient quality of life and often leads to acute urinary retention and surgical intervention. While effective treatments are available, many BPH patients do not respond or develop resistance to treatment. To understand molecular determinants of clinical symptom persistence after initiating BPH treatment, we investigated gene expression profiles before and after treatments in the prostate transitional zone of 108 participants in the Medical Therapy of Prostatic Symptoms (MTOPS) Trial. Unsupervised clustering revealed molecular subgroups characterized by expression changes in a large set of genes associated with resistance to finasteride, a 5α-reductase inhibitor. Pathway analyses within this gene cluster found finasteride administration induced changes in fatty acid metabolism, amino acid metabolism, immune response, steroid hormone metabolism, and kinase activity within the transitional zone. We found that patients without this transcriptional response were highly likely to develop clinical progression, which is expected in 13.2% of finasteride-treated patients. Importantly, a patient's transcriptional response to finasteride was associated with their pre-treatment kinase expression. Further, we identified novel expression signatures of finasteride resistance among the transcriptionally responded patients. These patients showed different gene expression profiles at baseline and increased prostate transitional zone volume compared to the patients who responded to the treatment. Our work suggests molecular mechanisms of clinical resistance to finasteride treatment that could be potentially helpful for personalized BPH treatment as well as new drug development to increase patient drug response.

The influence of environmental factors related to Juvenile Dermatomyositis (JDM), its course and refractoriness to treatment.

OBJECTIVE: To evaluate the influence of environmental factors and prematurity relating to juvenile dermatomyositis (JDM), its course and refractoriness to treatment. METHODS: A case-control study with 35 patients followed up at a tertiary hospital and 124 healthy controls, all residents of São Paulo. Patients were classified according to monocyclic, polycyclic or chronic disease courses and refractoriness to treatment. The daily concentrations of pollutants (inhalable particulate matter-PM10, sulfur dioxide-SO2, nitrogen dioxide-NO2, ozone-O3 and carbon monoxide-CO) were provided by the Environmental Company of São Paulo. Data from the population were obtained through a questionnaire. RESULTS: Fifteen patients had monocyclic courses, and 19 polycyclic/chronic courses. Eighteen patients were refractory to treatment. Maternal occupational exposure to inhalable agents (OR = 17.88; IC 95% 2.15-148.16, p = 0.01) and exposure to O3 in the fifth year of life (third tertile > 86.28µg/m3; OR = 6.53, IC95% 1.60-26.77, p = 0.01) were risk factors for JDM in the multivariate logistic regression model. The presence of a factory/quarry at a distance farther than 200 meters from daycare/school (OR = 0.22; IC 95% 0.06-0.77; p = 0.02) was a protective factor in the same analysis. Prematurity, exposure to air pollutants/cigarette smoke/sources of inhalable pollutants in the mother's places of residence and work during the gestational period were not associated with JDM. Prematurity, maternal exposure to occupational pollutants during pregnancy as well as patient's exposure to ground-level pollutants up to the fifth year of life were not associated with disease course and treatment refractoriness. CONCLUSION: Risk factors for JDM were maternal occupational exposure and exposure to O3 in the fifth year of life.

Targeted memory reactivation to augment treatment in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder with traumatic memories at its core. Post-treatment sleep may offer a unique time window to increase therapeutic efficacy through consolidation of therapeutically modified traumatic memories. Targeted memory reactivation (TMR) enhances memory consolidation by presenting reminder cues (e.g., sounds associated with a memory) during sleep. Here, we applied TMR in PTSD patients to strengthen therapeutic memories during sleep after one treatment session with eye movement desensitization and reprocessing (EMDR). PTSD patients received either slow oscillation (SO) phase-targeted TMR, using modeling-based closed-loop neurostimulation (M-CLNS) with EMDR clicks as a reactivation cue (n = 17), or sham stimulation (n = 16). Effects of TMR on sleep were assessed through high-density polysomnography. Effects on treatment outcome were assessed through subjective, autonomic, and fMRI responses to script-driven imagery (SDI) of the targeted traumatic memory and overall PTSD symptom level. Compared to sham stimulation, TMR led to stimulus-locked increases in SO and spindle dynamics, which correlated positively with PTSD symptom reduction in the TMR group. Given the role of SOs and spindles in memory consolidation, these findings suggest that TMR may have strengthened the consolidation of the EMDR-treatment memory. Clinically, TMR vs. sham stimulation resulted in a larger reduction of avoidance level during SDI. TMR did not disturb sleep or trigger nightmares. Together, these data provide first proof of principle that TMR may be a safe and viable future treatment augmentation strategy for PTSD. The required follow-up studies may implement multi-night TMR or TMR during REM sleep to further establish the clinical effect of TMR for traumatic memories.

Rare Variant in MRC2 Associated With Familial Supraventricular Tachycardia and Wolff-Parkinson-White Syndrome.

BACKGROUND: Accessory pathways are a common cause of supraventricular tachycardia (SVT) and can lead to sudden cardiac death in otherwise healthy children and adults when associated with Wolff-Parkinson-White syndrome. The goal of this study was to identify genetic variants within a large family with structurally normal hearts affected by SVT and Wolff-Parkinson-White syndrome and determine causality of the gene deficit in a corresponding mouse model. METHODS: Whole exome sequencing performed on 2 distant members of a 3-generation family in which multiple members were affected by SVT or Wolff-Parkinson-White pattern (preexcitation) on ECG identified MRC2 as a candidate gene. Serial electrocardiograms, intracardiac electrophysiology studies, echocardiography, optical mapping studies, and histology were performed on both Mrc2 mutant and WT (wild-type) mice. RESULTS: A rare HET (heterozygous) missense variant c.2969A>G;p.Glu990Gly (E990G) in MRC2 was identified as the leading candidate gene variant segregating with the cardiac phenotype following an autosomal-dominant Mendelian trait segregation pattern with variable expressivity. In vivo electrophysiology studies revealed reentrant SVT in E990G mice. Optical mapping studies in E990G mice demonstrated abnormal retrograde conduction, suggesting the presence of an accessory pathway. Histological analysis of E990G mouse hearts showed a disordered ECM (extracellular matrix) in the annulus fibrosus. Finally, Mrc2 knockdown in human cardiac fibroblasts enhanced accelerated cell migration. CONCLUSIONS: This study identified a rare nonsynonymous variant in the MRC2 gene in individuals with familial reentrant SVT, Wolff-Parkinson-White ECG pattern, and structurally normal hearts. Furthermore, Mrc2 knock-in mice revealed an increased incidence of reentrant SVT and bypass tract formation in the setting of preserved cardiac structure and function.

Anticancer potential of NSAID-derived tris(pyrazolyl)methane ligands in iron(II) sandwich complexes.

Tris(pyrazolyl)methane (tpm), 2,2,2-tris(pyrazolyl)ethanol (tpmOH) and its esterification derivatives with ibuprofen and flurbiprofen (tpmIBU and tpmFLU) were used as ligands to obtain complexes of the type [Fe(tpmX)2]Cl2 (1-4). The tpmIBU and tpmFLU ligands and corresponding complexes 3 and 4 were characterized by IR and multinuclear NMR spectroscopy, and the structure of tpmIBU was elucidated by single crystal X-ray diffraction. Complexes 1-4 were also assessed for their behaviour in aqueous media (solubility in D2O, octanol/water partition coefficient, stability in physiological-like conditions). The antiproliferative activity of ligands and complexes was determined on A2780, A2780cis and A549 cancer cell lines and the non-cancerous HEK 293T and BJ cell lines. The ligands and complexes were investigated for their ability to inhibit COX-2 (cyclooxygenase) and HNE (4-hydroxynonenal) enzymes. Complexes 3 and 4 exhibited cytotoxicity that may be attributed predominantly to their bioactive fragments, while DNA binding and enhancement of ROS production do not appear to play any significant role.

Associations of Microbleeds and Their Topography With Imaging and CSF Biomarkers of Alzheimer Pathology in Individuals With Down Syndrome.

BACKGROUND AND OBJECTIVES: Cerebral hemorrhages are an exclusion criterion and potential adverse effect of antiamyloid agents. It is, therefore, critical to characterize the natural history of cerebral microbleeds in populations genetically predisposed to Alzheimer disease (AD), such as Down syndrome (DS). We aimed to assess microbleed emergence in adults with DS across the AD spectrum, defining their topography and associations with clinical variables, cognitive outcomes, and fluid and neuroimaging biomarkers. METHODS: This cross-sectional study included participants aged 18 years or older from the Down-Alzheimer Barcelona Neuroimaging Initiative and Sant Pau Initiative on Neurodegeneration with T1-weighted and susceptibility-weighted images. Participants underwent comprehensive assessments, including apolipoprotein E (APOE) genotyping; fluid and plasma determinations of beta-amyloid, tau, and neurofilament light; cognitive outcomes (Cambridge Cognitive Examination and modified Cued Recall Test); and vascular risk factors (hypertension, diabetes mellitus, and dyslipidemia). We manually segmented microbleeds and characterized their topography. Associations between microbleed severity and AD biomarkers were explored using between-group comparisons (none vs 1 vs 2+) and multivariate linear models. RESULTS: We included 276 individuals with DS and 158 healthy euploid controls (mean age = 47.8 years, 50.92% female). Individuals with DS were more likely to have microbleeds than controls (20% vs 8.9%, p < 0.001), with more severe presentation (12% with 2+ vs 1.9%). Microbleeds increased with age (12% 20-30 years vs 60% > 60 years) and AD clinical stage (12.42% asymptomatic, 27.9% prodromal, 35.09% dementia) were more common in APOEε4 carriers (26% vs 18.3% noncarriers, p = 0.008), but not associated with vascular risk factors (p > 0.05). Microbleeds were predominantly posterior (cerebellum 33.66%; occipital 14.85%; temporal 21.29%) in participants with DS. Associations with microbleed severity were found for neuroimaging and fluid AD biomarkers, but only hippocampal volumes (standardized ß = -0.18 [-0.31, -0.06], p < 0.005) and CSF p-tau-181 concentrations (ß = 0.26 [0.12, 0.41], p < 0.005) survived regression controlling for age and disease stage, respectively. Microbleeds had limited effect on cognitive outcomes. DISCUSSION: In participants with DS, microbleeds present with a posterior, lobar predominance, are associated with disease severity, but do not affect cognitive performance. These results suggest an interplay between AD pathology and vascular lesions, implicating microbleeds as a risk factor limiting the use of antiamyloid agents in this population.

Updates in diagnosis and treatment of pediatric antiphospholipid syndrome.

PURPOSE OF REVIEW: This review offers an overview of the most important recent articles on pediatric APS. RECENT FINDINGS: Non-thrombotic extra criteria manifestations were prevalent in pediatric APS. Pregnancy morbidity has been described as the first manifestation of APS at youth age, impairing gestational outcomes. The 2023 APS criteria were developed for adult APS patients, and there is still a lack of pediatric-specific APS criteria. Catastrophic APS was more commonly reported as the initial manifestation of pediatric APS than in adults. Regarding treatment, direct oral anticoagulants have been recently approval for pediatric patients with venous thrombosis. New approaches have been proposed for severe cases, for arterial thrombosis, and rituximab for refractory cases. Recurrences typically occurred early and were associated with older age at diagnosis. Current studies highlighted the multifaceted nature of pediatric APS. Further large prospective multicenter studies evaluating new medications capable of reducing recurrence risk and improving prognosis in this population will be required.

Targeting calpain-2-mediated junctophilin-2 cleavage delays heart failure progression following myocardial infarction.

Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created a novel knock-in mouse model by removing residues 479-SPAGTPPQ-486 to prevent calpain-2-mediated cleavage at this site. Functional and molecular assessment of cardiac function post-MI in cleavage site deletion (CSD) mice showed preserved cardiac contractility and reduced dilation, reduced JPH2-CTP levels, attenuated adverse remodeling, improved T-tubular structure, and normalized SR Ca2+-handling. Adenovirus mediated calpain-2 knockdown in mice exhibited similar findings. Pulldown of CTP followed by proteomic analysis revealed valosin-containing protein (VCP) and BAG family molecular chaperone regulator 3 (BAG3) as novel binding partners of JPH2. Together, our findings suggest that blocking calpain-2-mediated JPH2 cleavage may be a promising new strategy for delaying the development of HF following MI.

Correlative Analysis of ATM, RB1, ERCC2, and FANCC Mutations and Pathologic Complete Response After Neoadjuvant Chemotherapy in Patients with Muscle-invasive Bladder Cancer: Results from the SWOG S1314 Trial.

We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy.

Group B Streptococcus Sequence Type 103 as Human and Bovine Pathogen, Brazil.

Group B Streptococcus sequence type 103 is known primarily as a bovine mastitis pathogen. In Brazil, it has circulated in cattle and humans since the 1990s. It lacks scpB and, in humans, was found only among carriage isolates. Bovine-human interspecies transmission may have contributed to its evolution and spread.

Metallocompounds as anticancer agents against osteosarcoma.

Metallocompounds are a class of anticancer compounds largely used in the treatment of several types of solid tumors, including bone cancer. Osteosarcoma (OS) is a primary malignant bone tumor that frequently affects children, adolescents and young adults. It is a very invasive type of tumor, so ∼40% of patients develop distant metastases, showing elevated mortality rates. In this review, we present an outline of the chemistry and antitumor properties of metal-based compounds in preclinical (in vitro and in vivo) and clinical OS models, focusing on the relationship between structure-activity, molecular targets and the study of the mechanism of action involved in metallocompound anticancer activity.

Influence of adiposity and sex on SARS-CoV-2 antibody response in vaccinated university students: A cross-sectional ESFUERSO study.

Prior studies have identified various determinants of differential immune responses to COVID-19. This study focused on the Ig-G anti-RBD marker, analyzing its potential correlations with sex, vaccine type, body fat percentage, metabolic risk, perceived stress, and previous COVID-19 exposure. In this study, data (available in S1 Data) were obtained from 108 participants from the ESFUERSO cohort, who completed questionnaires detailing their COVID-19 experiences and stress levels assessed through the SISCO scale. IgG anti-RBD concentrations were quantified using an ELISA assay developed by UNAM. Multiple regression analysis was employed to control for covariates, including sex, age, body fat percentage, body mass index (BMI), and perceived stress. This sample comprised young individuals (average age of 21.4 years), primarily consisting of females (70%), with a substantial proportion reporting a family history of diabetes, hypertension, or obesity. Most students had received the Moderna or Pfizer vaccines, and 91% displayed a positive anti-RBD response. A noteworthy finding was the interaction between body fat percentage and sex. In males, increased adiposity was associated with decreased Ig-G anti-RBD concentration; in females, the response increased. Importantly, this pattern remained consistent regardless of the vaccine received. No significant associations were observed for dietary habits or perceived stress variables. This research reports the impact of sex and body fat percentage on the immune response through Ig-G anti-RBD levels to COVID-19 vaccines. The implications of these findings offer a foundation for educational initiatives and the formulation of preventive policies aimed at mitigating health disparities.