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Abstract The calmodulin-binding transcription activator (CAMTA) family contributes to stress responses in many plant species. The Oryza sativa ssp. japonica genome harbors seven CAMTA genes; however, intraspecific variation and functional roles of this gene family have not been determined. Here, we comprehensively evaluated the structure and characteristics of the CAMTA genes in japonica rice using bioinformatics approaches and RT-qPCR. Within the CAMTA gene and promoter sequences, 527 single nucleotide polymorphisms were retrieved from 3,024 rice accessions. The CAMTA genes could be subdivided into 5–14 haplotypes. Association analyses between haplotypes and phenotypic traits, such as grain weight and salt stress parameters, identified phenotypic differences between rice subpopulations harboring different CAMTA haplotypes. Co-expression analyses and the identification of CAMTA-specific binding motifs revealed candidate genes regulated by CAMTA. A Gene Ontology functional enrichment analysis of 690 co-expressed genes revealed that CAMTA genes have key roles in defense responses. An interaction analysis identified 30 putative CAMTA interactors. Three genes were identified in co-expression and interaction network analyses, suggesting that they are potentially regulated by CAMTAs. Based on all information obtained together with the phenotypes of the CRISPR-Cas9 knockout mutant lines of three OskCAMTA genes generated, CAMTA1 likely plays important roles in the response to salt stress in rice. Overall, our findings suggest that the CAMTA gene family is involved in development and the salt stress response and reveal candidate target genes, providing a basis for further functional characterization.

Abstract Poor inhibitory control contributes to deficits in emotion regulation, which are often targeted by treatments for major depressive disorder (MDD), including cognitive behavioral therapy (CBT). Brain regions that contribute to inhibitory control and emotion regulation overlap; thus, inhibitory control might relate to response to CBT. In this study, we examined whether baseline inhibitory control and resting state functional connectivity (rsFC) within overlapping emotion regulation-inhibitory control regions predicted treatment response to internet-based CBT (iCBT). Participants with MDD were randomly assigned to iCBT (N = 30) or a monitored attention control (MAC) condition (N = 30). Elastic net regression was used to predict post-treatment Patient Health Questionnaire-9 (PHQ-9) scores from baseline variables, including demographic variables, PHQ-9 scores, Flanker effects (interference, sequential dependency, post-error slowing), and rsFC between the dorsal anterior cingulate cortex, bilateral anterior insula (AI), and right temporoparietal junction (TPJ). Essential prognostic predictor variables retained in the elastic net regression included treatment group, gender, Flanker interference response time (RT), right AI-TPJ rsFC, and left AI-right AI rsFC. Prescriptive predictor variables retained included interactions between treatment group and baseline PHQ-9 scores, age, gender, Flanker RT, sequential dependency effects on accuracy, post-error accuracy, right AI-TPJ rsFC, and left AI-right AI rsFC. Inhibitory control and rsFC within inhibitory control-emotion regulation regions predicted reduced symptom severity following iCBT, and these effects were stronger in the iCBT group than in the MAC group. These findings contribute to a growing literature indicating that stronger inhibitory control at baseline predicts better outcomes to psychotherapy, including iCBT.

Abstract Stress in early life can affect the progeny and increase the risk to develop psychiatric and cardiometabolic diseases across generations. The cross-generational effects of early life stress have been modeled in mice and demonstrated to be associated with epigenetic factors in the germline. While stress is known to affect gut microbial features, whether its effects can persist across life and be passed to the progeny is not well defined. Here we show that early postnatal stress in mice shifts the fecal microbial composition (binary Jaccard index) throughout life, including abundance of eight amplicon sequencing variants (ASVs). Further effects on fecal microbial composition, structure (weighted Jaccard index), and abundance of 16 ASVs are detected in the progeny across two generations. These effects are not accompanied by changes in bacterial metabolites in any generation. These results suggest that changes in the fecal microbial community induced by early life traumatic stress can be perpetuated from exposed parent to the offspring.

IntroductionOwing to advances in high-throughput genome sequencing, QTL-Seq mapping of salt tolerance traits is a major platform for identifying soil-salinity tolerance QTLs to accelerate marker-assisted selection for salt-tolerant rice varieties. We performed QTL-BSA-Seq in the seedling stage of rice from a genetic cross of the extreme salt-sensitive variety, IR29, and “Jao Khao” (JK), a Thai salt-tolerant variety.MethodsA total of 462 F2 progeny grown in soil and treated with 160 mM NaCl were used as the QTL mapping population. Two high- and low-bulk sets, based on cell membrane stability (CMS) and tiller number at the recovery stage (TN), were equally sampled. The genomes of each pool were sequenced, and statistical significance of QTL was calculated using QTLseq and G prime (G′) analysis, which is based on calculating the allele frequency differences or Δ(SNP index).ResultsBoth methods detected the overlapping interval region, wherein CMS-bulk was mapped at two loci in the 38.41–38.85 Mb region with 336 SNPs on chromosome 1 (qCMS1) and the 26.13–26.80 Mb region with 1,011 SNPs on chromosome 3 (qCMS3); the Δ(SNP index) peaks were −0.2709 and 0.3127, respectively. TN-bulk was mapped at only one locus in the overlapping 38.26–38.95 Mb region on chromosome 1 with 575 SNPs (qTN1) and a Δ(SNP index) peak of −0.3544. These identified QTLs in two different genetic backgrounds of segregating populations derived from JK were validated. The results confirmed the colocalization of the qCMS1 and qTN1 traits on chromosome 1. Based on the CMS trait, qCMS1/qTN1 stably expressed 6%–18% of the phenotypic variance in the two validation populations, while qCMS1/qTN1 accounted for 16%–20% of the phenotypic variance in one validation population based on the TN trait.ConclusionThe findings confirm that the CMS and TN traits are tightly linked to the long arm of chromosome 1 rather than to chromosome 3. The validated qCMS-TN1 QTL can be used for gene/QTL pyramiding in marker-assisted selection to expedite breeding for salt resistance in rice at the seedling stage.

Abstract Synthetic glucocorticoids (GC), such as dexamethasone, are extensively used to treat chronic inflammation and autoimmune disorders. However, long-term treatments are limited by various side effects, including muscle atrophy. GC activities are mediated by the glucocorticoid receptor (GR), that regulates target gene expression in various tissues in association with cell-specific co-regulators. Here we show that GR and the lysine-specific demethylase 1 (LSD1) interact in myofibers of male mice, and that LSD1 connects GR-bound enhancers with NRF1-associated promoters to stimulate target gene expression. In addition, we unravel that LSD1 demethylase activity is required for triggering starvation- and dexamethasone-induced skeletal muscle proteolysis in collaboration with GR. Importantly, inhibition of LSD1 circumvents muscle wasting induced by pharmacological levels of dexamethasone, without affecting their anti-inflammatory activities. Thus, our findings provide mechanistic insights into the muscle-specific GC activities, and highlight the therapeutic potential of targeting GR co-regulators to limit corticotherapy-induced side effects.

Abstract Calcium carbonate (CaCO3) is abundant on Earth, is a major component of marine biominerals and thus of sedimentary and metamorphic rocks and it plays a major role in the global carbon cycle by storing atmospheric CO2 into solid biominerals. Six crystalline polymorphs of CaCO3 are known—3 anhydrous: calcite, aragonite, vaterite, and 3 hydrated: ikaite (CaCO3·6H2O), monohydrocalcite (CaCO3·1H2O, MHC), and calcium carbonate hemihydrate (CaCO3·½H2O, CCHH). CCHH was recently discovered and characterized, but exclusively as a synthetic material, not as a naturally occurring mineral. Here, analyzing 200 million spectra with Myriad Mapping (MM) of nanoscale mineral phases, we find CCHH and MHC, along with amorphous precursors, on freshly deposited coral skeleton and nacre surfaces, but not on sea urchin spines. Thus, biomineralization pathways are more complex and diverse than previously understood, opening new questions on isotopes and climate. Crystalline precursors are more accessible than amorphous ones to other spectroscopies and diffraction, in natural and bio-inspired materials.

Abstract Trauma-related intrusive memories (TR-IMs) are hallmark symptoms of posttraumatic stress disorder (PTSD), but their neural correlates remain partly unknown. Given its role in autobiographical memory, the hippocampus may play a critical role in TR-IM neurophysiology. The anterior and posterior hippocampi are known to have partially distinct functions, including during retrieval of autobiographical memories. This study aimed to investigate the relationship between TR-IM frequency and the anterior and posterior hippocampi morphology in PTSD. Ninety-three trauma-exposed adults completed daily ecological momentary assessments for fourteen days to capture their TR-IM frequency. Participants then underwent anatomical magnetic resonance imaging to obtain measures of anterior and posterior hippocampal volumes. Partial least squares analysis was applied to identify a structural covariance network that differentiated the anterior and posterior hippocampi. Poisson regression models examined the relationship of TR-IM frequency with anterior and posterior hippocampal volumes and the resulting structural covariance network. Results revealed no significant relationship of TR-IM frequency with hippocampal volumes. However, TR-IM frequency was significantly negatively correlated with the expression of a structural covariance pattern specifically associated with the anterior hippocampus volume. This association remained significant after accounting for the severity of PTSD symptoms other than intrusion symptoms. The network included the bilateral inferior temporal gyri, superior frontal gyri, precuneus, and fusiform gyri. These novel findings indicate that higher TR-IM frequency in individuals with PTSD is associated with lower structural covariance between the anterior hippocampus and other brain regions involved in autobiographical memory, shedding light on the neural correlates underlying this core symptom of PTSD.

Understanding the density-dependent impacts of an invasive predator is integral for predicting potential consequences for prey populations. Functional response experiments are used to assess the rate of prey consumption and a predator’s ability to search for and consume prey at different resource densities. However, results can be highly context-dependent, limiting their extrapolation to natural ecosystems. Here, we examined how simulated habitat complexity, through the addition of substrate in which prey can escape predation, affects the functional response of invasive European green crabs (Carcinus maenas) foraging on two different bivalve species. Green crabs feeding on varnish clams (Nuttallia obscurata) shifted from a Type II hyperbolic functional response in the absence of substrate to density-independent consumption when prey could bury. Green crabs ate few Japanese littleneck clams (Venerupis philippinarum) under all densities, such that no functional response curve of any type could be produced and their total consumption was always density independent. However, the probability of at least one Japanese littleneck clam being consumed increased significantly with initial clam density and crab claw size across all treatments. At mean crab claw size and compared to trials without substrate, the proportion of varnish clams consumed were 4.2 times smaller when substrate was present, but substrate had a negligible effect (1.2 times) on Japanese littlenecks. The proportion of varnish clams consumed increased with crab claw size and were higher across both substrate conditions than the proportion of Japanese littlenecks consumed; however, the proportion of Japanese littleneck clams consumed increased faster with claw size than that of varnish clams. Our results suggest that including environmental features and variation in prey species can influence the density-dependent foraging described by functional response experiments. Incorporating replicable features of the natural environment into functional response experiments is imperative to make more accurate predictions about the impact of invasive predators on prey populations.

ABSTRACT: Palicourea marcgravii is a lethal toxic plant widely distributed in Brazil. Ingestion of this plant causes cardiotoxic effects in animals, leading to acute heart failure without evident macroscopic changes in the heart due to the rapid progression of the disease. Currently, the diagnosis is confirmed based on microscopic identification of characteristic renal lesions. Although troponin is used as a biomarker for myocardial lesions in human and veterinary medicine, its serum levels in sheep poisoned with P. marcgravii remain unknown. The objective of this study was to determine serum levels of troponin I and evaluate its expression in incipient heart lesions in sheep. Eight male sheep were experimentally intoxicated with 1g kg-1 of fresh P. marcgravii plants. The animals were physically examined every two hours, and blood samples were collected before the administration of the plant material and during the agonizing period immediately before death. Additionally, necropsy and immunohistochemistry were performed on cardiac tissue samples. All animals presented minimal serum levels of troponin I before plant administration, with a significant increase in these levels immediately before death, indicating leakage due to the cardiac injury. These results confirm the hypothesis that troponin is released into the bloodstream before morphological changes in the myocardium can be observed through conventional microscopy and immunohistochemical testing. These findings contribute to understanding the pathological mechanisms of this toxicity and may assist in the early diagnosis and treatment of affected animals.

Cognitive impairment has a profound deleterious impact on long-term outcomes of glioma surgery. The human insula, a deep cortical structure covered by the operculum, plays a role in a wide range of cognitive functions including interceptive thoughts and salience processing. Both low-grade (LGG) and high-grade gliomas (HGG) involve the insula, representing up to 25% of LGG and 10% of HGG. Surgical series from the past 30 years support the role of primary cytoreductive surgery for insular glioma patients; however, reported cognitive outcomes are often limited to speech and language function. The breath of recent neuroscience literature demonstrates that the insula plays a broader role in cognition including interoceptive thoughts and salience processing. This article summarizes the vast functional role of the healthy human insula highlighting how this knowledge can be leveraged to improve the care of patients with insular gliomas.

Abstract Single-molecule fluorescence experiments have transformed our understanding of complex materials and biological systems. Whether single molecules are used to report on their nano-environment or provide for localization, understanding their blinking dynamics (i.e., stochastic fluctuations in emission intensity under continuous illumination) is paramount. We recently demonstrated another use for blinking dynamics called blink-based multiplexing (BBM), where individual emitters are classified using a single excitation laser based on blinking dynamics, rather than color. This study elucidates the structure-activity relationships governing BBM performance in a series of model rhodamine, BODIPY, and anthraquinone fluorophores that undergo different photo-physical and-chemical processes during blinking. Change point detection and multinomial logistic regression analyses show that BBM can leverage spectral fluctuations, electron and proton transfer kinetics, as well as photostability for molecular classification—even within the context of a shared blinking mechanism. In doing so, we demonstrate two- and three-color BBM with ≥ 93% accuracy using spectrally-overlapped fluorophores.

Abstract Background Sexual and gender minority (SGM) persons experience stark health disparities. Efforts to mitigate disparities through medical education have met some success. However, evaluations have largely focused on subjective perspectives rather than objective measures. This study aimed to quantify Boston University School of Medicine’s sexual and gender minority (SGM) education through surveys of course directors (CDs) and medical students regarding where SGM topics were taught in the preclerkship medical curriculum. Responses were compared to identify concordance between faculty intention and student perceptions regarding SGM education. Methods A cross-sectional survey was distributed to preclerkship CDs and current medical students in Spring 2019 and 2021, respectively, regarding where in the mandatory preclerkship curriculum CDs deliberately taught and where first- and second-year students recalled having learned 10 SGM topic domains. Results 64.3% of CDs (n = 18), 47.0% of the first-year class (n = 71), and 67.3% of the second-year class (n = 101) responded to the surveys. Results indicate that, as anticipated, deliberate SGM teaching correlates with greater student recall as students recalled topics that were reported by CDs as intentionally taught at a significantly higher rate compared to those not intentionally taught (32.0% vs. 15.3%; p

Abstract Background Endometriosis affects 1 in 9 women, yet it is poorly understood with long diagnostic delays, invasive diagnoses, and poor treatment outcomes. Characterised by the presence of endometrial-like tissue outside of the uterus, its main symptoms are pain and infertility. Endometriosis often co-occurs with other conditions, which may provide insights into the origins of endometriosis. Methods Here a polygenic risk score phenome-wide association study of endometriosis was conducted in the UK Biobank to investigate the pleiotropic effects of a genetic liability to endometriosis. The relationship between the polygenic risk score for endometriosis and health conditions, blood and urine biomarkers and reproductive factors were investigated separately in females, males and females without an endometriosis diagnosis. The relationship between endometriosis and the blood and urine biomarkers was further investigated using genetic correlation and Mendelian randomisation approaches to identify causal relationships. Results Multiple health conditions, blood and urine biomarkers and reproductive factors were associated with genetic liability to endometriosis in each group, indicating many endometriosis comorbidities are not dependent on the physical manifestation of endometriosis. Differences in the associated traits between males and females highlighted the importance of sex-specific pathways in the overlap of endometriosis with many other traits. Notably, an association of genetic liability to endometriosis with lower testosterone levels was identified. Follow-up analysis utilising Mendelian randomisation approaches suggested lower testosterone may be causal for both endometriosis and clear cell ovarian cancer. Conclusions This study highlights the diversity of the pleiotropic effects of genetic risk to endometriosis irrespective of a diagnosis of endometriosis. A key finding was the identification of a causal effect of the genetic liability to lower testosterone on endometriosis using Mendelian randomisation.

Abstract WHO grade II and III gliomas demonstrate diverse biological behaviors resulting in variable survival outcomes. In the context of glioma prognosis, machine learning (ML) approaches could facilitate the navigation through the maze of factors influencing survival, aiding clinicians in generating more precise and personalized survival predictions. Here we report the utilization of ML models in predicting survival at 12, 24, 36, and 60 months following grade II and III glioma diagnosis. From the National Cancer Database, we analyze 10,001 WHO grade II and 11,456 grade III cranial gliomas. Using the area under the receiver operating characteristic (AUROC) values, we deploy the top-performing models in a web application for individualized predictions. SHapley Additive exPlanations (SHAP) enhance the interpretability of the models. Top-performing predictive models are the ones built with LightGBM and Random Forest algorithms. For grade II gliomas, the models yield AUROC values ranging from 0.813 to 0.896 for predicting mortality across different timeframes, and for grade III gliomas, the models yield AUROCs ranging from 0.855 to 0.878. ML models provide individualized survival forecasts for grade II and III glioma patients across multiple clinically relevant time points. The user-friendly web application represents a pioneering digital tool to potentially integrate predictive analytics into neuro-oncology clinical practice, to empower prognostication and personalize clinical decision-making.

ABSTRACT Francisella tularensis is a highly infectious Gram-negative bacterial pathogen capable of animal-to-human transmission. Due to its remarkable pathogenicity and potential for widespread public health impact, F. tularensis is classified as a high-priority pathogen by the Centers for Disease Control and Prevention. The historical development of Francisella as a bioweapon, coupled with the ease of engineering antibiotic-resistant strains, has spurred interest in the discovery of novel antibiotics. A library of drug-like compounds was screened for their ability to inhibit the growth of Francisella novicida, a biosafety level-2 surrogate for F. tularensis. Tolfenpyrad, a pesticide without previously identified antibacterial activity, was among the most potent inhibitors. Tolfenpyrad appears to uniquely target Francisella, as related species were sensitive, whereas bacteria in other genera were resistant. To identify Francisella pathways conferring sensitivity to tolfenpyrad, whole-genome sequencing of tolfenpyrad-resistant isolates was performed. Point mutations in two genes conferred resistance to osrR, a transcriptional regulator, and nuoM, a subunit of the electron transport chain. OsrR point mutants displayed attenuated growth in interferon gamma (IFN-γ)-stimulated macrophages but not in untreated macrophages, indicating that OsrR plays a role in resistance to IFN-γ-stimulated clearance of intracellular bacteria. OsrR point mutants are hypersensitive to reactive oxygen species, suggesting a mechanism by which they are rapidly cleared from IFN-γ-treated macrophages. This work identifies a novel Francisella-specific antibiotic activity and the metabolic pathways targeted. Moreover, we provide amino acid-level details of a Francisella protein that governs sensitivity to free radicals. IMPORTANCE Francisella species are highly pathogenic bacteria that pose a threat to global health security. These bacteria can be made resistant to antibiotics through facile methods, and we lack a safe and protective vaccine. Given their history of development as bioweapons, new treatment options must be developed to bolster public health preparedness. Here, we report that tolfenpyrad, a pesticide that is currently in use worldwide, effectively inhibits the growth of Francisella. This drug has an extensive history of use and a plethora of safety and toxicity data, making it a good candidate for development as an antibiotic. We identified mutations in Francisella novicida that confer resistance to tolfenpyrad and characterized a transcriptional regulator that is required for sensitivity to both tolfenpyrad and reactive oxygen species.

Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. Results: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Currently, West-Nile virus (WNV) is spreading worldwide to colder regions due to climate change. Human mortality and morbidity are prevalent and steadily increasing, associated with costs to public health systems. Therefore, the question of the impact of scientific engagement arises. What trends, barriers, and incentives for research related to global burdens are important in this context? To answer these questions, this study provides detailed insights into the publication patterns of WNV research and interprets them using several parameters, such as absolute and relative publication indices and socioeconomic and epidemiological characteristics. It is shown that national interests combined with regional outbreaks significantly influence publication intensity. Thus, a correlation between national publication volume and the number of WNV cases was observed. In contrast to most life science topics, the scientific interest in WNV significantly decreased after 2006. The USA, as the main actor in WNV research, is at the centre of international networking. Recently, European countries are also getting involved according to their new-emerging outbreaks. The results demonstrate national interest in research activities with a lack of globally focused approaches that are urgently needed to better understand and assess the distribution and characteristics of WNV.HighlightsThere is a correlation between national WNV cases and the number of publications.The declining trend in WNV research does not correspond to the growing prevalence.USA as most-publishing country is also at the centre of networking WNV research.France is the primary network partner for African and Middle Eastern countries.

Abstract Chromatin is the physical substrate of the genome that carries the DNA sequence and ensures its proper functions and regulation in the cell nucleus. While a lot is known about the dynamics of chromatin during programmed cellular processes such as development, the role of chromatin in experience-dependent functions remains not well defined. Accumulating evidence suggests that in brain cells, environmental stimuli can trigger long-lasting changes in chromatin structure and tri-dimensional (3D) organization that can influence future transcriptional programs. This review describes recent findings suggesting that chromatin plays an important role in cellular memory, particularly in the maintenance of traces of prior activity in the brain. Inspired by findings in immune and epithelial cells, we discuss the underlying mechanisms and the implications for experience-dependent transcriptional regulation in health and disease. We conclude by presenting a holistic view of chromatin as potential molecular substrate for the integration and assimilation of environmental information that may constitute a conceptual basis for future research.

Abstract The mechanisms that prevent regeneration of irradiated (IR) salivary glands remain elusive. Bulk RNAseq of IR versus non-IR human salivary glands showed that neurotrophin signaling is highly disrupted post-radiation. Neurotrophin receptors (NTRs) were significantly upregulated in myoepithelial cells (MECs) post-IR, and single cell RNAseq revealed that MECs pericytes, and duct cells are the main sources of neurotrophin ligands. Using two ex vivo models, we show that nerve growth factor (NGF) induces expression of MEC genes during development, and upregulation of NTRs in adult MECs is associated with stress-induced plasticity and morphological abnormalities in IR human glands. As MECs are epithelial progenitors after gland damage and are required for proper acinar cell contraction and secretion, we propose that MEC-specific upregulation of NTRs post-IR disrupts MEC differentiation and potentially impedes the ability of the gland to regenerate.

OBJECTIVES/GOALS: While the evolving treatment paradigm for Glioblastoma (GBM) leverages different modalities to improve outcomes, treatment access might be limited by cost and disparities. This study explores the influence of race and social determinants of health (SDoH) on healthcare access and outcomes of GBM patients in a large metropolitan area over a decade. METHODS/STUDY POPULATION: Our institution’s tumor registry (2009-2019) was queried to identify our GBM cohort. Data were supplemented by electronic health records to include demographics, outcome, NCI Comorbidity Index, and the Agency for Healthcare Research and Quality (AHRQ) socioeconomic status (SES) index. RESULTS/ANTICIPATED RESULTS: Of the 559 GBM records, 361 unique patients met the inclusion criteria, and 43% were Non-White. Non-White patients predominantly comprised the lowest AHRQ SES index quartile and had longer hospital stays (LOS; p

Abstract Background Nuclear receptors are transcription factors of central importance in human biology and associated diseases. Much of the knowledge related to their major functions, such as ligand and DNA binding or dimerization, derives from functional studies undertaken in classical model animals. It has become evident, however, that a deeper understanding of these molecular functions requires uncovering how these characteristics originated and diversified during evolution, by looking at more species. In particular, the comprehension of how dimerization evolved from ancestral homodimers to a more sophisticated state of heterodimers has been missing, due to a too narrow phylogenetic sampling. Here, we experimentally and phylogenetically define the evolutionary trajectory of nuclear receptor dimerization by analyzing a novel NR7 subgroup, present in various metazoan groups, including cnidarians, annelids, mollusks, sea urchins, and amphioxus, but lost in vertebrates, arthropods, and nematodes. Results We focused on NR7 of the cephalochordate amphioxus B. lanceolatum. We present a complementary set of functional, structural, and evolutionary analyses that establish that NR7 lies at a pivotal point in the evolutionary trajectory from homodimerizing to heterodimerizing nuclear receptors. The crystal structure of the NR7 ligand-binding domain suggests that the isolated domain is not capable of dimerizing with the ubiquitous dimerization partner RXR. In contrast, the full-length NR7 dimerizes with RXR in a DNA-dependent manner and acts as a constitutively active receptor. The phylogenetic and sequence analyses position NR7 at a pivotal point, just between the basal class I nuclear receptors that form monomers or homodimers on DNA and the derived class II nuclear receptors that exhibit the classical DNA-independent RXR heterodimers. Conclusions Our data suggest that NR7 represents the “missing link” in the transition between class I and class II nuclear receptors and that the DNA independency of heterodimer formation is a feature that was acquired during evolution. Our studies define a novel paradigm of nuclear receptor dimerization that evolved from DNA-dependent to DNA-independent requirements. This new concept emphasizes the importance of DNA in the dimerization of nuclear receptors, such as the glucocorticoid receptor and other members of this pharmacologically important oxosteroid receptor subfamily. Our studies further underline the importance of studying emerging model organisms for supporting cutting-edge research.

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood–brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology.

Im Rahmen der Wahlprüfung für kommunale Wahlbeamte steht der demokratische Rechtsstaat in Thüringen zwischen Skylla und Charybdis. Eine eindrucksvolle Illustration dieses Dilemmas liefert aktuell die Überprüfung einer Landratswahl in Südthüringen. Nachdem der AfD-Politiker und Landtagsabgeordnete Robert Sesselmann zum Landrat von Sonneberg gewählt wurde, kündigte das Landesverwaltungsamt Thüringen an, dessen Eignung unter anderem wegen seiner Mitgliedschaft in dem vom Verfassungsschutz als „erwiesen rechtsextremistisch“ eingestuften AfD-Landesverband zu überprüfen. Schon die Ankündigung rief lautstarke Kritik hervor. Der Blick auf die verfahrensrechtliche Ausgestaltung relativiert einen Großteil der an den Behörden geübten Kritik und zeigt, dass die gesetzgeberische Entscheidung in Thüringen die Chronologie des nun beschrittenen Weges vorzeichnet.

Hepatocyte Nuclear Factor 4 (HNF4) is a transcription factor (TF) belonging to the nuclear receptor (NR) family that is expressed in liver, kidney, intestine and pancreas. It is a master regulator of liver-specific gene expression, in particular those genes involved in lipid transport and glucose metabolism and is crucial for the cellular differentiation during development. Dysregulation of HNF4 is linked to human diseases, such as type I diabetes (MODY1) and hemophilia. Here, we review the structures of the isolated HNF4 DNA binding domain (DBD) and ligand binding domain (LBD) and that of the multidomain receptor and compare them with the structures of other NRs. We will further discuss the biology of the HNF4α receptors from a structural perspective, in particular the effect of pathological mutations and of functionally critical post-translational modifications on the structure-function of the receptor.

Ocean warming and marine heatwaves induced by climate change are impacting coral reefs globally, leading to coral bleaching and mortality. Yet, coral resistance and resilience to warming are not uniform across reef sites and corals can show inter- and intraspecific variability. To understand changes in coral health and to elucidate mechanisms of coral thermal tolerance, baseline data on the dynamics of coral holobiont performance under non-stressed conditions are needed. We monitored the seasonal dynamics of algal symbionts (family Symbiodiniaceae) hosted by corals from a chronically warmed and thermally variable reef compared to a thermally stable reef in southern Taiwan over 15 months. We assessed the genera and photochemical efficiency of Symbiodiniaceae in three coral species: Acropora nana, Pocillopora acuta, and Porites lutea. Both Durusdinium and Cladocopium were present in all coral species at both reef sites across all seasons, but general trends in their detection (based on qPCR cycle) varied between sites and among species. Photochemical efficiency (i.e., maximum quantum yield; Fv/Fm) was relatively similar between reef sites but differed consistently among species; no clear evidence of seasonal trends in Fv/Fm was found. Quantifying natural Symbiodiniaceae dynamics can help facilitate a more comprehensive interpretation of thermal tolerance response as well as plasticity potential of the coral holobiont.

Predicting the impacts of predatory invasive species is important for prioritising conservation interventions. Functional response experiments, which examine consumption by predators in relation to prey density, are a useful way to assess the potential strength of novel predator-prey relationships. However, such experiments are often conducted without consideration of sex or only with males to reduce invasion risk. Here, we compared the functional responses of male and female European green crabs (Carcinus maenas), a global invader, feeding on varnish clams (Nuttallia obscurata) to test whether the two sexes have similar potential for impact. We also examined potential correlates of predation behaviour by measuring sex-specific movement and prey choice. Both sexes displayed a Type II hyperbolic functional response, which can destabilise prey populations at low prey densities. However, males and females exhibited some differences in foraging behaviour. Female green crabs had slightly lower attack rates, which were not linked to sex differences in movement, and slightly longer handling times, which were not linked to sex differences in prey choice. These small, non-significant differences nevertheless translated into significantly greater functional response ratios, which are used to predict the ecological impact of invasive species, for males than females. There was no difference in the proportion of clams consumed between males and females with similar crusher claw heights, but females have smaller crusher claws on average, hence they consumed a smaller proportion of clams. Repeated surveys of four populations of European green crabs established in British Columbia, Canada, showed that sex ratio is highly variable. Taken together, these results and population-level modelling suggest that trying to evaluate the potential impact of European green crabs on clam populations by sampling only males could result in overestimation, even in populations that have male-biased sex-ratios. Consumer sex might generally be an important feature to consider when using functional response experiments to forecast the impact of new invasive species, especially those with marked sexual dimorphism that affect foraging.

Abstract Fishing can drive major ecological change in coastal ecosystems and is typically examined through top‐down trophic impacts. However, the massive removal of biomass can also disrupt key ecological bottom‐up processes, though how these effects shape ecosystems is poorly understood. Here, we examined the ecological roles of two species of commercially exploited sea cucumbers thought to promote primary productivity in nutrient‐poor environments through nutrient provisioning and sediment processing. Using a large‐scale field experiment, we tested whether simulated sea cucumber fishing affected seagrass productivity in a natural system comprising reef and seagrass patches that varied in abundance of vertebrate nutrient providers (i.e., fishes). Our findings were scale‐ and metric‐specific: while we could not detect a change in patch‐level seagrass productivity in response to simulated sea cucumber fishing, individual leaf extension rates were ~15% lower at sites where all sea cucumbers were removed, relative to the highest density, unfished sites. Interestingly, there was no concomitant effect of nutrients from the more abundant reef‐associated fishes, which contribute far more nutrients overall than sea cucumbers. This suggests that sea cucumbers are likely mediating seagrass growth through mechanisms other than direct nutrient provisioning, perhaps through processes associated with sediment processing. Our study demonstrates the potential consequences of under‐regulated and unmonitored sea cucumber fishing on foundation species like seagrasses, while highlighting the importance of taking a community‐based approach to these types of field experiments.

Cholesterol biosynthesis is a highly regulated pathway, with over 20 enzymes controlled at the transcriptional and posttranslational levels. While some enzymes remain stable, increased sterol levels can trigger degradation of several synthesis enzymes via the ubiquitin-proteasome system. Of note, we previously identified four cholesterol synthesis enzymes as substrates for one E3 ubiquitin ligase, membrane-associated RING-CH-type finger 6 (MARCHF6). Whether MARCHF6 targets the cholesterol synthesis pathway at other points is unknown. In addition, the posttranslational regulation of many cholesterol synthesis enzymes, including the C4-demethylation complex (sterol-C4-methyl oxidase-like, SC4MOL; NAD(P)-dependent steroid dehydrogenase-like, NSDHL; hydroxysteroid 17-beta dehydrogenase, HSD17B7), is largely uncharacterized. Using cultured mammalian cell lines (human-derived and Chinese hamster ovary cells), we show SC4MOL, the first acting enzyme of C4-demethylation, is a MARCHF6 substrate and is rapidly turned over and sensitive to sterols. Sterol depletion stabilizes SC4MOL protein levels, while sterol excess downregulates both transcript and protein levels. Furthermore, we found SC4MOL depletion by siRNA results in a significant decrease in total cell cholesterol. Thus, our work indicates SC4MOL is the most regulated enzyme in the C4-demethylation complex. Our results further implicate MARCHF6 as a crucial posttranslational regulator of cholesterol synthesis, with this E3 ubiquitin ligase controlling levels of at least five enzymes of the pathway.

Abstract The objective of this pilot clinical study was to identify salivary biomarkers that are associated with periodontal disease and measures of diabetic autonomic dysfunction. Saliva samples from 32 participants were obtained from 3 groups: healthy (H), type 1 diabetes mellitus (DM), and type 1 diabetes mellitus with neuropathy (DMN). Based on the periodontal examination, individuals’ mean Periodontal Screening and Recording scores were categorized into two groups (periodontally healthy and gingivitis), and correlated to specific salivary inflammatory biomarkers assessed by a customized protein array and enzyme assay. The mean salivary IgA level in DM was 9211.5 ± 4776.4 pg/ml, which was significantly lower than H (17,182.2 ± 8899.3 pg/ml). IgA in DMN with healthy periodontium was significantly lower (5905.5 ± 3124.8 pg/ml) compared to H, although IgA levels in DMN patients with gingivitis (16,894. 6 ± 7084.3) were not. According to the result of a logistic regression model, IgA and periodontal condition were the indicators of the binary response given by H versus DM, and H versus DMN, respectively. These data suggest that selected salivary biomarkers, such as IgA, combined with a periodontal examination prior to obtaining salivary samples can offer a non-invasive method to assess risk for developing diabetic neuropathy.

Abstract As human activities increase in intensity and extent, ecosystems face growing threats from multiple stressors. Successful management requires identifying measurable targets, which is challenging because of data limitations, nonlinear ecosystem responses, and potentially shifting targets under multiple stressors. To identify critical management values and determine whether these values shift in the presence of multiple stressors, we use eelgrass (Zostera marina) meadows as a model system. We reviewed 20 studies that measured the effects of light and temperature on eelgrass performance, providing 109 unique study–site–treatment combinations. We modeled the interactive effect of temperature and light on eelgrass population growth rate (i.e., lateral shoot production rates) using a hierarchical generalized additive model and predicted population growth rates across a range of light levels and temperatures. We found that two critical performance metrics of population growth, zero‐growth and maximum growth rates, shifted across a gradient of light and temperature, suggesting that fixed management targets linked to population growth rates might be unsuitable for managing meadows under multiple stressors. Our approach bridges the gap between data from laboratory and field studies and could be developed into an interactive management tool.

Summary: Background: Within the UK, limited research has examined migration and suicide risk. To assist with tailoring mental health care to the needs of different migrant groups, it is important to identify the clinical profile and antecedents to suicide. Methods: We focussed on two groups of migrants: those resident in the UK for less than 5 years (recent migrants) and those seeking permission to stay in the UK. Data on mental health patients who died by suicide in the UK between 2011 and 2019 were obtained as part of the National Confidential Inquiry into Suicide and Safety in Mental Health. Findings: 13,948 patients died by suicide between 2011 and 2019: 593 were recent migrants with 48 seeking permission to stay in the UK. The overall suicide rate between 2011 and 2017 for patients seeking to stay was 23.8/100,000 (95% CI 17.3–32.1). There was some uncertainty around this estimate but it appeared higher than the general population suicide rate of 10.6/100,000 population (95% CI 10.5–10.7; p = .0001) for the same period. A higher proportion of migrants were from an ethnic minority group (15% recent migrants vs. 70% seeking to remain vs. 7% non-migrants) and more were viewed as at low long-term risk of suicide (63% recent migrants vs. 76% seeking to remain vs. 57% non-migrants). A higher proportion of recent migrants died within three months of discharge from psychiatric in-patient care (19% vs. 14%) compared to non-migrants. Proportionally more patients seeking to remain had a diagnosis of schizophrenia and other delusional disorders (31% vs. 15%) and more had experienced recent life events compared to non-migrants (71% vs. 51%). Interpretation: A higher proportion of migrants had severe or acute illness at the time of their suicide. This may be linked to a range of serious stressors and/or lack of connection with services that could have identified signs of illness early. However, clinicians often viewed these patients as low risk. Mental health services should consider the breadth of stressors migrants may face and adopt a multi-agency approach to suicide prevention. Funding: The Healthcare Quality Improvement Partnership.

In highly diverse systems such as coral reefs, many species appear to fulfil similar ecological roles, suggesting that they might be ecologically equivalent. However, even if species provide similar functions, the magnitude of those roles could modulate their impact within ecosystems. Here, we compare the functional contributions of two common, co-occurring Caribbean sea cucumber species, Holothuria mexicana and Actynopyga agassizii, in terms of ammonium provisioning and sediment processing on Bahamian patch reefs. We quantified these functions through empirical measures of ammonium excretion, and in situ observations of sediment processing coupled with fecal pellet collections. On a per-individual level, H. mexicana excreted approximately 23% more ammonium and processed approximately 53% more sediment per hour than A. agassizii. However, when we combined these species-specific functional rates to species abundances to produce reef-wide estimates, we found that A. agassizii contributed more than H. mexicana to sediment processing at 57% of reefs (1.9 times more per unit area across all surveyed reefs), and more to ammonium excretion at 83% of reefs (5.6 times more ammonium per unit area across all surveyed reefs), owing to its higher abundance. We conclude that sea cucumber species can differ in the rates at which they deliver per capita ecosystem functions but their ecological impacts at the population level depend on their abundance at a given location.

Nowadays, solving problems is substantial for the social relationship human. Computational Thinking (CT) emerges as an interdisciplinary thought process encompassing mental abilities to help students solve and understand problems. Researchers invest in the methodological proposal of activities aimed at CT stimulation, educational approaches, and the conception of technologies that support these activities’ execution. Educational Robotics (ER) is one of these technologies that stand out at different educational levels to favor teamwork, logical thinking, and creativity, skills intimately articulated with the computing paradigm. The main objective of this work is to investigate the impact of ER activities on CT development and subjects learning in the Technical and Vocational Education in High School. For this, we accomplished a study of intervention research type with students and teachers analyzing quantitative and qualitative aspects. The results indicate that the introduction of ER can favor students in the development of CT skills and learning High School subjects.

Abstract Background Unreduced gametes, a driving force in the widespread polyploidization and speciation of flowering plants, occur relatively frequently in interspecific or intergeneric hybrids. Studies of the mechanisms leading to 2n gamete formation, mainly in the wheat tribe Triticeae have shown that unreductional meiosis is often associated with chromosome asynapsis during the first meiotic division. The present study explored the mechanisms of meiotic nonreduction leading to functional unreduced gametes in an interspecific Trifolium (clover) hybrid with three sub-genomes from T. ambiguum and one sub-genome from T. occidentale. Results Unreductional meiosis leading to 2n gametes occurred when there was a high frequency of asynapsis during the first meiotic division. In this hybrid, approximately 39% of chromosomes were unpaired at metaphase I. Within the same cell at anaphase I, sister chromatids of univalents underwent precocious separation and formed laggard chromatids whereas paired chromosomes segregated without separation of sister chromatids as in normal meiosis. This asynchrony was frequently accompanied by incomplete or no movement of chromosomes toward the poles and restitution leading to unreduced chromosome constitutions. Reductional meiosis was restored in progeny where asynapsis frequencies were low. Two progeny plants with approximately 5 and 7% of unpaired chromosomes at metaphase I showed full restoration of reductional meiosis. Conclusions The study revealed that formation of 2n gametes occurred when asynapsis (univalent) frequency at meiosis I was high, and that normal gamete production was restored in the next generation when asynapsis frequencies were low. Asynapsis-dependent 2n gamete formation, previously supported by evidence largely from wheat and its relatives and grasshopper, is also applicable to hybrids from the dicotyledonous plant genus Trifolium. The present results align well with those from these widely divergent organisms and strongly suggest common molecular mechanisms involved in unreduced gamete formation.

The use of digital media through chatting, online conferencing, or browsing has become a leisure activity for many people, but it is not necessarily characterized by caution. Given the possibilities for misuse of data, the question of whether users actually implement security precautions and pay attention to protection of their data is important. The present study examines whether the use of digital media or security precautions is associated with age, commitment to technology (feelings of competence and control in dealing with technology), and flexible goal adjustment (the capacity to adjust personal goals in difficult life situations). In addition, we examine whether age differences in the use of social media (e.g., Facebook, WhatsApp, Telegram, Skype, and Zoom) are moderated by the commitment to technology and flexible goal adjustment. A total of 841 adults between 19 and 71 years of age (Mage=43.57; SD=15.12) participated in a cross-sectional questionnaire study. Age was positively correlated with security precautions but negatively with the use of social media. Security precautions and the use of digital social networks were correlated significantly with general flexibility of goal adjustment and technology commitment, even after age and gender were controlled with a structural equation model. Moderation analyses revealed that the relation between social media use and age was weaker among participants with higher degrees of technology commitment and flexible goal adjustment. We discuss the extent to which flexible goal adjustment and technology commitment can provide a mental precondition that promotes both digitized leisure activity and security precautions.

Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates its truncated form. This preserves SM activity and downstream pathway flux during hypoxia. These results uncover a feedforward mechanism that allows SM to accommodate fluctuating substrate levels and may contribute to its widely reported oncogenic properties.

Abstract Mint oil is a key source of natural flavors with wide industrial applications. Two unbalanced polyploid cultivars named Native (Mentha Spicata L) and Scotch (M. × gracilis Sole) are the main producers of spearmint type oil, which is characterized by high levels of the monoterpenes (−)-carvone and (−)-limonene. These cultivars have been the backbone of spearmint oil production for decades, while breeding and improvement remained largely unexplored, in part, due to sterility in cultivated lines. Here we show that sexual breeding at the diploid level can be leveraged to develop new varieties that produce spearmint type oil, along with the improvement of other important traits. Using field trials and GC-FID oil analysis we characterized plant materials from a public germplasm repository and identified a diploid accession that exhibited 89.5% increase in oil yield, compared to the industry standard, and another that produces spearmint type oil. Spearmint-type oil was present at high frequency in a segregating F2 population (32/160) produced from these two accessions. Field-testing of ten of these F2 lines showed segregation for oil yield and confirmed the production of spearmint-type oil profiles. Two of these lines combined high yield and spearmint-type oil with acceptable analytic and sensory profiles. These results demonstrate that spearmint-type oil can be produced in a diploid background with high yield potential, providing a simpler genetic system for the development of improved spearmint varieties.

The enzymatic pathway of cholesterol biosynthesis has been well characterized. However, there remain several potential interacting proteins that may play ancillary roles in the regulation of cholesterol production. Here, we identified ERG28 (chromosome 14 open reading frame 1 [C14orf1]), a homologue of the yeast protein Erg28p, as a player in mammalian cholesterol synthesis. ERG28 is conserved from yeast to humans but has been largely overlooked in mammals. Using quantitative RT-PCR, luciferase assays, and publicly available chromatin immunoprecipitation sequencing data, we found that transcription of this gene is driven by the transcription factor SREBP-2, akin to most cholesterol synthesis enzymes, as well as identifying sterol-responsive elements and cofactor binding sites in its proximal promoter. Based on a split luciferase system, ERG28 interacted with itself and two enzymes of cholesterol synthesis (NSDHL and SC4MOL). Huh7 ERG28-KO cell lines were generated, revealing reduced total cholesterol levels in sterol-depleted environments. In addition, radiolabeled metabolic flux assays showed a 60–75% reduction in the rate of cholesterol synthesis in the KO versus wild-type cells, which could be rescued by expression of ectopic ERG28. Unexpectedly, KO of ERG28 also impaired the activation of SREBP-2 under sterol-replete conditions, by a yet-to-be defined mechanism. These results indicate that ERG28 is clearly involved in cholesterol synthesis, although the precise role this noncatalytic protein plays in this complex metabolic pathway remains to be fully elucidated. A deeper understanding of ERG28, and other ancillary proteins of cholesterol synthesis, may help inform therapeutic strategies for diseases associated with aberrant cholesterol metabolism.

Abstract Increased intraabdominal pressure (IAP) during laparoscopy can reduce venous return, but changes in respiratory system mechanics and their effect in left cardiac function are not well documented. This study evaluated the effects of different IAPs on respiratory mechanics and cardiac function in 10 healthy nonpregnant adult Santa Ines ewes randomly submitted to a crossover study using different IAPs: 0 mm Hg (G1), 10 mm Hg (G2), 12 mmHg (G3), and 15 mmHg (G4). Animals were anesthetized and mechanically ventilated (VT = 15 ml/kg; positive end‐expiratory pressure = 3 cmH2O; FiO2 = 1.0). Pneumoperitoneum was induced by Hasson's trocar cannula. Variables were measured at INITIAL (IAP, 0 mmHg) and FINAL time points for each IAP after 1 h. At FINAL, driving airway pressure (ΔP,RS), and percentage fraction of dead space (Vd/Vt) were higher in G3 and G4 than G1 (p = 0.002, difference in means [MD] 4.60, 95% CI: 7.91–1.28, and p

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Sertoli cells are somatic cells in testis essential for spermatogenesis, that support the development, maturation, and differentiation of germ cells. Sertoli cells are metabolically highly active and physiologically regulated by external signals, particularly factors in the blood stream. In disease conditions, circulating pathological signals may affect Sertoli cells and consequentially, alter germ cells and fertility. While the effects of stress on reproductive cells have been well studied, how Sertoli cells respond to stress remains poorly characterized. We used a mouse model of early postnatal stress to assess the effects of stress on Sertoli cells. We developed an improved strategy based on intracellular stainings and obtained enriched preparations of Sertoli cells from exposed males. We show that adult Sertoli cells have impaired electron transport chain (ETC) pathways and that several components of ETC complexes particularly complex I, III, and IV are persistently affected. We identify serum as potential mediator of the effects of stress on Sertoli cells by showing that it can recapitulate ETC alterations in primary cells. These results highlight Sertoli cells as cellular targets of stress in early life that can keep a trace of exposure until adulthood.

Abstract Chromoanagenesis is a catastrophic event that involves localized chromosomal shattering and reorganization. In this study, we report a case of chromoanagenesis resulting from defective meiosis in the MEIOTIC ASYNAPTIC MUTANT 1 (asy1Arabidopsis thalianaasy1- Plain Language SummaryChromoanagenesis is a complex and catastrophic event that results in severely restructured chromosomes. It has been identified in cancer cells and in some plant samples, after specific triggering events. Here, we identified this kind of genome restructuring in a mutant that exhibits defective meiosis in the model plant system Arabidopsis thaliana

ABSTRACT: The present study aimed to identify and describe cardiac alterations in sheep experimentally poisoned with Palicourea marcgravii through analysis of serum cardiac biomarkers (serum troponin I and creatine kinase - CK-MB) and electro and echocardiographic assessments to contribute to a better understanding of the poisoning pathophysiology. P. marcgravii is the main plant within a group of 22 species that cause sudden death in Brazil; its toxic principle is sodium monofluoroacetate. Eight healthy crossbreed male sheep, aged between five and twelve months, weighing 14 to 27kg, were evaluated. The animals received 1g kg-1 of P. marcgravii plants orally. The sheep were evaluated before administering the plant (T0) through electro and echocardiography and blood collection to assess cardiac biomarkers (CK-MB and cTnI). Collections and analyses were repeated every four hours until the animal’s death. During the study, there was the presence of extravasation of serum troponin I carried out in a qualitative test, with positive values at time T4, and the serum CK-MB biomarker had a peak at T4 and slightly decreased at T8. The electro and echocardiographic examinations showed that the cause of death in these animals was due to acute heart failure characterized by arrhythmias, tachycardia/ventricular fibrillation, drop in cardiac output, left ventricular (LV) systolic dysfunction by the progressive decrease in the LV ejection fraction (EF), decrease in LV fractional shortening (FS), and decrease in aortic flow velocity and aortic flow gradient. This study seems to be the first to evaluate cardiac alterations in sheep poisoned by P. marcgravii through cardiac biomarkers and electro and echocardiographic exams.

Fear extinction is the basis of exposure therapies for posttraumatic stress disorder (PTSD), but half of patients do not improve. Predicting fear extinction in individuals with PTSD may inform personalized exposure therapy development. The participants were 125 trauma-exposed adults (96 female) with a range of PTSD symptoms. Electromyography, electrocardiogram, and skin conductance were recorded at baseline, during dark-enhanced startle, and during fear conditioning and extinction. Using a cross-validated, hold-out sample prediction approach, three penalized regressions and conventional ordinary least squares were trained to predict fear-potentiated startle during extinction using 50 predictor variables (5 clinical, 24 self-reported, and 21 physiological). The predictors, selected by penalized regression algorithms, were included in multivariable regression analyses, while univariate regressions assessed individual predictors. All the penalized regressions outperformed OLS in prediction accuracy and generalizability, as indexed by the lower mean squared error in the training and holdout subsamples. During early extinction, the consistent predictors across all the modeling approaches included dark-enhanced startle, the depersonalization and derealization subscale of the dissociative experiences scale, and the PTSD hyperarousal symptom score. These findings offer novel insights into the modeling approaches and patient characteristics that may reliably predict fear extinction in PTSD. Penalized regression shows promise for identifying symptom-related variables to enhance the predictive modeling accuracy in clinical research.

The blood-brain barrier (BBB), while being the gatekeeper of the central nervous system (CNS), is a bottleneck for the treatment of neurological diseases. Unfortunately, most of the biologicals do not reach their brain targets in sufficient quantities. The antibody targeting of receptor-mediated transcytosis (RMT) receptors is an exploited mechanism that increases brain permeability. We previously discovered an anti-human transferrin receptor (TfR) nanobody that could efficiently deliver a therapeutic moiety across the BBB. Despite the high homology between human and cynomolgus TfR, the nanobody was unable to bind the non-human primate receptor. Here we report the discovery of two nanobodies that were able to bind human and cynomolgus TfR, making these nanobodies more clinically relevant. Whereas nanobody BBB00515 bound cynomolgus TfR with 18 times more affinity than it did human TfR, nanobody BBB00533 bound human and cynomolgus TfR with similar affinities. When fused with an anti-beta-site amyloid precursor protein cleaving enzyme (BACE1) antibody (1A11AM), each of the nanobodies was able to increase its brain permeability after peripheral injection. A 40% reduction of brain Aβ1–40 levels could be observed in mice injected with anti-TfR/BACE1 bispecific antibodies when compared to vehicle-injected mice. In summary, we found two nanobodies that could bind both human and cynomolgus TfR with the potential to be used clinically to increase the brain permeability of therapeutic biologicals.