Biology subjects

Torres, J.

Publications and source records attributed to Torres, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Extracellular matrix mechanical cues (dys)regulate metabolic redox homeostasis due to impaired autophagic flux

Extracellular matrix (ECM) stiffness is increasingly recognized as a critical regulator of cellular behavior, governing processes such as proliferation, differentiation, and metabolism. Neurodegenerative diseases are characterized by mitochondrial dysfunction, oxidative stress, impaired autophagy, and progressive softening of the brain tissue, yet research into how mechanical cues influence cellular metabolism in this context remains scarce. In this study, we evaluated the long-term effects of brain-compliant, soft ECM on mitochondrial bioenergetics, redox balance, and autophagic capacity in neuronal cells. Using human neuroblastoma (SH-SY5Y) and mouse hippocampal (HT22) cell lines, as well as primary mouse neurons, we observed that prolonged exposure to soft ECM resulted in mitochondrial bioenergetic dysfunction, redox imbalance, and disrupted autophagic flux. These findings were consistently validated across both human and mouse neuronal cells. Our data indicate a decreased maximal autophagic capacity in cells exposed to long-term soft ECM, potentially due to an imbalance in autophagosome formation and degradation, as demonstrated by decreased LC3 II levels following chloroquine-induced autophagic flux inhibition. This impairment in autophagy was coupled with increased cellular oxidative stress, further indicating metabolic alterations. These findings emphasize the critical role of ECM stiffness in regulating neuronal cell metabolism and suggest that prolonged exposure to soft ECM may mimic key aspects of neurodegenerative disease pathology, thereby enhancing the physiological relevance of in vitro models. This study underscores the necessity for further research into ECM mechanics as a contributing factor in neurodegenerative disease progression and as a potential target for therapeutic strategies.

cell biology↗

bioRxiv2024

Neddylation regulates the development and function of excitatory neurons

The development and function of neurons is orchestrated by a plethora of regulatory mechanisms that control the abundance, localization, interactions, and function of proteins. A key role in this regard is assumed by post-translational protein modifications (PTMs). While some PTM types, such as phosphorylation or ubiquitination, have been explored comprehensively, PTMs involving ubiquitin-like modifiers (Ubls) have remained comparably enigmatic (Ubls). This is particularly true for the Ubl Nedd8 and its conjugation to proteins, i.e. neddylation, in nerve cells. In the present study, we generated a conditional Nedd8 knock-out mouse line and examined the consequences of Nedd8-deletion in cultured postmitotic glutamatergic neurons. Our findings reveal that Nedd8-ablation in young glutamatergic neurons causes alterations in the expression of developmental transcription factors that control neuronal differentiation, ultimately leading to defects in the development of a mature glutamatergic neuronal phenotype. Apparent manifestations of these defects include increased vGlut2 expression levels, reduced vGlut1 and endophilin 1 expression levels, reduced dendrite complexity, and increased transmitter release probability. Collectively, our results highlight a pivotal role for neddylation in controlling the fate of glutamatergic neurons and excitatory synaptic transmission. HighlightsO_LIReduced dendrite complexity in Nedd8-deficient neurons C_LIO_LIIncreased synaptic vesicle fusion probability in Nedd8-deficient neurons C_LIO_LIAltered synaptic vesicle cycling in Nedd8-deficient neurons C_LIO_LINeddylation controls the maturation of glutamatergic neurons C_LI Graphical AbstractResearch Topic

neuroscience↗

bioRxiv2024

Draft genome sequence of the glasshouse-potato aphid Aulacorthum solani

AO_SCPLOWBSTRACTC_SCPLOWAulacorthum solani is a worldwide agricultural pest aphid capable of feeding on a wide range of host plants. This insect causes mechanical damage to crops and is a vector of plant viruses. We found that the publicly available genome for A. solani is contaminated with another aphid species, and we produced a new genome using a barcoded isogenic laboratory line. We produced Oxford Nanopore and Illumina reads to generate a draft assembly, and we sequenced RNA to aid in the annotation of our assembly. Our A. solani draft genome is 671 Mbp containing 7,020 contigs with an N50 length of 196 kb with a BUSCO completeness of 98.6%. Out of the 24,981 genes predicted by E-GAPx, 22,804 were annotated with putative functions based on homology to other aphid species. This genome will provide a useful resource for the community of researchers studying aphids from agricultural and genomic perspectives.

genomics↗

bioRxiv2024

Composition of saliva metabolome is significantly associated with SARS-CoV2 infection and with severity of COVID-19 disease

BackgroundThe metabolome of COVID-19 patients has been studied sparsely, with most research focusing on a limited number of plasma metabolites or small cohorts. This is the first study to test saliva metabolites in COVID-19 patients in a comprehensive way, revealing significant changes linked to disease severity and highlighting saliva is potential as a non-invasive diagnostic tool. MethodsWe included 30 asymptomatic subjects with no prior COVID-19 infection or vaccination, 102 patients with mild SARS-CoV-2 infection, and 61 hospitalized patients with confirmed SARS-CoV-2 status. Saliva samples were analyzed using hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS/MS) in positive and negative ionization modes. ResultsSignificant changes in metabolites were identified in COVID-19 patients, with distinct patterns based on disease severity. Healthy individuals exhibited a well-regulated bacterial network, while severe cases showed disordered microbial networks. Elevated dipeptides such as Val-Glu and Met-Gln in moderate cases suggest specific protease activity related to SARS-CoV-2. Increased acetylated amino acids like N-Acetylserine and N-Acetylhistidine indicate potential biomarkers for stress and disease severity. Bacterial metabolites, including muramic acid and indole-3-carboxaldehyde, were higher in mild-moderate cases, indicating oral microbiota changes. In severe cases, polyamines and organ damage-related metabolites, such as N-acetylspermine and 3-methylcytidine, were significantly increased. Interestingly, metabolites reduced in moderate cases were elevated in severe cases. ConclusionsSaliva metabolomics offers insight into disease progression and potential biomarkers for COVID-19.

bioinformatics↗

bioRxiv2024

Profiling extremophile bacterial communities recovered from a mining tailing against soil ecosystems through comparative genome-resolved metagenomics and evolutionary analysis

Microbial communities inhabiting mining environments harbor a diverse array of bacteria with specialized metabolic capacities adapted to extreme conditions. Here, we utilized comparative genome-resolved metagenomics of a high-quality Illumina-sequenced sample from the Cauquenes copper tailing in central Chile. We investigate the metabolic roles and evolutionary behaviors of the resident microorganisms, focusing on capacities related to copper, iron, and sulfur metabolism. We recovered 44 medium and high-quality metagenome-assembled genomes (MAGs), primarily classified belonging to phylum Actinobacteriota (21), Proteobacteria (10), and Acidobacteriota (6). These MAGs were compared to the Global Soil MAGs project (SMAG catalog), which includes bacteria from conventional or natural ecosystems, to uncover specialized properties of mining bacteria. Notably, we discovered a new phylum, Nitrospirota_A, and provided insights into the unexplored taxonomic classifications at the lowest ranks such as genus and species. Functional potential analysis revealed that the mining community has enhanced molecular capabilities associated with sulfur and copper metabolism. Evolutionary analysis revealed that mining genes involved in targeted metabolism are under strong negative selection, indicating conservative evolutionary pressure within the mining environment. In particular, it was possible to identify a MAG from the genus Acidithrix with a global dN/dS ratio greater than 1, suggesting positive selection. Additionally, core proteins essential for bacterial survival, such as flagellar motors, cell cycle regulators, and biogenesis proteins, were also under positive selection. The latter points to the need for enhanced mobility in these microorganisms to locate resources efficiently. We demonstrate that copper mining communities are diverse and possess a significant metabolic repertoire under extreme conditions in sulfur and copper proteins. Those specialized genes appear to be in a conservative state rather than undergoing adaptive evolution. This study enhances our understanding of extremophile mining microbiomes, highlighting their high variability in classification, metabolic functions, evolution, and adaptation, which can be leveraged for further biotechnological applications.

genomics↗

bioRxiv2024

An application of the MR-Horse method to reduce selection bias in genome-wide association studies of disease progression

Genome-wide association studies (GWAS) of disease progression are vulnerable to collider bias caused by selection of participants with disease at study entry. This bias introduces spurious associations between disease progression and genetic variants that are truly only associated with disease incidence. Methods of statistical adjustment to reduce this bias have been published, but rely on assumptions regarding the genetic correlation of disease incidence and disease progression which are likely to be violated in many human diseases. MR-Horse is a recently published Bayesian method to estimate the parameters of a general model of genetic pleiotropy in the setting of Mendelian Randomisation. We adapted this method to provide bias-reduced GWAS estimates of associations with disease progression, robust to the genetic correlation of disease incidence and disease progression and robust to the presence of pleiotropic variants with effects on both incidence and progression. We applied this adapted method to simulated GWAS of disease incidence and progression with pleiotropic variants and varying degrees of genetic correlation. When significant genetic correlation was present, the MR-Horse method produced less biased estimates than unadjusted analyses or analyses adjusted using other existing methods. Type 1 error rates with the MR-Horse method were consistently below the nominal 5% level, at the expense of a modest reduction in power. We then applied this method to summary statistics from the CKDGen consortium GWAS of kidney function decline. MR-Horse attenuated the effects of variants with known likely biased effects in the CKDGen GWAS, whilst preserving effects at loci with likely true effects.

genetics↗

bioRxiv2024

Repeat modules and N-linked glycans define structure and antigenicity of a critical enterotoxigenic E. coli adhesin

Enterotoxigenic Escherichia coli (ETEC) cause hundreds of millions of cases of infectious diarrhea annually, predominantly in children from low-middle income regions. Notably, in children, as well as human volunteers challenged with ETEC, diarrheal severity is significantly increased severity in blood group A (bgA) individuals. EtpA, is a secreted glycoprotein adhesin that functions as a blood group A lectin to promote critical interactions between ETEC and blood group A glycans on intestinal epithelia for effective bacterial adhesion and toxin delivery. EtpA is highly immunogenic resulting in robust antibody responses following natural infection and experimental challenge of human volunteers with ETEC. To understand how EtpA directs ETEC-blood group A interactions and stimulates adaptive immunity, we mutated EtpA, mapped its glycosylation by mass-spectrometry (MS), isolated polyclonal (pAbs) and monoclonal antibodies (mAbs) from vaccinated mice and ETEC-infected human volunteers, and determined structures of antibody-EtpA complexes by cryo-electron microscopy. Both bgA and mAbs that inhibited EtpA-bgA interactions and ETEC adhesion, bound to the C-terminal repeat domain highlighting this region as crucial for ETEC pathogen-host interaction. MS analysis uncovered extensive and heterogeneous N-linked glycosylation of EtpA and cryo-EM structures revealed that mAbs directly engage these unique glycan containing epitopes. Finally, electron microscopy-based polyclonal epitope mapping revealed antibodies targeting numerous distinct epitopes on N and C-terminal domains, suggesting that EtpA vaccination generates responses against neutralizing and decoy regions of the molecule. Collectively, we anticipate that these data will inform our general understanding of pathogen-host glycan interactions and adaptive immunity relevant to rational vaccine subunit design. Author summaryEnterotoxigenic E. coli (ETEC), a leading cause of diarrhea disproportionately affecting young children in low-income regions, are a priority for vaccine development. Individuals possessing A blood-type are more susceptible to severe cholera-like disease. EtpA, a secreted, immunogenic, blood group A binding protein, is a current vaccine target antigen. Here, we determined the atomic structure of EtpA in complex with protective as well as non-protective monoclonal antibodies targeting two different domains of the protein, allowing us to pinpoint key regions involved in blood-group A antigen recognition and uncover the mechanism of antibody-based protection. In addition, we show through mass-spectrometry that EtpA is extensively and heterogeneously glycosylated at surface-exposed asparagine residues by a promiscuous and low-fidelity glycosyltransferase, EtpC, and that this unique form of bacterial glycosylation is critical for to development of protective immune responses. Lastly, polyclonal antibodies from vaccinated mice as well as monoclonal antibodies obtained from ETEC-infected human volunteers revealed that the highly antigenic surface of EtpA exhibits both protective and non-protective epitopes. These results greatly expand our understanding of ETEC pathogenesis, and the immune responses elicited by these common infections, providing valuable information to aid in the rational design and testing of subunit vaccines.

microbiology↗

bioRxiv2024

The transcriptional regulator Lrp activates the expression of genes involved in tilivalline enterotoxin biosynthesis in Klebsiella oxytoca

The toxigenic Klebsiella oxytoca strains secret the tilivalline enterotoxin, which causes antibiotic-associated hemorrhagic colitis. The tilivalline is a non-ribosomal peptide synthesized by enzymes encoded in two divergent operons clustered in a pathogenicity island. The transcriptional regulator Lrp (leucine-responsive regulatory protein) controls the expression of several bacterial genes involved in virulence. In this work, we determined the transcriptional expression of aroX and npsA, the first genes of each tilivalline biosynthetic operon in K. oxytoca MIT 09-7231 wild-type and its derivatives {Delta}lrp mutant and complemented strains. The results show that Lrp directly activates the transcription of both aroX and npsA genes by binding to the intergenic regulatory region in a leucine-dependent manner. Furthermore, the lack of Lrp significantly diminished the cytotoxicity of K. oxytoca on HeLa cells due to tilivalline reduced production. Altogether, our data highlight Lrp as a new regulator by which cytotoxin-producing K. oxytoca strains control the expression of genes involved in the biosynthesis of their main virulence factor. IMPORTANCETilivalline is an enterotoxin that is a hallmark for the cytotoxin-producing K. oxytoca strains, which cause antibiotic-associated hemorrhagic colitis. The biosynthesis of tilivalline is driven by enzymes encoded by the aroX- and NRPS-operons. In this study, we discovered that the transcriptional regulator Lrp directly activates expression of the aroX- and NRPS-operons and, in turn, tilivalline biosynthesis. Our results underscore a molecular mechanism by which tilivalline production by toxigenic K. oxytoca strains is regulated and shed further light on developing strategies to prevent the intestinal illness caused by this enteric pathogen.

molecular biology↗

bioRxiv2023

Fast and efficient root phenotyping via pose estimation

Image segmentation is commonly used to estimate the location and shape of plants and their external structures. Segmentation masks are then used to localize landmarks of interest and compute other geometric features that correspond to the plants phenotype. Despite its prevalence, segmentation-based approaches are laborious (requiring extensive annotation to train), and error-prone (derived geometric features are sensitive to instance mask integrity). Here we present a segmentation-free approach which leverages deep learning-based landmark detection and grouping, also known as pose estimation. We use a tool originally developed for animal motion capture called SLEAP (Social LEAP Estimates Animal Poses) to automate the detection of distinct morphological landmarks on plant roots. Using a gel cylinder imaging system across multiple species, we show that our approach can reliably and efficiently recover root system topology at high accuracy, few annotated samples, and faster speed than segmentation-based approaches. In order to make use of this landmark-based representation for root phenotyping, we developed a Python library (sleap-roots) for trait extraction directly comparable to existing segmentation-based analysis software. We show that landmark-derived root traits are highly accurate and can be used for common downstream tasks including genotype classification and unsupervised trait mapping. Altogether, this work establishes the validity and advantages of pose estimation-based plant phenotyping. To facilitate adoption of this easy-to-use tool and to encourage further development, we make sleap-roots, all training data, models, and trait extraction code available at: https://github.com/talmolab/sleap-roots and https://osf.io/k7j9g/.

plant biology↗

bioRxiv2023

A deep catalog of protein-coding variation in 985,830 individuals

Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants. Individuals of African, Admixed American, East Asian, Middle Eastern, and South Asian ancestry account for 20% of this Exome dataset. Our catalog of variants includes approximately 10.5 million missense (54% novel) and 1.1 million predicted loss-of-function (pLOF) variants (65% novel, 53% observed only once). We identified individuals with rare homozygous pLOF variants in 4,874 genes, and for 1,838 of these this work is the first to document at least one pLOF homozygote. Additional insights from the RGC-ME dataset include 1) improved estimates of selection against heterozygous loss-of-function and identification of 3,459 genes intolerant to loss-of-function, 83 of which were previously assessed as tolerant to loss-of-function and 1,241 that lack disease annotations; 2) identification of regions depleted of missense variation in 457 genes that are tolerant to loss-of-function; 3) functional interpretation for 10,708 variants of unknown or conflicting significance reported in ClinVar as cryptic splice sites using splicing score thresholds based on empirical variant deleteriousness scores derived from RGC-ME; and 4) an observation that approximately 3% of sequenced individuals carry a clinically actionable genetic variant in the ACMG SF 3.1 list of genes. We make this important resource of coding variation available to the public through a variant allele frequency browser. We anticipate that this report and the RGC-ME dataset will serve as a valuable reference for understanding rare coding variation and help advance precision medicine efforts.

genetics↗

bioRxiv2022

Absolute scattering length density profile of liposome bilayers obtained by SAXS combined with GIXOS - a tool to determine model biomembrane structure

Lipid membranes play an essential role in biology, acting as host matrices for biomolecules like proteins and facilitating their functions. Their structures, and structural responses to physiologically relevant interactions, i.e. with membrane proteins, provide key information for understanding biophysical mechanisms. Hence, there is a crucial need of methods to understand the effects of membrane host molecules on the lipid bilayer structure. Here, we present a purely experimental method for obtaining the absolute scattering length density (SLD) profile and the area per lipid of liposomal bilayers, by aiding the analysis of small angle X-ray scattering (SAXS) data with the volume of bare headgroups obtained from fast (20-120s) grazing incidence off-specular scattering (GIXOS) data from monolayers of the same model membrane lipid composition. The GIXOS data experimentally demonstrate that the variation of the bare headgroup volume upon lipid packing density change is small enough to allow its usage as a reference value without knowing the lipid packing stage in a bilayer. This approach also bares the advantage that the reference volume is obtained at the same aqueous environment as used for the model membrane bilayers. We demonstrate the validity of this method using several typical membrane compositions, as well as one example of a phospholipid membrane with an incorporated transmembrane peptide. This methodology allows to obtain absolute scale values rather than relative scale by using solely X-ray-based instrumentation, retaining a similar resolution of SAXS experiments. The presented method has high potential to understand structural effects of membrane proteins on the biomembrane structure.

biophysics↗

bioRxiv2022

Anti-integrin αvβ6 autoantibodies are a novel predictive biomarker in ulcerative colitis

Background and AimsBetter biomarkers for prediction of ulcerative colitis (UC) development and prognostication are needed. Anti-integrin v{beta}6 autoantibodies (anti-v{beta}6) have been described in UC patients. Here, we tested for the presence of anti-v{beta}6 antibodies in the pre-clinical phase of UC and studied their association with disease-related outcomes after diagnosis. MethodsAnti-v{beta}6 were measured in 4 longitudinal serum samples collected from 82 subjects who later developed UC and 82 matched controls from a Department of Defense pre-clinical cohort (PREDICTS). In a distinct, external validation cohort (GEM), we tested 12 pre-UC subjects and 49 matched controls. Further, anti-v{beta}6 were measured in 2 incident UC cohorts (COMPASS n=55 and OSCCAR n=104) and associations between anti-v{beta}6 and UC-related outcomes were defined using Cox proportional-hazards model. ResultsAnti-v{beta}6 were significantly higher among individuals who developed UC compared to controls up to 10 years before diagnosis in PREDICTS. The anti-v{beta}6 seropositivity was 12.2% 10 years before diagnosis and increased to 52.4% at the time of diagnosis in subjects who developed UC compared with 2.7% in controls across the 4 timepoints. Anti-v{beta}6 predicted UC development with an AUC of at least 0.8 up to 10 years before diagnosis. The presence of anti-v{beta}6 in pre-clinical UC samples was validated in the GEM cohort. Finally, high anti-v{beta}6 was associated with a composite of adverse UC-outcomes including hospitalization, disease extension, colectomy, systemic steroid use and/or escalation to biologic therapy in recently diagnosed UC. ConclusionAnti-integrin v{beta}6 auto-antibodies precede the clinical diagnosis of UC by up to 10 years and are associated with adverse UC-related outcomes.

immunology↗

bioRxiv2022

Diversity, composition, and networking of saliva microbiota distinguish the severity of COVID-19 episodes as revealed by an analysis of 16S rRNA variable V1-V3 regions sequences

BackgroundStudies on the role of the oral microbiome in SARS-CoV-2 infection and severity of the disease are limited. We aimed to characterize the bacterial communities present in the saliva of patients with varied COVID-19 severity to learn if there are differences in the characteristics of the microbiome among the clinical groups. MethodsWe included asymptomatic subjects with no previous COVID-19 infection or vaccination; patients with mild respiratory symptoms, positive or negative for SARS-CoV-2 infection; patients that required hospitalization because of severe COVID-19 with oxygen saturation below 92%, and fatal cases of COVID-19. Saliva samples collected before any treatment were tested for SARS-CoV-2 by PCR. Oral microbiota in saliva was studied by amplification and sequencing of the V1-V3 variable regions of 16S gene using a Illumina MiSeq platform. ResultsWe found significant changes in diversity, composition, and networking in saliva microbiota of patients with COVID-19, as well as patterns associated with severity of disease. The presence or abundance of several commensal species and opportunistic pathogens were associated with each clinical stage. Patterns of networking were also found associated with severity of disease: a highly regulated bacterial community (normonetting) was found in healthy people whereas poorly regulated populations (disnetting) were characteristic of severe cases. ConclusionsCharacterization of microbiota in saliva may offer important clues in the pathogenesis of COVID-19 and may also identify potential markers for prognosis in the severity of the disease. Importance of the workSARS-CoV-2 infection is the most severe pandemic of humankind in the last hundred years. The outcome of the infection ranges from asymptomatic or mild to severe and even fatal cases, but reasons for this remain unknown. Microbes normally colonizing the respiratory tract form communities that may mitigate the transmission, symptoms, and severity of viral infections, but very little is known on the role of these microbial communities in the severity of COVID-19. We aimed to characterize the bacterial communities in saliva of patients with different severity of COVID-19 disease, from mild to fatal cases. Our results revealed clear differences in the composition and in the nature of interactions (networking) of the bacterial species present in the different clinical groups and show community-patterns associated with disease severity. Characterization of the microbial communities in saliva may offer important clues to learn ways COVID-19 patients may suffer from different disease severities.

microbiology↗

bioRxiv2022

Genotyping, sequencing and analysis of 140,000 adults from the Mexico City Prospective Study

The Mexico City Prospective Study (MCPS) is a prospective cohort of over 150,000 adults recruited two decades ago from the urban districts of Coyoacan and Iztapalapa in Mexico City. We generated genotype and exome sequencing data for all individuals, and whole genome sequencing for 10,000 selected individuals. We uncovered high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Native American, European and African ancestry, with extensive admixture from indigenous groups in Central, Southern and South Eastern Mexico. Native Mexican segments of the genome had lower levels of coding variation, but an excess of homozygous loss of function variants compared with segments of African and European origin. We estimated population specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Native Mexico at exome variants, all available via a public browser. Using whole genome sequencing, we developed an imputation reference panel which outperforms existing panels at common variants in individuals with high proportions of Central, South and South Eastern Native Mexican ancestry. Our work illustrates the value of genetic studies in populations with diverse ancestry and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States where the Hispanic/Latino population is predominantly of Mexican descent.

genetics↗

bioRxiv2022

CD4 binding-site antibodies induced by a subtype B HIV-1 envelope trimer

In the last decade considerable advances have been made towards the design of HIV-1 vaccines that induce neutralizing antibodies (NAbs). Despite the progress, no vaccine is able to consistently elicited broadly neutralizing antibodies (bNAbs). Here we present a case study of a rabbit that was immunized with a subtype B native like envelope glycoprotein (Env) trimer, AMC016 SOSIP.v4.2, with a dense and intact glycan shield, followed by a trivalent combination of subtype B trimers. After the priming phase serum from this animal neutralized several heterologous subtype B neutralization resistant (tier 2) viruses. Subsequent immunization with the trivalent combination of subtype B trimers further increased the breadth and potency of the NAb response. EM based polyclonal epitope mapping revealed that a cross reactive CD4 binding-site (CD4bs) antibody response, that was present after priming with the monovalent trimer and boosting with the trivalent combination, was most likely responsible for the broad neutralization. While anecdotal, this study provides proof-of-concept that native-like Env trimers are capable of inducing CD4bs-directed bNAb responses and should guide efforts to improve the consistency with which such responses are generated.

immunology↗

bioRxiv2022

The Intrinsically Disordered Region of Coronins Fine-tunes Oligomerization and Actin Polymerization

Coronins are highly conserved actin-binding proteins (ABPs) in the eukaryotic kingdom for polymerizing actin cytoskeleton. The biochemical activity of coronins is primarily mediated by the structural N-terminal {beta}-propeller and the C-terminal helical coiled-coil (CC) domains, but less is known about the function of a middle nonconserved region, the "unique region (UR)". The coronin UR is an intrinsically disordered region (IDR). Herein, we demonstrate that the low complexity of the UR is a conserved signature of the coronin protein family, and the UR/IDR exhibits a striking evolutionary correlated pattern associated with sequence length. By analyzing the role of the IDR in coronins via coarse-grained simulations, we reveal that evolutionary selection of IDR length is coupled with the oligomerization of IDR-containing proteins (IDPs) to provide optimal functional output. By integrating biochemical and cell biology experiments and protein engineering, we found that the IDR regulates Crn1 biochemical activity, both in vivo and in vitro, by fine-tuning CC domain oligomerization and maintaining Crn1 in a tetrameric state. The IDR-guided optimization of Crn1 oligomerization is critical for Arp2/3-mediated actin polymerization.

cell biology↗

bioRxiv2021

Selective pressure on membrane proteins drives the evolution of Helicobacter pylori Colombian subpopulations

Helicobacter pylori have coevolved with mankind since its origins, adapting to different human groups. In America H. pylori has evolved in several subpopulations specific for regions or even countries. In this study we analyzed the genome of 163 Colombian strains along with 1,113 strains that represent worldwide H. pylori populations to better discern the ancestry and adaption to Colombian people. Population structure was inferred with FineStructure and chromosome painting identifying the proportion of ancestries in Colombian isolates. Phylogenetic relationship was analyzed using the SNPs present in the core genome. Also, a Fst analysis was done to identify the gene variants with the strongest fixation in the identified Colombian subpopulations in relation to their parent population hspSWEurope. Worldwide, population structure analysis allowed the identification of two Colombian subpopulations, the previously described hspSWEuropeColombia and a novel subpopulation named hspColombia. In addition, three subgroups of H. pylori were identified within hspColombia that follow their geographic origin. The Colombian H. pylori subpopulations represent an admixture of European, African and Native indigenous ancestry; although some genomes showed a high proportion of self-identity, suggesting a strong adaption to these mestizo Colombian groups. The Fst analysis identified 82 SNPs significantly fixed in 26 genes of the hspColombia subpopulation that encode mainly for outer membrane proteins and proteins involved in central metabolism. The strongest fixation indices were identified in genes encoding the membrane proteins HofC, HopE, FrpB-4 and Sialidase A. These findings demonstrate that H. pylori has evolved in Colombia to give rise to subpopulations following a geographical structure, evolving to an autochthonous genetic pool, drive by a positive selective pressure especially on genes encoding for outer membrane proteins.

genomics↗

bioRxiv2021

Copy number alterations and epithelial-mesenchymal transition genes in diffuse and intestinal gastric cancers in Mexican patients

Gastric cancer (GC) is a malignancy with the highest mortality among diseases of the digestive system worldwide. The study of GC-alterations is crucial to understand tumor biology, to establish important aspects of cancer prognosis and treatment response. Here, we purified DNA and performed whole-genome analysis with high-density arrays in samples from Mexican patients diagnosed with GC: diffuse (DGC) or intestinal (IGC), or non-atrophic gastritis (NAG) samples that served as controls. We identified shared and unique copy number alterations (CNA) between these altered tissues involving key genes and signaling pathways associated with cancer, allowing their molecular distinction and identification of the most relevant molecular functions impacted. When focused on epithelial-mesenchymal transition (EMT) genes, our bioinformatic analysis revealed that the altered network associated with chromosomal alterations included 11 genes shared between DGC, IGC, and NAG, as well as 19 DGC- and 7 IGC-exclusive genes, whose main molecular functions included adhesion, angiogenesis, migration, metastasis, morphogenesis, proliferation, and survival. This study presents the first whole-genome high-density array study in GC from Mexican patients and reveals shared and exclusive CNA-genes in DGC and IGC. In addition, we provide a bioinformatically predicted network focused on CNA-altered genes involved in the EMT, associated with the hallmarks of cancer, as well as precancerous alterations that could lead to gastric cancer. ImplicationsMolecular signatures of diffuse and intestinal GC, predicted bioinformatically, involve common and distinct CNA-EMT genes related to the hallmarks of cancer that are potential candidates for screening GC biomarkers, including early stages.

cancer biology↗