Biology subjects

Soares, D.

Publications and source records attributed to Soares, D..

13 recordsLinked to original sources

bioRxiv2026

Designing antimicrobials with programmable mechanism and safety

Antimicrobial peptides (AMPs) are a promising solution to antimicrobial resistance, yet generative models for their design cannot control the physicochemical properties and motifs that shape activity and selectivity. Here, we present OmegAMP, a conditional diffusion framework controlling net charge, mean hydrophobicity, and sequence length, supporting de novo, analog, and motif-guided design. Across 204 wet-lab characterized peptides, de novo generation yielded antimicrobials with broad activity against multidrug-resistant Gram-negative isolates. Analog generation converted six inactive prototypes into antimicrobials, with the prototype determining each analog's membrane-disruption mode and mammalian-cell safety. Motif-guided analog generation preserved lipopolysaccharide engagement of active prototypes, and a redesigned non-antimicrobial leucine zipper acquired antimicrobial activity while retaining DNA-perturbing character in vitro. In murine skin and thigh infection models, leads reduced bacterial burden, with a motif-guided DNA-perturbing lead matching the fluoroquinolone control systemically. OmegAMP opens a programmable route to new peptide antibiotics whose mechanism and safety follow from the chosen prototype.

bioinformatics↗

bioRxiv2020

Blunting of insulin-stimulated glucose uptake in brown adipose tissue induces systemic metabolic dysregulation in female mice

The role of brown adipose tissue (BAT) in thermogenesis is widely appreciated, whereas its more recently described role in whole-body metabolism is not as well understood. Here we demonstrate that deletion of Rab10 from brown adipocytes reduces insulin-stimulated glucose transport by inhibiting translocation of the GLUT4 glucose transporter to the plasma membrane. This blunting of glucose uptake into brown adipocytes induces glucose intolerance and insulin-resistance in female but not male mice. The defect in glucose uptake does not affect the thermogenic function of BAT, and the dysregulation of whole-body metabolism is independent of the thermogenic function of BAT, thereby revealing a metabolism-specific role for BAT in female mice. The reduced glucose uptake induced by RAB10 deletion disrupts ChREBP regulation of the expression of de novo lipogenesis-related (DNL) genes, providing a link between DNL in BAT and whole-body metabolic regulation that is independent of thermogenesis.

physiology↗

bioRxiv2020

Evolutionary and homeostatic changes in morphology of visual dendrites of Mauthner cells in Astyanax blind cavefish

Mauthner cells are the largest neurons in the hindbrain of teleost fish and most amphibians. Each cell has two major dendrites thought to receive segregated streams of sensory input: the lateral dendrite receives mechanosensory input while the ventral dendrite receives visual input. These inputs, which mediate escape responses to sudden stimuli, may be modulated by the availability of sensory information to the animal. To understand the impact of the absence of visual information on the morphologies of Mauthner cells during development and evolutionary time scales, we examined Astyanax mexicanus. This species of tetra is found in two morphs: a seeing surface fish and a blind cavefish. We compared the structure of Mauthner cells in surface fish raised under daily light conditions, surface fish that raised in constant darkness, and two independent lineages of cave populations. The length of ventral dendrites of Mauthner cells in dark-raised surface larvae were longer and more branched, while in both cave morphs the ventral dendrites were smaller or absent. The absence of visual input in surface fish with normal eye development leads to a homeostatic increase in dendrite size, whereas over evolution, the absence of light led to the loss of eyes and a phylogenetic reduction in dendrite size. Consequently, homeostatic mechanisms are under natural selection that provide adaptation to constant darkness.

neuroscience↗

bioRxiv2020

A common human variant of GIPR improves systemic glucose homeostasis in a sexual dimorphic manner

Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To isolate the contribution of GIPR in metabolic control, we generated a mouse model of the GIPR-Q354 variant (GIPR-Q350 mice). Female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulated ex vivo during glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in {beta}-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN). Consequently, our data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.

physiology↗

bioRxiv2019

Hunting strategies and the lateral line of Astyanax mexicanus larva

The lateral line is the primary modality fish use to create a hydrodynamic image of their environment. These images contribute to a variety of behaviors, from rheotaxis to escape responses. Here we discern the contributions of visual and lateral line modalities in hunting behavior of larvae that have developed under different photic conditions. In particular, cave animals have a hypertrophied sense of mechanosensation, and we studied the common animal model cavefish Astyanax mexicanus and its closest related surface relative. We raised larvae in a diurnal light-dark regimen and in complete darkness. We then examined the distribution of neuromasts in their lateral lines, and their hunting performance in light and dark conditions, with and without the contribution of the lateral line. We report that all larva depend on the lateral line for success in hunting and that surface fish raised in the dark have a greater dependency on the lateral line,

evolutionary biology↗

bioRxiv2019

Spooky interaction at a distance in cave and surface dwelling electric fishes

Glass knifefish (Eigenmannia) are a group of weakly electric fishes found throughout the Amazon basin. We made recordings of the electric fields of two populations of freely behaving Eigenmannia in their natural habitats: a troglobitic population of blind cavefish (Eigenmannia vicentespelaea) and a nearby epigean (surface) population (Eigenmannia trilineata). These recordings were made using a grid of electrodes to determine the movements of individual fish in relation to their electrosensory behaviors. The strengths of electric discharges in cavefish were larger than in surface fish, which may be a correlate of increased reliance on electrosensory perception and larger size. Both movement and social signals were found to affect the electrosensory signaling of individual Eigenmannia. Surface fish were recorded while feeding at night and did not show evidence of territoriality. In contrast, cavefish appeared to maintain territories. Surprisingly, we routinely found both surface and cavefish with sustained differences in electric field frequencies that were below 10 Hz despite being within close proximity of less than one meter. A half century of analysis of electrosocial interactions in laboratory tanks suggest that these small differences in electric field frequencies should have triggered the jamming avoidance response. Fish also showed significant interactions between their electric field frequencies and relative movements at large distances, over 1.5 meters, and at high differences in frequencies, often greater than 50 Hz. These interactions are likely envelope responses in which fish alter their EOD frequency in relation to changes in the depth of modulation of electrosocial signals.

neuroscience↗

bioRxiv2019

Evolutionary increases in catecholamine signaling may underlie the emergence of adaptive traits and behaviors in the blind cavefish, Astyanax mexicanus

Evolutionary changes in catecholamine neurotransmitters such as dopamine and noradrenaline can lead to habitat specific behaviors. We used tyrosine hydroxylase, a conserved precursor to the biosynthesis of dopamine and noradrenaline, to compare catecholaminergic neurons in the brain of a species undergoing allopatric speciation. The teleost fish Astyanax mexicanus is extant in two readily available forms, an ancestral river dwelling form (surface) and various derived blind cave forms (cavefish). Adaptation to nutrient poor cave life without predation has led to marked differences in the behavior of this species. The cavefish has lost defensive responses, such as stimulus aversion, found in the ancestral surface fish and instead displays enhanced food seeking behaviors. This is reflected by an increase in catecholamine immunoreactivity in the cavefish brain in regions associated with non-visual sensory perception, motor control pathways, attention, and endocrine release. These neuroanatomical regions include the olfactory system, the basal telencephalon, the preoptic nuclei, the posterior tuberculum, caudal hypothalamus, and isthmus. These results indicate that the evolutionary shift from aversive defensive responses to attractive exploratory behaviors was driven by increases in the size and/or quantity of catecholaminergic neurons in the cavefish brain.

neuroscience↗

bioRxiv2019

Translation elongation factor 1A2 (eEF1A2) is encoded by one of four closely related eef1a genes and is dispensable for survival in zebrafish

Zebrafish are valuable model organisms for the study of human single-gene disorders: they are genetically manipulable, their development is well understood, and mutant lines with measurable, disease-appropriate phenotypic abnormalities can be used for high throughput drug screening approaches. However, gene duplication events in zebrafish can result in redundancy of gene function, masking loss of function phenotypes and thus confounding this approach to disease modelling. Furthermore, recent studies have yielded contrasting results depending on whether specific genes are targeted using genome editing to make mutant lines, or whether morpholinos are used (morphants). De novo missense mutations in the human gene EEF1A2, encoding a tissue-specific translation elongation factor, cause severe neurodevelopmental disorders; there is a real need for a model system in which to study these disorders and we wanted to explore the possibility of a zebrafish model. We identified four eef1a genes and examined their developmental and tissue-specific expression patterns: eef1a1l1 is first to be expressed whilst eef1a2 is only detected later during development. We then determined the effects of introducing null mutations into eEF1A2 in zebrafish using CRISPR/Cas9 gene editing, in order to compare the results with previously described morphants, and with the severe neurodegenerative lethal phenotype of eEF1A2-null mice. In contrast with both earlier analysis in zebrafish using morpholinos and with the mouse eEF1A2-null mice, disruption of the eef1a2 gene in zebrafish is compatible with normal lifespan. The resulting lines, however, may provide a valuable platform for studying the effects of expression of mutant human eEF1A2 mRNA.

genetics↗

bioRxiv2019

Retinal morphology in Astyanax mexicanus during degeneration

The teleost Astyanax mexicanus is extant in two readily available forms. One that lives in Mexican rivers and various convergent forms that live in nearby caves. These fish are born with eyes but in the cavefish they degenerate during development. It is known that the lens of cavefish undergoes apoptosis and that some cells in the neuroretina also die. It has not been described, however, if glia and various components of the neuroretina form before complete eye degeneration. Here we examined the development of the retina of the closest living ancestor that lives in the rivers and members of two lineages of cavefish. We report that although the neuroretina is smaller and more compact, it has all cell types and layers including amacrine cells and Muller glia. While various makers for photoreceptors are present in the cavefish inner segments, the outer segments of the photoreceptors in cavefish are missing from the earliest stages examined. This shows that the machinery for visual transducing discs might still be present but not organized in one part of the cell. It is interesting to note that the deficiencies in Astyanax cavefish resemble retinal diseases, such as retinitis pigmentosa.

neuroscience↗

bioRxiv2019

Variation in cephalic neuromasts surface and cave-dwelling fishes of the family Amblyopsidae (Teleostei: Percopsiformes)

Cave adaptation has led to unique sensory specializations to compensate for the lack of visual cues in aphotic subterranean habitats. As the role of vision is reduced or disappears, other sensory modalities become hypertrophied allowing cave-adapted organisms to successfully detect and interact their surrounding environment. The array of aquatic subterranean habitats, from fast-flowing streams and waterfalls, to quiet phreatic pools, presents a diverse palette to examine what possible sensory solutions have evolved against a backdrop of complete darkness. Mechanosensation is enhanced in many subterranean animals to such an extent that a longer appendage is recognized as a prominent troglomorphic adaptation in many metazoans. Fishes, however, not only interact with the environment using their fins, but also with specialized sensory organs to detect hydrodynamic events. We hypothesize that subterranean adaptation drives the hypertrophy of the mechanosensory lateral line, but that other environmental forces dictate the specific neuromast phenotype. To this end, we studied differences in the cephalic lateral line of the fishes in the North American family Amblyopsidae, which includes surface, cave-facultative, and cave-obligate species. None of the taxa we examined possessed canal neuromasts on the head. Primarily surface-dwelling species, Chologaster cornuta and Forbesichthys agassizii, possessed receded neuromasts throughout most of the head, with a few on papillae located in front of the nostrils and on ventral grooves on each side of the mouth. The cavefishes Amyblopsis spelaea and Typhlichthys subterraneous possessed papillate superficial neuromasts all over the head. We speculate that the change from the surface to the cave environment has led to papillate neuromasts in this group, which are likely shaped to detect the hydrodynamic characteristics of the boundary layer created by the swimming fish. Moving sensory organs from the surface of the body out into the boundary layer could increase sensitivity to high frequency stimuli created by prey, predators, and conspecifics.

zoology↗

bioRxiv2017

tDCS changes in motor excitability are specific to orientation of current flow

Measurements and models of current flow in the brain during transcranial Direct Current Stimulation (tDCS) indicate stimulation of regions in-between electrodes. Moreover, the cephalic cortex result in local fluctuations in current flow intensity and direction, and animal studies suggest current flow direction relative to cortical columns determines response to tDCS. Here we test this idea by measuring changes in cortico-spinal excitability by Transcranial Magnetic Stimulation Motor Evoked Potentials (TMS-MEP), following tDCS applied with electrodes aligned orthogonal (across) or parallel to M1 in the central sulcus. Current flow models predicted that the orthogonal electrode montage produces consistently oriented current across the hand region of M1 that flows along cortical columns, while the parallel electrode montage produces none-uniform current directions across the M1 cortical surface. We find that orthogonal, but not parallel, orientated tDCS modulates TMS-MEPs. We also show modulation is sensitive to the orientation of the TMS coil (PA or AP), which is through to select different afferent pathways to M1. Our results are consistent with tDCS producing directionally specific neuromodulation in brain regions in-between electrodes, but shows nuanced changes in excitability that are presumably current direction relative to column and axon pathway specific. We suggest that the direction of current flow through cortical target regions should be considered for targeting and dose-control of tDCS.\n\nHighlights O_LIDirection of current flow is important for tDCS after-effects.\nC_LIO_LItDCS modulates excitability between two electrodes.\nC_LIO_LItDCS differentially modulates PA and AP inputs into M1.\nC_LI\n\nAbbreviations\n\nFundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

neuroscience↗

bioRxiv2017

Evolution Of Coprophagy And Nutrient Absorption In A Cave Salamander

The transition from carnivory to omnivory is poorly understood. The ability to feed at more than one trophic level theoretically increases an animals fitness in a novel environment. Because of the absence of light and photosynthesis, most subterranean ecosystems are characterized by very few trophic levels, such that food scarcity is a challenge in many subterranean habitats. One strategy against starvation is to expand diet breadth. Grotto salamanders (Eurycea spelaea) are known to ingest bat guano deliberately, challenging the general understanding that salamanders are strictly carnivorous. Here we tested the hypothesis that grotto salamanders have broadened their diet related to cave adaptation and found that, although coprophagous behavior is present, salamanders are unable to acquire sufficient nutrition from bat guano alone. Our results suggest that the coprophagic behavior has emerged prior to physiological or gut biome adaptations.

animal behavior and cognition↗

bioRxiv2016

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here, we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results suggest that variants in the DISC1 Interactome effect the risk of psychiatric illness through altered expression of schizophrenia-associated genes. The biological impact of rare variants highlighted here merit further study.

genetics↗