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Hernandez, J.

Publications and source records attributed to Hernandez, J..

At least 19 recordsLinked to original sources

Historical Areas of Hybridization in Two Striped Emerald Dragonfly Species

The Hine's Emerald (Somatochlora hineana) is a federally endangered North American dragonfly, which has experienced significant declines due to anthropogenic forces including human encroachment into its sensitive spring fed wetland habitat and climate change. Previous research indicates hybridization with its ecologically generalist and widespread conspecific, the Clamp-Tipped Emerald (Somatochlora tenebrosa), which may induce hybridization-mediated extinction or genetic swamping. The aim of this paper is to investigate the patterns of hybridization between S. hineana and S. tenebrosa by inferring historical species ranges using Paleoecological niche modeling (PaleoENM), examining genetic structure using haplotype networks, and determining gene flow with introgression tests, shedding light on how, why, when, or where hybridization occurs in these species. Our results reveal evidence of hybridization occurring between S. hineana and S. tenebrosa among populations in Benzie County, Michigan and a newly discovered hybrid individual in Oregon County, Missouri. PaleoENM models show patterns of contact and separation across the Pleistocene, highlighting potential hybridization events throughout periods of glaciation. Finally, Introgression tests reveal evidence for unidirectional hybridization, which may result in genetic swamping of the endangered Hine's Emerald. Such studies provide essential genetic context for conserving ecologically sensitive and endangered species, identifying conservation priorities, and determining whether hybridization and introgression pose additional threats to the long-term genetic integrity and persistence of endangered populations.

molecular biology↗

A cognitive representation in primary visual cortex modulated by vision

Primary visual cortex (V1) is a critical substrate for mammalian vision. Traditionally, visual inputs are thought to be the main drivers of V1 activity, with internal signals playing a modulatory role. Here we show that this relationship is inverted for a large fraction of V1 neurons. In rats completing a navigation task in darkness, these neurons encoded progress along physically distinct paths with a shared turn structure. Under illumination, visual stimuli gain-modulated this path-invariant activity rather than replacing it with stimulus-driven responses. Path-invariant V1 neurons were also preferentially coordinated with hippocampal ensembles during sharp-wave ripples, linking them to a brain-wide network involved in learning. These findings establish that an internal model of the world can serve as a primary driver of activity in sensory cortex.

neuroscience↗

VesSynth: Tubes Are All You Need for Robust Cross-Scale Cross-Modal 3D Vessel Segmentation

The cerebral vasculature is central to brain function, with alterations linked to numerous cerebrovascular and neurological disorders. Yet, no single imaging modality can capture the entire cerebral vascular network in humans. Instead, an array of techniques are sensitized to different spatial scales, while trading off resolution for coverage. Magnetic Resonance Imaging (MRI) typically resolves only large pial vessels, while high-resolution microscopy allows micrometer-scale vessels to be mapped over limited spatial extents. These techniques must therefore be combined to obtain a complete mapping of the cerebral angioarchitecture, which underscores the need for automatic, cross-modal vessel segmentation. Here, we introduce VesSynth, a flexible vessel segmentation framework that achieves state-of-the-art accuracy across multiple modalities and spatial resolutions (MR, optical and X-ray imaging), despite being trained entirely on synthetic data. By enabling consistent vascular mapping across scales, this framework paves the way to comprehensive investigation of cerebrovascular organization and its role in health and disease.

bioengineering↗

CREB/CRTC2-Induced GPR65 Orchestrates Th17 Metabolic Fitness and Pathogenic Effector Function

GPR65 has been shown to be a critical regulator of Th17 cell pathogenicity. Loss of GPR65 in mice results in a decrease in Th17 cells and reduced susceptibility to a mouse model of multiple sclerosis. The CREB/CRTC2 pathway has emerged as an important regulator of immune function. We have previously shown that the CREB/CRTC2 pathway modulates autoimmune disease by promoting differentiation of Th17 cells. In this study we performed RNA-seq to identify Th17 genes regulated by the CREB/CRTC2 pathway. Our RNA-seq analysis led us to uncover the first mechanism of regulation of the orphan receptor GPR65 by the CREB/CRTC2 pathway. We show that GPR65 is a target of the CREB/CRTC2 pathway through expression studies and chromatin immunoprecipitation. In addition, we show that targeting GPR65 with small molecules alters the expression of IL-17A. Understanding the regulation of GPR65 will be crucial in developing small molecules to treat patients with Th17 cell-mediated disorders.

immunology↗

Meta-learning is expressed through altered prefrontal cortical dynamics

Learning where and when rewards like food and water are available is essential for survival1,2. In the simplest cases where resource availability is stable, animals can learn reward contingencies by integrating outcomes across repeated samples of each possible action. In more natural settings, however, reward availability is governed by structured higher-order rules such as depletion and repletion over time. To adapt flexibly to such changing environments, optimal choices require meta-learning wherein animals learn how to learn from external feedback, ultimately enabling them to infer the underlying reward structure from abstract, generalizable rules rather than relying solely on recent outcomes3,4. The existence of meta-learning in animal behavior is well established3-8, yet the neural circuits and computations that implement it remain poorly understood9-11. Here we investigated meta-learning using a spatial foraging task in which rats acquired a depletion-repletion rule that regulated reward availability, and carried out longitudinal, high-density recordings from the medial prefrontal cortex (mPFC). We show that meta-learning engages specific, systematic changes in mPFC neural dynamics that embed the learned rule and thereby alter how the network learns action values from reward outcomes. These dynamics are based on mixed coding of task structure and value in individual mPFC neurons. At the population level, this coding organizes into low-dimensional dynamical motifs that generalize across task conditions. As meta-learning progresses, these motifs are reshaped to instantiate both rule-guided inference of future states before outcome delivery and rule-based value updating during the outcome period. These results indicate that meta-learning sculpts pre-existing prefrontal dynamics to support the acquisition of new, generalizable reward-learning strategies.

neuroscience↗

Differentiation of naive into memory-phenotype CD8+ T cells does not promote the breakdown of peripheral tolerance in irradiated mice

Lymphodepletion, which is currently used as adjuvant for adoptive cytotoxic T cell immunotherapy in cancer, promotes the breakdown of peripheral CD8+ T cell tolerance. Under lymphopenic conditions, naive T cells proliferate due to a greater availability of homeostatic cues. Proliferating CD8+ T cells acquire a phenotype and functionality that is similar to memory cells and are termed memory-like cells. Since memory cells are thought to have a lower activation threshold than naive cells, it has been proposed that differentiation of potentially autoreactive CD8+ T cells into memory-like cells could drive the breakdown of tolerance under lymphopenic conditions. Here we studied whether lymphopenia induced proliferation and differentiation are required to overcome CD8+ T cell cross-tolerance in irradiated mice. Surprisingly, we found that blocking homeostatic proliferation by IL-7 neutralization did not prevent self-reactivity. CD8+ T cells that remained in a naive state still became effectors upon antigen cross-presentation as efficiently as memory-like cells. Nonetheless, lymphopenia induced proliferation did enhance CD8+ T cell mediated self-reactivity at low T cell frequencies by increasing autoreactive T cell numbers. Thus, although homeostatic proliferation enhances CD8+ T cell anti-self responses, differentiation into memory-like cells is not essential for the breakdown of cross-tolerance after irradiation.

immunology↗

Gastric cancer treatment target identified from an accelerated Helicobacter-induced gastric cancer mouse model

Helicobacter pylori (H. pylori) infection and consequent inflammation leads to gastric cancer (GC). Despite the prevalence of this bacterium and availability of genomic data, targeted therapies for GC are still early in development. Previously in our accelerated Helicobacter-induced gastric cancer mouse model we identified several differentially expressed genes (DEGs), including PSMB8 (proteasome subunit beta type 8, also called LMP7); one of the immune subunits of the immunoproteasome, which has been associated with disease severity in multiple cancers. We observed elevated expression of PSMB8 in our accelerated gastric cancer model, in the human gastric cancer cell line (MKN45), and in gastric cancer patient samples. Moreover, we identified carfilzomib as a potential drug that targets PSMB8. Therefore, to test its efficacy against gastric cancer, nude mice were subcutaneously implanted with MKN45 derived tumors and treated with carfilzomib, alone or in combination with 5-fluorouracil (5-FU), the standard care drug. The effectiveness of drug treatment was measured by tumor growth, cell proliferation, and apoptosis. We observed that carfilzomib retarded tumor growth, inhibited cell proliferation and induced apoptosis. These results strongly suggest that carfilzomib has a robust anti-tumor activity and is a suitable drug candidate for targeted therapy in gastric cancer.

cancer biology↗

Single cell spatial proteomics maps human liver zonation patterns and their vulnerability to fibrosis

Understanding protein distribution patterns across tissue architecture is crucial for deciphering organ function in health and disease. Here, we applied single-cell Deep Visual Proteomics to perform spatially-resolved proteome analysis of individual cells in native tissue. We combined this with a novel strategic cell selection pipeline and a continuous protein gradient mapping framework to investigate larger clinical cohorts. We generated a comprehensive spatial map of the human hepatic proteome by analyzing hundreds of individual hepatocytes from 18 individuals. Among more than 2,500 proteins per cell about half exhibited zonated expression patterns. Cross-species comparison with mouse data revealed conserved metabolic functions and human-specific features of liver zonation. Analysis of fibrotic samples demonstrated widespread disruption of protein zonation, with pericentral proteins being particularly susceptible. Our study provides a comprehensive resource of human liver organization while establishing a broadly applicable framework for spatial proteomics analyses along tissue gradients.

molecular biology↗

Tumor cell villages define the co-dependency of tumor and microenvironment in liver cancer

Spatial cellular context is crucial in shaping intratumor heterogeneity. However, understanding how each tumor establishes its unique spatial landscape and what factors drive the landscape for tumor fitness remains significantly challenging. Here, we analyzed over 2 million cells from 50 tumor biospecimens using spatial single-cell imaging and single-cell RNA sequencing. We developed a deep learning-based strategy to spatially map tumor cell states and the architecture surrounding them, which we referred to as Spatial Dynamics Network (SDN). We found that different tumor cell states may be organized into distinct clusters, or villages, each supported by unique SDNs. Notably, tumor cell villages exhibited village-specific molecular co-dependencies between tumor cells and their microenvironment and were associated with patient outcomes. Perturbation of molecular co-dependencies via random spatial shuffling of the microenvironment resulted in destabilization of the corresponding villages. This study provides new insights into understanding tumor spatial landscape and its impact on tumor aggressiveness.

cancer biology↗

Investigating Cement-Based Surfaces as a Sustainable Flooring Solution to Improve Ascaris Egg Removal and Inactivation in Low-Resource Settings

Soil-transmitted helminths, like Ascaris, are significant contributors to disease burden in low- and middle-income countries (LMICs). Infections are associated with growth faltering and mortality in children and are often transmitted through contact with eggs in fecally contaminated soil. Interventions, like replacing household soil floors with cement-based alternatives, may reduce exposure to Ascaris eggs, but there are currently no estimates on the removal or survival of Ascaris eggs on cement-based surfaces. This study addresses that knowledge gap by evaluating the removal of Ascaris eggs from mopping and the survival of Ascaris eggs on two cement-based mixes: an Ordinary Portland Cement (OPC) mortar and an OPC mortar with fly ash, which provides a more sustainable alternative to the OPC mortar mix. We assessed egg survival at two temperatures representing the dry (15{degrees}C) and wet (34{degrees}C) seasons in Bangladesh using two different egg enumeration methods. After mopping, over 92% of viable eggs were removed from surfaces, with no significant differences between cement-based mixes (p = 0.51). The first-order decay rate constants (k) of Ascaris eggs were similar between mix designs (p = 0.62) but varied significantly between temperatures (p = 4.2 x 10-25) and egg enumeration methods (p = 2.4 x 10-8). The k values were of greater magnitude at 34{degrees}C compared to at 15{degrees}C. At 15{degrees}C, k values were not significantly different from zero, indicating no inactivation. The k values we obtained were comparable to those reported in previous studies for different matrices, indicating comparable inactivation of Ascaris eggs on cement-based surfaces compared to liquid and semi-solid matrices. These results provide some of the first estimates of removal efficiencies and inactivation times in realistic environmental conditions for Ascaris on surfaces while supporting the use of OPC mortar mix designs with fly ash in interventions to reduce Ascaris transmission in rural LMIC households. Author SummarySoil-transmitted helminths, like Ascaris, are parasites that are major contributors to disease in children and women of childbearing age in low- and middle-income countries. Interventions, like replacing soil floors in households with cement-based flooring, may reduce exposure to Ascaris eggs which cause infections, but there is little information on how or why these interventions may be effective. This study investigates the effectiveness of simple cleaning methods, like mopping, in removing Ascaris eggs from cement-based surfaces and explores how long these eggs can survive on these surfaces under different environmental conditions. We tested two types of cement-based surfaces, a traditional cement-based mortar mix, and a more sustainable cement-based mortar mix, and found that mopping removed over 92% of Ascaris eggs, with no differences between cement mixes. Experiments simulating wet and dry seasonal conditions showed that Ascaris eggs survive longer in cooler environments, again with no differences between cement mixes. These findings provide important insights into the role of cement-based flooring in interrupting disease transmission and suggest sustainable cement-based mortar mixes are a feasible alternative to traditional cement-based mortar mixes.

microbiology↗

Evaluating the Survival and Removal of Escherichia coli from Surfaces Made with Traditional and Sustainable Cement-Based Materials in Field-Relevant Conditions

Soil household floors are common in low- and middle-income countries (LMICs) and can serve as reservoirs of enteric pathogens. Cement-based floors may interrupt pathogen transmission, but little is known about pathogen survival or removal from cement-based surfaces. This study investigated the survival of Escherichia coli (E. coli), an indicator of fecal contamination, on cement-based surfaces and evaluated its reduction through common household activities (mopping, sweeping, and walking). We compared E. coli fate on three mixes: 1) Ordinary Portland Cement (OPC) concrete (used in the United States), 2) OPC mortar (used in Bangladesh), and 3) OPC mortar with fly ash (a sustainable alternative to the Bangladesh mix). Additionally, we compared outcomes on cement-based surfaces with and without soil and at two temperatures representing the dry and wet seasons in Bangladesh. After 4 hours on the cement-based surfaces, E. coli decayed more than 1.1 log10(C/Co) under all conditions tested, which is significantly faster than in bulk soils. The higher temperature increased the decay rate constant (p = 5.56*10-8) while soil presence decreased it (p = 2.80*10-6). Sweeping and mopping resulted in high levels of removal for all mixes, with a mean removal of 71% and 78%, respectively, versus 22% for walking. The concrete and mortar mix designs did not impact E. coli survival or removal (p > 0.20). Cement-based floors made with a fly ash mix performed similarly to traditional cement-based floors, supporting its potential use as a more sustainable intervention to reduce fecal contamination in rural LMIC household settings. ImportanceCement-based surfaces may serve as a health intervention to reduce the fecal-oral transmission of pathogens in household settings, but there is a critical lack of evidence about the fate of indicator organisms on these surfaces, especially in field-relevant conditions. This study provides some of the first insights into E. coli survival on cement-based surfaces and the effectiveness of daily activities for removing E. coli. Additionally, this study explores the fate of E. coli on cement-based surfaces made with fly ash (which contributes fewer CO2 emissions) versus traditional cement mixes. We found that E. coli had similar survival and removal across all mix designs, demonstrating that fly ash mixes are feasible for use in household settings (e.g., in floors). The findings enhance understanding of fecal-oral transmission pathways and support the use of fly ash mixes in cement-based flooring in future epidemiologic studies assessing effects on enteric disease burdens.

microbiology↗

Transcriptional responses to priority effects in nectar yeast

Priority effects, where the order and timing of species arrival influence the assembly of ecological communities, have been observed in a variety of taxa and habitats. However, the genetic and molecular basis of priority effects remains unclear in most cases, hindering the mechanistic understanding of priority effects. We sought to gain such understanding for the common nectar yeast Metschnikowia reukaufii, which engages in strong priority effects with other species of nectar yeast, including M. rancensis, another species commonly found in the nectar of our study plant, the hummingbird-pollinated Diplacus (Mimulus) aurantiacus. After inoculation into two contrasting types of synthetic nectar simulating early arrival of M. rancensis, we conducted whole-transcriptome sequencing of 108 genetically diverse strains of M. reukaufii. We found that several genes were differentially expressed in M. reukaufii strains when the nectar had been conditioned by growth of M. rancensis. Many of these genes were associated with amino acid metabolism, consistent with our previous finding that early-arriving species limit late-arriving species growth by reducing amino acid availability. Furthermore, investigation of expression quantitative trait loci (eQTLs) revealed that genes involved in amino acid transport and resistance to antifungal compounds were enriched in genetic variants, with differing effects on gene expression based on priority effects of M. rancensis. These results demonstrate that intraspecific variation in the ability of nectar yeasts to respond to nutrient limitation and direct fungal competition may underpin the molecular mechanisms of priority effects.

ecology↗

Regional specialization manifests in the reliability of neural population codes

The brain has the remarkable ability to learn and guide the performance of complex tasks. Decades of lesion studies suggest that different brain regions perform specialized functions in support of complex behaviors1-3. Yet recent large-scale studies of neural activity reveal similar patterns of activity and encoding distributed widely throughout the brain4-6. How these distributed patterns of activity and encoding are compatible with regional specialization of brain function remains unclear. Two frontal brain regions, the dorsal medial prefrontal cortex (dmPFC) and orbitofrontal cortex (OFC), are a paradigm of this conundrum. In the setting complex behaviors, the dmPFC is necessary for choosing optimal actions2,7,8, whereas the OFC is necessary for waiting for3,9 and learning from2,7,9-12 the outcomes of those actions. Yet both dmPFC and OFC encode both choice- and outcome-related quantities13-20. Here we show that while ensembles of neurons in the dmPFC and OFC of rats encode similar elements of a cognitive task with similar patterns of activity, the two regions differ in when that coding is consistent across trials ("reliable"). In line with the known critical functions of each region, dmPFC activity is more reliable when animals are making choices and less reliable preceding outcomes, whereas OFC activity shows the opposite pattern. Our findings identify the dynamic reliability of neural population codes as a mechanism whereby different brain regions may support distinct cognitive functions despite exhibiting similar patterns of activity and encoding similar quantities.

neuroscience↗

Foraging guild structure of seabirds

An ecological guild is a group of species that exploit the same resources, or that exploit the same or different resources in a related way. We built The Foraging Guilds of Seabirds database (FGSdb) by compiling a global database of 311 seabird species (from a total of 346 known) and assigning to each of them their diet types and foraging strategy. Across all seabirds, there were found 22 diets and 30 strategies. The number of diet categories for a species varied between 1 and 11, and the number of strategies varied from 1 to 9, with averages of 2.71 and 3.65, being the ratio diet/strategies of 0.74 ([~]3/4), meaning that on average with four strategies they can exploit up to 3 diet items. Beyond this description, we show that the Gusein-Zade model fits well both the frequency rank and number of species per guild distributions. Our database and analyses provide a useful resource database for future studies and demonstrate simple rules behind guild structure.

ecology↗

VPS8D, a CORVET subunit, is required to maintain the contractile vacuole complex in Tetrahymena thermophila

Contractile vacuole complexes (CVCs) are complex osmoregulatory organelles, with vesicular (bladder) and tubular (spongiome) subcompartments. The mechanisms that underlie their formation and maintenance within the eukaryotic endomembrane network are poorly understood. In the Ciliate Tetrahymena thermophila, six differentiated CORVETs (class C core vacuole/endosome tethering complexes), with Vps8 subunits designated A-F, are likely to direct endosomal trafficking. Vps8Dp localizes to both bladder and spongiome. We show by inducible knockdown that VPS8D is essential to CVC organization and function. VPS8D knockdown increased susceptibility to osmotic shock, tolerated in the wildtype but triggering irreversible lethal swelling in the mutant. The knockdown rapidly triggered contraction of the spongiome and lengthened the period of the bladder contractile cycle. More prolonged knockdown resulted in disassembly of both the spongiome and bladder, and dispersal of proteins associated with those compartments. In stressed cells where the normally singular bladder is replaced by numerous vesicles bearing bladder markers, Vps8Dp concentrated conspicuously at long-lived inter-vesicle contact sites, consistent with tethering activity. Similarly, Vps8Dp in cell-free preparations accumulated at junctions formed after vacuoles came into close contact. Also consistent with roles for Vps8Dp in tethering and/or fusion were the emergence in knockdown cells of multiple vacuole-related structures, replacing the single bladder. SynopsisIn the Ciliate Tetrahymena thermophila, VPS8D, which encodes a subunit of a non-conventional CORVET complex, is an essential determinant of the contractile vacuole complex (CVC). VPS8D knockdown results in retraction and dispersal of the spongiome, and disappearance of the bladder, reinforcing the view that CVCs arise from endosomal trafficking. Intermediate knockdown phenotypes and Vps8Dp localization support a role in homotypic tethering. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/566071v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@b652c6org.highwire.dtl.DTLVardef@1f456f7org.highwire.dtl.DTLVardef@79ab8dorg.highwire.dtl.DTLVardef@1edbf74_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

De novo designed Hsp70 activator dissolves intracellular condensates

Protein quality control (PQC) is carried out in part by the chaperone Hsp70, in concert with adapters of the J-domain protein (JDP) family. The JDPs, also called Hsp40s, are thought to recruit Hsp70 into complexes with specific client proteins. However, the molecular principles regulating this process are not well understood. We describe the de novo design of a set of Hsp70 binding proteins that either inhibited or stimulated Hsp70s ATPase activity; a stimulating design promoted the refolding of denatured luciferase in vitro, similar to native JDPs. Targeting of this design to intracellular condensates resulted in their nearly complete dissolution. The designs inform our understanding of chaperone structure-function relationships and provide a general and modular way to target PQC systems to condensates and other cellular targets.

biochemistry↗

Activation of the TRIF pathway and downstream targets results in the development of precancerous lesions during infection with Helicobacter.

Helicobacter pylori (H. pylori) infection is an established cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the mechanism by which infection with H. pylori causes these disorders is still not clearly understood. This is due to insufficient knowledge of pathways that promote H. pylori-induced disease progression. We have established a Helicobacter-induced accelerated disease progression mouse model, which involves infecting mice deficient in the myeloid differentiation primary response 88 gene (Myd88-/-) with H. felis. Using this model, we report here that that progression of H. felis-induced inflammation to high-grade dysplasia was associated with activation of type I interferon (IFN-I) signaling pathway and upregulation of related downstream target genes, IFN-stimulated genes (ISGs). These observations were further corroborated by the enrichment of ISRE motifs in the promoters of upregulated genes. Further we showed that H. felis-induced inflammation in mice deficient in Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-{beta} (TRIF, TrifLps2) did not progress to severe gastric pathology, indicating a role of the TRIF signaling pathway in disease pathogenesis and progression. Indeed, survival analysis in gastric biopsy samples from gastric cancer patients illustrated that high expression of Trif was significantly associated with poor survival in gastric cancer.

cancer biology↗

A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling

In the liver, mitochondria are exposed to different concentrations of nutrients due to their spatial positioning across the periportal (PP) and pericentral (PC) axis. How these mitochondria sense and integrate these signals to respond and maintain homeostasis is not known. Here, we combined intravital microscopy, spatial proteomics, and functional assessment to investigate mitochondrial heterogeneity in the context of liver zonation. We found that PP and PC mitochondria are morphologically and functionally distinct; beta-oxidation was elevated in PP regions, while lipid synthesis was predominant in the PC mitochondria. In addition, comparative phosphoproteomics revealed spatially distinct patterns of mitochondrial composition and potential regulation via phosphorylation. Acute pharmacological modulation of nutrient sensing through AMPK and mTOR shifted mitochondrial phenotypes in the PP and PC regions, linking nutrient gradients across the lobule and mitochondrial heterogeneity. This study highlights the role of protein phosphorylation in mitochondrial structure, function, and overall homeostasis in hepatic metabolic zonation. These findings have important implications for liver physiology and disease.

cell biology↗