bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of DNA breathing to physical interactions with transcription factors
Authors: Butt Waqaas , Lai Ben , Chiu Tsu-Pei , Bhattarai Manish , Qian Sheng , Bishop Alan R. , Duan Jubao , Alexandrov Boian S. , Rohs Remo , He Xin 
Published: January 2025

AbstractInteraction between transcription factors (TFs) and DNA plays a key role in regulating gene expression. It is generally believed that these interactions are controlled through recognition of DNA core motifs by TFs. Nevertheless, several studies pointed out the limitation of this view, in particular, DNA sequence variants influencing TF binding are often located outside of core motifs. One possible explanation is that the physical properties of DNA may play a role in TF-DNA interactions. Recent studies have supported the importance of DNA shape features, especially in flanking regions of core motifs. Another important physical property of DNA is DNA breathing, the spontaneous opening of double-stranded DNA through thermal motions. But there have been few genomic studies of the role of DNA breathing in TF-DNA interactions. In this work, we analyzed in vitro TF-DNA binding data of three TFs and found that DNA breathing features inside or near core motifs are correlated with binding affinity. This suggests that these TFs may prefer locally and temporally melted DNA formed through breathing. We extended the analysis to 44 TFs with in vivo ChIP-seq binding data. We found that for a large proportion of TFs, their breathing features in or near core motifs are associated with binding, but the sign and magnitude of these associations vary substantially across TF families. Altogether, our study supports the hypothesis that DNA breathing features near binding motifs contribute to TF-DNA interactions.Author SummaryProper regulation of when and where genes are expressed is crucial to biological development and function. This process is largely controlled by interaction of transcription factors (TFs) with DNA sequences. The recognition of specific DNA sequences by TFs is important to ensure that only the correct genes are activated. Extensive work has shown that TFs prefer to bind certain DNA sequence patterns of 6-20 bp, known as motifs. However, the structure of DNA molecules may also play a role. In this work, we explored the role of DNA breathing, which refers to spontaneous opening of double strand DNA due to thermal motions. This process creates transient, single-strand “bubbles” in DNA. Through examining TF-DNA binding data of >60 TFs, we found that the propensity of DNA forming bubbles near motifs is often associated with binding affinity of DNA sequence. Interestingly the patterns of these associations seem to vary with TFs. Altogether, our results highlighted the potential of DNA breathing in influencing TF-DNA interactions.
Multimodal Neuroimaging Reveals Distinct Characteristics of Levodopa-Induced Dyskinesias inde novoParkinson’s Disease Patients
Authors: Shukla Sakshi , Patnaik Mantosh , Kumar Aditya , Tinaz Sule , Thirugnanasambandam Nivethida 
Published: January 2025

AbstractLevodopa-induced dyskinesia (LID) is a significant treatment complication that affects a substantial proportion of Parkinson’s disease (PD) patients. Our understanding of the neural basis of LID remains limited, partly due to the small sample sizes in existing neuroimaging studies.In this study, we utilized structural MRI data from the Parkinson’s Progression Markers Initiative (PPMI) database, including de novo PD patients (104 non-dyskinetic for a least 3 years after diagnosis and 120 who developed dyskinesia) and 100 age- and sex-matched healthy controls. Additionally, we analyzed resting-state functional MRI data from a subset of these participants to investigate connectivity differences among the groups.Our analysis revealed no significant baseline volumetric differences between dyskinetic and non-dyskinetic PD patients. However, the thickness of frontal and sensorimotor cortices were significantly greater in dyskinetic patients. In the subcortical regions, vertex-based shape analysis identified localized surface growth in the left caudate and left pallidum, as well as surface morphology changes in the bilateral pallidum in dyskinetics. Resting-state functional connectivity analysis revealed stronger connectivity between the putamen, inferior frontal gyrus, and sensory cortex in dyskinetic PD patients compared to non-dyskinetics.These findings suggest that specific morphological and functional changes in the motor cortical-basal ganglia circuitry of de novo PD patients may predispose them to LID over time. Additionally, the altered functional connectivity patterns reinstate the role of the inferior frontal gyrus in the pathophysiology of dyskinesia and suggest that it might be a suitable target for neuromodulatory interventions, consistent with previous reports.
Cell atlases and the Developmental Foundations of the Phenotype
Authors: Lou Alicia , Chagoyen Mónica , Poyatos Juan F 
Published: January 2025

AbstractIt is widely acknowledged that development shapes phenotypes, yet the extent to which genes with similar expression patterns during development lead to equivalent organismal phenotypes when mutated remains unclear. Here, we propose addressing this issue, which we term the 𝒟evelopment–to– 𝒫henotype, or 𝒟–𝒫, rule, by leveraging single-cell gene expression atlases and phenotypic ontologies, usingCaenorhabditis elegansas a model system. This framework quantifies the proportionality between developmental expression and phenotypic similarities, demonstrating that the relationship holds on average. Genes that strongly fulfill the rule exhibit broad “housekeeping” expression and are associated with systemic phenotypes, whereas weak similarities correspond to specific expression patterns and specialized phenotypes. Deviations from the 𝒟–𝒫 rule provide insights into developmental divergence and phenotypic degeneracy, highlighting genes with narrow functional roles but systemic phenotypic impact. Furthermore, genes that closely adhere to the rule exhibit the highest pleiotropic impact on organismal traits. Our analysis also identifies cell types, such as ASK neurons, as key mediators of phenotype-specific gene contributions, exemplified by their association with chemosensory behavior and chemotaxis. These findings validate the 𝒟–𝒫 rule and underscore the role of cells as critical mediators of the genotypephenotype map, offering a unified framework to understand the developmental origins of phenotypic complexity.
Treatment outcomes of bedaquiline-resistant tuberculosis: a retrospective and matched cohort study
Authors: Mdlenyani Lindokuhle , Mohamed Zahraa , Stadler Jacob AM , Mtwa Nomfuneko , Meintjes Graeme , Warren Robin , Kuhlin Johanna , Wasserman Sean 
Published: January 2025

AbstractBackgroundRising prevalence of bedaquiline resistance undermines benefits from this life-saving drug for rifampicin-resistant tuberculosis (RR-TB). Despite increasing awareness, patient-level outcomes for bedaquiline-resistant TB have not been well-characterised and case management poorly defined.MethodsWe conducted a retrospective cohort study with matched controls at a TB referral hospital in South Africa. Cases included patients ≥13 years with a phenotypic bedaquiline-resistantMycobacterium tuberculosisisolate identified between January 2018 and June 2023. Matched controls (1:1) with bedaquiline-susceptible RR-TB were selected from a prospective observational study conducted at the same facility. Primary outcomes included time to sputum culture conversion (SCC), a modified WHO-defined unfavourable outcome, and TB-free survival (alive, with SCC, and in care or treatment completed) through 18 months. Adjusted analyses used Cox proportional hazards models.FindingsEighty-two patients with bedaquiline-resistant TB were included; 57 (70%) were HIV-positive and 17 (21%) had no prior exposure to bedaquiline or clofazimine. Bedaquiline was prescribed for 72 (88%) and meropenem (plus amoxicillin-clavulanate) for 32 (39%) after submission of the sputum sample with the first bedaquiline-resistantMycobacterium tuberculosisisolate. At 18 months, 43 (52%) patients achieved TB-free survival; 17 (20%) failed to achieve sustained SCC, there were 19 (23%) deaths, and 50 (80%) survivors (n=63) were still on treatment. WHO treatment outcomes following treatment initiation were unfavourable in 54 (67%) patients, driven by treatment failure in 35 (43%). Median time to SCC after treatment initiation was 175 (IQR 100–254) days in the bedaquiline resistant cohort and 32 days (IQR 30–42 days) in the matched bedaquiline susceptible cohort. Baseline smear microscopy grade (HR 0·41, 95% CI 0·23–0·73, p=0·003) and bedaquiline resistance (HR 0·06, 95% CI 0·02–0·23, p<0·001) were associated with reduced SCC.InterpretationCurrent treatment options for bedaquiline-resistant TB result in prolonged therapy, delayed microbiological responses, and poor clinical outcomes.FundingThis work was partially supported by the South African Medical Research Council (grant number MRC-RFA-SHIP 02–2018). JK was funded by Swedish Heart & Lung Foundation (20220859 and 20240774) Swedish Society of Medicine (SLS-985976). SW was supported by the National Institutes of Health (U01AI170426) and the Bill & Melinda Gates Foundation. GM was supported by the Wellcome Trust (214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787).
Integrating Macroeconomic and Public Health Impacts in Social Planning Policies for Pandemic Response
Authors: Cornfeld Ofer , Niu Kaicheng , Neeman Oded , Roswell Michael , Steinbach Gabi , Beckett Stephen J. , Wardi Yorai , Weitz Joshua S. , Yashiv Eran 
Published: January 2025

AbstractInfectious disease outbreaks with pandemic potential present challenges for mitigation and control. Policymakers make decisions to reduce disease-associated morbidity and mortality while also minimizing socioeconomic costs of control. Despite ongoing efforts and widespread recognition of the challenge, there remains a paucity of decision tool frameworks that integrate epidemic and macroeconomic dynamics. Here, we propose and analyze an econo-epidemic model to identify robust planning policies to limit epidemic impacts while maintaining economic activity. The model couples epidemic dynamics, behavioral change, economic activity, and feasible policy plans informed by respiratory disease threats of pandemic concern. We compare alternative fixed, dynamic open-loop optimal control, and feedback control policies via a welfare loss framework. We find that open loop policies that adjust employment dynamically while maintaining a flat epidemic curve in advance of the uncertain arrival of population-scale vaccination outperform fixed employment reduction policies. However, open loop policies are highly sensitive to misestimation of parameters associated with intrinsic disease strength and feedback between economic activity and transmission, leading to potentially significant increases in welfare loss. In contrast, feedback control policies guided by open loop dynamical targets of the time-varying reproduction number perform near-optimally when parameters are well-estimated, while significantly outperforming open loop policies whenever disease features and population-scale behavioral response are misestimated – as they inevitably are. These findings present a template for integrating principled economic models with epidemic scenarios to identify vulnerabilities in policy responses and expand policy options in preparation for future pandemics.
Detection of anti–SARS-CoV-2 mucosal IgA in clinical saliva samples after a dose of Novavax COVID-19 vaccine
Authors: Zhu Mingzhu , Massuda Edmond , Patel Urvashi , Chau Gordon , Kalkeri Raj , Cloney-Clark Shane , Smith Katherine , Neal Susan , Plested Joyce S. , Mallory Raburn M. , Bennett Chijioke 
Published: January 2025

AbstractImmunoglobulin (Ig) A acts as a first line of defense against respiratory pathogens. Mucosal IgA in salivary and nasal passages has a rapid response to antigens and can play a protective role against reinfection. The mainstay for analyzing SARS-CoV-2 infection and vaccine efficacy has been assessment of serum IgG levels; however, validated assays for assessment of mucosal IgA in clinical samples are necessary as new and adapted measures are generated to combat immune-evasive viral variants. A mucosal IgA assay was developed and tested through assessment of IgA levels in salivary samples from participants of the 2019nCoV-314/NCT05973006study. These participants had previously received ≥2 mRNA-based COVID-19 vaccinations prior to enrollment and received a single intramuscular study dose of NVX-CoV2601 (XBB.1.5) or bivalent vaccine (NVX-CoV2601 + NVX-CoV2373 [Wuhan]). Salivary samples were collected prior to vaccination on day 0 and on day 28 to assess response post vaccination. Both vaccine groups elicited a significant increase in anti–SARS-CoV-2 spike IgA against XBB.1.5. Furthermore, cross-reactivity via identification of anti-JN.1 and anti-Wuhan IgA was also observed. The detection of IgA in clinical mucosal samples through this assay will be a valuable tool in supporting vaccine development.
Reduced levels of synaptic vesicle protein 2A in the extracellular vesicles and brain of Alzheimer’s disease- associations with Aβ, tau and synaptophysin
Authors: Nussbaumer Jana , Barve Aatmika , Zufferey Valentin , Espourteille Jeanne , Kirabali Tunahan , Konietzko Uwe , Razansky Daniel , Rominger Axel , Nordberg Agneta , Buée Luc , Colin Morvane , Nitsch Roger M. , Hock Christoph , Richetin Kevin , Ni Ruiqing 
Published: January 2025

AbstractBackgroundSynaptic dysfunction plays an important role in Alzheimer’s disease (AD) and is an emerging imaging and fluid biomarker. Here, we aimed to assess the regional expression of synaptic vesicle glycoprotein 2A (SV2A) in the brain and extracellular vesicles of AD patients and its associations with the APOE ε4 allele, amyloid-β, tau pathologies, and other synaptic markers.MethodsMass spectrometry-based synaptosome proteomics was performed on brain-derived extracellular vesicles (BdEVs) isolated from the frontal cortex of 17 AD patients and 4 NCs. Immunohistochemical staining for SV2A, synaptophysin, amyloid-β and phospho-tau was performed on postmortem tissue from the frontal, temporal, and entorhinal cortices and hippocampus of 40 AD patients and 44 nondemented controls (NCs).ResultsReduced levels of synaptic proteins, including synaptotagamin, GAP43, SYT1, SNAP25 and 14-3-3ζ, were positively correlated with SV2A and negatively correlated with GFAP and NEFL in BdEVs from AD patients and NCs. We detected lower levels of SV2A in the hippocampus and entorhinal cortex of AD compard to NCs, and in APOE ε4 carriers than in noncarriers. SV2A levels were positively correlated with synaptophysin and negatively correlated with the levels of the amyloid-β, phospho-tau, and Braak stages.ConclusionsThis study provides postmortem evidence of synaptic markers and reduced regional levels of SV2A in brain tissue slices and BdEVs from AD patients compared with NCs and in APOE ε4 carriers compared to non-carriers. SV2A could serve as a valuable marker for monitoring synaptic degeneration in AD.
Minimization of gene editing off-target effects by tissue restriction of expression
Authors: Kim Nam-Gyun , Aubert Martine , Haick Anoria K. , Massa Paola A. , Loprieno Michelle A. , Walter Marius , Kim Hyeong Geon , Nunley B. Ethan , Xie Hong , Stensland Laurence , Klouser Lindsay M. , Pérez-Osorio Ailyn C. , Stone Daniel , Roychoudhury Pavitra , Jerome Keith R. 
Published: January 2025

ABSTRACTTherapeuticin vivogene editing with highly specific nucleases has the potential to revolutionize treatment for a wide range of human diseases, including genetic disorders and latent viral infections like herpes simplex virus (HSV). However, challenges regarding specificity, efficiency, delivery, and safety must be addressed before its clinical application. A key concern is the risk of off-target effects, which can cause unintended and potentially harmful genetic changes. We previously developed a curativein vivogene editing approach to eliminate latent HSV using HSV-specific meganuclease delivered by an AAV vector. In this study, we investigate off-target effects of meganuclease by identifying potential off-target sites through GUIDE-tag analysis and assessing genetic alterations using amplicon deep sequencing in tissues from meganuclease treated mice. Our results show that meganuclease expression driven by a ubiquitous promoter leads to high off-target gene editing in the mouse liver, a non-relevant target tissue. However, restricting the meganuclease expression with a neuron-specific promoter and/or a liver-specific miRNA target sequence efficiently reduces off-target effects in both liver and trigeminal ganglia. These findings suggest that incorporation of regulatory DNA elements for tissue-specific expression in viral vectors can reduce off-target effects and improve the safety of therapeuticin vivogene editing.
Perinatal circadian desynchronization disrupts sleep and prefrontal cortex function in adult offspring
Authors: Roberts Brandon L. , Wang Jiexin , Chargui Haifa , Cupertino Nathan C. , Sorensen Walker , Karatsoreos Ilia N. 
Published: January 2025

AbstractSleep and circadian (daily) rhythms impact nearly all aspects of physiology and are critical for optimal organismal function. Disruption of the clock can lead to significant metabolic disorders, neuropsychiatric illness, and cognitive dysfunction. Our lab has previously shown that environmental circadian desynchronization (ECD) in adults alters the anatomical structure and neurophysiological function of prefrontal cortex (PFC) neurons, PFC mediated behaviors, as well as sleep quality. As the PFC undergoes significant development in utero and early life, and maternal disturbances during this period can have significant long-term ramifications, we hypothesized that disrupting the circadian environment of dams during the perinatal period would alter sleep and PFC function in adult offspring. Using a mouse model of ECD we investigated how perinatal ECD (pECD) modulates sleep quality in adult offspring. We also determined how pECD impacts PFC neural function in adult offspring usingex vivopatch-clamp electrophysiology, exploring how pECD alters synaptic function and action potential dynamics. We found that male pECD mice trended toward increased total sleep during the inactive (light) period with shorter sleep bouts during the active (dark) period. pECD did not change sleep behavior in female mice. Independent of time of day, pECD altered post-synaptic dynamics of excitatory neurotransmitter release onto plPFC pyramidal neurons. There was also a loss of time-of-day effects on cell endogenous properties in male pECD mice. Thus, pECD clearly alters sleep behavior and PFC function in male mice. However, female mice appear protected against the effects of pECD in these measures. Together, these experiments form the foundation for future studies to understand the lifelong neurobehavioral impact of pECD.
Protective mechanisms against Alzheimer’s Disease in APOE3-Christchurch homozygous astrocytes
Authors: Tian Xinran , Rivera Erica Keane , Nikitina Arina A. , Hwang Inyoung , Smith Jennifer A. , Cho Youngsuh J. , Sala-Jarque Julia , DuBose Austin , Andriola Clare , Gollan-Myers Toby , Kosik Kenneth S. 
Published: January 2025

AbstractThe APOE3-Christchurch (APOE3-Ch) variant has been linked to reduced Alzheimer’s Disease (AD) risk, but its protective mechanisms remain unclear. This study explores the neuroprotective phenotype of APOE3-Ch astrocytes, focusing on lipid metabolism and tau processing. APOE3-Ch astrocytes demonstrate enhanced tau oligomer uptake via HSPG- and LRP1-mediated pathways, facilitated by elevated HSPG expression, and achieve superior tau degradation through lysosomal pathways and proteasomal pathways, in contrast to wild-type astrocytes, which primarily use proteasomal mechanisms. Transcriptomic analysis reveals upregulation of genes involved in endocytosis and cell projection assembly, explaining enhanced tau uptake and clearance in APOE3-Ch astrocytes. Lipidomic profiling identifies reduced levels of pathological lipids such as ceramides and gamma-linolenic acid (GLA), potentially mitigating neuroinflammation. These findings provide insight into the protective mechanisms of APOE3-Ch astrocytes and underscore their potential as therapeutic targets for tauopathy and neurodegeneration in AD.TeaserAPOE3-Christchurch astrocytes enhance tau clearance and mitigate neurotoxic lipid accumulation, unveiling protective mechanisms against Alzheimer’s.
GETgene-AI: A Framework for Prioritizing Actionable Cancer Drug Targets
Authors: Gu Adrian , Chen Jake Y 
Published: January 2025

ABSTRACTIdentifying actionable drug targets is a critical challenge in cancer research, where high-dimensional genomic data and the complexity of tumor biology often hinder effective prioritization. To address this, we developedGETgene-AI, a novel computational framework that integrates network-based prioritization, machine learning, and automated literature analysis to identify and rank potential therapeutic targets. Central to GETgene-AI is theG.E.T. strategy, which combines three data streams: mutational frequency (G List), differential expression (E List), and known drug targets (T List). These components are iteratively refined and ranked using theBiological Entity Expansion and Ranking Engine (BEERE), leveraging protein-protein interaction networks, functional annotations, and experimental evidence. Additionally, GETgene-AI incorporates GPT-4o, an advanced large language model, to automate literature-based ranking, reducing manual curation and increasing efficiency.In this study, we applied GETgene-AI to pancreatic cancer as a case study. The framework successfully identified high-priority targets such asPIK3CAandPRKCA, validated through experimental evidence and clinical relevance. Benchmarking against GEO2R and STRING demonstrated GETgene-AI’s superior performance, achieving higher precision, recall, and efficiency in prioritizing actionable targets. Moreover, the framework mitigated false positives by deprioritizing genes lacking functional or clinical significance.While demonstrated on pancreatic cancer, the modular design of GETgene-AI enables scalability across diverse cancers and diseases. By integrating multi-omics datasets with advanced computational and AI-driven approaches, GETgene-AI provides a versatile and robust platform for accelerating cancer drug discovery. This framework bridges computational innovations with translational research to improve patient outcomes.