Biology subjects

Perez, J.

Publications and source records attributed to Perez, J..

30 records · Page 2Linked to original sources

bioRxiv2022

Separating the effects of sex hormones and sex chromosomes on behavior in the African pygmy mouse Mus minutoides, a species with XY female sex reversal.

In mammals, most sex differences in phenotype are controlled by gonadal hormones, but recent work on transgenic mice have shown that sex chromosomes can have a direct influence on sex-specific behaviors. In this study, we take advantage of the naturally occurring sex reversal in a mouse species, Mus minutoides, to investigate for the first time the relationship between sex chromosomes, hormones and behaviors in a wild species. In this model, a feminizing variant of the X chromosome, named X*, produces three types of females with different sex chromosome complements (XX, XX*, and X*Y), associated with alternative behavioral phenotypes, while all males are XY. We thus compared the levels of three major circulating steroid hormones (testosterone, corticosterone and estradiol) in the four sex genotypes to disentangle the influence of sex chromosomes and sex hormones on behavior. First, we did not find any difference in testosterone levels in the three female genotypes, although X*Y females are notoriously more aggressive. Second, in agreement with their lower anxiety-related behaviors, X*Y females and XY males display lower baseline corticosterone concentration than XX and XX* females. Instead of a direct hormonal influence, this result rather suggests that sex chromosomes may have an impact on the baseline corticosterone level, which in turn may influence behaviors. Third, estradiol concentrations do not explain the enhanced reproductive performance and maternal care behavior of the X*Y females compared to the XX and XX* females. Overall, this study highlights that most of the behaviors varying along with sex chromosome complement of this species are driven by genetic factors rather than steroid hormone concentrations.

evolutionary biology↗

bioRxiv2022

Heterologous Expression of NoxA Confers Aerotolerance in Clostridium sporogenes

Clostridium is a genus of Gram-positive obligate anaerobic bacteria. Some species of Clostridium, including C. sporogenes, may be of use in bacteria-mediated cancer therapy. Spores of Clostridium are inert in healthy normoxic tissue, but germinate when in the hypoxic regions of solid tumors, causing tumor regression. However, such treatments fail to completely eradicate tumors because of higher oxygen levels rise at the tumors outer rim. In this study, we demonstrate that a degree of aerotolerance can be introduced to C. sporogenes by transfer of the noxA gene from C. aminovalericum. NoxA is a water-forming NADH oxidase enzyme. Thus, its activity has no detrimental effect on cell viability. In addition to its potential in cancer treatment, the noxA-expressing strain described here could be used to alleviate challenges related to oxygen sensitivity of C. sporogenes in biomanufacturing.

microbiology↗

bioRxiv2022

Genotypic sex shapes maternal care in the African Pygmy mouse, Mus minutoides

AO_SCPLOWBSTRACTC_SCPLOWSexually dimorphic behaviours, such as parental care, have long been thought to be driven mostly, if not exclusively, by gonadal hormones. In the past two decades, a few studies have challenged this view, highlighting the direct influence of the sex chromosome complement (XX vs XY or ZZ vs ZW). The African pygmy mouse, Mus minutoides, is a wild mouse species with naturally occurring XY sex reversal induced by a third, feminizing X* chromosome, leading to three female genotypes: XX, XX* and X*Y. Here, we show that sex reversal in X*Y females shapes a divergent maternal care strategy from both XX and XX* females, rather than altering care quality. In addition, we show that sex reversal may also impact the dopaminergic system in the anteroventral periventricular nucleus of the hypothalamus, consistent with one component of maternal care: pup retrieval. Combining behavioural ecology and neurobiology in a rodent subject to natural selection, we evaluate potential candidates for the neural basis of maternal behaviours and strengthen the underestimated role of the sex chromosomes in shaping sex differences in brain and behaviours. All things considered, we further highlight the emergence of a third sexual phenotype, challenging the binary view of phenotypic sexes.

evolutionary biology↗

bioRxiv2021

Multiple Sex Chromosome Drivers in a Mammal with Three Sex Chromosomes

A few mammals have unusual sex determining systems whereby fertile XY females live alongside XX females and XY males. These systems are regarded as evolutionary paradoxes because of the production of sex-reversed individuals and non-viable embryos, but they nevertheless seem stable over evolutionary time. Several hypotheses have been proposed to account for their stability, including models involving sex chromosome drive (i.e., biased transmission of sex chromosomes to the next generation). Here we corroborate this hypothesis in Mus minutoides, a close relative of the house mouse in which the presence of XY females is due to the evolution of a third sex chromosome: a feminizing X. Through extensive molecular sexing of pups at weaning, we reveal the existence of a remarkable male sex chromosome drive system in this species, whereby direction and strength of drive is conditional upon the genotype of males partners: males transmit their Y to almost 80% of their offspring when mating with XX females, and only 36% when mating with XY females. Using mathematical modelling, we explore the joint evolution of these unusual sex-determining and drive systems, revealing that different sequences of events could have led to the evolution of this bizarre system, and that the "conditional" nature of sex chromosome drive stabilizes the feminizing X, and even precludes a return to a standard XX/XY system.

evolutionary biology↗

bioRxiv2021

Timing of transcriptomic peripheral blood mononuclear cell responses of sheep to Fasciola hepatica infection differs from those of cattle, reflecting different disease phenotypes

Infection with the zoonotic trematode Fasciola hepatica, common in many regions with a temperate climate, leads to delayed growth and loss of productivity in cattle, while infection in sheep can have more severe effects, potentially leading to death. Previous transcriptomic analyses revealed upregulation of TGFB1, cell death and Toll-like receptor signalling, T-cell activation, and inhibition of nitric oxide production in macrophages in response to infection. However, the differences between ovine and bovine responses have not yet been explored. The objective of this study was to further investigate the transcriptomic response of ovine peripheral blood mononuclear cells (PBMC) to F. hepatica infection, and to elucidate the differences between ovine and bovine PBMC responses. Sixteen male Merino sheep were randomly assigned to infected or control groups (n = 8 per group) and orally infected with 120 F. hepatica metacercariae. Transcriptomic data was generated from PBMC at 0, 2 and 16 weeks post-infection (wpi), and analysed for differentially expressed (DE) genes between infected and control animals at each time point (analysis 1), and for each group relative to time 0 (analysis 2). Analysis 2 was then compared to a similar study performed previously on bovine PBMC. A total of 453 DE genes were found at 2 wpi, and 2 DE genes at 16 wpi (FDR < 0.1, analysis 1). Significantly overrepresented biological pathways at 2 wpi included role of PKR in interferon induction and anti-viral response, death receptor signalling and RIG-I-like receptor signalling, which suggested that an activation of innate response to intracellular nucleic acids and inhibition of cellular apoptosis were taking place. Comparison of analysis 2 with the previous bovine transcriptomic study revealed that anti-inflammatory response pathways which were significantly overrepresented in the acute phase in cattle, including IL-10 signalling, Th2 pathway, and Th1 and Th2 activation were upregulated only in the chronic phase in sheep. We propose that the earlier activation of anti-inflammatory responses in cattle, as compared with sheep, may be related to the general absence of acute clinical signs in cattle. These findings offer scope for "smart vaccination" strategies for this important livestock parasite.

immunology↗

bioRxiv2021

Endomembrane targeting of human OAS1 p46 augments antiviral activity

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from host cell innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense viral RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flavivirus, picornavirus, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform strongly associates with COVID-19 severity. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests early control of SARS-CoV-2 replication through OAS1-p46 is an important determinant of COVID-19 severity.

immunology↗

bioRxiv2020

Fibroblasts as an Alternative to Mesenchymal Stem Cells with Successful Treatment and Immune Modulation in EAE Model of Multiple Sclerosis

The immune modulatory potential of mesenchymal stem cells (MSCs) is well known and is the basis for multiple clinical trials in treatment of autoimmune conditions. Unfortunately, MSCs are relatively rare, difficult to expand in culture, and methods of obtaining MSCs are complicated and expensive. In contrast, fibroblasts are found in copious amounts in various tissues, are a robust cellular population, and can be cultured without need for costs associated with culture media. Previous studies by our group and others have demonstrated fibroblasts possess regenerative activities. In the current study we demonstrated: a) fibroblasts inhibit mixed lymphocyte reaction; b) suppress T cell activation; c) inhibit DC maturation; and d) stimulate T regulatory (Treg) cell formation. Importantly, administration of fibroblasts in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis resulted in disease inhibition, which was abrogated upon depletion of Treg cells. This data, combined with existing clinical safety data on fibroblast administration, supports the clinical translation of fibroblast-based therapies for multiple sclerosis.

immunology↗

bioRxiv2019

Disentangling the Effects of Asymmetry, Shape Fluctuations, Disorder, and Atomic Details on SAXS Curves of Soft Matter Complexes

Small-angle X-ray scattering (SAXS) is a widely used experimental technique, providing structural and dynamic insight into soft-matter complexes and biomolecules under near-native conditions. However, interpreting the one-dimensional scattering profiles in terms of three-dimensional structures and ensembles remains challenging, partly because it is poorly understood how structural information is encoded along the measured scattering angle. We combined all-atom SAXS-restrained ensemble simulations, simplified continuum models, and SAXS experiments of a n-dodecyl-{beta}-D-maltoside (DDM) micelle to decipher the effects of model asymmetry, shape fluctuations, atomic disorder, and atomic details on SAXS curves. Upon interpreting the small-angle regime, we find remarkable agreement between (i) a two-component tri-axial ellipsoid model fitted against the data with (ii) a SAXS-refined all-atom ensemble. However, continuum models fail at wider angles, even if they account for shape fluctuations, disorder, and asymmetry of the micelle. We conclude that modelling atomic details is mandatory for explaining SAXS curves at wider angles.

biophysics↗

bioRxiv2019

The TMEM106B rs1990621 protective variant is also associated with increased neuronal proportion

BackgroundIn previous studies, we observed decreased neuronal and increased astrocyte proportions in AD cases in parietal brain cortex by using a deconvolution method for bulk RNA-seq. These findings suggested that genetic risk factors associated with AD etiology have a specific effect in the cellular composition of AD brains. The goal of this study is to investigate if there are genetic determinants for brain cell compositions.\n\nMethodsUsing cell type composition inferred from transcriptome as a disease status proxy, we performed cell type association analysis to identify novel loci related to cellular population changes in disease cohort. We imputed and merged genotyping data from seven studies in total of 1,669 samples and derived major CNS cell type proportions from cortical RNAseq data. We also inferred RNA transcript integrity number (TIN) to account for RNA quality variances. The model we performed in the analysis was: normalized neuronal proportion [~] SNP + Age + Gender + PC1 + PC2 + median TIN.\n\nResultsA variant rs1990621 located in the TMEM106B gene region was significantly associated with neuronal proportion (p=6.40x10-07) and replicated in an independent dataset. The association became more significant as we combined both discovery and replication datasets in multi-tissue meta-analysis (p=9.42x10-09) and joint analysis (p=7.66x10-10). This variant is in high LD with rs1990622 (r2 = 0.98) which was previously identified as a protective variant in FTD cohorts. Further analyses indicated that this variant is associated with increased neuronal proportion in participants with neurodegenerative disorders, not only in AD cohort but also in cognitive normal elderly cohort. However, this effect was not observed in a younger schizophrenia cohort with a mean age of death < 65. The second most significant loci for neuron proportion was APOE, which suggested that using neuronal proportion as an informative endophenotype could help identify loci associated with neurodegeneration.\n\nConclusionThis result suggested a common pathway involving TMEM106B shared by aging groups in the present or absence of neurodegenerative pathology may contribute to cognitive preservation and neuronal protection.

neuroscience↗

bioRxiv2019

Global transcriptome analysis of the Myxococcus xanthus multicellular developmental program

The bacteria Myxococcus xanthus exhibit a complex multicellular life cycle. In the presence of nutrients, cells prey cooperatively. Upon starvation, they enter a developmental cycle wherein cells aggregate to produce macroscopic fruiting bodies filled with resistant myxospores. We used RNA-Seq technology to examine the global transcriptome of the 96 h developmental program. This data revealed that many genes were sequentially expressed in discrete modules, with expression peaking during aggregation, in the transition from aggregation to sporulation, or during sporulation. Analysis of genes expressed at each specific time point provided a global framework integrating regulatory factors coordinating motility and differentiation in the developmental program. These data provided insights as to how starving cells obtain energy and precursors necessary for assembly of fruiting bodies and into developmental production of secondary metabolites. This study offers the first global view of developmental transcriptional profiles and provides an important scaffold for future studies. IMPACT STATEMENTInvestigation of global gene expression profiles during formation of the Myxococcus xanthus specialized biofilm reveals a genetic regulatory network that coordinates cell motility, differentiation, and secondary metabolite production.

microbiology↗

bioRxiv2019

Intrinsic checkpoint deficiency during cell cycle re-entry from quiescence

The authors find that human cells re-entering the cell cycle from quiescence have both an impaired p53-dependent DNA replication origin licensing checkpoint and slow origin licensing. This combination makes every first S phase underlicensed and hypersensitive to replication stress. ABSTRACTTo maintain tissue homeostasis, cells transition between cell cycle quiescence and proliferation. An essential G1 process is Minichromosome Maintenance complex (MCM) loading at DNA replication origins to prepare for S phase, known as origin licensing. A p53-dependent origin licensing checkpoint normally ensures sufficient MCM loading prior to S phase entry. We used quantitative flow cytometry and live cell imaging to compare MCM loading during the long first G1 upon cell cycle entry and the shorter G1 phases in the second and subsequent cycles. We discovered that despite the longer G1 phase, the first G1 after cell cycle re-entry is significantly underlicensed. As a result, the first S phase cells are hypersensitive to replication stress. This underlicensing is from a combination of slow MCM loading with a severely compromised origin licensing checkpoint. The hypersensitivity to replication stress increases over repeated rounds of quiescence. Thus, underlicensing after cell cycle re-entry from quiescence distinguishes a higher risk cell cycle that promotes genome instability.

cell biology↗

bioRxiv2019

Rice bran supplementation modulates growth, microbiome and metabolome in weaning infants: a clinical trial in Nicaragua and Mali

Rice bran supplementation provides nutrients, prebiotics and phytochemicals that enhance gut immunity, reduce enteric pathogens in mice and diarrhea in neonatal pigs, and warranted attention for improvement of environmental enteric dysfunction (EED) in children at risk. EED is a condition that drives childhood stunting via intestinal dysbiosis and impaired nutrient metabolism. This study investigated effects of rice bran supplementation on growth, EED biomarkers, gut microbiome and metabolome in weaning infants from 6 to 12 months old in Nicaragua and Mali. Healthy infants were randomized to a control group or rice bran group that received daily supplementation at increasing doses each month. Stool microbiomes were characterized using 16S rDNA amplicon sequencing. Stool metabolomes were analyzed using ultra-high-performance liquid-chromatography tandem mass-spectrometry. Statistical comparisons were completed at 6, 8, and 12 months of age. Daily consumption of rice bran was safe and feasible for infant growth, decreasing alpha-1 antitrypsin levels, and modulating gut microbiome and metabolome when compared to control. Rice bran merits investigation as a practical intervention strategy that could decrease EED prevalence and risk for children from low- and middle-income countries where rice is grown as a staple food, and bran is used as animal feed or wasted. One Sentence SummaryDietary rice bran supplementation during infant weaning from 6-12 months of age improved growth outcomes, modulated environmental enteric dysfunction biomarkers, and supported metabolism by the gut microbiome. The authors declare no competing financial or non financial interests to disclose as defined by Nature Research. There are also no other interests that might be perceived to influence the results and/or discussion reported in this paper. Correspondence and requests for materials should be addressed to Dr. Elizabeth Ryan (e.p.ryan@colostate.edu).

clinical trials↗