Biology subjects

Gomes, P.

Publications and source records attributed to Gomes, P..

7 recordsLinked to original sources

bioRxiv2026

The loss of Tau in the adult brain triggers neuroplastic, epigenetic and behavioral deficits

INTRODUCTIONAccumulation of pathological Tau precipitates neuronal malfunction in Alzheimers disease (AD). However, the impact of loss of normal Tau function in the adult brain, independently of Tau aggregates, remains unclarified. METHODSWe used a mouse model with conditional mapt knocking-down in forebrain of 5-7 months old animals (cTau-KO), a virus-driven selective Tau knockdown in wild-types (WT) and Tau re-expression approaches, accompanied by neurostructural, epigenetic, proteomic, electrophysiological, neurochemical and behavioral analyses. RESULTSLoss of Tau in the adult brain of cTau-KOs triggers neuronal atrophy and malfunction, epigenetic as well cognitive and mood deficits. Importantly, these perturbations were confirmed by selective Tau loss in WT adult brain and reverted by Tau re-expression or pharmacologically-induced epigenetic correction in cTau-KOs. DISCUSSIONOur findings highlight the contribution of loss of normal Tau function in the adult brain malfunction that could be relevant in diverse brain pathologies beyond AD, associated to Tau and its dysfunction.

neuroscience↗

bioRxiv2026

Phage Endolysin Enables Targeted Manipulation of the Small Intestinal Microbiota and Uncovers Niche Overlap Between Oral and Butyrate-Producing Taxa

Oral bacterial overgrowth in the small intestine has been associated with dysbiosis, impaired nutrient absorption, and stunted growth in undernourished children, a condition referred to as small intestinal oral bacterial overgrowth (SIOBO). Here, we explore the use of a phage-derived lysin as a precision antimicrobial to selectively target Streptococcus salivarius within complex microbial communities. Through a newly developed, medium-throughput bioinformatic and wet-lab pipeline we identified, cloned and produced a prophage-encoded lysin from S. salivarius and demonstrated its potent and specific lytic activity against a panel of 49 clinical S. salivarius strains from stunted children, while sparing related species such as S. mitis, S. parasanguinis and S. thermophilus. Application of the lysin to human stool-derived in vitro communities and to mice colonized with S. salivarius led to an approximate 2-3 log reduction in S. salivarius abundance while preserving overall bacterial community composition. However, we observed a negative correlation between S. salivarius and Coprococcus comes in vitro, and Eubacterium xylanophilum, Akkermansia, Lactobacillus and Ruminococcus in vivo. Spent medium assays confirmed niche overlap between 10 clinical strains of S. salivarius and 28 different taxa involved in butyrate production. Together, these results suggest that phage-derived lysins can offer multiple benefits by selectively removing ectopically colonized oral taxa and indirectly promoting beneficial anaerobes.

microbiology↗

bioRxiv2021

Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production

Chronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimers disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-{beta} (A{beta}) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in A{beta} overproduction remains an open question. Here, we find that hippocampal Rab35 levels are decreased not only by stress/GC but also by aging, another AD risk factor. Moreover, Rab35 negatively regulates A{beta} production by sorting amyloid precursor protein (APP) and {beta}-secretase (BACE1) out of the endosomal network, where they interact to produce A{beta}. Interestingly, Rab35 coordinates distinct intracellular trafficking events for BACE1 and APP, mediated by its effectors OCRL and ACAP2, respectively. Finally, we show that Rab35 overexpression prevents the amyloidogenic trafficking of APP and BACE1 induced by high GC levels. These studies identify Rab35 as a key regulator of APP processing and suggest that its downregulation may contribute to stress- and AD-related amyloidogenesis.

neuroscience↗

bioRxiv2019

Lactation curve model with explicit representation of perturbations as a phenotyping tool for dairy livestock precision farming.

BackgroundUnderstanding the effects of environment on livestock provides valuable information on how farm animals express their production potential, and on their welfare. Ruminants often face perturbations that affect their performance. Evaluating the effect of these perturbations on animal performance could provide metrics to quantify how animals cope with their environment and therefore, better manage them. In dairy systems, milk production records can be used to evaluate perturbations because (1) they are easily accessible, (2) the overall dynamics throughout the lactation process have been widely described, and (3) perturbations often occur and cause milk loss. In this study, a lactation curve model with explicit representation of perturbations was developed.\n\nMethodsThe perturbed lactation model is made of two components. The first one describes a theoretical unperturbed lactation curve (unperturbed lactation model), and the second describes deviations from the unperturbed lactation model. The model was fitted on 319 complete lactation data from 181 individual dairy goats allowing for the characterization of individual perturbations in terms of their starting date, intensity, and shape.\n\nResultsThe fitting procedure detected a total of 2,354 perturbations with an average of 7.40 perturbations per lactation. Loss of production due to perturbations varied between 2% and 19%. Results show that the number of perturbations is not the major factor explaining the loss in milk yield over the lactation, suggesting that there are different types of animal response to challenging factors.\n\nConclusionsBy incorporating explicit representation of perturbations, the model allowed the characterization of potential milk production, deviations induced by perturbations (loss of milk), and thereby comparison between animals. These indicators are likely to be useful to move from raw data to decision support tools in dairy production.

zoology↗

bioRxiv2019

Drivers of HIV-1 transmission: the Portuguese case

BackgroundPortugal has one of the most severe HIV-1 epidemic in Western Europe. Two subtypes circulate in parallel since the beginning of the epidemic. Comparing their transmission patterns and its association with transmitted drug resistance (TDR) is important to pinpoint transmission hotspots and to develop evidence-based treatment guidelines.\n\nMethods3599 HIV-1 naive patients collected between 2001 and 2014 were included in the study. Sequences obtained from drug resistance testing were used for subtyping, TDR determination and transmission clusters (TC) analyses.\n\nResultsSubtype B transmission was significantly associated with young males, while subtype G was associated with older heterosexuals. Young males infected with subtype B were more likely to be included in TC. Consistently, a decreasing trend of prevalence and transmission of subtype G in Portuguese originated people was observed. Active TCs were associated with subtype B-infected males residing in Lisbon. TDR was significantly different when comparing subtypes B (10.8% [9.5-12.2]) and G (7.6% [6.4-9.0]) (p=0.001).\n\nDiscussionTC analyses shows that the subtype B epidemic is active and fueled by young male patients residing in Lisbon and that transmission of subtype G in Portugal is decreasing. Despite similar treatment rates for both subtypes in Portugal, TDR is different between subtypes.

molecular biology↗

bioRxiv2019

The limbic circuit for response vigour

Motivation can be defined as the amount of energy an animal puts into actions to achieve goals. This not a static property but can be learned. Recently, abstract models have been developed for this kind of learning which propose that tonic dopamine is responsible to energise behaviour. However the underlying circuitry is still not understood and it is still unclear how tonic dopamine acts on the motor system to energise behaviour. In this paper we present a limbic system model of response invigoration which is based on neurophysiological data and anatomical connections. We argue that the indirect pathway from NAcc core D2 neurons via the ventral pallidum to the SNr conveys response vigour, while the direct pathway from NAcc core D1 neurons is responsible for action selection. Once this detailed anatomically mapped circuit has been established we then condense this realistic model into an abstract model which then shows that tonic DA acts in a multiplicative way on the motor output and thus is able to energise behaviour. We demonstrate the model with both a simulated and real robot experiment.

neuroscience↗

bioRxiv2018

Endo-lysosomal sorting and degradation of Tau mediates glucocorticoid-driven hippocampalmalfunction

Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimers disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD, and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.

neuroscience↗