Biology subjects

Torres, F.

Publications and source records attributed to Torres, F..

12 recordsLinked to original sources

bioRxiv2026

Bone Marrow Mesenchymal Stem Cells Therapy for Premature Ovarian Insufficiency: A Systematic Review and Meta-analysis of Preclinical Studies

BackgroundPremature ovarian insufficiency (POI) affects approximately 1% of women under 40 and is characterized by elevated levels of gonadotropins, reduced estradiol, impaired folliculogenesis, and infertility. Bone marrow-derived mesenchymal stem cell (BM-MSC)-based therapy has emerged as a promising regenerative strategy in preclinical POI models. This systematic review and meta-analysis evaluated BM-MSC-based interventions, including cell transplantation and secretome/extracellular vesicle administration, in animal models of POI. MethodsA systematic review and meta-analysis was conducted following PRISMA guidelines. PubMed, Web of Science, Scopus, ScienceDirect, and the Cochrane Library were searched from inception to February 19, 2025. Preclinical studies assessing BM-MSC-based interventions in animal models of POI were included. ResultsThirty-four studies comprising 1,357 animals were included. Compared with controls, BM-MSC-based therapy increased serum estradiol (standardized mean difference [SMD] 3.11; 95% confidence interval [CI] 2.38-3.84) and anti-Mullerian hormone (SMD 1.86; 95% CI 1.03-2.69), while reducing follicle-stimulating hormone (SMD -3.54; 95% CI -4.37 to -2.71) and luteinizing hormone (SMD -3.44; 95% CI -5.17 to -1.70). Follicular counts increased across developmental stages, with fewer atretic follicles. Reproductive outcomes improved, including normal estrous cycles (risk ratio [RR] 7.80; 95% CI 3.15-19.34), pregnancy occurrence (RR 3.72; 95% CI 2.14-6.44), and offspring number (SMD 1.57; 95% CI 1.04-2.09). ConclusionBM-MSC-based therapy consistently improved hormonal, follicular, and reproductive outcomes in preclinical POI models. More well-designed, standardized, and adequately controlled studies to confirm these findings are warranted. Systematic review registration: CRD42023449053

cell biology↗

bioRxiv2026

Environmental DNA reveals hidden eukaryotic diversity and fine-scale community patterns across seascape areas in the Northern Red Sea

Understanding how reef-associated biodiversity responds to seascape features is essential for monitoring and conserving coral reef ecosystems. Environmental DNA (eDNA) from seawater provides access to benthopelagic eukaryotic diversity but its relationship with benthic structure remains poorly understood. We conducted simultaneous assessment of benthopelagic eDNA derived from near-reef seawater and benthic photoquadrat surveys across 12 coral reef sites in the northern Red Sea, spanning three seascape regions: the Gulf of Aqaba, nearshore Northern Red Sea (NRS), and offshore NRS. We examined whether spatial patterns in benthopelagic eDNA communities were structured across regions and whether variation in benthic cover explained differences in eDNA-derived assemblages obtained from water samples. Benthopelagic eDNA revealed fine-scale spatial structuring across regions but showed non-significant whole-community correlation with benthic composition. When examined by major taxonomic groups, taxon-specific relationships emerged, with some taxa (i.e., Micromonas sp.) showing increasing relative abundances in reefs characterized by lower benthic complexity. While traditional photoquadrat surveys captured 72 benthic sessile taxa including dominant benthic groups (e.g. hard corals and algae) across four eukaryotic phyla, benthopelagic eDNA documented a broader range of eukaryotic diversity, including planktonic, cryptic, and low abundant taxa spanning 35 phyla. Notably, eDNA detected cryptic organisms overlooked by visual surveys, such as the giant clam Tridacna sp., even where present but not recorded in photoquadrats. Our results demonstrate that benthopelagic eDNA and visual surveys provide complementary perspectives on reef biodiversity. Rather than serving as a direct proxy for benthic structure, benthopelagic eDNA captures spatial and taxonomic patterns that may be overlooked by visual transects, supporting its use in seascape-scale biodiversity assessments and conservation planning efforts in dynamic and understudied reef systems.

ecology↗

bioRxiv2025

Engineering SIRPα conformational plasticity to reveal a cryptic pocket suitable for structure-based drug design

The protein-protein interaction between Signal Regulatory Protein alpha (SIRP) and CD47 is a critical immune checkpoint that enables tumor immune escape, making it a key target for cancer immunotherapy. While antibody-based therapies exist, the development of small-molecule inhibitors has been hindered by the flat, featureless binding interface. Here, we report the discovery of a novel, druggable cryptic pocket within the SIRP D1 domain (the WYF pocket), revealed through a structure-based fragment screening campaign using x-ray crystallography. This pocket, defined by residues Trp38, Tyr50, and Phe74, is only accessible in a conformation that is incompatible with CD47 binding, making it a candidate for structure-based drug design and immune checkpoint inhibitor development. Through a combination of NMR spectroscopy, molecular dynamics simulations, and biophysical assays, we demonstrate that access to this cryptic site is dynamically controlled by a single "gatekeeper" residue, Gln52. The rotameric state of Gln52 dictates a conformational equilibrium between a "closed," state and a ligand-accessible "open" state. We validated this mechanism by engineering SIRP mutants to bias this equilibrium. A Q52F mutation locked the pocket in a closed state, abolishing both CD47 and fragment binding, while Q52A and Q52R mutations biased the protein toward an open state. These "open-biased" mutants not only exhibited decreased affinity for CD47 but also significantly improved binding to small-molecule fragments that inhibit the SIRP-CD47 interaction. This work reveals the intrinsic conformational plasticity of SIRP and establishes a validated structure-based roadmap for a new class of allosteric inhibitors. This flexibility-for-inhibition strategy functions by trapping a non-binding conformation and represents a broadly applicable framework for targeting this and other challenging immune checkpoints.

biochemistry↗

bioRxiv2025

Analysis of Essential Genes in Clostridioides difficile by CRISPRi and Tn-seq

Essential genes are interesting in their own right and as potential antibiotic targets. To date, only one report has identified essential genes on a genome-wide scale in Clostridioides difficile, a problematic pathogen for which treatment options are limited. That foundational study used large-scale transposon mutagenesis to identify 404 protein-encoding genes as likely to be essential for vegetative growth of the epidemic strain R20291. Here, we revisit the essential genes of strain R20291 using a combination of CRISPR interference (CRISPRi) and transposon-sequencing (Tn-seq). First, we targeted 181 of the 404 putatively essential genes with CRISPRi. We confirmed essentiality for >90% of the targeted genes and observed morphological defects for >80% of them. Second, we conducted a new Tn-seq analysis, which identified 346 genes as essential, of which 283 are in common with the previous report and might be considered a provisional essential gene set that minimizes false positives. We compare the list of essential genes to those of other bacteria, especially Bacillus subtilis, highlighting some noteworthy differences. Finally, we used fusions to red fluorescent protein (RFP) to identify 18 putative new cell division proteins, three of which are conserved in Bacillota but of largely unknown function. Collectively, our findings provide new tools and insights that advance our understanding of C. difficile. IMPORTANCEClostridioides difficile is an opportunistic pathogen for which better antibiotics are sorely needed. Most antibiotics target pathways that are essential for viability. Here we use saturation transposon mutagenesis and gene silencing with CRISPR interference to identify and characterize genes required for growth on laboratory media. Comparison to the model organism B. subtilis reveals many similarities and a few striking differences that warrant further study and may include opportunities for developing antibiotics that kill C. difficile without decimating the healthy microbiota needed to keep C. difficile in check.

microbiology↗

bioRxiv2025

Frequency-Dependent Neurostimulation in Whole Brain Network models

BackgroundBrain stimulation at specific frequencies has been shown to have therapeutic effects for certain neurological disorders. However, it remains unclear how these oscillatory inputs interact with neuronal dynamics and what drives this frequency selectivity. Here, we propose that this is achieved by targeting specific brain circuits through frequency-selective network entrainment. MethodsTo demonstrate that this type of entrainment can occur in the brain connectome structure, we use a minimal physics-based model of coupled oscillators that preserves only the essential structural connectivity of real brain networks. Using this model, we test how periodic stimulation influences network oscillatory dynamics, identifying sub-networks that synchronize with specific stimulation frequencies. Furthermore, we validate the suitability of the model to reproduce well-known frequency-selective entrainment using visual and auditory periodic stimulation. ResultsOur model reproduces selective network entrainment, whereby distinct stimulation frequencies favor the synchrony of different sub-networks. Crucially, entrainment exhibits a physics-predicted inverse relationship with frequency: lower-frequency stimulation favors broader synchrony across the network, while higher-frequency inputs produce spatially confined effects. These patterns emerge purely from network structure and oscillatory physics, independent of biological details. ConclusionThis physics-based approach elucidates the fundamental mechanistic principles governing frequency-selective brain network stimulation. Our minimal model demonstrates that selective entrainment of specific subnetworks can be achieved through frequency selection alone, largely determined by network structure and oscillatory dynamics. These findings provide a theoretical foundation for understanding how network architecture determines stimulation selectivity, supporting the development of principled approaches to targeted neuromodulation. Author summaryIn this work, we explore how external rhythmic stimulation interacts with the brains own rhythms. We use a physics-based model that represents the brain as a network of interconnected oscillators, linked according to the human connectome. Through this model, we show that stimulation effects are not limited to the targeted region but spread across the network, depending on the stimulation frequency, its spatial location and the underlying network dynamics. Our results reveal that low-frequency rhythms promote large-scale synchrony, while high-frequency rhythms engage more localized areas, all emerging from the brains structural connections and communication delays. The simulated cortical activation exhibits a frequency-selective profile that aligns strongly with that estimated from sensory-evoked electroencephalographic activity. This agreement suggests that differences between individuals in how their brain networks operate may explain why stimulation affects each person differently. Our findings offer a mechanistic framework for designing personalized stimulation protocols, illustrating how computational modeling can guide the optimization of noninvasive brain stimulation in both research and clinical contexts.

bioengineering↗

bioRxiv2024

Reconstructing the deep phylogeny of the MAPK signaling network: functional specialization via multi-tier coevolutionary expansion

The mitogen-activated protein kinase (MAPK) signaling network is a three-tier cascade that regulates key cellular responses in eukaryotes. However, the evolutionary origins of its complex interactions and functional diversity remain poorly understood. Here, we conducted a comprehensive phylogenetic analysis of MAPK components across Eukarya to delineate divergences of non-human orthologs of human paralogs along the human evolutionary backbone. We identified two major pulses of coevolutionary expansion: one predating the divergence of fungi and animals, and another predating the origin of animals. Our reconstruction also infers a polyphyletic origin for the atypical MAPKs. Integrating functional literature across eukaryotic taxa with our reconstructed trees reveals that the two clades of MAP3K, Sterile-like (STE) and tyrosine kinase-like (TKL), had distinct evolutionary trajectories and influences on downstream pathway diversification. STEs that function as MAP3Ks are conserved across extant eukaryotes. Despite the absence of TKL MAP3Ks in many early diverging eukaryotes, the expansion of TKL MAP3Ks aligns phylogenetically and functionally with that of the downstream MAP2Ks and MAPKs. We thus propose that the MAPK network originated as a STE-regulated pathway, and that subsequent radiations of the TKLs drove the diversification of downstream components and top-down finetuning of pathway specificity. We thus provide an evolutionary framework for generating novel hypotheses on the functional diversity of this key signaling network, including potential insights into the evolution of animal multicellularity. Our study demonstrates that phylogenetics can offer new perspectives towards understanding complex cellular physiology. SignificanceThe mitogen-activated protein kinase (MAPK) signaling network responds to various signals and regulates basic cell physiology including proliferation and apoptosis. This three-tier network is universal in eukaryotes, but there is great functional diversity among different homologs as well as different taxa. Here we compared amino acid sequences to reconstruct MAPK evolutionary history as a network. We found that the three levels expand in parallel, showcasing a special case of coevolution. Two distinct pulses of network expansion predate the origin of animals, indicating that the functional diversity of human MAPK network proteins originate from ancient evolutionary radiations. Together, our study provides a critical look at the deep history of this important network.

evolutionary biology↗

bioRxiv2022

Metabolic switch in the aging astrocyte evidenced via integrative approach comprising network and transcriptome analyses

Dysregulated central-energy metabolism is a hallmark of brain aging. Supplying enough energy for neurotransmission relies on the neuron-astrocyte metabolic network. To identify genes contributing to age-associated brain functional decline, we formulated an approach to analyze the metabolic network by integrating flux, network structure and transcriptomic databases of neurotransmission and aging. Our findings support that during brain aging: 1) The astrocyte undergoes a metabolic switch from aerobic glycolysis to oxidative phosphorylation, decreasing lactate supply to the neuron, while the neuron suffers intrinsic energetic deficit by downregulation of Krebs cycle genes, including mdh1 and mdh2 (Malate-Aspartate Shuttle); 2) Branched-chain amino acid degradation genes were downregulated, identifying dld as a central regulator; 3) Ketone body synthesis increases in the neuron, while the astrocyte increases their utilization, in line with neuronal energy deficit in favor of astrocytes. We identified candidates for preclinical studies targeting energy metabolism to prevent age-associated cognitive decline.

neuroscience↗

bioRxiv2021

Macrophage migration inhibitory factor is a valid drug target at the intersection of herpes simplex virus 1 replication and Alzheimer's disease-relevant cellular pathology

The viral life cycle usurps host cellular factors, redirecting them from physiological functions to viral needs thereby revealing their "moonlighting" functions, disturbing cellular proteostasis, and increasing risk of specific, virus-associated protein misfolding diseases (PMD). Identifying such virus-repurposed host proteins therefore allow study of fundamental cellular events leading to associated "sporadic" PMD. Here, we identified a small molecule with unprecedented activity against neurotropic herpes simplex virus 1 (HSV-1) modulating an allosteric site of Macrophage Migration Inhibitory Factor (MIF). The compound efficiently reduced HSV-1-mediated tau phosphorylation or aggregation in vitro and in vivo, even without HSV-1 infection. The lead compound specifically interacted with an oxidized conformer of MIF (oxMIF) from either recombinant MIF or post-mortem brain homogenates of patients with Alzheimers disease (AD). OxMIF thus participates in a host-viral interface connecting HSV-1 infection, and possibly other external stressors, with tau cellular pathology characteristic for PMD, including Alzheimes disease.

microbiology↗

bioRxiv2021

Chemotherapy induces a YAP1-dependent fetal conversion to human Colorectal Cancer cells that is predictive of poor patient outcome

Current therapy against colorectal cancer is based on DNA-damaging agents that eradicate highly proliferative malignant cells. Whether sublethal chemotherapy affects tumor cell behavior and impacts on patient outcome is primarily unstudied. We now show that sublethal chemotherapy imposes a quiescent-like state to p53 wildtype human colorectal cancer (CRC) cells that is linked to the acquisition of a fetal phenotype downstream of YAP1, similar to that observed after intestinal damage. CRC cells displaying this fetal phenotype exhibit tumor- initiating activity comparable to untreated cells but superior metastatic capacity. Notably, nuclear YAP1 accumulation, or detection of the fetal signature in tumors predict poor prognosis in CRC patients carrying p53 wildtype tumors. Collectively, our results uncover a potential adverse response of tumor cells to suboptimal chemotherapy, and identify nuclear YAP1 and fetal conversion of colorectal tumors as biomarkers for prognosis and therapy prescription. Statement of significanceChemotherapy induces a quiescent-like phenotype to colorectal cancer cells that is linked to the acquisition of a YAP1-dependent fetal signature. Notably, this signature is predictive of patient outcome in different cohorts of human colorectal cancer.

cancer biology↗

bioRxiv2021

Selection of stimulus parameters for enhancing slow wave sleep events with a Neural-field theory thalamocortical computational model

Slow-wave sleep cortical brain activity, conformed by slow-oscillations and sleep spindles, plays a key role in memory consolidation. The increase of the power of the slow-wave events, obtained by auditory sensory stimulation, positively correlates to memory consolidation performance. However, little is known about the experimental protocol maximizing this effect, which could be induced by the power of slow-oscillation, the number of sleep spindles, or the timing of both events co-occurrence. Using a mean-field model of thalamocortical activity, we studied the effect of several stimulation protocols, varying the pulse shape, duration, amplitude, and frequency, as well as a target-phase using a closed-loop approach. We evaluated the effect of these parameters on slow-oscillations (SO) and sleep-spindles (SP), considering: (i) the power at the frequency bands of interest, (ii) the number of SO and SP, (iii) co-occurrences between SO and SP, and (iv) synchronization of SP with the up-peak of the SO. The first three targets are maximized using a decreasing ramp pulse with a pulse duration of 50 ms. Also, we observed a reduction in the number of SO when increasing the stimulus energy by rising its amplitude. To assess the target-phase parameter, we applied closed-loop stimulation at 0{o}, 45{o}, and 90{o} of the phase of the narrow-band filtered ongoing activity, at 0.85 Hz as central frequency. The 0{o} stimulation produces better results in the power and number of SO and SP than the rhythmic or aleatory stimulation. On the other hand, stimulating at 45{o} or 90{o} change the timing distribution of spindles centers but with fewer co-occurrences than rhythmic and 0{o} phase. Finally, we propose the application of closed-loop stimulation at the rising zero-cross point using pulses with a decreasing ramp shape and 50 ms of duration for future experimental work. Author summaryDuring the non-REM (NREM) phase of sleep, events that are known as slow oscillations (SO) and spindles (SP) can be detected by EEG. These events have been associated with the consolidation of declarative memories and learning. Thus, there is an ongoing interest in promoting them during sleep by non-invasive manipulations such as sensory stimulation. In this paper, we used a computational model of brain activity that generates SO and SP, to investigate which type of sensory stimulus -shape, amplitude, duration, periodicity- would be optimal for increasing the events frequency and their co-occurrence. We found that a decreasing ramp of 50 ms duration is the most effective. The effectiveness increases when the stimulus pulse is delivered in a closed-loop configuration triggering the pulse at a target phase of the ongoing SO activity. A desirable secondary effect is to promote SPs at the rising phase of the SO oscillation.

neuroscience↗

bioRxiv2019

MgO nanoparticles coated with Polyethylene Glycol as carrier for 2-Methoxyestradiol anticancer drug.

Novel Magnesium Oxide (MgO) nanoparticles (NPs) modified with the polymer poliethylene glycol (PEG) were synthesized as carrier for the anticancer drug 2-Methoxyestradiol (2ME) to improve its clinical application. The functionalized NPs were characterized by Infrared spectroscopy with Fourier transform to elucidate the vibration modes of this conjugate, indicating the formation of the MgO-PEG-2ME nanocomposite. The studies of absorption and liberation determined that MgO-PEG-2ME NPs incorporated 98.51 % of 2ME while liberation of 2ME was constant during 7 days at pH 2, 5 and 7.35. Finally, the MgO-PEG-2ME NPs decreased the viability of the prostate cancer cell line LNCap suggesting that this nanocomposite is suitable as a drug delivery system for anticancer prostate therapy.

cancer biology↗

bioRxiv2018

A Public Database on Traumatic Brachial Plexus Injury

We hereby present the first worldwide public digital database centred on adult Traumatic Brachial Plexus Injury (TBPI). This initiative aims at reducing distance between clinical and experimental practice and encouraging data sharing and reuse. Detailed electronic questionnaires made with the free software LimeSurvey were designed to collect patients epidemiological, physical and clinical data. The freely available software Neuroscience Experiments System (NES) was employed to support data storage and management. First results of this effort concern data collected from 109 Brazilian adult TBPI patients with varying degrees of functional impairment. The sample is composed by large majority of men (84.4%), mean age of 32.1 (11.3 SD) years old, victims of motorcycle accidents (67%). The similarity of this dataset basic descriptors with those from previous reports in TBPI validates the strategies employed herein. Managing data from diverse provenance in TBPI may allow identifying functional markers related to the patients clinical improvement and foster the development of new investigative tools to unveil its mechanisms.

neuroscience↗