bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of rice-based gluten-free muffins enriched with tigernut
dietary fiber
Authors: Na Yoo-Jin , Olawuyi Ibukunoluwa Fola , Cho Ha-Seong , Said Nurul Saadah Binti , Lee Wonyoung
Published: January 2024

The effects of tigernut dietary fiber (TDF: 5, 10, and 20% w/w) inclusion
in rice muffin formulations on the functional and pasting properties of
composite powders, as well as the nutritional and sensory properties of muffins
were investigated. The results showed a significant (p<0.05) proportional
increase in the water and oil holding capacity as TDF increased in the powder
blends. Moreover, pasting viscosity was found to decrease with the inclusion of
TDF. TDF muffins showed improved nutritional quality, with increased protein
(~14%), insoluble fiber (~128%) and total fiber
(~34%) contents compared to 100% rice muffins. Also,
TDF-muffins had lower baking losses (~22%) and better texture,
including firmness and chewiness. Sensory scores of TDF-muffins (up to
10% w/w) showed similar consumer acceptability for all parameters
considered. Overall, this study suggests tigernut fiber as a functional additive
that balances the growing consumers’ demands for healthy and quality
gluten-free rice muffins.
Influence of social determinants of health on quality of life in patients with multimorbidity
Authors: Ruiz-Baena José María , Moreno-Juste Aida , Poblador-Plou Beatriz , Castillo-Jimena Marcos , Calderón-Larrañaga Amaia , Lozano-Hernández Cristina , Gimeno-Miguel Antonio , Gimeno-Feliú Luis A ,   MULTIPAP GROUP
Published: January 2024

Background

Multimorbidity, especially among older patients, is one of the biggest challenges faced by modern medicine, and is influenced by social determinants of health, giving rise to health inequalities in the population. Here, we sought to determine the influence of social determinants of health on quality of life in patients with multimorbidity.

Methods and Materials

This cross-sectional observational study included 573 patients aged 65–74 with multimorbidity (≥3 diseases) and polypharmacy (≥5 drugs). Corresponding data was taken drawn from the Spanish MULTIPAP study, and included social and demographic variables, and data on health-related quality of life and overall self-perceived health status, assessed using the 5-level version of the EuroQol 5-dimensional questionnaire (EQ-5D-5L). Descriptive, bivariate and multivariate analyses with logistic regression models were performed.

Results

Mean patient age was 69.7 years, 55.8% of patients were female, 59.7% belonged to low social classes (V, VI), a monthly income of 1051–€1850 predominated, and the median number of diseases in the same patient was 6. Factors associated with higher quality of life were male gender (OR=1.599, p=0.013), a higher educational level (OR=1.991, p=0.036), an absence of urban vulnerability (OR=1.605, p=0.017), and the presence of medium social support (OR=1.689, p=0.017). Having a higher number of diseases was associated with poorer quality of life (OR=0.912, p=0.017).

Conclusions

Our findings describe associations between social determinants of health and quality of life in patients aged 65–74 years with multimorbidity and polypharmacy. More illnesses, female gender, a lower education level, urban vulnerability, and less social support are associated with poorer quality of life, underscoring the need for a biopsychosocial approach in patient care.
Unveiling the regulatory role of GRP7 in ABA signal-mediated mRNA translation efficiency regulation
Authors: Zhang Jing , Xu Yongxin , Tian Fa’an , He Chongsheng , Yu Xiang , Yang Xiaofei , Ding Yiliang , Xiao Jun
Published: January 2024

Abscisic acid (ABA) is a crucial phytohormone involved in plant growth and stress responses. Although ABA has been implicated in the regulation of translation efficiency inArabidopsis thaliana, the underlying mechanism remains largely unknown. In this study, we discovered that ABA treatment modulates globally translation efficiency (TE) by affecting pre-rRNA processing in the nucleolus and ribosome distribution status in the cytoplasm. The regulation of TE by ABA was largely abolished in mutants of ABA signaling core components, such as receptors PYRABACTIN RESISTANCE1/PYRABACTIN-LIKE/REGULATORY COMPONENTS OF ABA RECEPTORS (PYR/PYL/RACRs), the protein phosphatase 2Cs (PP2Cs), and the SNF1-related protein kinase 2s (SnRK2s). ABA treatment reduced the protein levels of glycine-rich RNA binding protein 7 (GRP7) in the signaling core components-dependent manner. Ribo-seq and CLIP-seq analyses unveiled GRP7’s role in governing the TE of a substantial proportion of ABA-regulated genes, although independent of directly binding to the respective mRNAs. Furthermore, GRP7 directly bound to pre-rRNA and interacted with Ribosomal protein S6 (RPS6A), RPS14A and RPL36aA in the nucleolus to regulate rRNA processing. Additionally, GRP7 associated with mature polysome in the cytoplasm and is hypersensitive to translation inhibitor anisomycin when loss of function. Collectively, our study unveils the role of GRP7 in mediating translation regulation in ABA signaling, providing a novel regulatory model for plants to response to environmental stresses.
Beta2-Adrenergic Agonists in Treatment for Parkinsonism, with Implications for Neurodegenerative and Neoplastic Disorders
Authors: Inchiosa Mario A.
Published: January 2024

There is a long record of observations suggesting that β2-adrenergic agonists may have therapeutic value in Parkinson’s disease. Recent studies have focused on the possible role of β2-receptor agonists in suppressing the formation of α-synuclein protein, the component of Lewy bodies. Levalbuterol, the pure levo isomer of the β2 selective agonist, albuterol, has been found to possess significant anti-inflammatory activity, a property that may have the potential to suppress cytokine mediated degeneration of dopaminergic neurons and progression of Parkinsonism. All the β2 agonist and anti-inflammatory activities of albuterol reside in the levo isomer. The dextro isomer of albuterol substantially negates the efficacies of the levo form. Epinephrine, the prototypical β2 agonist and certain other adrenergic agents, when modeled in the Harvard/MIT Broad Institute genomic database, CLUE, demonstrated strong associations with the gene-expression signatures of drugs possessing glucocorticoid receptor agonist activity. Gene-expression signatures generated by the interaction of the adrenergic drugs of interest in 8 human tumor cell lines were compared with the entire CLUE database of more than 8,000 agents. The signatures were summarized for their consistency (connectivity) across all 8 cell lines and ranked for their relative degree of similarity to the agents in the database. Possible associations with anti-inflammatory activity of glucocorticoids promptedin vivobiological confirmation for levalbuterol and related agonists in the Jackson Laboratory human peripheral blood mononuclear cell (PBMC)-engrafted mouse. Levalbuterol inhibited the release of the eosinophil attractant chemokine, eotaxin-1 (specifically, CCL11), when the mice were challenged with mononuclear antibodies known to provoke cytokine release. Eotaxin is implicated in CNS and peripheral inflammatory disorders. Also, elaboration of the broad tumor-promoting angiogenic factor, VEGFa, and the pro-inflammatory cytokine, IL-13, from activated PBMCs were also inhibited by levalbuterol. These observations suggest possible translation to Parkinson’s disease, other neurodegenerative syndromes, and malignancies, by several mechanisms.
Annexin A1, Calreticulin and High Mobility Group Box 1 are elevated in Secondary Progressive Multiple Sclerosis: Does Immunogenic Cell Death Occur in Multiple Sclerosis?
Authors: Hejazi Mohammad Saeid , Jafari Sevda , Montazersaheb Soheila , Molavi Ommoleila , Hoseini Vahid , Talebi Mahnaz , Nikanfar Masoud
Published: January 2024

Multiple sclerosis (MS) is a chronic neuroinflammatory diseases characterized by demyelination of the nerve fibers. Immunogenic cell death (ICD) is a process, during which damaged and stressed cells release danger-associated molecular patterns (DAMPs) activating immune responses. This study aimed to elucidate the induction of ICD in MS diseases. To achieve this goal, the level of DAMPs including Annexin A1, calreticulin and HMGB1 was measured in the cerebrospinal fluid (CSF) of a secondary progressive multiple sclerosis (SPMS) patient in comparison to control group. Results showed significant upregulation (more than two- fold) of Annexin A1, calreticulin and HMGB1 in the CSF of the patient. Although further studies are suggested in this regard, this data could imply induction of ICD in MS. The proposed ICD might trigger immune response against neural cells resulting in neuroinflammation and demyelination in CNS in MS. Our observation could suggest inclusion of ICD interfering treatments in routine MS therapy.
Early pancreatic tissue necrosis diagnoses by perfusion CT; the study K-Pa
Authors: Herpe Guillaume , Renaud Claire , Tasu Jean-Pierre
Published: January 2024

PURPOSE

Acute pancreatitis (AP) is associated with high mortality and morbidity rates in case of necrotic forms. Risk assessment should be early performed to stratify patients into higher- and lower-risk of severe form to assist triage. In severe pancreatitis, capillary permeability increases, thereby contributing to capillary leakage which explains organ failures and or tissue necrosis. The aim of this study was therefore to evaluate pancreatic permeability by perfusion CT (pCT).

METHODS

From March 2018 to November 2018, patients with suspected AP and who underwent CT at admission were prospectively included. AP cases were classified according to the revised Atlanta classification. A permeability parameter, called k-trans, was measured from pCT in 3 pancreatic areas (normal parenchyma zone, defined by an area of normal CT pattern, pathological zone, defined as an area of parenchymal enlargement and or lack of enhancement and an intermediary zone defined by an area between normal and pathological areas) by to two observers. K-trans values in necrotic and interstitial forms for each zone were compared. To estimate reproducibility of the measure, inter-observer and intra-observer agreement was evaluated by a Bland and Altman test.

RESULTS

15 patients were enrolled (mean age 45.50 years old, +/-17.70). Four acute pancreatitis were necrotic, and 11 interstitial.

Mean k-trans in pathologic zone of necrotic forms was significantly lower (mean=0.08) than in interstitial (mean=0.53), p= 0.0003. In both forms, k-trans values were significantly lower in pathologic zones than in intermediary and normal zones and the higher k-trans values were obtained in intermediary zones. Intra-observer reproducibility was good. Inter-observer reproducibility was acceptable, one bias was reported, close to zero (−0.052) with limited statistic difference.

CONCLUSION

K-trans parameter, a well-known marker of tissue permeability, can be estimated by pCT. This parameter seems to be linked to local necrosis and could be used as a discriminant mean to diagnose necrotic from interstitial types of AP in the early phase of disease.
Blood transcriptomics reveal persistent SARS-CoV-2 RNA and candidate biomarkers in Long COVID patients
Authors: Menezes Soraya Maria , Jamoulle Marc , Carletto Maria Paula , Moens Leen , Meyts Isabelle , Maes Piet , Van Weyenbergh Johan
Published: January 2024

With an estimated 65 million individuals suffering from Long COVID, validated therapeutic strategies as well as non-invasive biomarkers are direly needed to guide clinical management. We used blood digital transcriptomics in search of viral persistence and Long COVID diagnostic biomarkers in a real-world, general practice-based setting with a long clinical follow-up. We demonstrate systemic SARS-CoV-2 persistence for more than 2 years after acute COVID-19 infection. A 2-gene biomarker, includingFYNand SARS-CoV-2 antisense RNA, correctly classifies Long COVID with 93.8% sensitivity and 91.7% specificity. Specific immune transcripts and immunometabolism score correlate to systemic viral load and patient-reported anxiety/depression, providing mechanistic links as well as therapeutic targets to tackle Long COVID.
Clonal haematopoiesis is associated with major adverse cardiovascular events in patients with hypertrophic cardiomyopathy
Authors: Scolari Fernando L. , Brahmbhatt Darshan , Abelson Sagi , Lee Deacon , Kim Raymond H , Pedarzadeh Ali , Sakhnini Ali , Adler Arnon , Chan Raymond H , Dick John , Rakowski Harry , Billia Filio
Published: January 2024

Background & Aims

The heterogeneous phenotype of hypertrophic cardiomyopathy (HCM) is still not fully understood. Clonal haematopoiesis (CH) is emerging as a cardiovascular risk factor potentially associated with adverse clinical events. The prevalence, phenotype and outcomes related to CH in HCM patients was evaluated.

Methods

Patients with HCM and available biospecimens from the Peter Munk Cardiac Centre Cardiovascular Biobank were subjected to targeted sequencing for 35 myeloid genes associated with CH. CH prevalence, clinical characteristics, morphological phenotypes assessed by echocardiogram and cardiac magnetic resonance and outcomes were assessed. All patients were evaluated for a 71-plex cytokines/chemokines, troponin I and B-type natriuretic peptide analysis. Major cardiovascular events (MACE) were defined as appropriate ICD shock, stroke, cardiac arrest, orthotopic heart transplant and death.

Results

Among the 799 patients, CH was found in 183 (22.9%) HCM patients with sarcomeric germline mutations. HCM patients with CH were more symptomatic and with a higher burden of fibrosis than those without CH. CH was associated with MACE in those HCM patients with sarcomeric germline mutations [adjusted HR of 3.46 (95% CI 1.25-9.52; p=0.016)], with the highest risk among those that hadDNMT3A, TET2andASXL1mutations [adjusted HR of 7.23 (95% CI 1.79-29.13) p=0.005]. Several cytokines (IL-1ra, IL-6, IL-17F, TGFa, CCL21, CCL1, CCL8, and CCL17), and troponin I were upregulated in gene-positive HCM patients with CH.

Conclusions

These results indicate that CH in patients with HCM is associated with worse clinical outcomes. In the absence of CH, gene-positive patients with HCM have lower rates of MACE.

KEY POINTS

Question

Does clonal haematopoiesis (CH) affect the phenotype and outcomes among hypertrophic cardiomyopathy (HCM) patients?

Findings

Among 799 patients, CH was found in 183 (22.9%) HCM patients. CH was associated with symptoms, a higher burden of fibrosis and major cardiovascular events. Several cytokines and troponin I were upregulated in gene-positive HCM patients with CH.

Meaning

CH helps to identify those HCM patients at risk for serious adverse events and unveils a potential inflammatory response mechanism that affects prognosis.
Evaluation of Clonal Hematopoiesis and Mosaic Loss of Y Chromosome in Cardiovascular Risk: an analysis in prospective studies
Authors: Fawaz S , Marti S , Dufossée M , Pucheu Y , Gaufroy A , Broitman J , Bidet A , Soumaré A , Munsch G , Tzourio C , Debette S , Trégouët DA , James C , Mansier O , Couffinhal T
Published: January 2024

Background

Clonal hematopoiesis of indeterminate potential (CHIP) was initially linked to a twofold increase in atherothrombotic events. However, recent investigations have revealed a more nuanced picture, suggesting that CHIP may confer only a modest rise in Myocardial Infarction (MI) risk. This observed lower risk might be influenced by yet unidentified factors that modulate the pathological effects of CHIP. Mosaic loss of Y chromosome (mLOY), a common marker of clonal hematopoiesis in men, has emerged as a potential candidate for modulating cardiovascular risk associated with CHIP. In this study, we aimed to ascertain the risk linked to each somatic mutation or mLOY and explore whether mLOY could exert an influence on the cardiovascular risk associated with CHIP.

Methods

We conducted an examination for the presence of CHIP and mLOY using targeted high-throughput sequencing and digital PCR in a cohort of 446 individuals. Among them, 149 patients from the CHAth study had experienced a first myocardial infarction (MI) at the time of inclusion (MI(+) subjects), while 297 individuals from the Three-City cohort had no history of cardiovascular events (CVE) at the time of inclusion (MI(-) subjects). All subjects underwent thorough cardiovascular phenotyping, including a direct assessment of atherosclerotic burden. Our investigation aimed to determine whether mLOY could modulate inflammation, atherosclerosis burden, and atherothrombotic risk associated with CHIP.

Results

CHIP and mLOY were detected with a substantial prevalence (45.1% and 37.7%, respectively), and their occurrence was similar between MI(+) and MI(-) subjects. Notably, nearly 40% of CHIP(+) male subjects also exhibited mLOY. Interestingly, neither CHIP nor mLOY independently resulted in significant increases in plasma hsCRP levels, atherosclerotic burden, or MI incidence. Moreover, mLOY did not amplify or diminish inflammation, atherosclerosis, or MI incidence among CHIP(+) male subjects. Conversely, in MI(-) male subjects, CHIP heightened the risk of MI over a five-year period, particularly in those lacking mLOY.

Conclusion

Our study highlights the high prevalence of CHIP and mLOY in elderly individuals. Importantly, our results demonstrate that neither CHIP nor mLOY in isolation substantially contribute to inflammation, atherosclerosis, or MI incidence. Furthermore, we find that mLOY does not exert a significant influence on the modulation of inflammation, atherosclerosis burden, or atherothrombotic risk associated with CHIP. However, CHIP may accelerate the occurrence of MI, especially when unaccompanied by mLOY. These findings underscore the complexity of the interplay between CHIP, mLOY, and cardiovascular risk, suggesting that large-scale studies with thousands more patients may be necessary to elucidate subtle correlations.
Exploiting a metabolic vulnerability in brain tumour stem cells using a brain-penetrant drug with safe profile
Authors: Burban Audrey , Tessier Cloe , Pinglaut Mathis , Guyon Joris , Galvis Johanna , Dartigues Benjamin , Toujas Maxime , Larroquette Mathieu , Luchman H Artee , Weiss Samuel , Nicot Nathalie , Klink Barbara , Nikolski Macha , Brisson Lucie , Mathivet Thomas , Bikfalvi Andreas , Daubon Thomas , Sharanek Ahmad
Published: January 2024

Glioblastoma (GB) remains one of the most treatment refractory and fatal tumour in humans. GB contains a population of self-renewing stem cells, the brain tumour stem cells (BTSC) that are highly resistant to therapy and are at the origin of tumour relapse. Here, we report, for the first time, that mubritinib potently impairs stemness and growth of patient-derived BTSCs harboring different oncogenic mutations. Mechanistically, by employing bioenergetic assays and rescue experiments, we provide compelling evidence that mubritinib acts on complex I of the electron transport chain to impair BTSC stemness pathways, self-renewal and proliferation. Global gene expression profiling revealed that mubritinib alters the proliferative, neural-progenitor-like, and the cell-cycling state signatures. We employedin vivopharmacokinetic assays to establish that mubritinib crosses the blood-brain barrier. Using preclinical models of patient-derived and syngeneic murine orthotopic xenografts, we demonstrated that mubritinib delays GB tumourigenesis, and expands lifespan of animals. Interestingly, its combination with radiotherapy offers survival advantage to animals. Strikingly, thorough toxicological and behavioral studies in mice revealed that mubritinib does not induce any damage to normal cells and has a well-tolerated and safe profile. Our work warrants further exploration of this drug in in-human clinical trials for better management of GB tumours.
Domain-general cognitive control processes in bilingual switching: evidence from midfrontal theta oscillations
Authors: Cui Ningjing , Piai Vitoria , Zheng Xiaochen Y.
Published: January 2024

Language control in bilingual speakers is thought to be implicated in effectively switching between languages, inhibiting the non-intended language, and continuously monitoring what to say and what has been said. It has been a matter of controversy concerning whether language control operates in a comparable manner to cognitive control processes in non-linguistic domains (domain-general) or if it is exclusive to language processing (domain-specific). As midfrontal theta oscillations have been considered as an index of cognitive control, examining whether a midfrontal theta effect is evident in tasks requiring bilingual control could bring new insights to the ongoing debate. To this end, we reanalysed the EEG data from two previous bilingual production studies where Dutch-English bilinguals named pictures based on colour cues. Specifically, we focused on three fundamental control processes in bilingual production: switching between languages, inhibition of the nontarget language, and monitoring of speech errors. Theta power increase was observed in switch trials compared to repeat trials, with a midfrontal scalp distribution. However, this midfrontal theta effect was absent in switch trials following a short sequence of same-language trials compared to a long sequence, suggesting a missing modulation of inhibitory control. Similarly, increased midfrontal theta power was observed when participants failed to switch to the intended language compared to correct responses. Altogether, these findings tentatively support the involvement of domain-general cognitive control mechanisms in bilingual switching.
The long distance relationship of regional amyloid burden and tau pathology spread
Authors: Hoenig Merle C. , Doering Elena , Bischof Gérard N. , Drzezga Alexander , van Eimeren Thilo ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2024

Introduction

Consistent with the amyloid-cascade-hypothesis, we tested whether regional amyloid burden is associated with tau pathology increases in spatially independent brain regions and whether functional connectivity serves as a mediator bridging the observed spatial gap between these pathologies.

Methods

Data of 98 amyloid-positive and 35 amyloid-negative subjects with baseline amyloid (18F-AV45) and longitudinal tau (18F-AV1451) PET were selected from ADNI. Annual tau change maps were computed. All images were z-transformed using the amyloid-negative subjects as reference. Z-maps of baseline amyloid and annual tau change were submitted to a parallel independent component analysis in GIFT, yielding six component pairs linking spatial patterns of baseline amyloid to longitudinal tau increase. Next, we used the region of maximum coefficient per component as seeds for functional connectivity analyses in a healthy control dataset. This resulted in six pairs of amyloid and tau seed-based networks (SBN). The spatial overlap between these SBNs and components (amyloid OR tau change) and the combined component pairs (amyloid AND tau change) were quantified.

Results

Amyloid SBNs presented greater spatial overlap with their respective amyloid components (24%-54%) than tau SBNs with the respective tau change components (16%-40%). However, the spatial combination of amyloid and tau component pairs showed highest spatial overlap with the amyloid SBNs (up to 62% vs. 39% for the tau SBNs).

Conclusion

Mechanistically, regional associations of amyloid and tau pathology may be driven by underlying large-scale functional networks. Functional connections may thereby transmit soluble amyloid to remote brain regions within the same network, likely triggering tau aggregation.
Sex-specific mechanisms underlie long-term potentiation at hippocampus-nucleus accumbens synapses
Authors: Copenhaver Ashley E. , LeGates Tara A.
Published: January 2024

Sex differences have complicated our understanding of the neurobiological basis of many behaviors that are key for survival. As such, continued elucidation of the similarities and differences between sexes is necessary in order to gain insight into brain function and vulnerability. The connection between the hippocampus (Hipp) and nucleus accumbens (NAc) is a crucial site where modulation of neuronal activity mediates reward-related behavior. Our previous work demonstrated that long-term potentiation (LTP) of Hipp-NAc synapses is rewarding, and that mice can make learned associations between LTP of these synapses and the contextual environment in which LTP occurred. Here, we investigate sex differences in the mechanisms underlying Hipp-NAc LTP using whole-cell electrophysiology and pharmacology. We found that males and females display similar magnitudes of Hipp-NAc LTP which occurs postsynaptically. However, LTP in females requires L-type voltage-gated Ca2+channels (VGCC) for postsynaptic Ca2+influx, while males rely on NMDA receptors (NMDAR). Additionally, females require estrogen receptor α (ERα) activity for LTP while males do not. These differential mechanisms converge as LTP in both sexes depends on CAMKII activity and occurs independently of dopamine-1 receptor (D1R) activation. Our results have elucidated sex-specific molecular mechanisms for LTP in an integral excitatory pathway that mediates reward-related behaviors, emphasizing the importance of considering sex as a variable in mechanistic studies. Continued characterization of sex-specific mechanisms underlying plasticity will offer novel insight into the neurophysiological basis of behavior, with significant implications for understanding how diverse processes mediate behavior and contribute to vulnerability to developing psychiatric disorders.

SIGNIFICANCE STATEMENT

Strengthening of Hipp-NAc synapses drives reward-related behaviors. Male and female mice have similar magnitudes of long-term potentiation (LTP) and both sexes have a predicted postsynaptic locus of plasticity. Despite these similarities, we illustrate here that sex-specific molecular mechanisms are used to elicit LTP. Given the bidirectional relationship between Hipp-NAc synaptic strength in mediating reward-related behaviors, the use of distinct molecular mechanisms may explain sex differences observed in stress susceptibility or response to rewarding stimuli. Discovery and characterization of convergent sex differences provides mechanistic insight into the sex-specific function of Hipp-NAc circuitry and has widespread implications for circuits mediating learning and reward-related behavior.
Dynamically driven correlations in elastic net models reveal sequence of events and causality in proteins
Authors: Erkip Albert , Erman Burak
Published: January 2024

Protein dynamics orchestrate allosteric regulation, but elucidating the sequence of events and causal relationships within these intricate processes remains challenging. We introduce the Dynamically Perturbed Gaussian Network Model (DP-GNM), a novel approach that uncovers the directionality of information flow within proteins. DP-GNM leverages time-dependent correlations to achieve two goals: identifying driver and driven residues and revealing communities of residues exhibiting synchronized dynamics. Applied to wild type and mutated structures of Cyclophilin A, DP-GNM unveils a hierarchical network of information flow, where key residues initiate conformational changes that propagate through the protein in a directed manner. This directional causality illuminates the intricate relationship between protein dynamics and allosteric regulation, providing valuable insights into protein function and potential avenues for drug design. Furthermore, DP-GNM’s potential to elucidate dynamics under periodic perturbations like the circadian rhythm suggests its broad applicability in understanding complex biological processes governed by environmental cycles.
Generative AI for Cell Type-Specific Fluorescence Image Generation of hPSC-derived Cardiac Organoid
Authors: Kandula Arun Kumar Reddy , Phamornratanakun Tanakit , Gomez Angello Huerta , El-Mokahal Marcel , Ma Zhen , Feng Yunhe , Yang Huaxiao
Published: January 2024

Abstract

Human pluripotent stem cell (hPSC)-derived cardiac organoid is the most recent three-dimensional tissue structure that mimics the structure and functionality of the human heart and plays a pivotal role in modeling heart development and disease. The hPSC-derived cardiac organoids are commonly characterized by bright-field microscopic imaging for tracking daily organoid differentiation and morphology formation. Although the brightfield microscope provides essential information about hPSC- derived cardiac organoids, such as morphology, size, and general structure, it does not extend our understanding of cardiac organoids on cell type-specific distribution and structure. Then, fluorescence microscopic imaging is required to identify the specific cardiovascular cell types in the hPSC-derived cardiac organoids by fluorescence immunostaining fixed organoid samples or fluorescence reporter imaging of live organoids. Both approaches require extra steps of experiments and techniques and do not provide general information on hPSC-derived cardiac organoids from different batches of differentiation and characterization, which limits the biomedical applications of hPSC-derived cardiac organoids. This research addresses this limitation by proposing a comprehensive workflow for colorizing phase contrast images of cardiac organoids from brightfield microscopic imaging using conditional Generative Adversarial Networks (GANs) to provide cardiovascular cell type-specific information in hPSC-derived cardiac organoids. By infusing these phase contrast images with accurate fluorescence colorization, our approach aims to unlock the hidden wealth of cell type, structure, and further quantifications of fluorescence intensity and area, for better characterizing hPSC-derived cardiac organoids.
Rapid dynamics of electrophysiological connectome states are heritable
Authors: Jun Suhnyoung , Malone Stephen M. , Iacono William G. , Harper Jeremy , Wilson Sylia , Sadaghiani Sepideh
Published: January 2024

Time-varying changes in whole-brain connectivity patterns, or connectome state dynamics, are a prominent feature of brain activity with broad functional implications. While infra-slow (<0.1Hz) connectome dynamics have been extensively studied with fMRI, rapid dynamics highly relevant for cognition are poorly understood. Here, we asked whether rapid electrophysiological connectome dynamics constitute subject-specific brain traits and to what extent they are under genetic influence. Using source-localized EEG connectomes during resting-state (N=928, 473 females), we quantified heritability of multivariate (multi-state) features describing temporal or spatial characteristics of connectome dynamics. States switched rapidly every ∼60-500ms. Temporal features were heritable, particularly, Fractional Occupancy (in theta, alpha, beta, and gamma bands) and Transition Probability (in theta, alpha, and gamma bands), representing the duration spent in each state and the frequency of state switches, respectively. Genetic effects explained a substantial proportion of phenotypic variance of these features: Fractional Occupancy in beta (44.3%) and gamma (39.8%) bands and Transition Probability in theta (38.4%), alpha (63.3%), beta (22.6%), and gamma (40%) bands. However, we found no evidence for heritability of spatial features, specifically states’ Modularity and connectivity pattern. We conclude that genetic effects strongly shape individuals’ connectome dynamics at rapid timescales, specifically states’ overall occurrence and sequencing.
Cognitive abilities are associated with rapid dynamics of electrophysiological connectome states
Authors: Jun Suhnyoung , Malone Stephen M. , Iacono William G. , Harper Jeremy , Wilson Sylia , Sadaghiani Sepideh
Published: January 2024

Time-varying changes in whole-brain connectivity patterns, or connectome state dynamics, hold significant implications for cognition. However, connectome dynamics at fast (> 1Hz) timescales highly relevant to cognition are poorly understood due to the dominance of inherently slow fMRI in connectome studies. Here, we investigated the behavioral significance of rapid electrophysiological connectome dynamics using source-localized EEG connectomes during resting-state (N=926, 473 females). We focused on dynamic connectome features pertinent to individual differences, specifically those with established heritability: Fractional Occupancy (i.e., the overall duration spent in each recurrent connectome state) in beta and gamma bands, and Transition Probability (i.e., the frequency of state switches) in theta, alpha, beta, and gamma bands. Canonical correlation analysis found a significant relationship between the heritable phenotypes of sub-second connectome dynamics and cognition. Specifically, principal components of Transition Probabilities in alpha (followed by theta and gamma bands) and a cognitive factor representing visuospatial processing (followed by verbal and auditory working memory) most notably contributed to the relationship. We conclude that the specific order in which rapid connectome states are sequenced shapes individuals’ cognitive abilities and traits. Such sub-second connectome dynamics may inform about behavioral function and dysfunction and serve as endophenotypes for cognitive abilities.
Spatial arrangement of the whiskers of harbor seals (Phoca vitulina) compared to whisker arrangements of house mice (Mus musculus) and brown rats (Rattus norvegicus)
Authors: Graff Matthew M. , Belli Hayley M. , Wieskotten Sven , Bresee Chris S. , Krüger Yvonne , Janssen Thomas L. , Dehnhardt Guido , Hartmann Mitra J.Z.
Published: January 2024

Whiskers (vibrissae) are important tactile sensors for most mammals. We introduce a novel approach to quantitatively compare 3D geometry of whisker arrays across species with different whisker numbers and arrangements, focusing on harbor seals (Phoca vitulina), house mice (Mus musculus) and Norway rats (Rattus norvegicus). Whiskers of all three species decrease in arclength and increase in curvature from caudal to rostral. They emerge from the face with elevation angles that vary linearly with dorsoventral position, and with curvature orientations that vary diagonally as linear combinations of dorsoventral and rostrocaudal positions. In seals, this diagonal varies linearly with horizontal emergence angles, and is orthogonal to the diagonal for rats and mice. This work provides the first evidence for common elements of whisker arrangements across species in different mammalian orders. Placing the equation-based whisker array on a CAD model of a seal head enables future mechanical studies of whisker-based sensing, including wake-tracking.

SUMMARY STATEMENT

We quantify the three-dimensional positions and orientations of the whiskers across the face of the harbor seal, and compare this geometry with the whisker arrays of rats and mice.
Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes
Authors: Patel Divyesh , Tiusanen Ville , Pihlajamaa Päivi , Sahu Biswajyoti
Published: January 2024

The combination of immunotherapy and epigenetic therapy is emerging as a promising approach for cancer therapy. Epigenetic therapy can induce derepression of transposable elements (TEs) that play a major role in activation of immune response against cancer cells. However, the molecular mechanism of TE regulation by distinct chromatin modifier enzymes (CME) and in the context of p53 is still elusive. Here, we used epigenetic drugs to inhibit distinct CMEs in p53 wild-type and p53-mutant colorectal and esophageal cancer cells. We show that distinct TEs subfamilies are derepressed by inhibition of different CMEs in a cell-type specific manner with loss of p53 resulting in stronger TE derepression. We show that KAP1, a known repressor of TEs, associates with stronger derepression of specific TE subfamilies such as LTR12C, indicating that KAP1 also has an activating role in TE regulation in cancer cells upon co-inhibition of DNMT and HDAC. Co-inhibition of DNMT and HDAC activates immune response by inducing inverted repeat Alu expression, reducing ADAR1-mediated Alu RNA editing, and inducing cell type-specific TE-chimeric transcript expression. Collectively, our study demonstrates that inhibition of different CMEs results in derepression of distinct TEs in cell type-specific manner and by utilizing distinct mechanistic pathways, providing insights for epigenetic therapies that could selectively enhance anti-tumor immunity in distinct cancer types.
Rapid learning of temporal dependencies at multiple timescales
Authors: Smith Cybelle M. , Thompson-Schill Sharon L. , Schapiro Anna C.
Published: January 2024

Our environment contains temporal information unfolding simultaneously at multiple timescales. How do we learn and represent these dynamic and overlapping information streams? We investigated these processes in a statistical learning paradigm with simultaneous short and long timescale contingencies. Human participants (N=96) played a game where they learned to quickly click on a target image when it appeared in one of 9 locations, in 8 different contexts. Across contexts, we manipulated the order of target locations: at a short timescale, the order of pairs of sequential locations in which the target appeared; at a longer timescale, the set of locations that appeared in the first vs. second half of the game. Participants periodically predicted the upcoming target location, and later performed similarity judgements comparing the games based on their order properties. Participants showed context dependent sensitivity to order information at both short and long timescales, with evidence of stronger learning for short timescales. We modeled the learning paradigm using a gated recurrent network trained to make immediate predictions, which demonstrated multilevel learning timecourses and patterns of sensitivity to the similarity structure of the games that mirrored human participants. The model grouped games with matching rule structure and dissociated games based on low-level order information more so than high-level order information. The work shows how humans and models can rapidly and concurrently acquire order information at different timescales.
5-Fluorouracil Treatment Represses Pseudouridine-Containing Small RNA Export into Extracellular Vesicles
Authors: Qu Sherman , Nelson Hannah , Liu Xiao , Semler Elizabeth , Michell Danielle L. , Massick Clark , Franklin Jeffrey L. , Karijolich John , Weaver Alissa M. , Coffey Robert J. , Liu Qi , Vickers Kasey C. , Patton James G.
Published: January 2024

5-fluorouracil (5-FU) has been used for chemotherapy for colorectal and other cancers for over 50 years. The prevailing view of its mechanism of action is inhibition of thymidine synthase leading to defects in DNA replication and repair. However, 5-FU is also incorporated into RNA causing toxicity due to defects in RNA metabolism, inhibition of pseudouridine modification, and altered ribosome function. Here, we examine the impact of 5-FU on the expression and export of small RNAs (sRNAs) into small extracellular vesicles (sEVs). Moreover, we assess the role of 5-FU in regulation of post-transcriptional sRNA modifications (PTxM) using mass spectrometry approaches. EVs are secreted by all cells and contain a variety of proteins and RNAs that can function in cell-cell communication. PTxMs on cellular and extracellular sRNAs provide yet another layer of gene regulation. We found that treatment of the colorectal cancer (CRC) cell line DLD-1 with 5-FU led to surprising differential export of miRNA snRNA, and snoRNA transcripts. Strikingly, 5-FU treatment significantly decreased the levels of pseudouridine on both cellular and secreted EV sRNAs. In contrast, 5-FU exposure led to increased levels of cellular sRNAs containing a variety of methyl-modified bases. Our results suggest that 5-FU exposure leads to altered expression, base modifications, and mislocalization of EV base-modified sRNAs.
The cytidine deaminase APOBEC3C has unique sequence and genome feature preferences
Authors: Brown Grant W.
Published: January 2024

APOBEC proteins are cytidine deaminases that restrict the replication of viruses and transposable elements. Several members of the APOBEC3 family, APOBEC3A, APOBEC3B, and APOBEC3H-I, can access the nucleus and cause what is thought to be indiscriminate deamination of the genome, resulting in mutagenesis and genome instability. Although APOBEC3C is also present in the nucleus, its deamination target preferences are unknown. By expressing humanAPOBEC3Cin a yeast model system, I have defined the APOBEC3C mutation signature, as well as the preferred genome features of APOBEC3C targets. The APOBEC3C mutation signature is distinct from those of the known cancer genome mutators APOBEC3A and APOBEC3B. APOBEC3C produces DNA strand-coordinated mutation clusters, and APOBEC3C mutations are enriched near the transcription start sites of active genes. Surprisingly, APOBEC3C lacks the bias for the lagging strand of DNA replication that is seen for APOBEC3A and APOBEC3B. The unique preferences of APOBEC3C constitute a mutation profile that will be useful in defining sites of APOBEC3C mutagenesis in human genomes.
Integrating complexity in population modelling: from matrix to dynamic models using the jellyfishCarybdea marsupialis
Authors: Flores-García Adrián , Yañez-Dobson John , Fonfría Eva S. , García-García David , Bordehore César
Published: January 2024

Matrix models are widely used in population ecology studies and are valuable for analysing population dynamics. Nonetheless, this approach is somewhat rigid in terms of generating complex scenarios. Starting from the values of the transition matrix, we can build a dynamic model to incorporate more biological-based reality into the model (e.g. polyp stage) and provide a higher flexibility in generating scenarios. As an example, we used the transition matrix calculated for a time series data of a population of the box jellyfishCarybdea marsupialis(L. 1758) in the Western Mediterranean in a previously published study. Dynamic models can help us to better understand the complex relationships that drive populations, test different hypotheses and compare scenarios. The dynamic model was developed in STELLA Architect, calibrated and optimised and it has been used to simulate various scenarios of ecological interest, including a decline in food supply, jellyfish removal strategies, changes in drift currents and changes in substrate availability for planulae to settle. A sensitivity analysis showed that polyp strobilation rate and strobilation pattern were two of the most sensitive variables. This matrix-to-dynamic model approach could be useful to integrate more biological complexity into population models and, in turn, obtain a better fit to the field data.
The blobulator: a webtool for identification and visual exploration of hydrophobic modularity in protein sequences
Authors: Pitman Connor , Santiago-McRae Ezry , Lohia Ruchi , Bassi Kaitlin , Joseph Thomas T. , Hansen Matthew E.B. , Brannigan Grace
Published: January 2024

Motivation

Clusters of hydrophobic residues are known to promote structured protein stability and drive protein aggregation. Recent work has shown that identifying contiguous hydrophobic residue clusters (termed “blobs”) has proven useful in both intrinsically disordered protein (IDP) simulation and human genome studies. However, a graphical interface was unavailable.

Results

Here, we present the blobulator: an interactive and intuitive web interface to detect intrinsic modularity in any protein sequence based on hydrophobicity. We demonstrate three use cases of the blobulator and show how identifying blobs with biologically relevant parameters provides useful information about a globular protein, two orthologous membrane proteins, and an IDP. Other potential applications are discussed, including: predicting protein segments with critical roles in tertiary interactions, providing a definition of local order and disorder with clear edges, and aiding in predicting protein features from sequence.

Availability

The blobulator GUI can be found atwww.blobulator.branniganlab.org, and the source code with pip installable command line tool can be found on GitHub atwww.GitHub.com/BranniganLab/blobulator.
Alcohol Sipping Patterns, Personality, and Psychopathology in Children: Moderating Effects of Dorsal Anterior Cingulate Cortex (dACC)
Authors: Ferariu Ana , Taylor Alexei , Chang Hansoo , Zhang Fengqing
Published: January 2024

Alcohol, the most consumed drug in the United States, is associated with various psychological disorders and abnormal personality traits. Despite extensive research on adolescent alcohol consumption, the impact of early alcohol sipping patterns on changes in personality and mental health over time remains unclear. There is also limited information on the latent trajectory of early alcohol sipping, beginning as young as 9-10 years old. The dorsal anterior cingulate cortex (dACC) is crucial for cognitive control and response inhibition. However, the role of dACC remains unclear in the relationship between early alcohol sipping and mental health outcomes and personality traits over time. Utilizing the large data from the Adolescent Brain and Cognitive Development study, we aim to comprehensively examine the longitudinal impact of early alcohol sipping patterns on psychopathological measures and personality traits in adolescents, filling crucial gaps in the literature. We identified three latent alcohol-sipping groups, which demonstrate distinct personality traits and depression score trajectories. Bilateral dACC activation during the stop-signal task moderated the effect of early alcohol sipping on personality and depression over time. Additionally, bidirectional effects were observed between alcohol sipping and personality traits. This study provides insights into the impact of early alcohol consumption on adolescent development.
A Wireless Wearable Ecosystem for Social Network Analysis in Free-living Animals
Authors: Gaidica Matt , Zhang Mengxiao , Dantzer Ben
Published: January 2024

Understanding the dynamics of animal social systems requires studying variation in contact and interaction, which is influenced by environmental conditions, resource availability, and predation risk, among other factors. Traditional (direct) observational methods have limitations, but advancements in sensor technologies and data analytics provide unprecedented opportunities to study these complex systems in naturalistic environments. Proximity logging and tracking devices, capturing movement, temperature, and social interactions, offer non-invasive means to quantify behavior and develop empirical models of animal social networks. However, challenges remain in integrating different data types, incorporating more sensor modalities, and addressing logistical constraints. To address these gaps, we developed a wireless wearable sensor system with novel features (called “Juxta”), including modular battery packs, memory management for combining data types, reconfigurable deployment modes, and a smartphone app for data collection. We present data from a pilot study on prairie voles (Microtus ochrogaster), which is a small mammal species that exhibits relatively complex social behavior. We demonstrate the potential for Juxta to increase our understanding of the social networks and behavior of free-living animals. Additionally, we propose a framework to guide future research in merging temporal, spatial, and event-driven data. By leveraging wireless technology, battery efficiency, and smart sensing modalities, our wearable ecosystem offers a scalable solution for real-time, high-resolution data capture and analysis in animal social network studies, opening new avenues for exploring complex social dynamics across species and environments.