bluuebunny/crossref_metadata_2025 huggingface dataset:
A chemodynamical analysis of bright metal-poor stars from the HESP-GOMPA survey – indications of a non-prevailing site for light r-process elements
Authors: Bandyopadhyay Avrajit , Beers Timothy C , Ezzeddine Rana , Sivarani Thirupathi , Nayak Prasanta K , Pandey Jeewan C , Saraf Pallavi , Susmitha Antony
Published: February 2024

We present a comprehensive analysis of the detailed chemical abundances for a sample of 11 metal-poor, very metal-poor, and extremely metal-poor stars ([Fe/H] = −1.65 to [Fe/H]  = −3.0) as part of the HESP-GOMPA (Galactic survey Of Metal Poor stArs) survey. The abundance determinations encompass a range of elements, including C, Na, Mg, Al, Si, Ca, Sc, Ti, Cr, Mn, Fe, Co, Ni, Cu, Zn, Sr, and Ba, with a subset of the brighter objects allowing for the measurement of additional key elements. Notably, the abundance analysis of a relatively bright highly r-process-enhanced (r-II) star (SDSS J0019+3141) exhibits a predominantly main r-process signature and variations in the lighter r-process elements. Moreover, successful measurements of thorium in this star facilitate stellar age determinations. We find a consistent odd–even nucleosynthesis pattern in these stars, aligning with expectations for their respective metallicity levels, thus implicating Type II supernovae as potential progenitors. From the interplay between the light and heavy r-process elements, we infer a diminishing relative production of light r-process elements with increasing Type II supernova contributions, challenging the notion that Type II supernovae are the primary source of these light r-process elements in the early Milky Way. A chemodynamical analysis based on Gaia astrometric data and our derived abundances indicates that all but one of our program stars are likely to be of accreted origin. Additionally, our examination of α-poor stars underscores the occurrence of an early accretion event from a satellite on a prograde orbit, similar to that of the Galactic disc.
Deciphering cometary outbursts: linking gas composition changes to trigger mechanisms
Authors: Müller Daniel R , Altwegg Kathrin , Berthelier Jean-Jacques , Combi Michael R , De Keyser Johan , Fuselier Stephen A , Garnier Philippe , Hänni Nora , Mall Urs , Rubin Martin , Wampfler Susanne F , Wurz Peter
Published: February 2024

Dust and gas outbursts are recurrent cometary phenomena, playing a crucial role in shaping the coma. Proposed outburst trigger mechanisms include cliff collapse, pressure pockets, and amorphous-to-crystalline phase transition of water ice; however, the underlying processes remain inadequately understood. In this study, we analyse Rosetta/ROSINA data from multiple outbursts on comet 67P/Churyumov-Gerasimenko and present the evolution of the gas composition in the comet’s coma during outburst events. We distinguish two distinct categories of cometary outbursts on the comet: water-driven events characterized by rapid (minutes to hours) changes in coma composition, and CO2-driven events displaying a slow, prolonged (hours to days) increase in highly volatile species. We tentatively associate these different gas composition patterns with different trigger mechanisms. Exposure of fresh ice due to cliff collapse leads to a notable water enhancement, while most perihelion outbursts coincide with substantial density increases of CO2. We propose that these CO2-driven events originate from subsurface gas-filled cavities, whose walls are suggested to have been sealed by earlier refreezing of CO2 migrating from warmer spots, hence increasing the cavity pressure required to burst.
Constraining ultralight axions with CSST weak gravitational lensing and galaxy clustering photometric surveys
Authors: Lin Hengjie , Deng Furen , Gong Yan , Chen Xuelei
Published: February 2024

Ultralight axion (ULA) can be one of the potential candidates for dark matter. The extremely low mass of the ULA can lead to a de Broglie wavelength the size of galaxies which results in a suppression of the growth of structure on small scales. In this work, we forecast the constraint on the ULA particle mass ma and relative fraction to dark matter fa = Ωa/Ωd for the forthcoming Stage IV space-based optical survey equipment CSST (China Space Station Telescope). We focus on the CSST cosmic shear and galaxy clustering photometric surveys, and forecast the measurements of shear, galaxy, and galaxy–galaxy lensing power spectra (i.e. 3 × 2 pt). The effects of neutrino, baryonic feedback, and uncertainties of intrinsic alignment, shear calibration, galaxy bias, and photometric redshift are also included in the analysis. After performing a joint constraint on all the cosmological and systematical parameters based on the simulated data from the theoretical prediction, we obtain a lower limit of the ULA particle mass log10 (ma/eV) ≥ −22.5 and an upper limit of the ULA fraction fa ≤ 0.83 at 95 per cent confidence level, and log10 (ma/eV) ≥ −21.9 with fa ≤ 0.77 when ignoring the baryonic feedback. We find that the CSST photometric surveys can improve the constraint on the ULA mass by about one order of magnitude, compared to the current constraints using the same kind of observational data.
Novel insights into the role of translesion synthesis polymerase in DNA incorporation and bypass of 5-fluorouracil in colorectal cancer
Authors: Averill Jameson R , Lin Jackson C , Jung John , Jung Hunmin
Published: February 2024

5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent in colorectal cancer, and resistance to 5-FU easily emerges. One of the mechanisms of drug action and resistance of 5-FU is through DNA incorporation. Our quantitative reverse-transcription PCR data showed that one of the translesion synthesis (TLS) DNA polymerases, DNA polymerase η (polη), was upregulated within 72 h upon 5-FU administration at 1 and 10 μM, indicating that polη is one of the first responding polymerases, and the only TLS polymerase, upon the 5-FU treatment to incorporate 5-FU into DNA. Our kinetic studies revealed that 5-fluoro-2′-deoxyuridine triphosphate (5FdUTP) was incorporated across dA 41 and 28 times more efficiently than across dG and across inosine, respectively, by polη indicating that the mutagenicity of 5-FU incorporation is higher in the presence of inosine and that DNA lesions could lead to more mutagenic incorporation of 5-FU. Our polη crystal structures complexed with DNA and 5FdUTP revealed that dA:5FdUTP base pair is like dA:dTTP in the active site of polη, while 5FdUTP adopted 4-enol tautomer in the base pairs with dG and HX increasing the insertion efficiency compared to dG:dTTP for the incorrect insertions. These studies confirm that polη engages in the DNA incorporation and bypass of 5-FU.
Comprehensive map of ribosomal 2′-O-methylation and C/D box snoRNAs in Drosophila melanogaster
Authors: Sklias Athena , Cruciani Sonia , Marchand Virginie , Spagnuolo Mariangela , Lavergne Guillaume , Bourguignon Valérie , Brambilla Alessandro , Dreos René , Marygold Steven J , Novoa Eva Maria , Motorin Yuri , Roignant Jean-Yves
Published: February 2024

During their maturation, ribosomal RNAs (rRNAs) are decorated by hundreds of chemical modifications that participate in proper folding of rRNA secondary structures and therefore in ribosomal function. Along with pseudouridine, methylation of the 2′-hydroxyl ribose moiety (Nm) is the most abundant modification of rRNAs. The majority of Nm modifications in eukaryotes are placed by Fibrillarin, a conserved methyltransferase belonging to a ribonucleoprotein complex guided by C/D box small nucleolar RNAs (C/D box snoRNAs). These modifications impact interactions between rRNAs, tRNAs and mRNAs, and some are known to fine tune translation rates and efficiency. In this study, we built the first comprehensive map of Nm sites in Drosophila melanogaster rRNAs using two complementary approaches (RiboMethSeq and Nanopore direct RNA sequencing) and identified their corresponding C/D box snoRNAs by whole-transcriptome sequencing. We de novo identified 61 Nm sites, from which 55 are supported by both sequencing methods, we validated the expression of 106 C/D box snoRNAs and we predicted new or alternative rRNA Nm targets for 31 of them. Comparison of methylation level upon different stresses show only slight but specific variations, indicating that this modification is relatively stable in D. melanogaster. This study paves the way to investigate the impact of snoRNA-mediated 2′-O-methylation on translation and proteostasis in a whole organism.
Are IMF programs raising greenhouse gas emissions in the Global South?
Authors: Soener Matthew
Published: February 2024

Are International Monetary Fund (IMF) programs raising greenhouse gas emissions in the Global South? I argue powerful actors structure markets in ways exacerbating climate change. This works through the IMF’s imposition of market coercion—specifically, currency devaluation, global openness and fiscal pressures from austerity. Countries respond to these conditions through extractivist strategies and productive growth to increase exports. To investigate this relationship, I use instrumental variables and difference-in-difference analyses for 130 countries between 1980 and 2018. Results show emissions increase from structural lending conditions but not when conditions afford borrowers more flexibility. This effect takes several years to manifest. While there is no single sector responsible for this change, agriculture, land-use changes and, to some extent, industry, have notable emission effects following an IMF program. Global South emissions are partly rooted in imposed austerity which raises important political questions about the climate crisis, development and international finance.
Making Use of Natural Language Processing to Better Understand Medical Students’ Self-Assessment of Clinical Skills
Authors: Turner Laurah , Weber Danielle E. , Santen Sally A. , Olex Amy L. , Baker Pamela , Overla Seth , Shu Derek , Randolph Anne , Kelleher Matt
Published: February 2024

Problem

Reflective practice is necessary for self-regulated learning. Helping medical students develop these skills can be challenging since they are difficult to observe. One common solution is to assign students’ reflective self-assessments, which produce large quantities of narrative assessment data. Reflective self-assessments also provide feedback to faculty regarding students’ understanding of content, reflective abilities, and areas for course improvement. To maximize student learning and feedback to faculty, reflective self-assessments must be reviewed and analyzed, activities that are often difficult for faculty due to the time-intensive and cumbersome nature of processing large quantities of narrative assessment data.

Approach

The authors collected narrative assessment data (2,224 students’ reflective self-assessments) from 344 medical students’ reflective self-assessments. In academic years 2019–2020 and 2021–2022, students at the University of Cincinnati College of Medicine responded to 2 prompts (aspects that surprised students, areas for student improvement) after reviewing their standardized patient encounters. These free-text entries were analyzed using TopEx, an open-source natural language processing (NLP) tool, to identify common topics and themes, which faculty then reviewed.

Outcomes

TopEx expedited theme identification in students’ reflective self-assessments, unveiling 10 themes for prompt 1 such as question organization and history analysis, and 8 for prompt 2, including sensitive histories and exam efficiency. Using TopEx offered a user-friendly, time-saving analysis method without requiring complex NLP implementations. The authors discerned 4 education enhancement implications: aggregating themes for future student reflection, revising self-assessments for common improvement areas, adjusting curriculum to guide students better, and aiding faculty in providing targeted upcoming feedback.

Next Steps

The University of Cincinnati College of Medicine aims to refine and expand the utilization of TopEx for deeper narrative assessment analysis, while other institutions may model or extend this approach to uncover broader educational insights and drive curricular advancements.
Learner Experiences of Preceptor Self-Disclosure of Personal Illness in Medical Education
Authors: Ene Ioana Cezara , Kocaqi Etri , Acai Anita
Published: February 2024

Purpose

The notion of physician invulnerability to illness contributes to the ongoing marginalization of physicians with personal experiences of illness and complicates professional identity development in medical learners. As such, physician self-disclosure of lived experiences as patients has seen an increasing role in medical education. Existing literature, centered on mental health, has characterized the positive effect of physician discussion of experience with mental illness on medical students and residents. However, the ways learners process and understand physician illness stories beyond this context and their use in education remain unclear. This study aimed to explore undergraduate medical students’ perspectives on physician illness discussions of both physical and mental illness, including their perceptions of its use as a pedagogical tool.

Method

This qualitative study followed an interpretive descriptive design using activity theory as a sensitizing concept. Semistructured interviews with medical students were conducted between January and April 2022 at McMaster University in Hamilton, Ontario, Canada. The authors analyzed transcripts using reflexive thematic analysis.

Results

Twenty-one medical students participated in interviews. Although rare, self-disclosure conversations occurred across varied settings and addressed diverse aspects of illness experiences. Discussions involved teaching of pathophysiology, career advice, and wellness guidance. Five themes were developed: the opposition of physicianhood, patienthood, and situating the learner identity; invisibility and stigmatization of physician illness; impact of preceptor stories on learners’ relationship with medicine; challenging the “rules” of physicianhood; and situating self-disclosure in medical education.

Conclusions

Students strongly appreciated physician self-disclosure conversations. Self-disclosure can act as an effective pedagogical tool by fostering expansive learning among medical students. Further research is necessary to explore physician perspectives and supports for self-disclosure in education.
Familial Intraductal Papillary Mucinous Neoplasm Associated With the Germline MSH6 Missense Variant and Progression of Pancreatic cancer
Authors: Tezuka Koji , Yamakawa Mitsunori , Murakami Ryoko , Hirai Ichiro , Toya Ryo , Suzuki Akihiko , Kawamura Hiroshi , Miyano Yuki , Sato Hidenori , Motoi Fuyuhiko
Published: February 2024

Objectives

Intraductal papillary mucinous neoplasm (IPMN) in individuals with at least one first-degree relative with IPMN is defined as familial IPMN. However, few studies have reported on familial IPMN, its clinical characteristics, or the associated genetic factors.

Materials and Methods

We report the case of a 58-year-old woman with multifocal IPMN and a mural nodule in the pancreatic body. The patient underwent a distal pancreatectomy and developed pancreatic head cancer 1 year and 6 months postoperatively. The patient had a family history of multifocal IPMN in her father. Therefore, a genetic predisposition to IPMN and pancreatic cancer was suspected. The patient was analyzed for germline variants, and the resected IPMN was subjected to immunohistochemical and somatic variant analyses.

Results

Next-generation sequencing revealed a heterozygous germline missense variant in exon 5 of MSH6 (c.3197A>G; Tyr1066Cys). The pathogenicity of this variant of uncertain significance was suspected based on multiple in silico analyses, and the same MSH6 variant was identified in the patient's father's colonic adenoma. The mural nodule in the pancreatic body was pathologically diagnosed as a high-grade IPMN with ossification and somatic KRAS and PIK3CA variants.

Conclusions

This case revealed a possible genetic factor for familial IPMN development and presented interesting clinicopathological findings.
Factors Influencing the Mammographic Screening Practices of South Asian Women in Hong Kong
Authors: Chan Dorothy Ngo Sheung , Kwok Cannas
Published: February 2024

Background

Breast cancer is a common type of cancer in South Asian women. Early detection by mammographic screening plays a significant role in improving survival rates. South Asian minorities in many countries have reported low mammographic screening rates.

Objective

This study aimed to understand the factors that influence mammographic screening uptake among South Asian women in Hong Kong.

Methods

This was a qualitative exploratory descriptive study. South Asian women 40 years or older with no history of breast cancer were recruited. In-depth face-to-face interviews were conducted following a semistructured interview guide. Thematic analysis was conducted to analyze the data.

Results

A total of 31 South Asian women consented to participate. Among them, only 7 had ever undergone mammographic screening. The following themes of facilitating factors were identified: (1) influence of doctors, family, and friends; (2) strong sense of commitment to the family; and (3) accessibility and availability of mammographic screening information and services. The following themes for barriers to screening were identified: (1) beliefs about health management and social norms, (2) lack of knowledge and understanding of breast cancer and mammographic screening, (3) logistical barriers, and (4) physical barriers.

Conclusion

This study identified important facilitators and barriers that influence the uptake of mammographic screening among South Asian women in Hong Kong.

Implications for Practice

The study findings can be used to guide the development and implementation of culturally relevant interventions to address barriers to screening, including the expected gender roles and responsibilities among women in their respective families.
Access to mental health services in urban areas: examine the availability, affordability, and accessibility of mental health services in urban settings, particularly for individuals with intersecting marginalized identities
Authors: Meng Xiangfei
Published: February 2024

Purpose of review

To offer an integrative overview of mental health services in urban areas across different social groups and underscore the challenges and potential solutions to improve access to mental health services in urban areas.

Recent findings

The process of urbanization places a lot of toll on the current mental health services system. Challenges to both mental health and mental health services include the elevated risk of some mental and behavioral health issues, the increased demand for mental health services, and the intensification of mental health inequalities. The phenomenon of mental health inequalities is exacerbated in urban areas, with certain disadvantaged population groups more likely to report higher mental health issues and difficulties in accessing mental health services. Targeted and dedicated strategies are warranted to develop and allocate resources to address the mental health services needs among those simultaneously with multiple disadvantaged social and economic characteristics.

Urbanization places a substantive burden on both mental health and mental health services and creates challenges to mental health services access. Integrative and multisectoral initiatives could shed light on effectively addressing the issues of access to mental health services in urban cities.
Mental health status among children and adolescents in one-child and multichild families: a meta-analysis of comparative studies
Authors: Chen Pan , Rao Shu-Ying , Zhang Wei , Jiang Yuan-Yuan , Xiang Yifan , Xiang Nicole Xun , Li Yan-Zhang , Zhu Han-Yu , Su Zhaohui , Cheung Teris , Zhang Qinge , Ng Chee H. , Xiang Yu-Tao
Published: February 2024

Purpose of review

Controversy remains about the difference in mental health status among children and adolescents between one-child and multichild families in China. Thus, we conducted a meta-analysis of studies comparing mental health status between both groups and explored their potential moderating factors.

Recent findings

Totally, 113 eligible studies encompassing 237 899 participants (one-child families: 83 125; multichild families: 154 774) were included. The pooled SMD of SCL-90 total score was −0.115 [95% confidence interval (95% CI): −0.152; −0.078; I
2 = 86.9%]. Specifically, children and adolescents from one-child families exhibited lower scores in terms of somatization (SMD = −0.056; 95% CI: −0.087; −0.026), obsessive-compulsive symptoms (SMD = −0.116; 95% CI: −0.154; −0.079), interpersonal sensitivity (SMD = −0.140; 95% CI: −0.171; −0.109), depression (SMD = −0.123; 95% CI: −0.159; −0.088); anxiety (SMD = −0.121; 95% CI: −0.151; −0.092); phobic anxiety (SMD = −0.124; 95% CI: −0.166; −0.081); paranoid ideation (SMD = −0.040; 95% CI: −0.070; −0.009); and psychoticism (SMD = −0.119; 95% CI: −0.148; −0.089). Study publication year was significantly associated with differences in mental health status between both groups (P = 0.015).

Children and adolescents from one-child families had better mental health status compared to those from multichild families in China. Future studies should investigate the underlying factors contributing to such mental health differences, and the potential interventions that could address these mental health problems.
Changing streetlighting schemes and the ecological availability of darkness
Authors: Morrell Sam , Hatchell Jennifer , Wordingham Freddy , Bennie Jonathan , Inston Maisy J. , Gaston Kevin J.
Published: February 2024

Artificial light at night (ALAN), from streetlights and other sources, has a wide variety of impacts on the natural environment. A significant challenge remains, however, to predict at intermediate spatial extents (e.g. across a city) the ALAN that organisms experience under different lighting regimes. Here we use Monte Carlo radiative Transfer to model the three-dimensional lighting environment at, and just above, ground level, on the spatial scales at which animals and humans experience it. We show how this technique can be used to model a suite of both real and hypothetical lighting environments, mimicking the transition of public infrastructure between different lighting technologies. We then demonstrate how the behaviour of animals experiencing these simulated lighting environments can be emulated to probe the availability of darkness, and dark corridors, within them. Our simulations show that no single lighting technology provides an unmitigated alleviation of negative impacts within urban environments, and that holistic treatments of entire lighting environments should be employed when understanding how animals use and traverse them.
Rodentibacter caecimuris comb. nov., arising from the heterotypic synonymy between Pasteurella caecimuris Lagkouvardos et al. 2016 and Rodentibacter heylii Adhikary et al. 2017
Authors: Li Meng-Syun
Published: February 2024

The misclassification of the species Pasteurella caecimuris Lagkouvardos et al. 2016 along with the heterotypic synonymy between P. caecimuris and Rodentibacter heylii Adhikary et al. 2017 has long been recognized. However, no formal assignment of P. caecimuris to its correct taxonomic position has been made accordingly and therefore the nomenclatural consequences have not been implemented. In the present study, the author first re-evaluates the taxonomic relationships of P. caecimuris using genome-based approaches, confirming the need of reclassification to the genus Rodentibacter and presenting evidence of the synonymy between R. heylii and P. caecimuris. Next, the author proposes a new name Rodentibacter caecimuris comb. nov. and, based on the priority of their specific epithets, treats Rodentibacter heylii as a later heterotypic synonym of Rodentibacter caecimuris.
Unveiling Movement Intention after Stroke: Integrating EEG and EMG for Motor Rehabilitation
Authors: López-Larraz Eduardo , Sarasola-Sanz Andrea , Birbaumer Niels , Ramos-Murguialday Ander
Published: February 2024

Detecting attempted movements of a paralyzed limb is a key step for neural interfaces for motor rehabilitation and restoration after a stroke. In this paper, we present a systematic evaluation of electroencephalographic (EEG) and electromyographic (EMG) activity to decode when stroke patients with severe upper-limb paralysis attempt to move their affected arm. EEG and EMG recordings of 35 chronic stroke patients were analyzed. We trained classifiers to discriminate between rest and movement attempt states relying on brain, muscle, or both types of features combined. Our results reveal that: i) EEG and residual EMG features provide complementary information to detect attempted movements, obtaining significantly higher decoding accuracy when both sources of activity are combined; ii) EMG-based, but not EEG-based, decoding accuracy correlates with the degrees of impairment of the patient; and iii) the percentage of patients that achieve decoding accuracy above the chance level strongly depends on the type of features considered, and can be as low as 50% of them if only ipsilesional EEG is used. These results offer new perspectives to develop improved neurotechnologies that establish a more accurate contingent link between the central and peripheral nervous system after a stroke, leveraging Hebbian learning and facilitating functional plasticity and recovery.
finsyncR, an R package to synchronize 27 years of fish and invertebrate data across the United States
Authors: Mahon Michael B. , Jones Devin K. , Hill Ryan A. , Brown Terry N. , Brown Ethan A. , Kunz Stefan , Rumschlag Samantha L.
Published: February 2024

The United States government collects some of the most comprehensive data on freshwater systems in existence, but barriers exist for new users to apply these data without institutional guidance. ‘finsyncR’ (fish andinvertebratesynchronizer inR) is an R package that streamlines the process of acquiring, processing, and integrating fish and macroinvertebrate datasets collected in streams and rivers, increasing access to cleaned data and ensuring straightforward application of the data. The data sources are the US Environmental Protection Agency’s National River and Streams Assessment and US Geological Survey’s BioData. The resulting datasets span 27 years (1993 to 2019) and include 8,115 sites, 15,169 sampling events, 963 macroinvertebrate genera, and 687 fish species. We document common challenges to working with these data including understanding sampling designs, harmonizing taxonomy, calculating densities and standardized abundances, accounting for differences in sampling effort, and considering improvements in taxonomic identifications. We anticipate this package will spur research exploring changes in fish and macroinvertebrate communities across space and time and the causes and consequences of those changes.
The Mayo Clinic Salivary Tissue-Organoid Biobanking: A Resource for Salivary Regeneration Research
Authors: Aalam Syed Mohammed Musheer , Varela Ana Rita , Khaderi Aalim , Mondesir Ronsard J , Mun Dong-Gi , Ding Andrew Zale , Lombaert Isabelle M.A. , Coppes Rob P , Emperumal Chitra Priya , Pandey Akhilesh , Janus Jeffery R , Kannan Nagarajan
Published: February 2024

The salivary gland (SG) is an essential organ that secretes saliva, which supports versatile oral function throughout life, and is maintained by elusive epithelial stem and progenitor cells (SGSPC). Unfortunately, aging, drugs, autoimmune disorders, and cancer treatments can lead to salivary dysfunction and associated health consequences. Despite many ongoing therapeutic efforts to mediate those conditions, investigating human SGSPC is challenging due to lack of standardized tissue collection, limited tissue access, and inadequate purification methods. Herein, we established a diverse and clinically annotated salivary regenerative biobanking at the Mayo Clinic, optimizing viable salivary cell isolation and clonal assays in both 2D and 3D-matrigel growth environments. Our analysis identified ductal epithelial cells in vitro enriched with SGSPC expressing the CD24/EpCAM/CD49f+ and PSMA- phenotype. We identified PSMA expression as a reliable SGSPC differentiation marker. Moreover, we identified progenitor cell types with shared phenotypes exhibiting three distinct clonal patterns of salivary differentiation in a 2D environment. Leveraging innovative label-free unbiased LC-MS/MS-based single-cell proteomics, we identified 819 proteins across 71 single cell proteome datasets from purified progenitor-enriched parotid gland (PG) and sub-mandibular gland (SMG) cultures. We identified distinctive co-expression of proteins, such as KRT1/5/13/14/15/17/23/76 and 79, exclusively observed in rare, scattered salivary ductal basal cells, indicating the potential de novo source of SGSPC. We also identified an entire class of peroxiredoxin peroxidases, enriched in PG than SMG, and attendant H2O2-dependent cell proliferation in vitro suggesting a potential role for PRDX-dependent floodgate oxidative signaling in salivary homeostasis. The distinctive clinical resources and research insights presented here offer a foundation for exploring personalized regenerative medicine.
A half-centre oscillator encodes sleep pressure
Authors: Hasenhuetl Peter S. , Sarnataro Raffaele , Vrontou Eleftheria , Rorsman H. Olof , Talbot Clifford B. , Brain Ruth , Miesenböck Gero
Published: February 2024

Oscillatory neural dynamics are an inseparable part of mammalian sleep. Characteristic rhythms are associated with different sleep stages and variable levels of sleep pressure, but it remains unclear whether these oscillations are passive mirrors or active generators of sleep. Here we report that sleep-control neurons innervating the dorsal fan-shaped body ofDrosophila(dFBNs) produce slow-wave activity (SWA) in the delta frequency band (0.2–1 Hz) that is causally linked to sleep. The dFBN ensemble contains one or two rhythmic cells per hemisphere whose membrane voltages oscillate in anti-phase between hyperpolarized DOWN and depolarized UP states releasing bursts of action potentials. The oscillations rely on direct interhemispheric competition of two inhibitory half-centres connected by glutamatergic synapses. Interference with glutamate release from these synapses disrupts SWA and baseline as well as rebound sleep, while the optogenetic replay of SWA (with the help of an intersectional, dFBN-restricted driver) induces sleep. Rhythmic dFBNs generate SWA throughout the sleep–wake cycle—despite a mutually antagonistic ‘flip-flop’ arrangement with arousing dopaminergic neurons—but adjust its power to sleep need via an interplay of sleep history-dependent increases in dFBN excitability and homeostatic depression of their efferent synapses, as we demonstrate transcriptionally, structurally, functionally, and with a simple computational model. The oscillatory format permits a durable encoding of sleep pressure over long time scales but requires downstream mechanisms that convert the amplitude-modulated periodic signal into binary sleep–wake states.
A simulated annealing algorithm for randomizing weighted networks
Authors: Milisav Filip , Bazinet Vincent , Betzel Richard , Misic Bratislav
Published: February 2024

Scientific discovery in connectomics relies on the use of network null models. To systematically evaluate the prominence of brain network features, empirical measures are compared against null statistics computed in randomized networks. Modern imaging and tracing technologies provide an increasingly rich repertoire of biologically meaningful edge weights. Despite the prevalence of weighted graph analysis in connectomics, randomization models that only preserve binary node degree remain most widely used. Here, to adapt network null models to weighted network inference, we propose a simulated annealing procedure for generating strength sequence-preserving randomized networks. This model outperforms other commonly used rewiring algorithms in preserving weighted degree (strength). We show that these results generalize to directed networks as well as a wide range of real-world networks, making them generically applicable in neuroscience and in other scientific disciplines. Furthermore, we introduce morphospace representation as a tool for the assessment of null network ensemble variability and feature preservation. Finally, we show how the choice of a network null model can yield fundamentally different inferences about established organizational features of the brain such as the rich-club phenomenon and lay out best practices for the use of rewiring algorithms in brain network inference. Collectively, this work provides a simple but powerful inferential method to meet the challenges of analyzing richly detailed next-generation connectomics datasets.
A generative model of the connectome with dynamic axon growth
Authors: Liu Yuanzhe , Seguin Caio , Betzel Richard F. , Akarca Danyal , Di Biase Maria A. , Zalesky Andrew
Published: February 2024

Connectome generative models, otherwise known as generative network models, provide insight into the wiring principles underpinning brain network organization. While these models can approximate numerous statistical properties of empirical networks, they typically fail to explicitly characterize an important contributor to brain organization – axonal growth. Emulating the chemoaffinity guided axonal growth, we provide a novel generative model in which axons dynamically steer the direction of propagation based on distance-dependent chemoattractive forces acting on their growth cones. This simple dynamic growth mechanism, despite being solely geometry-dependent, is shown to generate axonal fiber bundles with brain-like geometry and features of complex network architecture consistent with the human brain, including lognormally distributed connectivity weights, scale-free nodal degrees, small-worldness, and modularity. We demonstrate that our model parameters can be fitted to individual connectomes, enabling connectome dimensionality reduction and comparison of parameters between groups. Our work offers an opportunity to bridge studies of axon guidance and connectome development, providing new avenues for understanding neural development from a computational perspective.

Author Summary

Generative models of the human connectome provide insight into principles driving brain network development. However, current models do not capture axonal outgrowth, which is crucial to the formation of neural circuits. We develop a novel generative connectome model featuring dynamic axonal outgrowth, revealing the contribution of microscopic axonal guidance to the network topology and axonal geometry of macroscopic connectomes. Simple axonal outgrowth rules representing continuous chemoaffinity gradients are shown to generate complex, brain-like topologies and realistic axonal fascicle architectures. Our model is sufficiently sensitive to capture subtle interindividual differences in axonal outgrowth between healthy adults. Our results are significant because they reveal core principles that may give rise to both complex brain networks and brain-like axonal bundles, unifying neurogenesis across scales.
Efficient and reproducible generation of human iPSC-derived cardiomyocytes using a stirred bioreactor
Authors: Prondzynski Maksymilian , Bortolin Raul H. , Berkson Paul , Trembley Michael A. , Shani Kevin , Sweat Mason E. , Mayourian Joshua , Cordoves Albert M. , Anyanwu Nnaemeka J. , Tharani Yashasvi , Cotton Justin , Milosh Joseph B. , Walker David , Zhang Yan , Liu Fujian , Liu Xujie , Parker Kevin K. , Bezzerides Vassilios J. , Pu William T.
Published: February 2024

In the last decade human iPSC-derived cardiomyocytes (hiPSC-CMs) proved to be valuable for cardiac disease modeling and cardiac regeneration, yet challenges with scale, quality, inter-batch consistency, and cryopreservation remain, reducing experimental reproducibility and limiting clinical translation. Here, we report a robust cardiac differentiation protocol that uses Wnt modulation and a stirred suspension bioreactor to produce on average 124 million hiPSC-CMs with >90% purity using a variety of hiPSC lines (19 differentiations; 10 iPSC lines). After controlled freeze and thaw, bioreactor-derived CMs (bCMs) showed high viability (>90%), interbatch reproducibility in cellular morphology, function, drug response and ventricular identity, which was further supported by single cell transcriptomes. bCMs on microcontact printed substrates revealed a higher degree of sarcomere maturation and viability during long-term culture compared to monolayer-derived CMs (mCMs). Moreover, functional investigation of bCMs in 3D engineered heart tissues showed earlier and stronger force production during long-term culture, and robust pacing capture up to 4 Hz when compared to mCMs. bCMs derived from this differentiation protocol will expand the applications of hiPSC-CMs by providing a reproducible, scalable, and resource efficient method to generate cardiac cells with well-characterized structural and functional properties superior to standard mCMs.
Genetic diversity and connectivity of the invasive gastropod,Callinina georgiana(Caenogastropoda: Viviparidae) across a fragmented riverscape: a mitonuclear perspective
Authors: Abeyrathna Wijesooriya Arachchilage Nimanthi U , Davinack Andrew A.
Published: February 2024

Aquatic Invasive Species (AIS) are a significant threat to global freshwater biodiversity. This study focuses on the banded mystery snail,Callinina georgiana,an invasive species in the Adirondack region of northern New York – an important section of the New York Great Lakes Basin. This project aims to explore the genetic connectivity ofC. georgianawithin its invasive range using a combination of mitochondrial and nuclear markers.

Sampling was conducted in the Raquette River and adjacent waterways, with a total of 229 snails collected from 16 distinct populations distributed across eight different waterbodies. Also included were two populations from the species’ native range in the southern United States. DNA was extracted, and a 710 bp fragment of the mtDNA marker COI and a 351 bp fragment of nuclear marker Histone-3 (H3) were amplified. Population genetic analyses including haplotype patterning, AMOVA and genetic diversity estimates, neutrality tests and tests for isolation by distance (IBD) were performed to assess connectivity patterns.

Results showed moderate to high levels of genetic admixture within the snail’s invasive range as indicated by the lack of geographic patterning of haplotypes and low to moderate levels of genetic differentiation across multiple sites. Demographic analyses combined with high numbers of private haplotypes indicate population expansion. Interestingly, a case of mitonuclear discordance was detected for native and invasive populations as evident by incongruent haplotype patterns for the COI and H3 markers.

Callinina georgianaexhibits a high level of genetic connectivity in its invasive range. The presence of dams does not significantly affect gene flow, indicating that anthropogenic activities, such as boat traffic might be key in dispersing the snails across this fragmented freshwater system.

This study offers new insights into the dispersal and genetic structure of an invasive freshwater snail. It highlights the importance of considering anthropogenic factors when confronting complex patterns of genetic diversity. The findings are significant for biodiversity conservation and provide a basis for developing strategies to manage and contain the spread of AIS likeC. georgiana,especially in regions with high human activity.
CTAT-LR-fusion: accurate fusion transcript identification from long and short read isoform sequencing at bulk or single cell resolution
Authors: Qin Qian , Popic Victoria , Yu Houlin , White Emily , Khorgade Akanksha , Shin Asa , Wienand Kirsty , Dondi Arthur , Beerenwinkel Niko , Vazquez Francisca , AlKhafaji Aziz M. , Haas Brian J.
Published: February 2024

Gene fusions are found as cancer drivers in diverse adult and pediatric cancers. Accurate detection of fusion transcripts is essential in cancer clinical diagnostics, prognostics, and for guiding therapeutic development. Most currently available methods for fusion transcript detection are compatible with Illumina RNA-seq involving highly accurate short read sequences. Recent advances in long read isoform sequencing enable the detection of fusion transcripts at unprecedented resolution in bulk and single cell samples. Here we developed a new computational tool CTAT-LR-fusion to detect fusion transcripts from long read RNA-seq with or without companion short reads, with applications to bulk or single cell transcriptomes. We demonstrate that CTAT-LR-fusion exceeds fusion detection accuracy of alternative methods as benchmarked with simulated and real long read RNA-seq. Using short and long read RNA-seq, we further apply CTAT-LR-fusion to bulk transcriptomes of nine tumor cell lines, and to tumor single cells derived from a melanoma sample and three metastatic high grade serous ovarian carcinoma samples. In both bulk and in single cell RNA-seq, long isoform reads yielded higher sensitivity for fusion detection than short reads with notable exceptions. By combining short and long reads in CTAT-LR-fusion, we are able to further maximize detection of fusion splicing isoforms and fusion-expressing tumor cells. CTAT-LR-fusion is available at https://github.com/TrinityCTAT/CTAT-LR-fusion/wiki.
cMPL-Based Purification and Depletion of Human Hematopoietic Stem Cells: Implications for Pre-Transplant Conditioning
Authors: Araki Daisuke , Hong Sogun , Linde Nathaniel , Fisk Bryan , Redekar Neelam , Salisbury-Ruf Christi , Krouse Allen , Engels Theresa , Golomb Justin , Dagur Pradeep , Magnani Diogo M. , Wang Zhirui , Larochelle Andre
Published: February 2024

The transplantation of gene-modified autologous hematopoietic stem and progenitor cells (HSPCs) offers a promising therapeutic approach for hematological and immunological disorders. However, this strategy is often limited by the toxicities associated with traditional conditioning regimens. Antibody-based conditioning strategies targeting cKIT and CD45 antigens have shown potential in mitigating these toxicities, but their long-term safety and efficacy in clinical settings require further validation. In this study, we investigate the thrombopoietin (TPO) receptor, cMPL, as a novel target for conditioning protocols. We demonstrate that high surface expression of cMPL is a hallmark feature of long-term repopulating hematopoietic stem cells (LT-HSCs) within the adult human CD34+ HSPC subset. Targeting the cMPL receptor facilitates the separation of human LT-HSCs from mature progenitors, a delineation not achievable with cKIT. Leveraging this finding, we developed a cMPL-targeting immunotoxin, demonstrating its ability to selectively deplete host cMPLhighLT-HSCs with a favorable safety profile and rapid clearance within 24 hours post-infusion in rhesus macaques. These findings present significant potential to advance our understanding of human hematopoiesis and enhance the therapeutic outcomes ofex vivoautologous HSPC gene therapies.

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Effects of prenatal maternal immune activation and exposure to circadian disruption during adolescence: exploring the two-hit model of neurodevelopmental disorders
Authors: Delorme Tara C. , Arcego Danusa M. , Penichet Danae , O’Toole Nicholas , Huebener Nikki , Silveira Patrícia P. , Srivastava Lalit K. , Cermakian Nicolas
Published: February 2024

Background

Around 80% of individuals with neurodevelopmental disorders (NDDs) such as schizophrenia and autism spectrum disorders experience disruptions in sleep/circadian rhythms. We explored whether prenatal infection, an established risk factor for NDDs, and environmental circadian disruption synergistically induced sex-specific deficits in mice.

Methods

A maternal immune activation (MIA) protocol was used by injecting pregnant mice (at E9.5) with a viral mimic poly IC or saline. Then, juvenile/adolescent offspring (3-7 weeks old) were subjected to either standard lighting (12:12LD) or constant light (LL).

Results

We found interactions of the two factors on behaviors related to cognition, anxiety, and sociability. Also, poly IC exposure led to a more activated profile of hippocampal microglia in males only, while LL diminished these effects. Using RNA sequencing in the dorsal hippocampus, we found that poly IC exposure led to many differentially expressed genes in males (but not females), and fewer differentially expressed genes were observed after LL exposure. Using the WGCNA analysis, we found several significant gene modules positively associated with poly IC (in comparison to saline exposure) and LL (in comparison to LD exposure) in males, and less so in females. Interestingly, many of the identified hub bottleneck genes were homologous to human genes associated with both sleep/circadian rhythms and neurodevelopmental disorders as identified by GWA studies.

Conclusions

Our work demonstrates that in a mouse model of prenatal infection, disruptions in circadian rhythms induced by LL play a role in modulating the effects of MIA at behavioral, cellular, and molecular levels.
Proteomic Networks and Related Genetic Variants Associated with Smoking and Chronic Obstructive Pulmonary Disease
Authors: Konigsberg Iain R , Vu Thao , Liu Weixuan , Litkowski Elizabeth M , Pratte Katherine A , Vargas Luciana B , Gilmore Niles , Abdel-Hafiz Mohamed , Manichaikul Ani W , Cho Michael H , Hersh Craig P , DeMeo Dawn L , Banaei-Kashani Farnoush , Bowler Russell P , Lange Leslie A , Kechris Katerina J
Published: February 2024

Background

Studies have identified individual blood biomarkers associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. However, complex diseases such as COPD typically involve changes in multiple molecules with interconnections that may not be captured when considering single molecular features.

Methods

Leveraging proteomic data from 3,173 COPDGene Non-Hispanic White (NHW) and African American (AA) participants, we applied sparse multiple canonical correlation network analysis (SmCCNet) to 4,776 proteins assayed on the SomaScan v4.0 platform to derive sparse networks of proteins associated with current vs. former smoking status, airflow obstruction, and emphysema quantitated from high-resolution computed tomography scans. We then used NetSHy, a dimension reduction technique leveraging network topology, to produce summary scores of each proteomic network, referred to as NetSHy scores. We next performed genome-wide association study (GWAS) to identify variants associated with the NetSHy scores, or network quantitative trait loci (nQTLs). Finally, we evaluated the replicability of the networks in an independent cohort, SPIROMICS.

Results

We identified networks of 13 to 104 proteins for each phenotype and exposure in NHW and AA, and the derived NetSHy scores significantly associated with the variable of interests. Networks included known (sRAGE, ALPP, MIP1) and novel molecules (CA10, CPB1, HIS3, PXDN) and interactions involved in COPD pathogenesis. We observed 7 nQTL loci associated with NetSHy scores, 4 of which remained after conditional analysis. Networks for smoking status and emphysema, but not airflow obstruction, demonstrated a high degree of replicability across race groups and cohorts.

Conclusions

In this work, we apply state-of-the-art molecular network generation and summarization approaches to proteomic data from COPDGene participants to uncover protein networks associated with COPD phenotypes. We further identify genetic associations with networks. This work discovers protein networks containing known and novel proteins and protein interactions associated with clinically relevant COPD phenotypes across race groups and cohorts.