bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain age is longitudinally associated with sensorimotor impairment and mild cognitive impairment in subacute stroke
Authors: Marin-Pardo Octavio , Khan Mahir H. , Chakraborty Stuti , Borich Michael R. , Castillo Mayerly , Cole James H. , Cramer Steven C. , Donnelly Miranda R. , Fokas Emily E. , Fullmer Niko H. , Gumarang Jeanette R. , Hayes Leticia , Kim Hosung , Kumar Amisha , Marks Emily. A. , Rosario Emily R. , Schambra Heidi M. , Schweighofer Nicolas , Song Grace C. , Taga Myriam , Tavenner Bethany P. , Winstein Carolee , Liew Sook-Lei 
Published: January 2025

AbstractBACKGROUNDBrain age, a proxy of overall brain health estimated from structural neuroimaging, has been associated with sensorimotor performance in chronic stroke. Similarly, post-stroke cognitive outcomes have been associated with accelerated brain aging. However, the relationships between brain age, sensorimotor, and cognitive outcomes in early subacute stroke (<3 months after onset) are less understood.METHODSIn this work, we investigated associations between stroke survivors’ brain-predicted age difference (brain-PAD, quantified as a person’s brain age minus their chronological age) and longitudinal measurements of motor impairment (Fugl-Meyer Upper Extremity Assessment [FMUE]) and cognitive impairment (Montreal Cognitive Assessment [MoCA]) in subacute stroke. We used high-resolution T1-weighted MRIs from 44 participants at baseline and three months after stroke onset to investigate associations between brain-PAD, MoCA, and FMUE scores with robust linear mixed-effects regression models and mediation analyses.RESULTSWe found negative associations between baseline brain-PAD and FMUE at baseline (β=-0.87, p=0.029) and three months (β=-0.87, p=0.011). Baseline brain-PAD was also negatively correlated with MoCA at three months (β=-0.13, p=0.015) but not at baseline (β=-0.11, p=0.141). Baseline brain-PAD was not associated with changes in FMUE (β=-0.01, p=0.930) or MoCA (β=-0.03, p=0.579). Finally, MoCA was not associated with FMUE at either time point, nor did it mediate the relationship between brain-PAD and FMUE.CONCLUSIONOverall, we show that baseline brain age predicts both motor and cognitive outcomes at three months. However, motor and cognitive outcomes are not directly associated with one other. This suggests that brain age is representative of changes in multiple, distinct neurological pathways post-stroke. Further research with longer time intervals is needed to examine whether brain age also predicts chronic stroke outcomes.
Healthcare Unplugged: Disparities in Broadband Internet and Health Facility Access Among US Counties
Authors: Kohli Khushi , Wang Stephanie , Chou Cody , Jain Bhav , Shah Kavya M. , Kohli Mahi , Dee Edward Christopher , Palakodeti Sandeep 
Published: January 2025

ABSTRACTDespite telehealth expansion, access may remain lacking in high-burden communities with limited brick-and-mortar health facilities. We aimed to i) examine the relationship between broadband internet access and health facility availability and ii) explore disparities in broadband access. Using data from the 2017 National Neighborhood Data Archive, we obtained data on population density of outpatient care centers, diagnostic labs, and nursing/residential care facilities for 3133 US counties. Broadband access and sociodemographic data were obtained from the 2020 Mapping Broadband Health in America Platform and 2022 American Community Survey. Two-sample t-tests and multivariable linear regressions quantified the association between broadband internet access and health facility density, adjusting for sociodemographic covariates.Counties with low broadband access had 12% fewer outpatient care centers and 48% fewer diagnostic labs than counties with high broadband access (all P < 0.001). A 1% increase in county population without broadband corresponds with a decrease of 0.0451 outpatient care centers, 0.0237 diagnostic labs, and 0.0886 nursing/residential care facilities per 100,000 people (all P < 0.001). Counties with limited in-person health facilities face reduced access to broadband internet, particularly in rural, low-income communities. Expanding broadband infrastructure and health services in these regions is essential.
Flavoproteins as native and genetically encoded spin probes forin cellESR spectroscopy
Authors: Chauviré Timothée , Chandrasekaran Siddarth , Dunleavy Robert , Freed Jack H. , Crane Brian R. 
Published: January 2025

ABSTRACTFlavin cofactors are attractive Electron Spin Resonance (ESR) probes for proteins because cellular reductants and light can generate their semiquinone states. We have used ESR spectroscopy to study the bacterial transmembrane aerotaxis receptor (Aer) in its nativeEscherichia colimembrane environment. Optimization of the spectroscopic (electronic relaxation times) and cell growth (isotopic labeling) conditions allowed for measurements of Aer with its partners - the histidine kinase (CheA) and the coupling protein (CheW) - in native signaling arrays. Continuous-wave ESR measurements at room temperature showed a rigid Aer flavin immobilized in the cofactor pocket and Q-band electron nuclear double resonance (ENDOR) measurements identified a predominant anionic semiquinone radical statein cell. Q-band four-pulse double electron-electron resonance (4P-DEER) measurements indicated a 4.1 nm distance between the two flavins of an Aer homodimer, consistent with previousin vitromeasurements, but also revealed additional separationsin cellindicative of chemoreceptor arrays, not previously observed for Aer. For general application, we further developed a genetically encoded Light-Oxygen and Voltage (LOV) domain for incorporation into target proteins as an ESR probe of structural propertiesin cell. This approach provides a framework to elucidate protein oligomeric states and conformations that are difficult to reproducein vitro.
Effects of recombination on multi-drug resistance evolution inPlasmodium falciparummalaria
Authors: Tran Kien Trung , Nguyen Tran Dang , Weissman Daniel B , Li Eric Zhewen , Mok Sachel , Small-Saunders Jennifer L , Bousema Teun , Zupko Robert J , Tran Thu Nguyen-Anh , Boni Maciej F 
Published: January 2025

AbstractWhen multiple beneficial alleles are present in a population but not linked together in any one individual, there is no general evolutionary result that determines whether recombination will speed up or slow down the emergence and evolution of genotypes carrying multiple beneficial alleles. Translated to infectious disease control, this evolutionary uncertainty means that when multiple types of drug resistance are present we do not know whether recombination will act more strongly to (1) bring together single-resistant genotypes into multi-drug resistant (MDR) genotypes, or (2) break apart MDR genotypes into single-resistant genotypes. In this paper, we introduce a new version of an established and validated individual-based malaria transmission model where we have added individual mosquito bites, interrupted feeding by mosquitoes, 25 drug-resistance related loci, and individual recombination events of differentPlasmodium falciparumgenotypes inside the mosquito. Recombination amongP. falciparumgenotypes in this model occurs from two sources of variation, multi-clonal infections and interrupted feeding by mosquitoes, and we show that 80% to 97% of MDR recombinant falciparum genotypes are projected to occur from single uninterrupted bites on hosts with multi-clonal infections (for malaria prevalence > 5%). Increases in the model’s interrupted feeding rate slowly increase the number of recombination events occurring from interrupted feeds. A comparison of drug-resistance management strategies with this new model shows that, over a 15-year timeframe, triple artemisinin-combination therapies (ACT) strategies show the largest reductions in treatment failures and the longest delays until artemisinin resistance reaches a critical 1% threshold. Multiple first-line therapies (MFT) are second best under these criteria, and ACT cycling approaches are third best. MFT strategies generate a greater diversity of recombinant genotypes but fewer recombination events generating MDR and slower emergence of these recombinant MDR genotypes.
A direct interaction between the RNA-binding proteins Staufen and Tm1-I/C regulatesoskarmRNP composition and transport
Authors: Gaber Thomas , Grabowski Julia , Simon Bernd , Monecke Thomas , Williams Tobias , Roman Vera , Chao Jeffrey , Hennig Janosch , Ephrussi Anne , Niessing Dierk , Heber Simone 
Published: January 2025

AbstractIn theDrosophilafemale germline,oskarmessenger RNA is transported on microtubules from the nurse cells to the posterior pole of the oocyte, where it is translated. Transport ofoskartranscripts from the nurse cells into the oocyte requires dynein, while localization of the mRNAs within the oocyte to the posterior pole is dependent upon kinesin-1. Staufen, a dsRNA-binding protein, has been shown to bind theoskarmRNA transport complex in the oocyte and inactivate dynein; however, it remains unclear how kinesin is activated. Here, using surface plasmon resonance, nuclear magnetic resonance spectroscopy and RNA imaging within egg chambers, we demonstrate that Staufen directly interacts with Tm1, a non-canonical kinesin adaptor. This work provides a molecular explanation for the previously unclear role of Staufen inoskarmRNA localization.
LAG3 marks activated but hyporesponsive NK cells
Authors: Vasilyeva Valeria , Makinson Olivia , Chan Cynthia , Park Maria , O’Dwyer Colin , Ali Ayad , Ul Haq Khan Abrar , Tanese de Souza Christiano , Hasim Mohamed S. , Asif Sara , Kurdieh Reem , Abou-Hamad John , Yakubovich Edward , Hodgins Jonathan , Haddad Paul Al , Pietropaolo Giuseppe , Mazej Julija , Seo Hobin , Huang Quitong , Nersesian Sarah , Chay Damien , Jacquelot Nicolas , Cook David , Lee Seung-Hwan , Sciumè Giuseppe , Waggoner Stephen , Ardolino Michele , Marotel Marie 
Published: January 2025

AbstractNatural Killer (NK) cells are critical for immunosurveillance yet become dysfunctional in contexts such as chronic stimulation by viral infections or cancer. This phenomenon is similar to T cell exhaustion but less well characterized, which limits therapeutic interventions. As shown for T cells, NK cells often display an increased expression of immune checkpoint proteins (ICP) following chronic stimulation, and ICP blockade therapies are currently being explored for several cancer types, which have remarkable patient benefits. Nevertheless, the nature of ICP expression in NK cells is still poorly documented. In this study, we aimed to identify the conditions that lead to and the phenotype of immune checkpoint LAG3 (Lymphocyte-activation gene 3) expressing NK cells. Using various experimental models, we found that LAG3 is expressed by murine NK cells upon activation in different contexts, including in response to cancer and acute viral infections. LAG3 marks a subset of immature, proliferating and activated cells, which, despite activation, have a reduced capacity to respond to a broad range of stimuli. Further characterization also revealed that LAG3+ NK cells exhibit a transcriptional signature similar to that of exhausted CD8+ T cells. Taken together, our results support the use of LAG3 as a marker of dysfunctional NK cells across diverse chronic and acute inflammatory conditions.
Host and rabies virus gene expression is shaped by human brain cell type and reveals a preexisting pro-viral transcriptional state in astrocytes
Authors: Feige Lena , Young Karl , Cerapio Juan Pablo , Kozaki Tatsuya , Kergoat Lauriane , Libri Valentina , Ginhoux Florent , Hasan Milena , Ameur Lamya Ben , Chin Gregory , Goode Zach , Bourhy Hervé , Saunders Arpiar 
Published: January 2025

SummaryRabies virus (RABV) proteins play dual roles during the infection of complex neural tissue, the generation and spread of new virions and the active inhibition of cellular innate immune pathways, both contributing to rabies’ lethality. While spatially-distinct RABV protein residues specializing in virus-centric and immune-inhibitory functions have been identified, how these dual functions interact to shape infection outcomes across diverse types of host brain cells is unknown. To “unmask” and study how innate immune inhibition affects the transcriptional regulation of the human and viral genome with cellular resolution, we performed single-cell RNA sequencing of co-cultured human brain cell types, comparing infection dynamics of a wild-type RABV isolate virus to a mutant virus in which six critical point mutations in the phosphoprotein (P) and matrix (M) RABV proteins selectively neuter antagonism of interferon- and NF-κB- dependent cellular responses. Our analysis reveals that RABV gene expression is shaped by host cell type and that wild-type RABV infection induces small-scale, cell-type conserved transcriptional programs that may support infection by hijacking transcriptional feedback systems that control pro-viral host cell factors while minimizing anti-viral responses. In contrast to accepted models, disinhibited innate immune signaling increases RABV transcriptional output across infected cell types. Most strikingly, we discovered a subpopulation of astrocytes that supports an average of 6-fold higher viral mRNA expression through a massive host cell transcriptional change involving ∼38% of astrocyte expressed genes. Our analysis suggests that these astrocytes we term “pro-viral” are a rare subtype present in the human brain and are primed to play a protective role during viral infection in concert with interferon-sensitive microglia recalcitrant to infection.
Mild Behavioral Impairment as a Clinical Correlate of Early Neurodegeneration
Authors: Leow Yi Jin , Saffari Seyed Ehsan , Vipin Ashwati , Tanoto Pricilia , Binte Shaik Mohamed Salim Rasyiqah , Qiu Bocheng , Ismail Zahinoor , Kandiah Nagaendran 
Published: January 2025

ImportanceMild Behavioral Impairment(MBI), characterized by neuropsychiatric symptoms(NPS) that precede cognitive decline, may reflect early neurodegenerative changes. Identifying structural brain changes associated with MBI could enhance early risk stratification and intervention.ObjectiveTo investigate the association between MBI symptoms and cortical thinning as a structural marker of neurodegeneration in a Southeast Asian cohort.Design, Setting, and ParticipantsThis cross-sectional study analyzed baseline data from the Biomarkers and Cognition Study, Singapore(BIOCIS), a 5-year longitudinal study initiated in 2023 that recruits community participants across Singapore. Cross-sectional data from 1,145 participants(mean age: 62±13.5 years; 53% female) with normal cognition, subjective cognitive decline(SCD), or mild cognitive impairment(MCI) were included.Main Outcomes and MeasuresBehavioral symptoms were assessed using the Mild Behavioral Impairment Checklist(MBI-C), which captures NPS across five domains: decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and abnormal perception/false beliefs. Cortical thickness was measured using T1-weighted MRI, processed through FreeSurfer. The primary outcome was the relationship between MBI-C total and subdomain scores, and cortical thinning.ResultsHigher MBI-C Belief scores were associated with cortical thinning in the right hemisphere(β=- 0.0177;95% CI:-0.0342 to −0.0012;P=.035). Significant thinning was observed in specific regions - posterior banks of the superior temporal sulcus(β=-0.020;95% CI:-0.037 to −0.004;P=.013), fusiform gyrus(β=-0.021;95% CI:-0.037 to −0.005;P=.009), superior temporal gyrus(β=-0.020;95% CI:-0.037 to −0.002;P=.025), temporal pole(β=-0.018;95% CI:-0.034 to −0.003;P=.021), and transverse temporal gyrus(β=-0.020;95% CI:-0.036 to −0.004;P=.014). After false discovery rate(FDR) correction, the associations in the posterior banks of the superior temporal sulcus, fusiform gyrus, superior temporal gyrus, and transverse temporal gyrus remained significant(FDR P=.042–.045).In addition to these temporal regions, higher MBI-C Belief scores were significantly associated with cortical thinning in the right postcentral gyrus(β=-0.020;P=.012) and right supramarginal gyrus(β=- 0.021;P=.013), which remained significant post-FDR correction(FDR P=.039). The right insula(β=- 0.0174;P=.034) showed significant thinning, confirmed by FDR correction(FDR P=.037).Conclusions and RelevanceHigher MBI-C scores are linked to cortical thinning in brain regions essential for memory, spatial orientation, and emotional regulation. These findings support the use of MBI as an early marker of neurodegeneration, helping identify individuals at risk of cognitive decline. Incorporating MBI assessments into clinical practice could guide triaging of neuroimaging orders, optimizing healthcare resource use.
An in-cell approach to evaluate E3 ligases for use in targeted protein degradation
Authors: Zheng Yunan , Singh Anamika , Niu Zeqi , Marin Violeta , Young Jonathon , Richardson Paul , Hemshorn Marcus L. , Cooley Richard B. , Karplus P. Andrew , Warder Scott , Vasudevan Anil , Reitsma Justin M. , Mehl Ryan A. 
Published: January 2025

AbstractOne of the major challenges in evaluating the suitability of potential ∼700 E3 ligases for target protein degradation (TPD) is the lack of binders specific to each E3 ligase. Here we apply genetic code expansion (GCE) to encode a tetrazine-containing non-canonical amino acid (Tet-ncAA) site-specifically into the E3 ligase, which can be conjugated with strained trans-cyclooctene (sTCO) tethered to a neo-substrate protein binder by click chemistry within living cells. The resulting E3 ligase minimally modified and functionalized in an E3-ligand free (ELF) manner, can be evaluated for TPD of the neo-substrate. We demonstrate that CRBN encoded with clickable Tet-ncAA, either in the known immunomodulatory drug (IMiD)-binding pocket or across surface, can be covalently tethered to sTCO-linker-JQ1 and recruit BRD2/4 for CRBN mediated degradation, indicating the high plasticity of CRBN for TPD. The degradation efficiency is dependent on location of the Tet-ncAA encoding on CRBN as well as the length of the linker, showing the capability of this approach to map the surface of E3 ligase for identifying optimal TPD pockets. This ELF-degrader approach has the advantages of not only maintaining the native state of E3 ligase, but also allowing the interrogation of E3 ligases and target protein partners under intracellular conditions and can be applied to any known E3 ligase.
Warm temperature modifies cell fates to reduce stomata production in Arabidopsis
Authors: Saiz-Pérez Josué , Baekelandt Alexandra , Illescas-Miranda Jonatan , Sterck Lieven , Vuylsteke Marnik , Kim Eun-Ji , Guo Boyu , Desvoyes Bénédicte , Gutierrez Crisanto , Russinova Eugenia , Fenoll Carmen , Mena Montaña 
Published: January 2025

SUMMARYStomatal abundance decrease in Arabidopsis triggered by warm-temperature is attributed to PIF4-mediated repression ofSPEECHLESS(SPCH)expression. We identified the unknown developmental and transcriptional basis of this adaptive response.We traced stomatal lineages in vivo using cell-identity marker lines and mutants, quantified epidermal traits and conducted RNA sequencing under oscillating temperatures.Prolonged warm-temperature or PIF4-overexpression altered cell-fates, inducing diverted stomatal precursors (DPs) that lacked stomatal fate, accounting for stomata reduction. DPs originated from meristemoids that lostSPCHexpression, lackedMUTEexpression and exited the cell cycle. Short warm-temperature pulses allowed later recovery ofSPCHexpression, and did not induce DPs or stomata reduction. Comparison of transcriptomes obtained during warm-temperature pulses with stomatal lineage cell-specific profiles identified gene expression changes and contrasted their reversibility. Though warm-temperature silenced key stomatal drivers, most lineages formed stomata through partly modified transcriptional landscapes that promoted uncommitted cell identities and included alternative pathways.Expression changes in stomatal regulators and cell-fate changes explain lineage progression under fluctuating temperatures. Since short-term temperature oscillations prevail in natural conditions, the requirement of long warm-temperature exposure to trigger DPs would prevent stomata reduction by occasional temperature rises. Promoting uncommitted lineage stages provides flexibility to stomatal development under environmental changes.
Binding items to contexts through conjunctive neural representations with the Method of Loci
Authors: Huang Jiawen , Manglik Akshay , Dutra Nick , Tarder-Stoll Hannah , Chamberlain Taylor , Ajemian Robert , Zhang Qiong , Norman Kenneth A. , Baldassano Christopher 
Published: January 2025

AbstractSchematic prior knowledge can provide a powerful scaffold for episodic memories, yet the neural mechanisms underlying this scaffolding process are still poorly understood. A crucial step of the scaffolding process is the way in which details of a new episode are connected to an existing schema, forming a robust memory representation that can be easily accessed in the future. A unique testbed for studying this binding process is a mnemonic technique called the Method of Loci (MoL), in which people meaningfully connect items to be remembered with a well-learned list of imagined loci. We collected fMRI data from participants in 3 longitudinal sessions while they were enrolled in a month-long MoL training course, all of whom showed dramatic improvements in their ability to remember lists of 20 or 40 words. We obtained neural patterns when the loci and objects are presented by themselves, when they are combined into an integrated representation at encoding, and when the integrated representation was subsequently retrieved, as well as verbal descriptions from the participants about the way they associated each item to each locus. We found that in default mode network regions, including medial prefrontal cortex (mPFC), the combined representations of loci and items are highly conjunctive: the unified locus-item representation was substantially different from a linear combination of the isolated locus and item representation, reflecting the addition of new integrative details specific to each combined pair. The conjunctive component of the representation reflected the particular creative details generated by individual participants and increased over time as participants gained expertise in MoL. Our findings reveal a critical role for the default mode network in creating meaningful connections between new information and well-learned schematic contexts.