Biology subjects

Munoz, M.

Publications and source records attributed to Munoz, M..

18 recordsLinked to original sources

bioRxiv2026

Elevated cholesterol in APOE4 astrocytes drives mitochondrial cristae collapse and ATP synthase dysfunction

Cholesterol imbalance is a hallmark of major human diseases, including atherosclerosis and Alzheimers disease, both of which are also associated with mitochondrial dysfunction, yet the mechanistic links between cholesterol and mitochondria remain poorly understood. Here we show that elevated intracellular cholesterol in murine astrocytes expressing the Alzheimers disease risk variant APOE4 disrupts the inner mitochondrial membrane, manifesting as sparse, truncated cristae alongside an excess of cristae junction complexes. These structural abnormalities are accompanied by loss of respiratory chain complexes I and IV, and reduced respiration; nevertheless, low proton leak and reverse ATP synthase activity combine to generate an elevated mitochondrial membrane potential. Strikingly, APOE4 astrocytes are hypersensitive to the ATP synthase inhibitor oligomycin, demonstrating a profound dysfunction of the enzyme, and cholesterol sequestration with methyl-{beta}-cyclodextrin abrogates this toxicity, establishing elevated cholesterol as its proximate cause. Another method of targeting ATP synthase, epicatechin, which prevents the enzyme operating in reverse, attenuated both cholesterol- and respiratory chain inhibitor-induced cell death. Reciprocally, reducing intracellular cholesterol via nutrient restriction restored cristae architecture and partially rescued respiratory chain complex abundance. These findings identify mitochondrial cholesterol as a critical determinant of cristae architecture and ATP synthase function and suggest that cholesterol-driven mitochondrial dysfunction may be a unifying feature of cholesterol-related disorders from neurodegeneration to atherosclerosis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/742391v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@2e80a1org.highwire.dtl.DTLVardef@fecd32org.highwire.dtl.DTLVardef@51ba3corg.highwire.dtl.DTLVardef@199f3c6_HPS_FORMAT_FIGEXP M_FIG Elevated intracellular cholesterol in APOE4 astrocytes disrupts the inner mitochondrial membrane and ATP synthase, resulting in sparse cristae, increased ATP hydrolysis and heightened oligomycin sensitivity. The vulnerability to oligomycin is abrogated by cholesterol sequestration with cyclodextrin, indicating causality. These findings position cholesterol as a key determinant of the cristae landscape and ATP synthase function, highlighting the importance of the emerging field of mitochondrial-cholesterol crosstalk. C_FIG

cell biology↗

bioRxiv2026

Induced Estrogen Receptor SUMOylation drives SERD activity

The ligand dependent transcription factor estrogen receptor (ER) is a key driver of and important drug target in breast cancer. Patients with advanced disease are typically treated with selective ER degraders (SERDs), whose therapeutic activity is commonly attributed to induced ER protein degradation. Yet the exact mechanism and relevance of degradation for clinical efficacy remain unclear. We show that SERDs directly induce ER SUMOylation, thereby triggering degradation via SUMO-targeted ubiquitin ligases (STUbLs). Inactivation of STUbLs prevents ER degradation and counterintuitively further sensitizes breast cancer cells to SERDs, rather than conferring resistance. SERD efficacy is independent of ER degradation, challenging the degradation-centric model of SERD action. Instead, SUMOylation recruits transcriptional co-repressors, turning SUMOylated ER into a dominant-negative repressor. Thus, SUMOylation rather than degradation is the direct consequence and driver of SERD activity. Our findings position SUMO-inducing drugs as a hitherto underappreciated yet clinically validated therapeutic modality with broad applicability.

Cancer Biology↗

bioRxiv2025

Distinct cytotoxic cell subsets underlie protective and non-protective immunity to African swine fever virus

Limited understanding of African swine fever (ASF) immunity remains a major barrier to the rational development of safe and effective vaccines. While antibody-mediated protection is still poorly defined, growing evidence highlights a central role for cellular immunity. In particular, cytotoxic cells have emerged as key components to control ASF virus (ASFV) infection. However, the contribution of individual cytotoxic subsets across different virological and immunological contexts is not well characterised. Here, we investigated cytotoxic responses during BA71{Delta}CD2 live attenuated vaccine (LAV)-induced protection and during late-stage lethal ASFV infection, and demonstrated the involvement of different cytotoxic subsets in each scenario. Early increases in perforin-producing CD8{beta}+ T cells in blood after immunisation coincided with the onset of protection. At later time points, elevated levels of these cells after in vitro ASFV-specific stimulation correlated with survival to lethal challenge, supporting their central role in protective immunity. Additional correlates of protection during recall responses included CD4+CD8{beta}+ cytotoxic T cells, IFN{gamma}-producing cells, and ASFV-specific antibodies, illustrating the multifactorial nature of immunity to ASF. In contrast, pigs with acute ASF exhibited a distinct cytotoxic profile characterised by broad increases across multiple perforin-producing subsets. Although all of them showed reduced susceptibility to ASFV-induced lymphopenia, only perforin-producing NK and{gamma}{delta} T cells correlated with viremia, suggesting their active involvement during late disease. Together, these findings advance our understanding of cytotoxic responses to ASFV and identify cytotoxic T cells, alongside other immune components, as potential correlates of protection that may guide future vaccine development.

immunology↗

bioRxiv2025

Characterization of hippocampal subfields using histology-based annotated postmortem MRI: Lessons for in vivo segmentation II

High-resolution in vivo magnetic resonance imaging (MRI) of hippocampal subfields is a rapidly advancing field due to their implication in cognition, disorder, and disease. Hippocampal subfield segmentation on in vivo MRI is generally guided by postmortem reference material, which has been limited by small sample sizes that preclude comprehensive characterization of subfield border locations and their variability. Addressing this, we characterized hippocampal subfield border variability in two ultra-high-resolution postmortem MRI datasets with combined annotated histological sections, including cases with and without dementia. We examined: 1) the order of appearance and disappearance of subfields along the long axis of the hippocampus; 2) the order of appearance and disappearance of subicular subregions; 3) the medial-lateral position of subicular subregional boundaries along the hippocampal body; 4) the location of the CA3 relative to hippocampal head digitations; 5) the subfield borders in the hippocampal body relative to a volume proportion of the dark band; and 6) the association of hippocampal length and subiculum-CA1 border location with diagnosis, demographic factors, and factors related to postmortem imaging. Our findings reaffirmed that there is a consistent order of appearance and disappearance of subfields in the hippocampal head and tail, respectively. The subicular subregions exhibited a first in, last out order of appearance and disappearance, and pre/parasubiculum consistently occupied half of the subicular complex in coronal slices throughout the hippocampal body. Hippocampal head digitations were not a reliable landmark for CA3 appearance, but SRLM proportionality did offer a potentially consistent approach for estimating CA2 and CA3 subfield borders in relation to the hippocampal border. No clear relationship was found between the anatomical features and diagnosis, demographic factors, and factors related to postmortem imaging. These findings have implications for the development and harmonization of hippocampal subfield segmentation protocols and interpretation of high-resolution functional MRI studies of the human hippocampus.

neuroscience↗

bioRxiv2025

Universal phylogenetic inertia in body temperature evolution across endothermic and ectothermic tetrapods.

Species must adapt to persist in a changing world. As global temperatures rise, how species adapt and respond to thermal shifts is crucial for anticipating global patterns of biodiversity change. Land vertebrates can be divided into two major thermoregulatory strategies, endothermy and ectothermy. One might hypothesize that, given their reputation as being "cold blooded," ectotherms are thermal generalists, capable of operating across a greater range of body temperatures than endotherms and exhibit greater plasticity and evolvability in body temperature. However, a wide variety of traits and ecologies could modulate responses of thermal physiology to environmental change. Here, we employ macroevolutionary models to estimate the rate of adaptation of thermal physiology across squamates, mammals, and birds in the context of their ecology, physiology, and changing climatic conditions and whether there are fundamental differences in how the three clades respond to their environments. We find stronger relationships between squamates body temperature and their environment than in birds and mammals, significant effects of diel activity (nocturnal and diurnal) on body temperature evolution in all clades, and no effect of aquatic/terrestrial habits and rumination on the evolution of body temperature in mammals. Most surprisingly, our findings suggest shared limits on the evolution of thermal physiology across ectothermic and endothermic groups that argue for universal constraints on the rate of evolution in thermal physiology while explaining disparate patterns of body temperature and niche evolution across groups.

evolutionary biology↗

bioRxiv2025

CB2R-induced differentiation epigenetically restrains cancer plasticity enabling adaptive therapy

Cellular plasticity enables cancer cells to escape therapy by adopting stem-like or alternate lineage states. Here, we identify a mechanism by which cannabinoid receptor 2 (CB2R) activation promotes irreversible lineage commitment in breast cancer. Using patient-derived and murine organoids, we show that brief, low-dose exposure to CB2R agonists--either phytogenic or synthetic--induces a basal-to-luminal transition, accompanied by reduced self-renewal, invasiveness, and tumor-initiating potential. These changes are retained under conditions that normally promote dedifferentiation, including fibroblast co-culture, immune pressure, and mechanical shear stress. Mechanistically, CB2R engagement initiates a transient chromatin remodeling program, marked by early expression of pluripotency-associated genes followed by silencing and differentiation commitment. This epigenetically stabilized state renders tumor cells more responsive to tamoxifen and limits the emergence of resistant clones. Our findings uncover a previously unrecognized role for CB2R in modulating cancer cell identity and suggest new opportunities to constrain tumor plasticity by directing differentiation through a drug-responsive pathway.

cancer biology↗

bioRxiv2025

Untargeted Plasma Metabolomics in Canine Cognitive Dysfunction: The Naturally Occurring Alzheimer's Disease Analog in Dogs

IntroductionCanine Cognitive Dysfunction (CCD) is an increasingly prevalent naturally occurring neurodegenerative condition in senescent dogs that share neuropathological and clinical features with human Alzheimers disease (AD). Metabolic profiling allows for identification of new candidates for AD biomarkers, diagnostics, and therapeutics. Despite its translational potential, plasma metabolomic profiling of dogs with CDD has not been previously characterized. MethodsThis case-control study analyzed plasma samples from ten client-owned geriatric dogs, including five with severe CCD and five age-matched, clinically healthy controls. Untargeted plasma metabolomics was performed using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Multivariate and univariate statistical analyses identified significant metabolic differences between the groups. Metabolites were considered significant based on a variable importance in projection (VIP) score > 1.5, fold change (FC) > 2.0, and adjusted p-value < 0.05. ResultsFifteen metabolites across seven chemical classes were significantly altered in CCD dogs compared to controls, including glycerophospholipids, steroid derivatives, indoles, and mitochondrial-related compounds. Notably, elevated lysophosphatidic acid (LPA 20:2/0:0) and reduced ubiquinone-2 levels suggest dysregulation in neuroinflammatory and oxidative stress pathways. Cholesterol exhibited the highest FC and VIP scores, further reinforcing its role in AD pathogenesis. Hierarchical clustering and pathway enrichment analyses supported distinct metabolic signatures in CCD that mirror those observed in human AD. DiscussionThis is the first untargeted plasma metabolomic profiling of dogs with CCD, revealing systemic metabolic disturbances that align with AD pathophysiology. Data was collected from senescent community-dwelling companion dogs, which enhances the studys ecological and translational relevance. It supports the utility of CCD as an AD model and highlight candidate plasma biomarkers that warrant further investigation. Future longitudinal studies integrating metabolomics with neuroimaging, histopathology, and behavioral assessments are required to validate these findings and contribute to AD biomarker discovery and therapeutic development.

neuroscience↗

bioRxiv2025

Epigenetic Subtypes of High-Grade T1 Bladder Cancer Reveal Intra-Tumor Heterogeneity and Distinct Interactions with Tumor Microenvironment.

High-Grade T1 (HGT1) Non-Muscle Invasive Bladder Cancer (NMIBC) is a clinically heterogeneous disease, characterized by unpredictable treatment responses and limited tools for recurrence prediction. Although molecular classification efforts have been made, patient stratification still primarily relies on clinicopathological features, which offer limited clinical precision. In this study, we integrated chromatin profiling in bulk with single-nuclei(sn) RNA-seq, immunohistochemistry and spatial transcriptomics to define epigenetic subtypes of HGT1, characterize their heterogeneity, and investigate tumor-microenvironment interactions. Our findings reveal distinct chromatin profiles differentiating urothelial (URO) and micropapillary (MP) histological variants of high-risk HGT1. We identified three epigenetic states: two within the URO group, luminal-like inflammatory (LLI) and basal-like (BL), and a separate signature unique to MP tumors. Single-cell and spatial resolution approaches validated intratumoral heterogeneity and provided insight into subtype-specific microenvironmental contexts. Notably, [~]40% of URO tumors exhibited spatially distinct coexisting LLI and BL components. BL regions showed enrichment for angiogenesis and hypoxia pathways and were preferentially located near vascular stroma, while LLI regions showed to be located at the core of the tumor. MP tumors featured a markedly different microenvironment, characterized by diverse populations of cancer-associated fibroblasts (CAFs) and M2-polarized macrophages intermingled with tumor cells, suggesting a more immunosuppressive niche which could account for their worse clinical outcome. URO tumors, by comparison, showed a more immune-excluded phenotype. These findings provide a detailed molecular and spatial map of bladder cancer heterogeneity, highlighting how distinct epigenetic subtypes and histological variants are associated with tumor architecture and microenvironmental interactions. Our data underscore the need for subtype-specific therapeutic strategies to more effectively address the complexity already existing at HGT1 bladder cancer.

cancer biology↗

bioRxiv2025

Developing an anatomically valid segmentation protocol for anterior regions of the medial temporal lobe for neurodegenerative diseases

BackgroundThe anterior portion of the medial temporal lobe (MTL) is one of the first regions targeted by pathology in sporadic Alzheimers disease (AD) and Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) indicating a potential for metrics from this region to serve as imaging biomarkers. Leveraging a unique post-mortem dataset of histology and magnetic resonance imaging (MRI) scans we aimed to 1) develop an anatomically valid segmentation protocol for anterior entorhinal cortex (ERC), Brodmann Area (BA) 35, and BA36 for in vivo 3 tesla (T) MRI and 2) incorporate this protocol in an automated approach. MethodsWe included 20 cases (61-97 years old, 50% females) with and without neurodegenerative diseases (11 vs. 9 cases) to ensure generalizability of the developed protocol. Digitized MTL Nissl-stained coronal histology sections from these cases were annotated and registered to same-subject post-mortem MRI. The protocol was developed by determining the location of histological borders of the MTL cortices in relation to anatomical landmarks. Subsequently the protocol was applied to 15 cases twice, with a 2-week interval, to assess intra-rater reliability with the Dice Similarity Index (DSI). Thereafter it was implemented in our in- house Automatic Segmentation of Hippocampal Subfields (ASHS)-T1 approach and evaluated with DSIs. ResultsThe anterior histological border distances of ERC, BA35 and BA36 were evaluated with respect to various anatomical landmarks and the distance relative to the beginning of the hippocampus was chosen. To formulate segmentation rules, we examined the histological sections for the location of borders in relationship to anatomical landmarks in the coronal sections. The DSI for the anterior MTL cortices for the intra-rater reliability was 0.85-0.88 and for the ASHS-T1 against the manual segmentation was 0.62-0.65. DiscussionWe developed a reliable segmentation protocol and incorporated it in an automated approach. Given the vulnerability of the anterior MTL cortices to tau deposition in AD and LATE, the updated approach is expected to improve imaging biomarkers for these diseases.

neuroscience↗

bioRxiv2024

FAM162A is Crucial for Mitochondrial Structure, Dynamics, and Bioenergetics, Driving Cellular Protection and Longevity

IntroductionFAM162A is a mitochondrial protein evolutionarily conserved across taxa and ubiquitously expressed in various tissues. It is known for its role in hypoxia-induced apoptosis. However, paradoxically, FAM162A is overexpressed in cancer, where its pro-apoptotic function seems overridden, suggesting an alternative role associated with mitochondrial function and cell survival. Additionally, its precise localization and topology remain controversial. ObjectivesTo assess the role of FAM162A in mitochondrial structure, dynamics, and bioenergetics and its impact on cell viability, while establishing its precise localization, orientation, and topology. Additionally, to generate a transgenic Drosophila model overexpressing human FAM162A to evaluate its effects on organismal survival under normal and stress conditions. MethodsLocalization, orientation, and topology were determined by protease protection assays in COS7 cells. Loss-and gain-of-function experiments were performed to assess mitochondrial function and turnover by confocal microscopy, immunoblots and Seahorse technology. A transgenic Drosophila model overexpressing human FAM162A was generated to evaluate organismal survival under normal and stress conditions. ResultsFAM162A is essential for maintaining mitochondrial ultrastructure and bioenergetics, thereby influencing cell viability and stress resistance. Localization studies revealed that FAM162A resides predominantly in the inner mitochondrial membrane, particularly within the cristae, where it modulates the fusion protein OPA1. Transgenic Drosophila overexpressing human FAM162A exhibited increased lifespan and locomotor activity under both normal and heat stress conditions. ConclusionFAM162A emerges as a crucial player in maintaining mitochondrial integrity and bioenergetics. Its functional role, potentially mediated through interaction with OPA1, impacts mitochondrial health, stress resistance, cellular viability, and organismal longevity.

cell biology↗

bioRxiv2024

Comparative impact of porcine reproductive and respiratory virus and swine influenza A virus infections on respiratory lymph nodes B cells and macrophages.

Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) strongly impacts the pig rearing sector due to its persistence in infected animals. Interestingly, although the PRRSV family exhibits considerable genome variability, with the PRRSV-1 and PRRSV-2 subtypes having been finally classified in two different species (Betaarterivirus suid 1 and 2). Both viruses, as well as their derived-attenuated vaccine strains, persist for months, due in part to their ability to delay the appearance of neutralizing antibodies. Thanks to extensive efforts over the past years, we have developed the capability to perform in-depth analysis of the previously poorly understood porcine inverted lymph node (LN). In this study, by comparing the early stages of LN B cell maturation upon PRRSV-1 infection to those induced upon the acute swine influenza A virus infection, we highlighted PRRSV-specific mechanisms, including the expression of PD-L1 in efferent macrophages, the induction of extrafollicular plasmocytes, and the influx of inflammatory monocytes/macrophages. Studies on PRRSV-2 infections report observations compatible with our results, that thus might be generalized to all PRRSV-strains. Moreover, these mechanisms can be compared with those used by the human immunodeficiency virus (HIV) and the murine chronic lymphocytic choriomeningitis virus (LCMV) to hijack the immune response. These similarities can be harnessed to develop new strategies to improve the development of more efficient anti-PRRSV vaccines.

immunology↗

bioRxiv2024

Genetic and Epigenetic Characterization of Sarcoma Stem Cells Across Subtypes Identifies EZH2 as a Therapeutic Target

High-grade complex karyotype soft tissue sarcomas (STS) are a heterogeneous and aggressive set of cancers that share a common treatment strategy. Disease progression and failure to respond to anthracycline based chemotherapy, standard first-line treatment, is associated with poor patient outcomes. To address this, we investigated the contribution of STS cancer stem cells (STS-CSCs) to doxorubicin resistance. We identified a positive correlation between CSC abundance and doxorubicin IC50 in resistant cell lines. We investigated if a common genetic signature across STS-CSCs could be targeted. Utilizing patient derived samples from five sarcoma subtypes we identified Enhancer of Zeste homolog 2 (EZH2), a member of the polycomb repressive complex 2 (PRC2) responsible for H3K27 methylation as being enriched in the CSC population. EZH2 activity and a shared epigenetic profile was observed across subtypes. Targeting of EZH2 using Tazemetostat, an FDA approved inhibitor specifically ablated the STS-CSC population. Treatment of doxorubicin resistant cell lines with tazemetostat resulted in a decrease in the STS-CSC population. Further, co-treatment was not only synergistic in the parent cell lines, but restored chemosensitivity in doxorubicin resistant lines. These data confirm the presence of shared genetic programs across distinct subtypes of CSC-STS that can be therapeutically targeted.

cancer biology↗

bioRxiv2022

Characterization of Three Variants of SARS-CoV-2 in vivo Shows Host-Dependent Pathogenicity in Hamsters

Animal models are used in preclinical trials to test vaccines, antivirals, monoclonal antibodies, and immunomodulatory drug therapies against SARS-CoV-2. However, these drugs often do not produce equivalent results in human clinical trials. Here, we show how different animal models infected with some of the most clinically relevant SARS-CoV-2 variants, WA1/2020, B.1.617.2/Delta, B.1.1.529/Omicron and BA5.2/Omicron, have independent outcomes. We show that in mice, B.1.617.2 is more pathogenic, followed by WA1, while B.1.1.529 showed an absence of clinical signs. Only B.1.1.529 was able to infect C57BL/6J mice, which lack the human ACE2 receptor. B.1.1.529-infected ACE2 mice had different T cell profiles compared to infected K18-hACE2 mice, while viral shedding profiles and viral titers in lungs were similar between the ACE2 and the C57BL/6J mice. These data suggest B.1.1.529 virus adaptation to a new host and shows that asymptomatic carriers can accumulate and shed virus. Next, we show how B.1.617.2, WA1 and BA5.2/Omicron have similar viral replication kinetics, pathogenicity, and viral shedding profiles in hamsters, demonstrating that the increased pathogenicity of B.1.617.2 observed in mice is host-dependent. Overall, these findings suggest that small animal models are useful to parallel human clinical data, but the experimental design places an important role in interpreting the data. IMPORTANCEThere is a need to investigate SARS-CoV-2 variants phenotypes in different animal models due to the lack of reproducible outcomes when translating experiments to the human population. Our findings highlight the correlation of clinically relevant SARS-CoV-2 variants in animal models with human infections. Experimental design and understanding of correct animal models are essential to interpreting data to develop antivirals, vaccines, and other therapeutic compounds against COVID-19.

microbiology↗

bioRxiv2022

Discovering genomic regions associated with the phenotypic differentiation of European local pig breeds

BackgroundIntensive selection of modern pig breeds resulted in genetic improvement of productive traits while local pig breeds remained less performant. As they have been bred in extensive systems, they have adapted to specifical environmental conditions resulting in a rich genotypic and phenotypic diversity. This study is based on European local pig breeds genetically characterized using DNA-pool sequencing data and phenotypically characterized using breed level phenotypes related to stature, fatness, growth and reproductive performance traits. These data were analyzed using a dedicated approach to detect selection signatures linked to phenotypic traits in order to uncover potential candidate genes that may be under adaptation to specific environments. ResultsGenetic data analysis of European pig breeds revealed four main axes of genetic variation represented by Iberian and modern breeds (i.e. Large White, Landrace, and Duroc). In addition, breeds clustered according to their geographical origin, for example French Gascon and Basque breeds, Italian Apulo Calabrese and Casertana breeds, Spanish Iberian and Portuguese Alentejano breeds. Principal component analysis of phenotypic data distinguished between larger and leaner breeds with better growth potential and reproductive performance on one hand and breeds that were smaller, fatter, and had low growth and reproductive efficiency on the other hand. Linking selection signatures with phenotype identified 16 significant genomic regions associated with stature, 24 with fatness, 2 with growth and 192 with reproduction. Among them, several regions contained candidate genes with possible biological effect on stature, fatness, growth and reproduction performance traits. For example, strong associations were found for stature in two regions containing the ANXA4 and ANTXR1 genes, for fatness containing the DNMT3A and POMC genes and for reproductive performance containing the HSD17B7 gene. ConclusionsThe present study on European local pig breeds used a dedicated approach for searching selection signatures supported by phenotypic data at the breed level to identify potential candidate genes that may have adapted to different living environments and production systems. Results can be useful to define conservation programs of local pig breeds.

genetics↗

bioRxiv2020

FastMLST: A multi-core tool for multilocus sequence typing of draft genome assemblies

Multilocus Sequence Typing (MLST) is a precise microbial typing approach at the intra-species level for epidemiological and evolutionary purposes. It operates by assigning a sequence type (ST) identifier to each specimen, based on a combination of allelic sequences obtained for multiple housekeeping genes included in a defined scheme. The use of MLST has multiplied due to the availability of large numbers of genomic sequences and epidemiological data in public repositories. However, data processing speed has become problematic due to datasets massive size. Here, we present FastMLST, a tool that is designed to perform PubMLST searches using BLASTn and a divide-and-conquer approach. Compared to mlst, CGE/MLST, MLSTar, and PubMLST, FastMLST takes advantage of current multi-core computers to simultaneously type thousands of genome assemblies in minutes, reducing processing times by at least 16-fold and with more than 99.95% consistency. Availability and ImplementationThe source code, installation instructions and documentation are available at https://github.com/EnzoAndree/FastMLST

bioinformatics↗

bioRxiv2020

Prognostic significance of Substance P/ Neurokinin 1 receptor and its association with hormonal receptors in breast carcinoma

To evaluate the expression and Immunolocalization of Substance P (SP)/ Neurokinin-1 Receptor (NK-1R) in Breast Carcinoma (BC) patients and its association with routine proliferative markers (ER, PR, HER2/ neu and Ki-67). MethodsA cross-sectional study was performed on 34 cases of BC. There were 23 cases of group A (Grade III), 8 of group B (Grade II) and only 3 cases of group C (Grade I). Age range comprised of patients from 20-80 years and the mean age of patients was 45.74 years. HE, ER, PR, HER2 and Ki-67 staining was performed as routine biomarkers. Samples were then processed for immunomarkers study of Substance P and NK-1R immunohistochemistry was performed for few cases. Results14/23 cases (61%) of group A, 7/8 cases (88%) of group B and 2/3 (67%) cases of group C were SP positive. Overall, strong staining ([≥] 10% tumors cells), labeled as "3+", was observed in 9/14 (64.2%) cases of group A and 1/8 (12.5%) case of group B. Moderate staining labelled as "2+" (in [≥] 10% tumor cells) was observed in 3/14 (21.4%) cases of group A, 4/8 (50%) cases of group B. weak positive staining "1+" was observed in only 2/14 (14.28%) cases of group A, 2/8 (25%) cases of group B and all 2/2 (100%) cases of group C. ConclusionsSP and NK-1R is overexpressed in breast carcinomas and there is significant association between grade of tumor and their overexpression. It may serve as a novel biomarker for grading of BC. We also suggest that NK-1R antagonists as a potential therapeutic strategy to inhibit and manage BC. Key PointsO_LIImmunohistochemical expression of Substance P and Neurokinin 1 Receptor in breast carcinoma tissue was evaluated C_LIO_LIIt was strongly expressed in grade III, with maximum intensity C_LIO_LIIt may be investigated further for its role as prognostic and diagnostic marker C_LIO_LITherapeutic potential of Neurokinin-1 Receptor antagonists must be explored C_LI

pathology↗

bioRxiv2020

Comprehensive genome analyses of Sellimonas intestinalis, a potential biomarker of homeostasis gut recovery

Sellimonas intestinalis is a Gram positive and anaerobic bacterial species previously considered as uncultivable. Although little is known about this Lachnospiraceae family member, its increased abundance has been reported in patients who recovered intestinal homeostasis after dysbiosis events. In this context, the aim of this work was taken advantage of a culturomics protocol that allowed the recovery species extremely oxygen-sensitive from faecal samples, which led to the establishment of an S. intestinalis isolate. Whole genome sequencing and taxonomic allocation confirmation were the base to develop comparative analyses including 11 public genomes closely related. Phylogeographic analysis revealed the existence of three lineages (linage-I including isolates from Chile and France, linage-II from South Korea and Finland, and linage-III from China and one isolate from USA). Pangenome analysis on the established dataset revealed that although S. intestinalis seems to have a highly conserved genome (with 50.1% of its coding potential being part of the coregenome), some recombination signals were evidenced. The identification of cluster of orthologous groups revealed a high number of genes involved in metabolism, including amino acid and carbohydrate transport as well as energy production and conversion, which matches with the metabolic profile previously reported for healthy microbiota. Additionally, virulence factors and antimicrobial resistance genes were found (mainly in linage-III), which could favour their survival during antibiotic-induced dysbiosis. These findings provide the basis of knowledge about this species with potential as a bioindicator of intestinal homeostasis recovery and contribute to advance in the characterization of gut microbiota members with beneficial potential.

microbiology↗

bioRxiv2019

Lifetime changes in CD4 count, viral load suppression and adherence among adolescents living with HIV in urban Peru

IntroductionViral load suppression and adherence to combined antiretroviral therapy (cART) have been shown to be lower in adolescents than in other age groups; however, this relationship has not been documented longitudinally from childhood to adolescence and has rarely been examined outside of high-resource settings and sub-Saharan Africa. To address this knowledge gap, we quantified longitudinal changes in CD4 cell count, viral load suppression, and cART adherence in adolescents living with HIV in urban, Peru.\n\nMethodsWe conducted a retrospective chart review among adolescents ages 10-18 years on cART and receiving care at a large, public sector pediatric hospital as of December 2015. We abstracted clinical notes indicating nonadherence and viral load and CD4 counts from childhood to adolescence. We modeled the association between age and each outcome with restricted cubic splines accounting for multiple observations per person, and graphed study outcomes by age.\n\nResultsA median of 7.7 years (25th percentile=4.9, 75th percentile=10.2) of follow up were observed for 128 adolescents. Nearly 70% of patients had at least one nonadherence note and the proportion with nonadherence increased log-linearly with age (p<0.0001). The peak proportion with viral load suppression was 84% (95% CI: 79, 88) at age 13, which dropped to 67% (95% CI: 47, 83) by age 18. Mean CD4 count decreased at age 13, dropping from 723 cells/mm3 (95% CI: 666, 784) to 429 cells/mm3 (95% CI: 356, 517) by age 18.\n\nConclusionThis is the first report from Latin America to examine longitudinal changes in HIV outcomes from childhood into adolescence. Consistent with the limited evidence from other settings, decreases in viral load suppression and mean CD4 count occurred in early adolescence in tandem with increases in nonadherence. Adolescent-friendly cART adherence support interventions to target this critical period are urgently needed.

epidemiology↗