Biology subjects

Morales, S.

Publications and source records attributed to Morales, S..

10 recordsLinked to original sources

bioRxiv2026

A cross-sectional examination of immune adaptations during pregnancy in the ECHO Cohort

BackgroundPregnancy requires finely tuned immune changes that support implantation, placental development, maternal-fetal tolerance, and preparation for labor, yet the normative trajectories of circulating inflammatory proteins across gestation remain poorly defined. This cross-sectional study investigates how circulating inflammatory proteins vary with gestational age in pregnancy and examines the impacts of fundamental biological characteristics, such as gravidity and fetal sex. MethodsData were drawn from 1154 pregnant individuals from six study sites of the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Cohort. We used Olink high-throughput proteomic profiling to map cross-sectional associations between protein expression levels and gestational age at blood draw using linear, spline-based, and generalized additive modeling approaches. ResultsGeneralized additive models provided the best fit, revealing that immune changes across pregnancy were predominantly nonlinear. Sixty-one proteins showed significant associations with gestational age, with many exhibiting shared inflection points that aligned with major physiological transitions. A small subset of proteins also showed evidence of modification by fetal and maternal characteristics. CD244 displayed different gestational patterns by fetal sex, while CST5 and SIRT2 showed varied gestational associations by maternal gravidity. ConclusionThe findings highlight pregnancy as a sequence of coordinated immune transitions rather than a simple linear shift and provide one of the most detailed characterizations to date of circulating inflammatory protein dynamics across human gestation. Establishing these normative trajectories offers a crucial reference for detecting early deviations that may signal risk for pregnancy complications and for identifying biomarkers in maternal and fetal health research.

immunology↗

bioRxiv2025

Electroencephalography, pupillometry, and behavioral evidence for locus coeruleus-noradrenaline system related tonic hyperactivity in older adults

Neuroimaging studies have shown that age-related dysregulation of the locus coeruleus-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function in vivo, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyper- or hypoactivity, constraining our understanding of underlying mechanisms and hampers the development of targeted preventative interventions. In this study, we tested the hypothesis that cognitively healthy older adults sustain tonic LC hyperactivity, by acquiring electrophysiological, pupillometric, and behavioral measures during a passive and active auditory oddball paradigm. We capitalized on the LC-NA systems role in arousal regulation and manipulated state arousal using the unpredictable threat of electric shock. We hypothesized that if older adults maintain elevated LC activity compared with young adults, task-evoked noradrenergic responses would be less responsive to arousal in older adults. Consistent with this hypothesis, arousal elicited weaker behavioral responses, pupil dilation responses, and P300 event-related potentials in older adults compared with young adults. Linear mixed models revealed an arousal by modality interaction, showing that arousal differentially modulated attentional control to salient but task-irrelevant distractors between both age groups. Collectively, these findings support the hypothesis that aging is associated with tonic LC-NA system hyperactivity in humans, with neuromodulatory consequences for mechanisms of attentional control. Furthermore, the multimodal approach underscores the potential of non-invasive physiological markers to assess LC-NA system function throughout aging and identify individuals at elevated risk for neurodegenerative progression prior to the emergence of clinical biomarkers. Highlights- Behavioral, pupil and EEG data indicate LC-NA tonic hyperactivity in older adults. - Arousal modulates attentional control differently in young vs. older adults. - Older adults show increased distractibility from reduced habituation. - Arousal differentially modulates alpha power and aperiodic activity across age groups. - Phasic noradrenergic responses are modulated by state, arousal, and attention.

neuroscience↗

bioRxiv2024

Flanker task parameters are related to the strength of association between the ERN and anxiety: a meta-analysis

The error-related negativity (ERN)--an index of error monitoring--is associated with anxiety symptomatology. Although recent work suggests associations between the ERN and anxiety are relatively modest, little attention has been paid to how variation in task parameters may influence the strength of ERN-anxiety associations. To close this gap, the current meta-analysis assesses the possible influence of task parameter variation in the Flanker task--the most commonly used task to elicit the ERN--on observed ERN-anxiety associations. Here, we leveraged an existing open database of published/unpublished ERN-anxiety effect sizes, supplementing this database by further coding for variation in stimulus type (letter vs. arrow), response type (one-handed vs. two-handed), and block-level feedback (with vs. without). We then performed meta-regression analyses to assess whether variation in these Flanker task parameters moderated the effect size of ERN-anxiety associations. No evidence for an effect of stimulus type was identified. However, both response type and block-level feedback significantly moderated the magnitude of ERN-anxiety associations. Specifically, studies employing either a two-handed (vs. one-handed) task, or those with (vs. without) block-level feedback exhibited more than a two-fold increase in the estimated ERN-anxiety effect size. Thus, accounting for common variation in task parameters may at least partially explain apparent inconsistencies in the literature regarding the magnitude of ERN-anxiety associations. At a practical level, these data can inform the design of studies seeking to maximize ERN-anxiety associations. At a theoretical level, the results also inform testable hypotheses regarding the exact nature of the association between the ERN and anxiety.

neuroscience↗

bioRxiv2022

Distinct GSDMB protein isoforms and protease cleavage processes differentially control pyroptotic cell death and mitochondrial damage in cancer cells.

The formation of Gasdermin (GSDM) pores, leading to pyroptosis or other context-dependent consequences, is directly involved in multiple diseases. Gasdermin-B (GSDMB) plays complex and controversial roles in pathologies, with pyroptosis-dependent and independent functions. GSDMB is promising oncologic therapeutic target since it exhibits either antitumor function, when immunocyte-mediated Granzyme-A (GZMA) cleaves GSDMB releasing its cytotoxic N-terminal domain, or pro-tumoral activities (invasion, metastasis, and drug resistance). However, it is still unknown the precise regulatory mechanisms of GSDMB pyroptosis as well as the differential effects of the four translated GSDMB variants (GSDMB1-4, that differ in the alternative usage of exons 6-7) in this process. Here, we first prove that exon 6 translation (in the interdomain protein linker) is essential for pyroptosis, and therefore, GSDMB isoforms lacking this exon (GSDMB1-2) cannot provoke cancer cell death. Consistently, in large series of breast cancer samples GSDMB2 expression, and not of exon6-containing variants (GSDMB3-4), associates with unfavourable clinical-pathological parameters. Moreover, cellular, and biochemical analyses combined with confocal, live cell imaging, and electron microscopy studies, demonstrated that diverse GSDMB N-terminal constructs containing exon-6 induce mitochondrial damage (increased mitochondrial ROS, membrane potential loss and mitochondrial DNA release) together with pyroptotic membrane cell lysis. While exon-6 residues are not required for membrane or mitochondrial localization, we also identified other key residues for N-terminal domain cytotoxicity. Additionally, we demonstrated that all GSDMB variants share the cleavage sites for GZMA, Neutrophil Elastase (identified in this study) and caspases. Interestingly, whereas Neutrophil Elastase and caspases produce N-terminal fragments in all GSDMB isoforms with no pyroptotic activity, thus acting as a potential inhibitory mechanism, GZMA cleavage activates pyroptosis in an isoform-dependent way. Summarizing, our results have important implications for understanding the complex roles of GSDMB isoforms in cancer and other pathologies and for the future design of GSDMB-targeted therapies.

molecular biology↗

bioRxiv2021

HAPPILEE: The Harvard Automated Processing Pipeline In Low Electrode Electroencephalography, a standardized software for low density EEG and ERP data

Low-density Electroencephalography (EEG) recordings (e.g. fewer than 32 electrodes) are widely-used in research and clinical practice and enable scalable brain function measurement across a variety of settings and populations. Though a number of automated pipelines have recently been proposed to standardize and optimize EEG preprocessing for high-density systems with state-of-the-art methods, few solutions have emerged that are compatible with low-density systems. However, low-density data often include long recording times and/or large sample sizes that would benefit from similar standardization and automation with contemporary methods. To address this need, we propose the HAPPE In Low Electrode Electroencephalography (HAPPILEE) pipeline as a standardized, automated pipeline optimized for EEG recordings with low density channel layouts of any size. HAPPILEE processes task-free (e.g. resting-state) and task-related EEG, and event-related potential (ERP) data, from raw files through a series of processing steps including filtering, line noise reduction, bad channel detection, artifact rejection from continuous data, segmentation, and bad segment rejection that have all been optimized for low density data. HAPPILEE also includes post-processing reports of data and pipeline quality metrics to facilitate the evaluation and reporting of data quality and processing-related changes to the data in a standardized manner. We describe multiple approaches with both recorded and simulated EEG data to optimize and validate pipeline performance. The HAPPILEE pipeline is freely available as part of HAPPE 2.0 software under the terms of the GNU General Public License at: https://github.com/PINE-Lab/HAPPE.

neuroscience↗

bioRxiv2021

Microbial rhodopsins are increasingly favored over chlorophyll in High Nutrient Low Chlorophyll waters

Microbial rhodopsins are simple light-harvesting complexes that, unlike chlorophyll photosystems, have no iron requirements for their synthesis and phototrophic functions. Here we report the first environmental concentrations of rhodopsin along the Subtropical Frontal Zone off New Zealand, where Subtropical waters encounter the iron-limited Subantarctic High Nutrient Low Chlorophyll (HNLC) region. Rhodopsin concentrations were highest in HNLC waters where chlorophyll-a concentrations were lowest. Furthermore, while the ratio of rhodopsin to chlorophyll-a photosystems was on average 20 along the transect, this ratio increased to over 60 in HNLC waters. We further show that microbial rhodopsins are abundant in both picoplankton (0.2-3m) and in the larger (>3m) size fractions of the microbial community containing eukaryotic plankton and/or particle-attached prokaryotes. These findings suggest that rhodopsin phototrophy could be critical for microbial plankton to adapt to resource-limiting environments where photosynthesis and possibly cellular respiration are impaired. Originality-Significance statementHigh Nutrient Low Chlorophyll (HNLC) regimes cover approximately 30% of the global ocean surface and play a crucial role in the Earths carbon cycle. Here we show that microbial rhodopsins are particularly abundant in a HNLC region of the Subantarctic ocean, where chlorophyll abundance is relatively low and photosynthesis and respiration might be impaired due to iron limitation. These data suggest that rhodopsin phototrophy can contribute significantly to the energy budgets of HNLC regions, capturing meaningful amounts of light that cannot be channeled through photosynthesis.

ecology↗

bioRxiv2020

The Maryland Analysis of Developmental EEG (MADE) Pipeline

Compared to adult EEG, EEG signals recorded from pediatric populations have shorter recording periods and contain more artifact contamination. Therefore, pediatric EEG data necessitate specific preprocessing approaches in order to remove environmental noise and physiological artifacts without losing large amounts of data. However, there is presently a scarcity of standard automated preprocessing pipelines suitable for pediatric EEG. In an effort to achieve greater standardization of EEG preprocessing, and in particular for the analysis of pediatric data, we developed the Maryland Analysis of Developmental EEG (MADE) pipeline as an automated preprocessing pipeline compatible with EEG data recorded with different hardware systems, different populations, levels of artifact contamination, and length of recordings. MADE uses EEGLAB and functions from some EEGLAB plugins, and includes additional customizable features particularly useful for EEG data collected from pediatric populations. MADE processes event-related and resting state EEG from raw data files through a series of preprocessing steps and outputs processed clean data ready to be analyzed in time, frequency, or time-frequency domain. MADE provides a report file at the end of the preprocessing that describes a variety of features of the processed data to facilitate the assessment of the quality of processed data. In this paper we discuss some practical issues, which are specifically relevant to pediatric EEG preprocessing. We also provide custom-written scripts to address these practical issues. MADE is freely available under the terms of the GNU General Public License at https://github.com/ChildDevLab/MADE-EEG-preprocessing-pipeline.

neuroscience↗

bioRxiv2019

Adjusting ADJUST: Optimizing the ADJUST Algorithm for Pediatric Data Using Geodesic Nets

A major challenge for electroencephalograph (EEG) studies on pediatric populations is that large amounts of data are lost due to artifacts (e.g., movement and blinks). Independent component analysis (ICA) can separate artifactual and neural activity, allowing researchers to remove such artifactual activity and retain a greater percentage of EEG data for analyses. However, manual identification of artifactual components is time consuming and requires subjective judgment. Automated algorithms, like ADJUST and ICLabel, have been validated on adults using the international 10-20 system, but to our knowledge no such algorithms have been optimized for the geodesic sensor net, which is often used with infants and children. Therefore, in an attempt to automate artifact selection for pediatric data collected with geodesic nets, we modified ADJUSTs algorithm. Our \"adjusted-ADJUST\" algorithm was compared to the \"original-ADJUST\" algorithm and ICLabel in adults, children, and infants on three different performance measures: respective classification agreement with expert coders, the number of trials retained following artifact removal, and the reliability of the EEG signal after pre-processing with each algorithm. Overall, the adjusted-ADJUST algorithm performed better than the original-ADJUST algorithm and no ICA correction with adult and pediatric data. Moreover, it performed better than ICLabel for pediatric data. These results indicate that optimizing existing algorithms for data collected with a geodesic net improves artifact classification and retains more trials, potentially facilitating EEG studies with pediatric populations.

neuroscience↗

bioRxiv2019

K. pneumoniae ST258 genomic variability and bacteriophage susceptibility

Multidrug resistant carbapenemase-producing Klebsiella pneumoniae capable of causing severe disease in humans is classified as an urgent threat by health agencies worldwide. Bacteriophages are being actively explored as potential therapeutics against these multidrug resistant pathogens. We are currently developing bacteriophage therapy against carbepenem-resistant K. pneumoniae belonging to the genetically diverse, globally disseminated clonal group CG258. In an effort to define a robust experimental approach for effective selection of lytic viruses for therapy, we have fully characterized the bacterial genomes of 18 target strains, tested them against novel lytic bacteriophages, and generated phage-susceptibility profiles. The genomes of K. pneumoniae isolates carrying blaNDM and blaKPC were sequenced and isolates belonging to CG258 were selected for susceptibility testing using a panel of lytic bacteriophages (n=65). The local K. pneumoniae CG258 population was dominated by isolates belonging to sequence type ST258 clade 1 (86%). The primary differences between ST258 genomes were variations in the capsular locus (cps) and in prophage content. We showed that CG258-specific lytic phages primarily target the capsule, and that successful infection is blocked in many, post-adsorption, by immunity conferred by existing prophages. Five bacteriophages specifically active against K. pneumoniae ST258 clade 1 (n=5) belonging to the Caudovirales order were selected for further characterization. Our findings show that effective control of K. pneumoniae CG258 with phage will require mixes of diverse lytic viruses targeting all relevant cps variants and allowing for variable prophage content. These insights will facilitate identification and selection of therapeutic phage candidates against this serious pathogen.\n\nImportanceBacteriophages are natural agents that exclusively and selectively kill bacteria and have the potential to be useful in the treatment of multidrug resistant infections. K. pneumoniae CG258 is a main agent of life-threatening sepsis that is often resistant to last-line antibiotics. Our work highlights some key requirements for developing bacteriophage preparations targeting this pathogen. By defining the genomic profile of our clinical K. pneumoniae CG258 population and matching it with bacteriophage susceptibility patterns, we found that bacteriophage ability to lyse each strain correlates well with K. pneumoniae CG258 structural subtypes (capsule variants). This indicates that preparation of bacteriophage therapeutics targeting this pathogen should aim at including phages against each bacterial capsular subtype. This necessitates a detailed understanding of the diversity of circulating isolates in different geographical areas in order to make rational therapeutic choices.

microbiology↗

bioRxiv2018

Adolescent Cognitive Control, Theta Oscillations, and Social Motivation

Theta oscillations (4-8 Hz) provide an organizing principle of cognitive control, allowing goal-directed behavior that is conserved across species. In human adults, theta power over medial-frontal cortex (MFC) underlies monitoring, whereas theta synchrony between MFC and lateral-frontal regions reflects control recruitment. Prior work has not separated theta before/after motor responses, nor explained how medial-lateral synchrony drives different kinds of control behaviors. Thetas role during adolescence, a developmental window characterized by a motivation-control mismatch also remains unclear, preventing possible cross-species work. Here, adolescents performed a flanker task alone or under observation to increase social motivation. We separated theta dynamics immediately before/after motor responses, identifying functional dissociations. We also dissociate MFC connectivity with rostral/caudal frontal cortex and distinct forms of behavioral control, which further differed before/after response. Finally, social motivation was found to exclusively upregulate post-response error monitoring and changes in control to prevent future errors, as opposed to pre-response theta dynamics.

neuroscience↗