Biology subjects

Morales, M.

Publications and source records attributed to Morales, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Human Accelerated Regions regulate gene networks implicated in apical-to-basal neural progenitor fate transitions

The evolution of the human cerebral cortex involved modifications in the composition and proliferative potential of the neural stem cell (NSC) niche during brain development. Human Accelerated Regions (HARs) exhibit a significant excess of human-specific sequence changes and have been implicated in human brain evolution. Multiple studies support that HARs include neurodevelopmental enhancers with novel activities in humans, but their biological functions in NSCs have not been empirically assessed at scale. Here we conducted a direct-capture Perturb-seq screen repressing 180 neurodevelopmentally active HARs in human iPSC-derived NSCs with single-cell transcriptional readout. After profiling >188,000 NSCs, we identified a set of HAR perturbations with convergent transcriptional effects on gene networks involved in NSC apicobasal polarity, a cellular process whose precise regulation is critical to the developmental emergence of basal radial glia (bRG), a progenitor population that is expanded in humans. Across multiple HAR perturbations, we found convergent dysregulation of specific apicobasal polarity and adherens junction regulators, including PARD3, ABI2, SETD2, and PCM1. We found that the repression of one candidate from the screen, HAR181, as well as its target gene CADM1, disrupted apical PARD3 localization and NSC rosette formation. Our findings reveal interconnected roles for HARs in NSC biology and cortical development and link specific HARs to processes implicated in human cortical expansion.

neuroscience↗

bioRxiv2024

Resolving the three-dimensional interactome of Human Accelerated Regions during human and chimpanzee neurodevelopment

Human Accelerated Regions (HARs) are highly conserved across species but exhibit a significant excess of human-specific sequence changes, suggesting they may have gained novel functions in human evolution. HARs include transcriptional enhancers with human-specific activity and have been implicated in the evolution of the human brain. However, our understanding of how HARs contributed to uniquely human features of the brain is hindered by a lack of insight into the genes and pathways that HARs regulate. It is unclear whether HARs acted by altering the expression of gene targets conserved between HARs and their chimpanzee orthologs or by gaining new gene targets in human, a mechanism termed enhancer hijacking. We generated a high-resolution map of chromatin interactions for 1,590 HARs and their orthologs in human and chimpanzee neural stem cells (NSCs) to comprehensively identify gene targets in both species. HARs and their chimpanzee orthologs targeted a conserved set of 2,963 genes enriched for neurodevelopmental processes including neurogenesis and synaptic transmission. Changes in HAR enhancer activity were correlated with changes in conserved gene target expression. Conserved targets were enriched among genes differentially expressed between human and chimpanzee NSCs or between human and non-human primate developing and adult brain. Species-specific HAR gene targets did not converge on known biological functions and were not significantly enriched among differentially expressed genes, suggesting that HARs did not alter gene expression via enhancer hijacking. HAR gene targets, including differentially expressed targets, also showed cell type-specific expression patterns in the developing human brain, including outer radial glia, which are hypothesized to contribute to human cortical expansion. Our findings support that HARs influenced human brain evolution by altering the expression of conserved gene targets and provide the means to functionally link HARs with novel human brain features.

genomics↗

bioRxiv2024

High-Throughput Phenotyping of Seed Quality Traits Using Imaging and Deep Learning in Dry Pea

Seed traits, such as seed color and seed size, directly impact seed quality, affecting the marketability and value of dry peas [1]. Assessing seed quality is integral to a plant breeding programs to ensure optimal seed standards. This research introduced a phenotyping tool to assess seed quality traits specifically tailored for pulse crops, which integrates image processing with cutting-edge deep learning models. The proposed method is designed for automation, seamlessly processing a sequence of images while minimizing human intervention. The pipeline standardized red-green-blue (RGB) images captured from a color light box and used deep learning models to segment and detect seed features. Our method extracted up to 86 distinct seed characteristics, ranging from basic size metrics to intricate texture details and color nuances. Compared to traditional methods, our pipeline demonstrated a 95 percent similarity in seed quality assessment and increased time efficiency (from 2 weeks to 30 minutes for processing time). Specifically, we observed an improvement in the accuracy of seed trait identification by simply using an RGB value instead of a categorical, non-standard description, which allowed for an increase in the range of detectable seed quality characteristics. By integrating conventional image processing techniques with foundational deep learning models, this approach emerges as a pivotal instrument in pulse breeding programs, guaranteeing the maintenance of superior seed quality standards.

plant biology↗

bioRxiv2024

Vitamin D is Glucoprotective in Aging Males but Not Females

Type 2 diabetes is strongly linked to vitamin D deficiency in older adults. However, there is a discrepancy between clinical trials in adults on the efficacy of vitamin D treatment in prediabetes and diabetes. In addition, human data indicates there may be sexual dimorphism in the effect of vitamin D deficiency on dysglycemia that is more pronounced in men. These incongruities may be due to our limited understanding of the underlying mechanisms of vitamin D in glucose homeostasis among its vast target tissues across the body. Furthermore, vitamin D deficiency is diagnosed by low levels of a storage form of vitamin D, which may not be an accurate indicator of vitamin D status in these individuals. Thus, measuring expression levels of vitamin D receptor (VDR)-target genes across tissues involved in glucose regulation and vitamin D pathways may be a more promising marker of vitamin D status. Here we describe the sex-specific physiological effects of vitamin D supplementation in an aged, non-obese mouse model on glucose homeostasis and tissue-specific gene regulation.

physiology↗

bioRxiv2023

Niche Availability and Competitive Facilitation Control Proliferation of Bacterial Strains Intended for Soil Microbiome Interventions

Microbiome engineering, the rational manipulation of microbial communities and their habitats, is considered a crucial strategy to revert dysbiosis. However, the concept is in its infancy and lacks experimental support. Here we study the ecological factors controlling the proliferation of focal bacterial inoculants into taxa-complex soil communities and their impact on resident microbiota. We demonstrate using standardized soil microbiomes with different growth phases that the proliferation of typical soil inoculants depends on niche competition. By adding an artificial, inoculant selective niche to soil we improve inoculant proliferation and show by metatranscriptomics to give rise to a conjoint metabolic network in the soil microbiome. Furthermore, using random paired growth assays we demonstrate that, in addition to direct competition, inoculants lose competitiveness with soil bacteria because of metabolite sharing. Thus, the fate of inoculants in soil is controlled by niche availability and competitive facilitation, which may be manipulated by selective niche generation. TeaserTypical bacterial inoculants for soil microbiome engineering suffer from facilitating growth of native resident microorganisms

ecology↗

bioRxiv2023

Intercellular contact and cargo transfer between Müller glia and to microglia precede apoptotic cell clearance in the developing retina

To clarify our understanding of glial phagocytosis in retinal development, we used real-time imaging of larval zebrafish to provide cell-type specific resolution of this process. We show that radial Muller glia frequently participate in microglial phagocytosis while also completing a subset of phagocytic events. Muller glia (MG) actively engage with dying cells through initial target cell contact and phagocytic cup formation after which an exchange of the dying cell from MG to microglia often takes place. Additionally, we find evidence that Muller glia cellular material, possibly from the initial Muller cells phagocytic cup, is internalized into microglial compartments. Previously undescribed Muller cell behaviors were seen, including cargo splitting, wrestling for targets, lateral passing of cargo to neighbors, and engulfment of what is possibly synaptic puncta. Collectively, our work provides new insight into glial functions and intercellular interactions, which will allow future work to understand these behaviors on a molecular level. Summary StatementReal-time imaging of developing zebrafish retinas reveals intercellular exchanges between Muller glial cells and to microglia during the clearance of apoptotic cells.

developmental biology↗

bioRxiv2023

Incomplete dosage balance and dosage compensation in the ZZ/ZW Gila monster (Heloderma suspectum) revealed by de novo genome assembly

Reptiles exhibit a variety of modes of sex determination, including both temperature-dependent and genetic mechanisms. Among those species with genetic sex determination, sex chromosomes of varying heterogamety (XX/XY and ZZ/ZW) have been observed with different degrees of differentiation. Karyotype studies have demonstrated that Gila monsters (Heloderma suspectum) have ZZ/ZW sex determination and this system is likely homologous to the ZZ/ZW system in the Komodo dragon (Varanus komodoensis), but little else is known about their sex chromosomes. Here, we report the assembly and analysis of the Gila monster genome. We generated a de novo draft genome assembly for a male using 10X Genomics technology. We further generated and analyzed short-read whole genome sequencing and whole transcriptome sequencing data for three males and three females. By comparing female and male genomic data, we identified four putative Z-chromosome scaffolds. These putative Z-chromosome scaffolds are homologous to Z-linked scaffolds identified in the Komodo dragon. Further, by analyzing RNAseq data, we observed evidence of incomplete dosage compensation between the Gila monster Z chromosome and autosomes and a lack of balance in Z-linked expression between the sexes. In particular, we observe lower expression of the Z in females (ZW) than males (ZZ) on a global basis, though we find evidence suggesting local gene-by-gene compensation. This pattern has been observed in most other ZZ/ZW systems studied to date and may represent a general pattern for female heterogamety in vertebrates.

evolutionary biology↗

bioRxiv2022

A common neural code for meaning in discourse production and comprehension

How does the brain code the meanings conveyed by language? Neuroimaging studies have investigated this by linking neural activity patterns during discourse comprehension to semantic models of language content. Here, we applied this approach to the production of discourse for the first time. Participants underwent fMRI while producing and listening to discourse on a range of topics. We used a distributional semantic model to quantify the similarity between different speech passages and identified where similarity in neural activity was predicted by semantic similarity. When people produced discourse, speech on similar topics elicited similar activation patterns in a widely distributed and bilateral brain network. This network was overlapping with, but more extensive than, the regions that showed similarity effects during comprehension. Critically, cross-task neural similarities between comprehension and production were also predicted by similarities in semantic content. This result suggests that discourse semantics engages a common neural code that is shared between comprehension and production. Effects of semantic similarity were bilateral in all three RSA analyses, even while univariate activation contrasts in the same data indicated left-lateralised BOLD responses. This indicates that right-hemisphere regions encode semantic properties even when they are not activated above baseline. We suggest that right-hemisphere regions play a supporting role in processing the meaning of discourse during both comprehension and production.

neuroscience↗

bioRxiv2022

A greenhouse-based high-throughput phenotyping platform for identification and genetic dissection of resistance to Aphanomyces root rot in field pea

Aphanomyces root rot (ARR) is a devastating disease in field pea (Pisum sativum L.) that can cause up to 100% crop failure. Assessment of ARR resistance can be a rigorous, costly, time-demanding activity that is relatively low-throughput and prone to human errors. These limits the ability to effectively and efficiently phenotype the disease symptoms arising from ARR infection, which remains a perennial bottleneck to the successful evaluation and incorporation of disease resistance into new cultivars. In this study, we developed a greenhouse-based high throughput phenotyping (HTP) platform that moves along the rails above the greenhouse benches and captures the visual symptoms caused by Aphanomyces euteiches in field pea. We pilot tested this platform alongside with conventional visual scoring in five experimental trials under greenhouse conditions, assaying over 12,600 single plants. Precision estimated through broad-sense heritability (H2) was consistently higher for the HTP-indices (H2 Exg =0.86) than the traditional visual scores (H2 DSI=0.59), potentially increasing the power of genetic mapping. We genetically dissected variation for ARR resistance using the HTP-indices, and identified a total of 260 associated single nucleotide polymorphism (SNP) through genome-wide association (GWA) mapping. The number of associated SNP for HTP-indices was consistently higher with some SNP overlapped to the associated SNP identified using the visual scores. We identified numerous small-effect QTLs, with the most significant SNP explaining about 5 to 9% of the phenotypic variance per index, and identified previously mapped genes known to be involved in the biological pathways that trigger immunity against ARR, including Psat5g280480, Psat5g282800, Psat5g282880, and Psat2g167800. We also identified a few novel QTLs with small-effect sizes that may be worthy of validation in the future. The newly identified QTLs and underlying genes, along with genotypes with promising resistance identified in this study, can be useful for improving a long-term, durable resistance to ARR.

pathology↗

bioRxiv2022

Precipitation is the main axis of tropical phylogenetic turnover across space and time

Early natural historians - Compte de Buffon, von Humboldt and De Candolle - established ecology and geography as two principal axes determining the distribution of groups of organisms, laying the foundations for biogeography over the subsequent 200 years, yet the relative importance of these two axes remains unresolved. Leveraging phylogenomic and global species distribution data for Mimosoid legumes, an pantropical plant clade of 3,400 species, we show that the water availability gradient from deserts to rainforests dictates turnover of lineages within continents across the tropics. We demonstrate that 95% of speciation occurs within a precipitation niche, showing profound phylogenetic niche conservatism, and that lineage turnover boundaries coincide with isohyets of precipitation. We reveal similar patterns on different continents, implying that evolution and dispersal follow universal processes.

evolutionary biology↗

bioRxiv2022

The SARS-CoV-2 spike protein binds and modulates estrogen receptors

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 (ACE2) at the cell surface, which constitutes the primary mechanism driving SARS-CoV-2 infection. Molecular interactions between the transduced S and endogenous proteins likely occur post-infection, but such interactions are not well understood. We used an unbiased primary screen to profile the binding of full-length S against >9,000 human proteins and found significant S-host protein interactions, including one between S and human estrogen receptor alpha (ER). After confirming this interaction in a secondary assay, we used bioinformatics, supercomputing, and experimental assays to identify a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit and an S-ER binding mode. In cultured cells, S DNA transfection increased ER cytoplasmic accumulation, and S treatment induced ER-dependent biological effects and ACE2 expression. Noninvasive multimodal PET/CT imaging in SARS-CoV-2-infected hamsters using [18F]fluoroestradiol (FES) localized lung pathology with increased ER lung levels. Postmortem experiments in lung tissues from SARS-CoV-2-infected hamsters and humans confirmed an increase in cytoplasmic ER expression and its colocalization with S protein in alveolar macrophages. These findings describe the discovery and characterization of a novel S-ER interaction, imply a role for S as an NRC, and are poised to advance knowledge of SARS-CoV-2 biology, COVID-19 pathology, and mechanisms of sex differences in the pathology of infectious disease.

immunology↗

bioRxiv2022

Multi-trait genomic prediction improves selection accuracy for enhancing seed mineral concentrations in pea (Pisum sativum L.)

The superiority of multi-trait genomic selection (MT-GS) over univariate genomic selection (UNI-GS) can be improved by redesigning the phenotyping strategy. In this study, we used about 300 advanced breeding lines from North Dakota State University (NDSU) pulse breeding program and about 200 USDA accessions evaluated for ten nutritional traits to assess the efficiency of sparse testing in MT-GS. Our results showed that sparse phenotyping using MT-GS consistently outperformed UNI-GS when compared to partially balanced phenotyping using MT-GS. This strategy can be further extended to multi-environment multi-trait GS to improve prediction performance and reduce the cost of phenotyping and time-consuming data collection process. Given that MT-GS relies on borrowing information from genetically correlated traits and relatives, consideration should be given to trait combinations in the training and prediction sets to improve model parameters estimate and ultimately prediction performance. Our results point to heritability and genetic correlation between traits as possible parameters to achieve this objective.

genetics↗

bioRxiv2022

Modulation of brain activity by psycholinguistic information during naturalistic speech comprehension and production

Language processing requires the integration of diverse sources of information across multiple levels of processing. A range of psycholinguistic properties have been documented in previous studies as having influence on brain activation during language processing. However, most of those studies have used factorial designs to probe the effect of one or two individual properties using highly controlled stimuli and experimental paradigms. Little is known about the neural correlates of psycholinguistic properties in more naturalistic discourse, especially during language production. The aim of our study is to explore the above issues in a rich fMRI dataset in which participants both listened to recorded passages of discourse and produced their own narrative discourse in response to prompts. Specifically, we measured 13 psycholinguistic properties of the discourse comprehended or produced by the participants, and we used principal components analysis (PCA) to address covariation in these properties and extract a smaller set of latent language characteristics. These latent components indexed vocabulary complexity, sensory-motor and emotional language content, discourse coherence and speech quantity. A parametric approach was adopted to study the effects of these psycholinguistic variables on brain activation during comprehension and production. We found that the pattern of effects across the cortex was somewhat convergent across comprehension and production. However, the degree of convergence varied across language properties, being strongest for the component indexing sensory-motor language content. We report the full, unthresholded effect maps for each psycholinguistic variable, as well as mapping how these effects change along a large-scale cortical gradient of brain function. We believe that our findings provide a valuable starting point for future, confirmatory studies of discourse processing.

neuroscience↗

bioRxiv2022

Sub-second striatal dopamine dynamics assessed by simultaneous fast-scan cyclic voltammetry and fluorescence biosensor

Dopamine produces neuromodulation throughout the basal ganglia, cortex and other brain regions, and is implicated in movement control, neural mechanisms of reward and actions of misused substances. The efferent projections of dopaminergic neurons with somata in the substantia nigra pars compacta and ventral tegmental area strongly innervate different striatal subregions. While much is known about the function of these neurons, there is a relative deficiency of information about in vivo dopamine dynamics in the nigrostriatal projections, especially those to the dorsolateral striatum (DLS). In past studies, subsecond dopamine changes were measured predominantly with fast-scan cyclic voltammetry (FSCV) both in brain slices and in vivo. However, traditional FSCV has limitations in discriminating among catecholamines, and cannot be used for simultaneous measurement of both slow and fast/phasic dopamine changes. In addition, FSCV has been most useful for measuring dopamine in the ventral striatum in vivo with less utility for measurement in dorsolateral striatum. The development of genetically encoded dopamine sensors has provided a new approach to measuring slow and fast dopamine dynamics both in brain slices and in vivo, raising the hope of more facile measurement of in vivo dopamine measurements, including in areas where measurement was previously difficult with FSCV. To this end, we first evaluated dLight photometry in brain slices with simultaneous FSCV. We found that both techniques yielded comparable findings. However, differences were noted in responses to dopamine transporter inhibitors, including cocaine. We then used in vivo fiber photometry with dLight to examine responses to cocaine in DLS and compared responses during Pavlovian conditioning in DLS to two other striatal subregions. These experiments show that dopamine increases are readily detectable in DLS and provide new information about dopamine transient kinetics and slowly developing signaling during conditioning. Overall, our findings indicate that dLight photometry is well suited to measuring dopamine dynamics in a striatal region of great interest where such measurements were difficult previously.

neuroscience↗

bioRxiv2021

The information signature of diverging lineages

Divergence and speciation are the generators of biodiversity on Earth. Yet, we still seek to understand why species are unevenly distributed across taxa and geographic settings. This is partly because we lack a way to directly compare aspects of population divergence across unrelated species and an integrative quantitative framework for how geographical setting relates to genetic divergence. Here we postulate that, based on communications theory, there is a communications channel between Earths surface and the structuring of genomic information among populations. Each species is a separate receiver of this message. Organism traits determine the clarity of that channel. Calculating the partial information decomposition (PID) of genetic metrics under different evolutionary scenarios can measure the signature of this communication. We show in silico how the informational decomposition of 97,200 genetic lattices varies as lineages diverge. The decomposed nodes of Tajimas D, {theta}W, and {pi} show strong context-dependent information signatures, while FST was least informative. Specific decompositions detected whether lineages divergence with or without gene flow better than current SFS-based tools. The study of information in an evolutionary genomic and landscape context suggests it may be a helpful framework and for understanding the diversity of life across Earth and their coevolution.

evolutionary biology↗

bioRxiv2021

Similar neural networks respond to coherence during comprehension and production of discourse

When comprehending discourse, listeners engage default mode regions associated with integrative semantic processing to construct a situation model of its content. We investigated how similar networks are engaged when we produce, as well as comprehend, discourse. During fMRI, participants spoke about a series of specific topics and listened to discourse on other topics. We tested how activation was predicted by natural fluctuations in the global coherence of the discourse, i.e., the degree to which utterances conformed to the expected topic. The neural correlates of coherence were similar across speaking and listening, particularly in default mode regions. This network showed greater activation when less coherent speech was heard or produced, reflecting updating of mental representations when discourse did not conform to the expected topic. In contrast, regions that exert control over semantic activation showed task-specific effects, correlating negatively with coherence during listening but not during production. Participants who showed greater activation in left inferior prefrontal cortex also produced more coherent discourse, suggesting a specific role for this region in goal-directed regulation of speech content. Results suggest strong correspondence of discourse representations during speaking and listening. However, they indicate that the semantic control network plays different roles in comprehension and production.

neuroscience↗

bioRxiv2021

DeepStrain: A Deep Learning Workflow for the Automated Characterization of Cardiac Mechanics

Myocardial strain analysis from cinematic magnetic resonance imaging (cine-MRI) data could provide a more thorough characterization of cardiac mechanics than volumetric parameters such as left-ventricular ejection fraction, but sources of variation including segmentation and motion estimation have limited its wide clinical use. We designed and validated a deep learning (DL) workflow to generate both volumetric parameters and strain measures from cine-MRI data, including strain rate (SR) and regional strain polar maps, consisting of segmentation and motion estimation convolutional neural networks developed and trained using healthy and cardiovascular disease (CVD) subjects (n=150). DL-based volumetric parameters were correlated (>0.98) and without significant bias relative to parameters derived from manual segmentations in 50 healthy and CVD subjects. Compared to landmarks manually-tracked on tagging-MRI images from 15 healthy subjects, landmark deformation using DL-based motion estimates from paired cine-MRI data resulted in an end-point-error of 2.9 {+/-} 1.5 mm. Measures of end-systolic global strain from these cine-MRI data showed no significant biases relative to a tagging-MRI reference method. On 4 healthy subjects, intraclass correlation coefficient for intra-scanner repeatability was excellent (>0.95) for strain, moderate to excellent for SR (0.690-0.963), and good to excellent (0.826-0.994) in most polar map segments. Absolute relative change was within ~5% for strain, within ~10% for SR, and <1% in half of polar map segments. In conclusion, we developed and evaluated a DL-based, end-to-end fully-automatic workflow for global and regional myocardial strain analysis to quantitatively characterize cardiac mechanics of healthy and CVD subjects based on ubiquitously acquired cine-MRI data.

bioinformatics↗

bioRxiv2020

A diencephalic circuit for opioid analgesia but not positive reinforcement

Mu opioid receptor (MOR) agonists are potent analgesics, but also cause sedation, respiratory depression, and addiction risk. The epithalamic lateral habenula (LHb) signals aversive states including pain and we found it is a potent site for MOR-agonist analgesia. Importantly, LHb MOR activation is not reinforcing in the absence of noxious input. The LHb receives excitatory inputs from multiple sites including the ventral tegmental area, lateral hypothalamus, entopeduncular nucleus, and the lateral preoptic area of the hypothalamus (LPO). Here we report that LHb-projecting glutamatergic LPO neurons are excited by noxious stimulation and are preferentially inhibited by MOR selective agonists. Critically, optogenetic stimulation of LHb-projecting LPO neurons produces an aversive state that is relieved by LHb MOR activation, and optogenetic inhibition of LHb-projecting LPO neurons relieves the aversiveness of ongoing pain. Therefore, targeting this MOR sensitive forebrain circuit can relieve pain yet lower the risk of misuse by pain free individuals.

neuroscience↗