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Abstract We describe the geographical variation in tree species composition across Amazonian forests and show how environmental conditions are associated with species turnover. Our analyses are based on 2023 forest inventory plots (1 ha) that provide abundance data for a total of 5188 tree species. Within-plot species composition reflected both local environmental conditions (especially soil nutrients and hydrology) and geographical regions. A broader-scale view of species turnover was obtained by interpolating the relative tree species abundances over Amazonia into 47,441 0.1-degree grid cells. Two main dimensions of spatial change in tree species composition were identified. The first was a gradient between western Amazonia at the Andean forelands (with young geology and relatively nutrient-rich soils) and central–eastern Amazonia associated with the Guiana and Brazilian Shields (with more ancient geology and poor soils). The second gradient was between the wet forests of the northwest and the drier forests in southern Amazonia. Isolines linking cells of similar composition crossed major Amazonian rivers, suggesting that tree species distributions are not limited by rivers. Even though some areas of relatively sharp species turnover were identified, mostly the tree species composition changed gradually over large extents, which does not support delimiting clear discrete biogeographic regions within Amazonia.

Jaguar populations (Panthera onca) on the Ecuadorian coast are critically endangered, with only a few dozen individuals remaining in the region. In some areas, no records have been documented for decades. Between November 2023 and January 2024, independent camera trap monitoring in northwestern Ecuador yielded evidence of the presence of a jaguar, marking a significant recovery after seven years of absence in Manduriacu and at least 15 years in Junín. The jaguar was observed moving through an area of approximately 25 km, traversing forested and human-altered zones. Furthermore, additional evidence from the Ecominga Foundation and the Cielo Verde community indicated the occurrence of livestock attacks, which aligns with the typical predatory patterns observed in jaguar behavior. The attack site was located approximately 8 km from where the jaguar was initially recorded, suggesting that both events refer to the same individual. In response, local authorities inspected the area and organized community workshops. Furthermore, an Andean bear was recorded in Manduriacu during the same sampling period, confirming the co-occurrence of both species in the area. The documented movement of this jaguar, along with the presence of other species, underscores the imperative need to continue research and conservation initiatives in the region. These initiatives will ensure the protection and coexistence of wildlife and human populations in this highly biodiverse region.

Abstract BerryPortraits (Phenotyping of Ripening Traits) is open source Python-based image-analysis software that rapidly detects and segments berries and extracts morphometric data on fruit quality traits such as berry color, size, shape, and uniformity. Utilizing the YOLOv8 framework and community-developed, actively-maintained Python libraries such as OpenCV, BerryPortraits software was trained on 512 postharvest images (taken under controlled lighting conditions) of phenotypically diverse cranberry populations (Vaccinium macrocarpon Ait.) from the two largest public cranberry breeding programs in the U.S. The implementation of CIELAB, an intuitive and perceptually uniform color space, enables differentiation between berry color and berry brightness, which are confounded in classic RGB color channel measurements. Furthermore, computer vision enables precise and quantifiable color phenotyping, thus facilitating inclusion of researchers and data analysts with color vision deficiency. BerryPortraits is a phenotyping tool for researchers in plant breeding, plant genetics, horticulture, food science, plant physiology, plant pathology, and related fields. BerryPortraits has strong potential applications for other specialty crops such as blueberry, lingonberry, caneberry, grape, and more. As an open source phenotyping tool based on widely-used python libraries, BerryPortraits allows anyone to use, fork, modify, optimize, and embed this software into other tools or pipelines.

The Parque Estadual do Forno Grande is a fully protected area in the southern Espírito Santo State, Brazil. It belongs to the Atlantic Forest domain, with predominantly dense, ombrophilous, seasonal semi-deciduous forests and herbaceous/shrubby vegetation on rock outcrops. The area is recognised as highly important for conservation, designated as a priority biological area for protecting the Atlantic Forest's biodiversity. Although the importance of Protected Areas in conserving the Atlantic Forest biodiversity is unquestionable, it is crucial to understand the floristic patterns within these regions to develop effective conservation strategies. We utilised national online databases to compile species lists containing relevant information about their biodiversity. The updated list of vascular plants recorded in the Parque Estadual do Forno Grande is available in the “Catálogo de Plantas das Unidades de Conservação do Brasil” and it is presented here with further information on richness, endemism and conservation status.The Parque Estadual do Forno Grande harbours 958 species of vascular plants, of which 79.2% are angiosperms, 18.4% are ferns and 2.4% are lycophytes. Amongst these species, 44% are endemic to the Atlantic Forest. There are 58 threatened species, of which six are Critically Endangered, 39 are Endangered and 13 are Vulnerable. Amongst the threatened species, 51 are endemic to the Atlantic Forest. The number of records and the species richness in this area are notably high for Atlantic Forest standards. Our findings suggest that floristic inventories of Brazilian Protected Areas are a key contribution to the general perception of how much we still do not know about our flora. It also highlights the necessity of supporting floristic surveys in poorly-known areas, especially those remaining as forest remnants.

Seventy years ago, Robin Mole introduced the concept of the abscopal effect to describe a rare phenomenon. This occurs when local radiation triggers an immune-mediated reduction in tumors outside the treated area but within the same organism. Observing this effect has been linked to improved overall and progression-free survival in patients who experience it. While the abscopal effect was once considered rare, it is now being observed more frequently due to the combination of radiation with immunotherapy. As a result, more researchers are exploring this study area, which shows promise for excellent results. This review focuses explicitly on the immunological implications of activating the abscopal effect through ionizing radiation in the central nervous system and explores the potentially involved immunological pathways.

Iron and its alloys are attractive as biodegradable materials because of their low toxicity and suitable mechanical properties; however, they generally have a slow degradation rate. Given that corrosion is an electrochemical phenomenon where an exchange of electrons takes place, the application of magnetic fields from outside the body may accelerate the degradation of a ferrous temporary implant. In the present study, we have investigated the effect of alternating and direct low magnetic field (H = 6.5 kA/m) on the corrosion process of pure iron (Fe) and an iron-manganese alloy (FeMnC) in modified Hanks' solution. A 14-day static immersion test was performed on the materials. The corrosion rate was assessed by mass and cross-sectional loss measurements, scanning electron microscopy, X-ray diffractometry, Fourier-transform infrared spectroscopy and X-ray photoelectron spectroscopy before and after degradation. The results show that the presence of magnetic fields significantly accelerates the degradation rate of both materials, with the corrosion rate being twice as high in the case of Fe and almost three times as high for FeMnC. In addition, a homogenous degradation layer is formed over the entire surface and the chemical composition of the degradation products is the same regardless of the presence of a magnetic field.

Abstract Background Maternal obesity prepregnancy, as well as gestational overweight produced by high-sucrose diet, could be evolved to the cardiometabolic diseases in offspring during adulthood. Until then, the cardiometabolic diseases were ignored that have been presented or inherited in the offspring for overnutrition were ignored, depend on gender. We proposed that maternal prepregnancy obesity in CD1 mice, as well as gestational overweight produced by a high sucrose diet, develop to cardiometabolic disease in offspring and even if gender. For detection of the cardiometabolic diseases in a Murine model with a high sucrose diet (HSD), the time series formed by the RR intervals taken from lead I of the ECG has used the corresponding Poincare plot. The heart rate variability was characterized by the standard deviation of width and length SD1, SD2 respectively of the Poincare plot and the SD1/SD2 correlation index in addition was calculated between to gender and body weight. Results A maternal diet was based high sucrose diet and produced overweight on progeny in both sexes, but the cardiac arrhythmias depended on gender. Other results were due to the chronic effect of high sucrose diet in offspring with this intrauterine ambiance that contributes to changes in HRV, arrhythmias, and sinus pauses, also these phenomena were observed just in the male mice offspring with high sucrose diet during adulthood. Conclusions We propose, that the arrhythmias originated from fetal programming due to the maternal diet in mice model and produced alterations in the offspring female more than in the male, probably due to hormones.

The red macroalga Gracilaria parvispora is an introduced species in the Mexican Pacific. To date, there are no published studies on its sessile epibionts, including the hydrozoans and bryozoans, which are the dominant epibionts on macrophytes and of significant biological and economic interest.This study provides insight into the faunal diversity of hydroids growing on G. parvispora. A total of 185 thalli from both herbarium specimens and field samples collected from five sites in La Paz Bay were revised. Each thallus size and the presence of hydroid epibionts in each thallus region were registered. Eight different hydrozoan taxa were growing on the red macroalgae, including the first recorded observation of Obelia oxydentata in the Gulf of California. The sizes of the collected thalli were mostly under 7.0 cm, the maximum number of taxa per thallus was three and the thallus region containing the highest number of epibionts was in the middle. Significant differences were observed amongst the lengths of thalli with and without epibionts. The thalli with epibionts were larger than the thalli without epibionts. Similarly, significant differences were observed amongst the months. The pair-wise test revealed that each month exhibited distinctive epibiont taxa when compared to the others. This study highlights the lack of information on these associations. Further research is needed to understand whether introduced macroalgae can bring non-native epibiont species to an area.

The Tropical Indo-Pacific (TIP) includes about two thirds of the world’s tropical oceans and harbors an enormous number of marine species. The distributions of those species within the region is affected by habitat discontinuities and oceanographic features. As well as many smaller ones, the TIP contains seven large recognized biogeographic barriers that separate the Red Sea and Indian Ocean, the Indian from the Pacific Ocean, the central and eastern Pacific, the Hawaiian archipelago, the Marquesas and Easter Islands. We examined the genetic structuring of populations of Cirrhitichthys oxycephalus, a small cryptic species of reef fish, across its geographic range, which spans the longitudinal limits of the TIP. We assessed geographic variation in the mitochondrial cytb gene and the nuclear RAG1 gene, using 166 samples collected in 46 localities from the western to eastern edges of the TIP. Sequences from cytb show three well-structured groups that are separated by large genetic distances (1.58–2.96%): two in the Tropical Eastern Pacific (TEP), one at Clipperton Atoll another occupying the rest of that region and the third that ranges across the remainder of the TIP, from the central Pacific to the Red Sea and South Africa. These results indicate that the ~4,000 km wide Eastern Pacific Barrier between the central and eastern Pacific is an efficient barrier separating the two main groups. Further, the ~950 km of open ocean that isolates Clipperton Atoll from the rest of the TEP is also an effective barrier. Contrary to many other cases, various major and minor barriers from the Central Indo-Pacific to the Red Sea are not effective against dispersal by C. oxycephalus, although this species has not colonized the Hawiian islands and Easter Island. The nuclear gene partially supports the genetic structure evident in cytb, although all haplotypes are geographically mixed.

We present descriptions of two newly discovered species of Myxobolus (Myxobolidae) that infect Mugil curema: Myxobolus mundauensis n. sp. found in gills and Myxobolus patriciae n. sp. found in intestines. These descriptions are based on the morphology of myxospores, histological analysis, and sequencing of the small subunit ribosomal DNA (ssrDNA). The myxospores of both species differ in the width and length of their spore bodies, and their ssrDNA sequences showed a 10.6% difference. These findings support the identification of these parasites as distinct and previously unknown species. Phylogenetic analysis revealed a subclade consisting of species that parasitize Mugiliformes, with Myxobolus mundauensis n. sp. being closely related to Myxobolus maceioensis, and Myxobolus patriciae n. sp. being closely related to Myxobolus curemae. Our analysis aligns with previous research suggesting a strong correlation between host orders and phylogenetic patterns within the Myxobolidae family.

Parasitic otitis is an inflammatory process that can affect the external to internal cattle ear, causing discomfort in animals, impairing performance, and even leading to animal death. The infection was initially associated with nematodes of the Rhabditis genus in tropical and subtropical regions. Currently, the nematode species described as associated with bovine otitis are Metarhabditis costai, Metarhabditis freitasi, and, more recently, M. blumi. It is worth highlighting that there is still a lack of robust information regarding the morphological details, ultrastructural aspects, and molecular biology data of these species. The Metarhabditis genus is composed of seven species and two more have recently been added. The objective of this study is to update the morphological data using advanced microscopy techniques to emphasize and clarify the main morphological differences between three species of Metarhabditis currently associated with parasitic otitis. Samples of inflammatory exudate were collected from four adult female Gir cattle (Bos taurus indicus) on a farm in Itabira, Minas Gerais state, Brazil. Specimens were analyzed using light microscopy and scanning electron microscopy. Two species, M. costai and M. freitasi, were morphologically identified, consistent with previous reports. Scanning electron microscopy revealed new structural characteristics of the nematode species involved in parasitic otitis compared with M. blumi obtained from the CGC Center. Significant differences were observed in the male posterior region, bursa, and tail. Molecular analysis was conducted to differentiate these three species, and it was observed that the species first associated with otitis formed distinct clusters compared to M. blumi. However, it is important to note that further studies are needed to genetically characterize species of the Metarhabditis genus.

Abstract Actin dynamics control early T-cell receptor (TCR) signalling during T-cell activation. However, the precise regulation of initial actin rearrangements is not completely understood. Here, we have investigated the regulatory role of the phosphatase Slingshot-1 (SSH1) in this process. Our data show that SSH1 rapidly polarises to nascent cognate synaptic contacts and later relocalises to peripheral F-actin networks organised at the mature immunological synapse. Knockdown of SSH1 expression by CRISPR/Cas9-mediated genome editing or small interfering RNA reveal a regulatory role for SSH1 in CD3ε conformational change, allowing Nck binding and proper downstream signalling and immunological synapse organisation. TCR triggering induces SSH1-mediated activation of actin dynamics through a mechanism mediated by Limk-1 inactivation. These data suggest that during early TCR activation, SSH1 is required for rapid F-actin rearrangements that mediate initial conformational changes of the TCR, integrin organisation and proximal signalling events for proper synapse organisation. Therefore, the SSH1 and Limk-1 axis is a key regulatory element for full T cell activation.

SARS-CoV-2 is an obligatory intracellular pathogen that requires a lipid bilayer membrane for its transport to build its nucleocapsid envelope and fuse with the host cell. The biological membranes are constituted by phospholipids (PLs), and vitamin E (Vit E) protects them from oxidative stress (OS). The aim of this study was to demonstrate if treatment with Vit E restores the modified profile of the FA in PLs in serum from patients with coronavirus disease-19 (COVID-19). We evaluated Vit E, total fatty acids (TFAs), fatty acids of the phospholipids (FAPLs), total phospholipids (TPLs), 8-isoprostane, thromboxane B2 (TXB2), prostaglandins (PGE2 and 6-keto-PGF1α), interleukin-6 (IL-6), and C-reactive protein (CRP) in serum from 22 COVID-19 patients before and after treatment with Vit E and compared the values with those from 23 healthy subjects (HSs). COVID-19 patients showed a decrease in Vit E, TPLs, FAPLs, and TFAs in serum in comparison to HSs (p ≤ 0.01), and Vit E treatment restored their levels (p ≤ 0.04). Likewise, there was an increase in IL-6 and CRP in COVID-19 patients in comparison with HSs (p ≤ 0.001), and treatment with Vit E decreased their levels (p ≤ 0.001). Treatment with Vit E as monotherapy can contribute to restoring the modified FA profile of the PLs in the SARS-CoV-2 infection, and this leads to a decrease in lipid peroxidation, OS, and the inflammatory process.

Spatial epidemiology tools play a critical role in effectively allocating resources to curb the spread of animal diseases. This study focuses on classical scrapie (CS), an animal prion disease identified in Portugal, which infects small ruminant flocks and has been shown to be experimentally transmissible to wild cervids. Utilising remote sensing technologies and semi-automatic classification models, we aimed to evaluate the risk of interspecies prion transmission from domestic small ruminants to wild cervids (hosts). To achieve this, we gathered data related to hosts and infected small ruminant flocks. Furthermore, we collected and processed freely available, medium-resolution satellite imagery to derive vegetative and biophysical spectral indices capable of representing the primary habitat features. By employing a pixel-based species distribution model, we integrated the compiled geographical distribution data and spectral data with five supervised classification algorithms (random forest, classification tree analysis, artificial neural network, generalised linear model, and generalised additive model). The consensus map allowed accurate predictions of spatialised regions exhibiting spectral characteristics similar to where CS and its hosts were initially identified. By overlapping suitable territories for disease and host occurrence, we created a spatially explicit tool that assesses the risk of prion spill-over from domestic small ruminants to wild cervids. The described methodology is highly replicable and freely accessible, thus emphasising its practical utility. This study underscores the substantial contribution of model-based spatial analysis to disease monitoring and lays the groundwork for defining populations at risk and implementing targeted control and prevention strategies, thus safeguarding both animal and public health.

Worldwide, hypertension is the leading risk factor for cardiovascular disease and death. An estimated 122 million people, per the American Heart Association in 2023, have been diagnosed with this common condition. It is generally agreed that the primary goal in the treatment of hypertension is to reduce overall blood pressure to below 140/90 mmHg, with a more optimal goal of 130/80 mmHg. Common medications for treating hypertension include calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and diuretics. CCBs are one of the most widely studied agents and are generally recommended as first-line therapy alone and in combination therapies. This is largely based on the vast knowledge of CCB mechanisms and their minimal side effect profile. CCBs can be separated into two classes: dihydropyridine and non-dihydropyridine. Non-dihydropyridine CCBs act on voltage-dependent L-type calcium channels of cardiac and smooth muscle to decrease muscle contractility. Dihydropyridine CCBs act by vasodilating the peripheral vasculature. For many patients with only mild increases in systolic and diastolic blood pressure (e.g., stage 1 hypertension), the medical literature indicates that CCB monotherapy can be sufficient to control hypertension. In this regard, CCB monotherapy in those with stage 1 hypertension reduced renal and cardiovascular complications compared to other drug classes. Combination therapy with CCBs and angiotensin receptor blockers or angiotensin-converting enzyme inhibitors has been shown to be an effective dual therapy based on recent meta-analyses. This article is a review of calcium channel blockers and their use in treating hypertension with some updated and recent information on studies that have re-examined their use. As for new information, we tried to include some information from recent studies on hypertensive treatment involving calcium channel blockers.

Abstract The Mycoplasma Immunoglobulin Binding/Protease (MIB-MIP) system is a candidate ‘virulence factor present in multiple pathogenic species of the Mollicutes, including the fast-growing species Mycoplasma feriruminatoris. The MIB-MIP system cleaves the heavy chain of host immunoglobulins, hence affecting antigen-antibody interactions and potentially facilitating immune evasion. In this work, using -omics technologies and 5’RACE, we show that the four copies of the M. feriruminatoris MIB-MIP system have different expression levels and are transcribed as operons controlled by four different promoters. Individual MIB-MIP gene pairs of M. feriruminatoris and other Mollicutes were introduced in an engineered M. feriruminatoris strain devoid of MIB-MIP genes and were tested for their functionality using newly developed oriC-based plasmids. The two proteins are functionally expressed at the surface of M. feriruminatoris, which confirms the possibility to display large membrane-associated proteins in this bacterium. However, functional expression of heterologous MIB-MIP systems introduced in this engineered strain from phylogenetically distant porcine Mollicutes like Mesomycoplasma hyorhinis or Mesomycoplasma hyopneumoniae could not be achieved. Finally, since M. feriruminatoris is a candidate for biomedical applications such as drug delivery, we confirmed its safety in vivo in domestic goats, which are the closest livestock relatives to its native host the Alpine ibex.

Abstract Background The lack of standardized protocols for isolating extracellular vesicles (EVs), especially from biobank-stored blood plasma, translates to limitations for the study of new biomarkers. This study examines whether a combination of current isolation methods could enhance the specificity and purity of isolated EVs for diagnosis and personalized medicine purposes. Results EVs were isolated from healthy human plasma stored for one year by ultracentrifugation (UC), size exclusion chromatography (SEC), or SEC and UC combined (SEC + UC). The EV isolates were then characterized by transmission electron microscopy imaging, nanoparticle tracking analysis (NTA) and western blotting. Proteomic procedures were used to analyze protein contents. The presence of EV markers in all isolates was confirmed by western blotting yet this analysis revealed higher albumin expression in EVs-UC, suggesting plasma protein contamination. Proteomic analysis identified 542 proteins, SEC + UC yielding the most complex proteome at 364 proteins. Through gene ontology enrichment, we observed differences in the cellular components of EVs and plasma in that SEC + UC isolates featured higher proportions of EV proteins than those derived from the other two methods. Analysis of proteins unique to each isolation method served to identify 181 unique proteins for the combined approach, including those normally appearing in low concentrations in plasma. This indicates that with this combined method, it is possible to detect less abundant plasma proteins by proteomics in the resultant isolates. Conclusions Our findings reveal that the SEC + UC approach yields highly pure and diverse EVs suitable for comprehensive proteomic analysis with applications for the detection of new biomarkers in biobank-stored plasma samples.

Background Diagnosing periprosthetic joint infection (PJI) remains a significant challenge for healthcare professionals. Commonly utilized inflammatory markers include erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and white blood cells (WBC). Human β-defensin 1 (β-defensin) is an antimicrobial peptide elevated in infection, yet its diagnostic value for PJI has not been explored. The purpose of this study was to evaluate the efficacy of synovial β-defensin as a diagnostic marker for PJI and to compare its performance with ESR, serum CRP, and WBC. Methods We conducted a single-center retrospective study from October 2022 to June 2023. A total of 105 joint fluid samples from revision patients at the Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra were collected intraoperatively (71 hips, 34 knees) and frozen. According to MSIS criteria, 64 patients were defined as positive for PJI and the remaining 41 were negative. Synovial β-defensin levels were quantified using ELISA, serum CRP levels by immunoturbidimetry, and blood ESR and WBC were analyzed. Sensitivity and specificity were determined using ROC curves, and diagnostic performance was compared using the area under the curve (AUC). Cut-off values for diagnosing PJI were established. Results Levels of synovial β-defensin, ESR, serum CRP, and WBC were significantly higher in the PJI group compared to the non-PJI (P

Background Although My Jump 2® consistently presented excellent values of reliability and validity when compared to force platforms (FPs) and contact mats, to date no scientific investigation assessed the validity and reliability of My Jump 2® to measure jump height in visually impaired five-a-side soccer athletes. Thus, the study aimed at analyzing the validity and reliability of the My Jump 2® to measure the vertical jump of five-a-side soccer athletes. Methods Twelve visually impaired five-a-side soccer athletes, volunteered for this study. Each player performed five countermovement jumps (CMJs) and squat jumps (SJs) on a contact platform (CP) while they were simultaneously recorded using My Jump 2®. Results There was almost perfect agreement between the My Jump 2® and the contact platform measurements of CMJ (intraclass correlation coefficient = 0.99; p < 0.001) and SJ (intraclass correlation coefficient = 0.99; p < 0.001), heights for athletes during the first and second measurement days. Bland-Altman analysis showed a bias of 0.25 ± 0.5 cm; maximum SD = 1.3; minimum SD = −0.88 for CMJ, while that Bland-Altman analysis showed bias 0.18 ± 0.5 cm; maximum SD = 1.3; minimum SD = −0.96, for SJ. Conclusion We can conclude that the My Jump 2® is a valid and reliable method to measure CMJ and SJ in visually impaired five-a-side soccer athletes.

Freshwater crayfish are amongst the largest macroinvertebrates and play a keystone role in the ecosystems they occupy. Understanding the global distribution of these animals is often hindered due to a paucity of distributional data. Additionally, non-native crayfish introductions are becoming more frequent, which can cause severe environmental and economic impacts. Management decisions related to crayfish and their habitats require accurate, up-to-date distribution data and mapping tools. Such data are currently patchily distributed with limited accessibility and are rarely up-to-date. To address these challenges, we developed a versatile e-portal to host distributional data of freshwater crayfish and their pathogens (using Aphanomyces astaci, the causative agent of the crayfish plague, as the most prominent example). Populated with expert data and operating in near real-time, World of Crayfish™ is a living, publicly available database providing worldwide distributional data sourced by experts in the field. The database offers open access to the data through specialized standard geospatial services (Web Map Service, Web Feature Service) enabling users to view, embed, and download customizable outputs for various applications. The platform is designed to support technical enhancements in the future, with the potential to eventually incorporate various additional features. This tool serves as a step forward towards a modern era of conservation planning and management of freshwater biodiversity.

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.

The significance of STING1 gene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human STING1 alleles R71H-G230A-R293Q (HAQ) and G230A-R293Q (AQ) are carried by ~60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects of HAQ, AQ alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING1 mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using Sting1 knock-in mice expressing common human STING1 alleles HAQ, AQ, and Q293, we found that HAQ, AQ, and Q293 splenocytes resist STING1-mediated cell death ex vivo, establishing a critical role of STING1 residue 293 in cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice did not have CD4 T cellpenia. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING1 activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant HAQ, AQ alleles. STING1 research and STING1-targeting immunotherapy should consider STING1 heterogeneity in humans.

Summary: The “innate-like” T cell compartment, known as Tinn, represents a diverse group of T cells that straddle the boundary between innate and adaptive immunity. We explore the transcriptional landscape of Tinn compared to conventional T cells (Tconv) in the human thymus and blood using single-cell RNA sequencing (scRNA-seq) and flow cytometry. In human blood, the majority of Tinn cells share an effector program driven by specific transcription factors, distinct from those governing Tconv cells. Conversely, only a fraction of thymic Tinn cells displays an effector phenotype, while others share transcriptional features with developing Tconv cells, indicating potential divergent developmental pathways. Unlike the mouse, human Tinn cells do not differentiate into multiple effector subsets but develop a mixed type 1/type 17 effector potential. Cross-species analysis uncovers species-specific distinctions, including the absence of type 2 Tinn cells in humans, which implies distinct immune regulatory mechanisms across species.

Background: Cell migration is essential for the immune system and is frequently analyzed in adult non-pregnant animals but poorly explored in pregnant animals. However, a physiologic increased size in the spleen and periaortic lymph nodes had been reported in pregnant mice. Methods: Using a mouse model, we transferred PKH26-stained thymocytes and splenocytes from pregnant or non-pregnant animals to receptor mice in the presence or absence of pregnancy. Percentage of PKH-26 cells and Mean Fluorescence Intensity were calculated. Non-parametric ANOVA analysis was performed. Results: We detected that the percentage of PKH26+ thymocytes in the spleen, lymph nodes, and peripheral blood is higher in females than in males (p = 0.039). Our results showed a similar frequency of thymocytes and splenocytes from pregnant and non-pregnant mice located in receptor lymphoid organs (p > 0.05). Also, the location of marked cells was similar during the perinatal period (p > 0.05). Conclusions: The mobility of thymocytes and splenocytes in pregnant and non-pregnant mice is similar. Therefore, we suggest that the larger size of the spleen and periaortic lymph nodes noted previously in pregnant mice could result from the retention of leukocytes in the secondary lymphoid organs.

Summary: Maladaptive plasticity is linked to the chronification of diseases such as pain, but the transition from acute to chronic pain is not well understood mechanistically. Neuroplasticity in the central nucleus of the amygdala (CeA) has emerged as a mechanism for sensory and emotional-affective aspects of injury-induced pain, although evidence comes from studies conducted almost exclusively in acute pain conditions and agnostic to cell type specificity. Here, we report time-dependent changes in genetically distinct and projection-specific CeA neurons in neuropathic pain. Hyperexcitability of CRF projection neurons and synaptic plasticity of parabrachial (PB) input at the acute stage shifted to hyperexcitability without synaptic plasticity in non-CRF neurons at the chronic phase. Accordingly, chemogenetic inhibition of the PB→CeA pathway mitigated pain-related behaviors in acute, but not chronic, neuropathic pain. Cell-type-specific temporal changes in neuroplasticity provide neurobiological evidence for the clinical observation that chronic pain is not simply the prolonged persistence of acute pain.

The dysfunction of TAR DNA-binding protein 43 (TDP-43) is implicated in various neurodegenerative diseases, though the specific contributions of its toxic gain-of-function versus loss-of-function effects remain unclear. This study investigates the impact of TARDBP loss on cellular metabolism and viability using human-induced pluripotent stem cell-derived motor neurons and HeLa cells. TARDBP silencing led to reduced metabolic activity and cell growth, accompanied by neurite degeneration and decreased oxygen consumption rates in both cell types. Notably, TARDBP depletion induced a metabolic shift, impairing ATP production, increasing metabolic inflexibility, and elevating free radical production, indicating a critical role for TDP-43 in maintaining cellular bioenergetics. Furthermore, TARDBP loss triggered non-apoptotic cell death, increased ACSL4 expression, and reprogrammed lipid metabolism towards lipid droplet accumulation, while paradoxically enhancing resilience to ferroptosis inducers. Overall, our findings highlight those essential cellular traits such as ATP production, metabolic activity, oxygen consumption, and cell survival are highly dependent on TARDBP function.

It is known that conventional antigen presentation involves phagocytosis of antigens followed by its internalization in endocytic compartments and presentation of epitopes through MHC class II molecules for CD4 T cells. However, since 1976 a cross-presentation pathway has been studied, in which CD8 T cells are activated via MHC class I with antigens acquired through phagocytosis or endocytosis by dendritic cells (DCs). Among some important molecules involved in the cross-presentation, the C‐type lectin receptor of the Dectin‐1 cluster (CLECs), particularly the CLEC9A receptor, not only is expressed in dendritic cells but also presents a pivotal role in this context. In special, CLEC12A has been highlighted as a malaria pigment hemozoin (HZ) receptor. During Plasmodium infection, hemozoin crystals defend the parasite against heme toxicity within erythrocytes, as well as the released native HZ elicits pro-inflammatory responses and can induce cross-presentation. Particularly, this crystal can be synthesized from hematin anhydride and mimics the native form, and the gaps generated between the nanocrystal domains during its synthesis allow for substance coupling followed by its coating. Therefore, this study aimed to assess whether synthetic hemozoin (sHz) or hematin anhydride could be a nanocarrier and promote cross-presentation in dendritic cells. Firstly, it was verified that sHz can carry coated and coupled antigens, the compounds can associate to LAMP1-positive vesicles and decrease overall intracellular pH, which can potentially enhance the cross-presentation of ovalbumin and Leishmania infantum antigens. Thus, this study adds important data in the molecular intricacies of antigen presentation by showing not only the sHz immunomodulatory properties but also its potential applications as an antigen carrier.

Abstract Background Pseudomyxoma peritonei (PMP) is a rare peritoneal mucinous carcinomatosis with largely unknown underlying molecular mechanisms. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is the only therapeutic option; however, despite its use, recurrence with a fatal outcome is common. The lack of molecular characterisation of PMP and other mucinous tumours is mainly due to the physicochemical properties of mucin. Results This manuscript describes the first protocol capable of breaking the mucin barrier and isolating proteins from mucinous tumours. Briefly, mucinous tumour samples were homogenised and subjected to liquid chromatography using two specific columns to reduce mainly glycoproteins, albumins and immunoglobulin G. The protein fractions were then subjected to mass spectrometry analysis and the proteomic profile obtained was analysed using various bioinformatic tools. Thus, we present here the first proteome analysed in PMP and identified a distinct mucin isoform profile in soft compared to hard mucin tumour tissues as well as key biological processes/pathways altered in mucinous tumours. Importantly, this protocol also allowed us to identify MUC13 as a potential tumour cell marker in PMP. Conclusions In sum, our results demonstrate that this protein isolation protocol from mucin will have a high impact, allowing the oncology research community to more rapidly advance in the knowledge of PMP and other mucinous neoplasms, as well as develop new and effective therapeutic strategies.

Abstract Background Elephant seals exhibit extreme hypoxemic tolerance derived from repetitive hypoxia/reoxygenation episodes they experience during diving bouts. Real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessibility. Hence, we developed a proliferative arterial endothelial cell culture model from elephant seals and used RNA-seq, functional assays, and confocal microscopy to assess the molecular response to prolonged hypoxia. Results Seal and human endothelial cells exposed to 1% O2 for up to 6 h respond differently to acute and prolonged hypoxia. Seal cells decouple stabilization of the hypoxia-sensitive transcriptional regulator HIF-1α from angiogenic signaling. Rapid upregulation of genes involved in glutathione (GSH) metabolism supports the maintenance of GSH pools, and intracellular succinate increases in seal but not human cells. High maximal and spare respiratory capacity in seal cells after hypoxia exposure occurs in concert with increasing mitochondrial branch length and independent from major changes in extracellular acidification rate, suggesting that seal cells recover oxidative metabolism without significant glycolytic dependency after hypoxia exposure. Conclusions We found that the glutathione antioxidant system is upregulated in seal endothelial cells during hypoxia, while this system remains static in comparable human cells. Furthermore, we found that in contrast to human cells, hypoxia exposure rapidly activates HIF-1 in seal cells, but this response is decoupled from the canonical angiogenesis pathway. These results highlight the unique mechanisms that confer extraordinary tolerance to limited oxygen availability in a champion diving mammal.

Nearly 90% of oral cancers are characterized as oral squamous cell carcinoma (OSCC), representing the sixth most common type of cancer. OSCC usually evolves from oral potentially malignant disorders that, in some cases, are histologically consistent with a oral dysplasia. The levels of 1α,25 dihydroxyvitamin D3 (1,25-(OH)2D3; calcitriol), the active form of vitamin D3, have been shown to be decreased in patients with oral dysplasia and OSCC. Moreover, treatment with 1,25-(OH)2D3 has been proven beneficial in OSCC by inhibiting the Wnt/β-catenin pathway, a signaling route that promotes cell migration, proliferation, and viability. However, whether this inhibition mechanism occurs in oral dysplasia is unknown. To approach this question, we used dysplastic oral keratinocyte cultures and oral explants (ex vivo model of oral dysplasia) treated with 1,25-(OH)2D3 for 48 h. Following treatment with 1,25-(OH)2D3, both in vitro and ex vivo models of oral dysplasia showed decreased levels of nuclear β-catenin by immunofluorescence (IF) and immunohistochemistry (IHC). Consistently, reduced protein and mRNA levels of the Wnt/β-catenin target gene survivin were observed after treatment with 1,25-(OH)2D3. Moreover, 1,25-(OH)2D3 promoted membranous localization of E-cadherin and nuclear localization of vitamin D receptor (VDR). Functionally, DOK cells treated with 1,25-(OH)2D3 displayed diminished cell migration and viability in vitro.

Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal’s body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action’s molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect.

With the aging of the global population, neurodegenerative diseases are emerging as a major public health issue. The adoption of a less sedentary lifestyle has been shown to have a beneficial effect on cognitive decline, but the molecular mechanisms responsible are less clear. Here we provide a detailed analysis of the complex molecular, cellular, and systemic mechanisms underlying age-related cognitive decline and how lifestyle choices influence these processes. A review of the evidence from animal models, human studies, and postmortem analyses emphasizes the importance of integrating physical exercise with cognitive, multisensory, and motor stimulation as part of a multifaceted approach to mitigating cognitive decline. We highlight the potential of these non-pharmacological interventions to address key aging hallmarks, such as genomic instability, telomere attrition, and neuroinflammation, and underscore the need for comprehensive and personalized strategies to promote cognitive resilience and healthy aging.

The rapid resistance developed by pathogenic microorganisms against the current antimicrobial pool represents a serious global public health problem, leading to the search for new antibiotic agents. The scorpion Tityus stigmurus, an abundant species in Northeastern Brazil, presents a rich arsenal of bioactive molecules in its venom, with high potential for biotechnological applications. However, venom cytotoxicity constitutes a barrier to the therapeutic application of its different components. The objective of this study was to produce T. stigmurus-venom-loaded cross-linked chitosan nanoparticles (Tsv/CN) at concentrations of 0.5% and 1.0% to improve their biological antimicrobial activity. Polymeric nanoparticles were formed with a homogeneous particle size and spherical shape. Experimental formulation parameters were verified in relation to mean size (78%). Tsv/CN 1.0% demonstrated an ability to increase the antimicrobial venom effect against Staphylococcus aureus bacteria, exhibiting an MIC value of 44.6 μg/mL. It also inhibited different yeast species of the Candida genus, and Tsv/CN 0.5% and 1.0% led to a greater inhibitory effect of C. tropicalis and C. parapsilosis strains, presenting MIC values between 22.2 and 5.5 µg/mL, respectively. These data demonstrate the biotechnological potential of these nanosystems to obtain a new therapeutic agent with potential antimicrobial activity.

C-C Chemokine Receptor 7 (CCR7) mediates T-cell acute lymphoblastic leukemia (T-ALL) invasion of the central nervous system (CNS) mediated by chemotactic migration to C-C chemokine ligand 19 (CCL19). To determine if a CCL19 antagonist, CCL198-83, could inhibit CCR7-induced chemotaxis and signaling via CCL19 but not CCL21, we used transwell migration and Ca2+ mobilization signaling assays. We found that in response to CCL19, human T-ALL cells employ β2 integrins to invade human brain microvascular endothelial cell monolayers. In vivo, using an inducible mouse model of T-ALL, we found that we were able to increase the survival of the mice treated with CCL198-83 when compared to non-treated controls. Overall, our results describe a targetable cell surface receptor, CCR7, which can be inhibited to prevent β2-integrin-mediated T-ALL invasion of the CNS and potentially provides a platform for the pharmacological inhibition of T-ALL cell entry into the CNS.

Smith-Magenis syndrome (SMS) is a complex neurodevelopmental disorder with a birth incidence of 1:25,000. SMS is caused by haploinsufficiency of the retinoic acid-induced retinoic acid1 (RAI1) gene, determined by an interstitial deletion of ∼ 3.7 Mb (17p11.2, including the RAI1 gene) in 90 % of cases and a mutation on the RAI1 gene in only 10 % of cases. We generated and characterized a human pluripotent stem cell line (hIPSCs) derived from primary fibroblasts of a 17-year-old woman carrying a 17p11.2 deletion including the RAI1 gene.

Antimicrobial peptides (AMPs) are a promising tool with which to fight rising antibiotic resistance. However, pathogenic bacteria are equipped with several AMP defense mechanisms, whose contributions to AMP resistance are often poorly defined. Here, we evaluate the genetic determinants of resistance to an insect AMP, cecropin B, in the opportunistic pathogen Enterobacter cloacae. Single-cell analysis of E. cloacae's response to cecropin revealed marked heterogeneity in cell survival, phenotypically reminiscent of heteroresistance (the ability of a subpopulation to grow in the presence of supra-MIC concentration of antimicrobial). The magnitude of this response was highly dependent on initial E. cloacae inoculum. We identified 3 genetic factors which collectively contribute to E. cloacae resistance in response to the AMP cecropin: The PhoPQ-two-component system, OmpT-mediated proteolytic cleavage of cecropin, and Rcs-mediated membrane stress response. Altogether, our data suggest that multiple, independent mechanisms contribute to AMP resistance in E. cloacae.

Klebsiella pneumoniae is a global public health concern due to the rising myriad of hypervirulent and multidrug-resistant clones both alarmingly associated with high mortality. The molecular mechanisms underpinning these recalcitrant K. pneumoniae infection, and how virulence is coupled with the emergence of lineages resistant to nearly all present-day clinically important antimicrobials, are unclear. In this study, we performed a genome-wide screen in K. pneumoniae ECL8, a member of the endemic K2-ST375 pathotype most often reported in Asia, to define genes essential for growth in a nutrient-rich laboratory medium (Luria-Bertani [LB] medium), human urine, and serum. Through transposon directed insertion-site sequencing (TraDIS), a total of 427 genes were identified as essential for growth on LB agar, whereas transposon insertions in 11 and 144 genes decreased fitness for growth in either urine or serum, respectively. These studies not only provide further knowledge on the genetics of this pathogen but also provide a strong impetus for discovering new antimicrobial targets to improve current therapeutic options for K. pneumoniae infections.

Cullin-1-RING ubiquitin ligases (CRL1) or SCF1 (SKP1-CUL1-RBX1) E3 ubiquitin ligases are the largest and most extensively investigated class of E3 ligases in mammals that regulate fundamental processes, such as the cell cycle and proliferation. These enzymes are multiprotein complexes comprising SKP1, CUL1, RBX1, and an F-box protein that acts as a specificity factor by interacting with SKP1 through its F-box domain and recruiting substrates via other domains. E3 ligases are important players in the ubiquitination process, recognizing and transferring ubiquitin to substrates destined for degradation by proteasomes or processing by deubiquitinating enzymes. The ubiquitin-proteasome system (UPS) is the main regulator of intracellular proteolysis in eukaryotes and is required for parasites to alternate hosts in their life cycles, resulting in successful parasitism. Leishmania UPS is poorly investigated, and CRL1 in L. infantum, the causative agent of visceral leishmaniasis in Latin America, is yet to be described. Here, we show that the L. infantum genes LINF_110018100 (SKP1-like protein), LINF_240029100 (cullin-like protein-like protein), and LINF_210005300 (ring-box protein 1 -putative) form a LinfCRL1 complex structurally similar to the H. sapiens CRL1. Mass spectrometry analysis of the LinfSkp1 and LinfCul1 interactomes revealed proteins involved in several intracellular processes, including six F-box proteins known as F-box-like proteins (Flp) (data are available via ProteomeXchange with identifier PXD051961). The interaction of LinfFlp 1-6 with LinfSkp1 was confirmed, and using in vitro ubiquitination assays, we demonstrated the function of the LinfCRL1(Flp1) complex to transfer ubiquitin. We also found that LinfSKP1 and LinfRBX1 knockouts resulted in nonviable L. infantum lineages, whereas LinfCUL1 was involved in parasite growth and rosette formation. Finally, our results suggest that LinfCul1 regulates the S phase progression and possibly the transition between the late S to G2 phase in L. infantum. Thus, a new class of E3 ubiquitin ligases has been described in L. infantum with functions related to various parasitic processes that may serve as prospective targets for leishmaniasis treatment.

Summary: Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.

Cell sedimentation in 3D hydrogel cultures refers to the vertical migration of cells towards the bottom of the space. Understanding this poorly examined phenomenon may allow us to design better protocols to prevent it, as well as provide insights into the mechanobiology of cancer development. We conducted a multiscale experimental and mathematical examination of 3D cancer growth in triple negative breast cancer cells. Migration was examined in the presence and absence of Paclitaxel, in high and low adhesion environments and in the presence of fibroblasts. The observed behaviour was modeled by hypothesizing active migration due to self-generated chemotactic gradients. Our results did not reject this hypothesis, whereby migration was likely to be regulated by the MAPK and TGF-β pathways. The mathematical model enabled us to describe the experimental data in absence (normalized error

Saccharomyces cerevisiae has been conveniently used to produce Taxol® anticancer drug early precursors. However, the harmful impact of oxidative stress by the first cytochrome P450-reductase enzymes (CYP725A4-POR) of Taxol® pathway has hampered sufficient progress in yeast. Here, we evolved an oxidative stress-resistant yeast strain with three-fold higher titre of their substrate, taxadiene. The performance of the evolved and parent strains were then evaluated in galactose-limited chemostats before and under the oxidative stress by an oxidising agent. The interaction of evolution and oxidative stress was comprehensively evaluated through transcriptomics and metabolite profiles integration in yeast enzyme-constrained genome scale model. Overall, the evolved strain showed improved respiration, reduced overflow metabolites production and oxidative stress re-induction tolerance. The cross-protection mechanism also potentially contributed to better heme, flavin and NADPH availability, essential for CYP725A4 and POR optimal activity in yeast. The results imply that the evolved strain is a robust cell factory for future efforts towards Taxol© production.

INTRODUCCIÓN: Se pierde y desperdicia un tercio de la producción mundial de alimentos, situación que impacta en la seguridad alimentaria de la población, el desarrollo económico y el medio ambiente1,2. El objetivo fue analizar cuanti/cualitativamente el desperdicio de frutas y hortalizas (FyH), y los factores que inciden en su generación en los comercios minoristas. MATERIAL Y MÉTODOS: Estudio observacional, descriptivo y transversal. Se relevaron 30 comercios de la ciudad de La Calera, en el periodo 2022-2023. La investigación se desarrolló en el marco del proyecto Desperdicios de frutas y hortalizas en comercios minoristas (verdulerías) de Córdoba y Gran Córdoba. Análisis y caracterización en pos de un sistema alimentario sostenible, el cual contó con el respaldo de la secretaría de Investigación de la Universidad Siglo 21 y el financiamiento del Ministerio de Ciencia y Tecnología de la Provincia de Córdoba, según Resolución 2023/00000018. Se contactó a los titulares/encargados de los comercios, a quienes se les informó sobre el propósito del estudio, la garantía de confidencialidad sobre no dar a conocer su razón social y el manejo de datos, derecho de no participar de acuerdo con su disponibilidad e interés y de finalizar el cuestionario en el momento que lo desearan. Se respetó la voluntad de participar de cada encuestado mediante su consentimiento de manera verbal.

Summary: Resolving the molecular mechanisms of central B cell tolerance might unveil strategies that prevent autoimmunity. Here, using a mouse model of central B cell tolerance in which Forkhead box protein O1 (Foxo1) is either deleted or over-expressed in B cells, we show that deleting Foxo1 blocks receptor editing, curtails clonal deletion, and decreases CXCR4 expression, allowing high-avidity autoreactive B cells to emigrate to the periphery whereby they mature but remain anergic and short lived. Conversely, expression of degradation-resistant Foxo1 promotes receptor editing in the absence of self-antigen but leads to allelic inclusion. Foxo1 over-expression also restores tolerance in autoreactive B cells harboring active PI3K, revealing opposing roles of Foxo1 and PI3K in B cell selection. Overall, we show that the transcription factor Foxo1 is a major gatekeeper of central B cell tolerance and that PI3K drives positive selection of immature B cells and establishes allelic exclusion by suppressing Foxo1.

Summary: Fragile X syndrome (FXS) is associated with disrupted cognition and sleep abnormalities. Sleep loss negatively impacts cognitive function, and one untested possibility is that disrupted cognition in FXS is exacerbated by abnormal sleep. We tested whether ML297, a hypnotic acting on G-protein-activated inward-rectifying potassium (GIRK) channels, could reverse sleep phenotypes and disrupted memory in Fmr1−/y mice. Fmr1−/y mice exhibit reduced non-rapid eye movement (NREM) sleep and fragmented NREM architecture, altered sleep electroencephalogram (EEG) oscillations, and reduced EEG coherence between cortical areas; these are partially reversed following ML297 administration. Treatment following contextual fear or spatial learning restores disrupted memory consolidation in Fmr1−/y mice. During memory recall, Fmr1−/y mice show an altered balance of activity among hippocampal principal neurons vs. parvalbumin-expressing interneurons; this is partially reversed by ML297. Because sleep disruption could impact neurophysiological phenotypes in FXS, augmenting sleep may improve disrupted cognition in this disorder.

Immunosenescence is a phenomenon caused by changes in the immune system, and part of these changes involves an increase in circulating immunological biomarkers, a process known as “Inflammaging.” Inflammaging can be associated with many diseases related to older people. As the older population continues to grow, understanding changes in the immune system becomes essential. While prior studies assessing these alterations have been conducted in countries with Caucasian populations, this investigation marks a pioneering effort. The object of the study is to describe for the first time that the distribution of cytokines, chemokines, and growth factors serum levels, assessed by Luminex platform, has been examined in a Brazilian population-based study of older adult females and males by age. Blood samples from 2111 participants (≥50 years old) were analyzed at the baseline (2015/2016) of the ELSI-Brazil study. The exploratory variables considered in the study were age, sex, educational level, residence area, geographic region, alcohol and smoking consumption, physical activity, and self-reported medical diagnoses of hypertension, diabetes, asthma, arthritis, and cancer. The association between serum biomarker levels and age was assessed by a quantile regression model adjusted in the total population and stratified by sex. The significance level considered in the analysis was 0.05. The mean age of the participants was 62.9 years, with a slight majority of female (52.7 %). Differences were found between the sexes in the median circulating levels of the CCL11, CXCL10, and FGF biomarkers. Eight biomarkers showed significant associations with age, including the pro-inflammatory CXCL10, TNF-α, IL-6, IL-17, and IL-2; and type 2/regulatory CCL11 and IL-4, showing positive associations, and anti-inflammatory IL-1Ra showing a negative association. The results suggest similar associations between the sexes, revealing an inflammatory profile characterized by types 1 and 2. Remarkably, these findings reinforce the concept of the Inflammaging process in Brazilian population. These findings add novel insights to about the immunosenescence aspects in middle-income countries and help define biomarkers capable of monitoring inflammation in older adults.

Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by impaired motor coordination due to neurological defects and cerebellar dysfunction caused by the accumulation of cholesterol in endolysosomes. Besides the increase in lysosomal cholesterol, mitochondria are also enriched in cholesterol, which leads to decreased membrane fluidity, impaired mitochondrial function and loss of GSH, and has been shown to contribute to the progression of NPC disease. S-Adenosyl-l-methionine (SAM) regulates membrane physical properties through the generation of phosphatidylcholine (PC) from phosphatidylethanolamine (PE) methylation and functions as a GSH precursor by providing cysteine in the transsulfuration pathway. However, the role of SAM in NPC disease has not been investigated. Here we report that Npc1−/− mice exhibit decreased brain SAM levels but unchanged S-adenosyl-l-homocysteine content and lower expression of Mat2a. Brain mitochondria from Npc1−/− mice display decreased mitochondrial GSH levels and liquid chromatography-high resolution mass spectrometry analysis reveal a lower PC/PE ratio in mitochondria, contributing to increased mitochondrial membrane order. In vivo treatment of Npc1−/− mice with SAM restores SAM levels in mitochondria, resulting in increased PC/PE ratio, mitochondrial membrane fluidity and subsequent replenishment of mitochondrial GSH levels. In vivo SAM treatment improves the decline of locomotor activity, increases Purkinje cell survival in the cerebellum and extends the average and maximal life spam of Npc1−/− mice. These findings identify SAM as a potential therapeutic approach for the treatment of NPC disease.

Marfan syndrome (MFS) is a multisystem genetic disorder with over 3000 mutations described in the fibrillin 1 (FBN1) gene. Like MFS, other connective tissue disorders also require a deeper understanding of the phenotype-genotype relationship due to the complexity of the clinical presentation, where diagnostic criteria often overlap. Our objective was to identify mutations in patients with connective tissue disorders using a genetic multipanel and to analyze the genotype-phenotype associations in a cohort of Mexican patients. We recruited 136 patients with MFS and related syndromes from the National Institute of Cardiology. Mutations were identified using next-generation sequencing (NGS). To examine the correlation between mutation severity and severe cardiovascular conditions, we focused on patients who had undergone Bentall-de Bono surgery or aortic valve repair. The genetic data obtained allowed us to reclassify the initial clinical diagnosis across various types of connective tissue disorders. The transforming growth factor beta receptor 2 (TGFBR2) rs79375991 mutation was found in 10 out of 16 (63%) Loeys-Dietz patients. We observed a high prevalence (65%) of more severe mutations, such as frameshift indels and stop codons, among patients requiring invasive treatments like aortic valve-sparing surgery, Bentall and de Bono procedures, or aortic valve replacement due to severe cardiovascular injury. Although our study did not achieve precise phenotype-genotype correlations, it underscores the importance of a multigenetic panel evaluation. This could pave the way for a more comprehensive diagnostic approach and inform medical and surgical treatment decision-making.

Abstract Using 2.046 botanically-inventoried tree plots across the largest tropical forest on Earth, we mapped tree species-diversity and tree species-richness at 0.1-degree resolution, and investigated drivers for diversity and richness. Using only location, stratified by forest type, as predictor, our spatial model, to the best of our knowledge, provides the most accurate map of tree diversity in Amazonia to date, explaining approximately 70% of the tree diversity and species-richness. Large soil-forest combinations determine a significant percentage of the variation in tree species-richness and tree alpha-diversity in Amazonian forest-plots. We suggest that the size and fragmentation of these systems drive their large-scale diversity patterns and hence local diversity. A model not using location but cumulative water deficit, tree density, and temperature seasonality explains 47% of the tree species-richness in the terra-firme forest in Amazonia. Over large areas across Amazonia, residuals of this relationship are small and poorly spatially structured, suggesting that much of the residual variation may be local. The Guyana Shield area has consistently negative residuals, showing that this area has lower tree species-richness than expected by our models. We provide extensive plot meta-data, including tree density, tree alpha-diversity and tree species-richness results and gridded maps at 0.1-degree resolution.

Little is known on seabirds of the order Procellariiformes which visit the Brazilian oceanic islands. Herein, we present new records of five birds found stranded in the Fernando de Noronha archipelago: Fregetta tropica melanoleuca Salvadori, 1908, Ardenna grisea (Gmelin, 1789), Puffinus lherminieri Lesson, 1839, and Hydrobates leucorhous (Vieillot, 1818). Citizen‑science platforms include only one documentation for each of these species, but there is potential for greater detection. Pelagic birds have rarely been reported in recent decades, and continued monitoring is needed for better understanding of their distribution patterns.

The use of medicinal plants for the therapy of diseases of the digestive system, where the Andean peoples developed various forms of administration. The objective is to identify medicinal plants used in the therapy of ailments of the digestive system by the Andean inhabitants of Pampas, Tayacaja, Huancavelica, Peru. Methods: Non-probabilistic sampling, using the “snowball” technique, carrying out semi-structured surveys, allowing information to be collected on the prevalence of ailments or diseases of the digestive system treated with medicinal plants, with inhabitants over 20 years of age participating and using the medicinal plants in the therapy of your digestive system ailments, and exclude those inhabitants who do not comply with it. Results: A total of 16 families, 33 genera, and 34 species are reported, where the families that present the greatest abundance of species are Asteraceae and Lamiaceae. The widely used species are Minthostachys mollis (11.9%), Aloe vera (10.4%), Clinopodium bolivianum (9%), Artemisia absinthium (9%), and Matricaria chamomilla (8.2%). Concluding with the identification of a diversity of medicinal flora, used in the therapy of diseases of the digestive system, such as stomach pain, constipation, gallbladder ailments, gastritis, and gastrointestinal, and liver diseases.