bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Hydrocephalus Association Patient-Powered Interactive Engagement Registry (HAPPIER): Design and Initial Baseline Report
Authors: Jakopin Noriana E. , Lanjewar Samantha N. , Garzon Amanda , Gross Paul , Holubkov Richard , Moghekar Abhay , Preston Jason , Romanoski Margaret , Shannon Chevis N. , Tamber Mandeep S. , van der Willigen Tessa , Sloan Melissa , Chau Monica J. , Koschnitzky Jenna E. 
Published: October 2024

ABSTRACTObjectiveHydrocephalus is a neurological condition characterized by an accumulation of cerebrospinal fluid with no cure and limited treatments. There is a significant gap in hydrocephalus research where patients lack opportunities to voice their perspectives on their condition. The Hydrocephalus Association Patient-Powered Interactive Engagement Registry (HAPPIER) database was created to highlight the quality-of-life outcomes in hydrocephalus from a longitudinal perspective. HAPPIER ensures that the lived experiences of those affected by hydrocephalus are highlighted, and provides a platform for researchers to access this data or distribute their own surveys, ultimately aiming to improve patient-centered care and outcomes. This publication introduces the registry to the medical and scientific community by highlighting demographics, etiology, treatments, symptom profiles, and diagnosed comorbidities of the participants.MethodsHAPPIER was developed by the Hydrocephalus Association and a 10-member steering committee. Development of its surveys was informed by other registries with similar goals, existing surveys and assessments, and input from University of Utah Data Center faculty. The study population was recruited using social and traditional media, referrals from medical professionals, and advertisement at Hydrocephalus Association-sponsored events.ResultsOf the 691 survey participants (referring to those with hydrocephalus), 451 (65.3%) were individuals responding for themselves. 380 (55.0%) of the registry population was female, 594 (86.0%) was white, and 606 (87.7%) was from the United States and territories. The most common age reported for diagnosis was between 0 and 11 months (46.2%), and the most common hydrocephalus etiology reported was congenital hydrocephalus (43.8%). The most prevalent treatment reported was a shunt(s) (71.2%). The most commonly-reported symptom was headaches (60.3%), and 69.9% of participants reported being diagnosed with movement impairments and 70.8% with other health conditions.ConclusionHAPPIER is a novel database developed to address the gaps in data in non-clinical outcomes of hydrocephalus, which are critical to clinical care and understanding hydrocephalus in its totality. Patient perspectives and outcomes have been historically underrepresented. By directly engaging individuals living with hydrocephalus and their caregivers, HAPPIER is designed to incorporate essential patient perspectives through planned longitudinal data collection and patient surveys. These data are open to investigators interested in analyzing the collected data.
Misfolded alpha synuclein co-occurrence with Alzheimer’s disease proteinopathy
Authors: Jonaitis Erin M. , MacLeod Karen , Lamoureux Jennifer , Jeffers Beckie , Studer Rachel L. , Middleton John , Wilson Rachael E. , Chin Nathaniel A. , Okonkwo Ozioma C. , Bendlin Barbara B. , Asthana Sanjay , Carlsson Cynthia M. , Gallagher Catherine L. , Hermann Bruce , McEvoy Sean , Kollmorgen Gwendlyn , Zetterberg Henrik , Concha-Marambio Luis , Johnson Sterling C. , Lebovitz Russ M. , Langhough Rebecca E. 
Published: October 2024

AbstractINTRODUCTIONMulti-etiology dementia necessitates in-vivo markers of copathologies including misfoldedα-synuclein (syn). We measured misfolded syn aggregates (syn-seeds) via qualitative seed amplifcation assays (synSAA) and examined relationships with markers of Alzheimer’s disease (AD).METHODSCerebrospinal fluid (CSF) was obtained from 420 participants in two Wisconsin AD risk cohorts (35% male; 91% cognitively unimpaired; mean (SD) age, 65.42 (7.78) years; education, 16.17 (2.23) years). synSAA results were compared to phosphorylated tau (T), beta amyloid (A), and clinical outcomes. Longitudinal cognition was modeled with mixed effects.RESULTSSyn positivity (synSAA+) co-occurred with T (in synSAA+ vs synSAA-, 36% vs 20% T+; p=0.011) and with cognitive impairment (10% vs 7% MCI; 10% vs 0% dementia; p=0.00050). synSAA+ participants’ cognitive performance declined ∼40% faster than synSAA-for Digit Symbol, but not other tests.DISCUSSIONFindings support prevalent syn copathology in a mostly-unimpaired AD risk cohort. Future work will explore relationships with disease progression.
Omega-3 fatty acids and intracranial aneurysms: a Mendelian randomization study
Authors: Wei Dachao , Chen Xiheng , Gui Siming , Jiang Jia , Gao Yuan , Lin Jun , Deng Dingwei , You Wei , Lv Jian , Tang Yudi , Chen Ting , Yang Shu , Jin Hengwei , Jiang Yuhua , Liu Peng , Tai Hongfei , Liu Xinke , Ge Huijian , Lv Ming , Meng Fangang , Li Youxiang 
Published: October 2024

AbstractIntroductionRecent studies suggest that omega-3 polyunsaturated fatty acids (PUFAs) supplementation benefits for cardiovascular disease and abdominal aortic aneurysms, but its role in intracranial aneurysms (IAs) remains unclear. This study evaluates the effect of omega-3 PUFAs on IAs.Patients and methodsA two-sample Mendelian Randomization study (MR) was conducted to examine the associations between omega-3 PUFAs and IAs, as well as aneurysmal subarachnoid hemorrhage (aSAH). The largest genome-wide association study dataset was used for primary analysis, with replication using independent sources. Two-step MR was used to evaluate the mediating effects of nine aneurysm risk factors and 91 inflammatory cytokines.ResultsHigher genetically predicted levels of total omega-3, omega-3 percentage, and docosahexaenoic acid (DHA) were associated with reduced risks of IAs (combined OR 0.88, 95% CI 0.83-0.94, P<0.001; 0.86, 0.81-0.92, P<0.001; 0.84, 0.78-0.90, P<0.001, respectively) and aSAH (0.85, 0.79-0.91, P=0.009; 0.84, 0.75-0.93, P<0.001; 0.80, 0.71-0.90, P<0.001, respectively). Genetically predicted eicosapentaenoic acid level showed a tendency to increase risk (1.05, 1.01-1.10, P=0.022 for IAs; 1.11, 0.96-1.28, P=0.160 for aSAH). Mediation analysis revealed diastolic blood pressure (DBP) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated DHA’s effects on IAs (proportion mediated 8.5%, P=0.019; 25.2%, P=0.049) and aSAH (5.7%, P=0.024; 27.5%, P=0.041).ConclusionsOur study suggests that omega-3 PUFAs, particularly DHA, are associated with a reduced risk of IAs and aSAH. This association may be partially mediated by DBP and TRAIL.
Sex Differences in Management, Time to Intervention, and In-Hospital Mortality of Acute Myocardial Infarction and Non-Myocardial Infarction Related Cardiogenic Shock
Authors: Desai Anushka , Rani Rohan , Minhas Anum , Rahman Faisal 
Published: October 2024

AbstractBackgroundLimited data are available on sex differences in the time to treatment of cardiogenic shock (CS) with and without acute myocardial infarction (AMI).MethodsFor this retrospective cohort study, we used nationally representative hospital survey data from the National Inpatient Sample (years 2016-2021) to assess sex differences in interventions, time to treatment (within versus after 24 hours of admission), and in-hospital mortality for AMI-CS and non-AMI-CS, adjusting for age, race, income, insurance, comorbidities, and prior cardiac interventions.ResultsWe identified 1,052,360 weighted CS hospitalizations (60% non-AMI-CS; 40% AMI-CS). Women with CS had significantly lower rates of all interventions. For AMI-CS, women had a higher likelihood of in-hospital mortality after: revascularization (adjusted odds ratio (aOR) 1.15 [95% CI 1.09-1.22]), mechanical circulatory support (MCS) (1.15 [1.08-1.22]), right heart catheterization (RHC) (1.10 [1.02-1.19]) (all p<0.001). Similar trends were found for the non-AMI-CS group. Women with AMI-CS were less likely to receive early (within 24 hours of admission) revascularization (0.93 [0.89-0.96]), MCS (0.76 [0.73-0.80]), or RHC (0.89 [0.84-0.95]) than men; women with non-AMI-CS were less likely to receive early revascularization (0.78 [0.73-0.84]), IABP (0.85 [0.78-0.94]), pLVAD (0.88 [0.77-0.99]) or RHC (0.83 [0.79-0.88]) than men (all p<0.001). For both types of CS, in-hospital mortality was not significantly different between men and women receiving early ECMO, pLVAD, or PCI.ConclusionsSex disparities in the frequency of treatment of CS persist on a national scale, with women being more likely to die following treatment and less likely to receive early treatment. However, when comparing patients who received early treatment, in-hospital mortality does not differ significantly when men and women are treated equally within 24 hours of admission. Early intervention if clinically indicated could mitigate sex-based differences in CS outcomes and should be made a priority in the management of CS.Clinical PerspectiveWhat is new?Women have increased in-hospital mortality with cardiogenic shock and have lower odds of early intervention (within 24 hours of admission) compared to men.When men and women with cardiogenic shock are treated equally in terms of early intervention within 24 hours of admission, sex differences in in-hospital mortality disappear.What are the clinical implications?Sex-based disparities are present in the utilization of treatment and time to intervention for patients with cardiogenic shock.Early recognition and intervention for cardiogenic shock among women should be considered to improve clinical outcomes.
Phylogenetically and ecologically delimited species pool affect the inference of age-dependent extinction
Authors: Gonçalves-Neto Salatiel , Quental Tiago B. 
Published: October 2024

AbstractAccording to Van Valen’s seminal work (1973), extinction occurs at a constantly stochastic rate within ecologically homogeneous groups or adaptive zones, giving long and short-lived species equal chances of extinction. Van Valen highlighted the difficulty in defining and identifying the species pool within an adaptive zone, but fundamentally viewed it through ecological factors. Most studies have used taxonomically or phylogenetically defined species pools to test the “Law of Constant Extinction.” Here, we investigate how different species pools defined by phylogeny or ecology influence the inference of age-independent extinction. Using the Canidae fossil record and a Bayesian framework, we show that species pools defined by phylogeny or ecology exhibit different age-dependent extinction dynamics. The age-dependent extinction (ADE) signal varies depending on the species pool choice, time window, and taxonomic level. Within phylogenetic species pools, we observe mixed evidence for ADE, with both positive—older species more likely to go extinct (Hesperocyoninae and Borophaginae)—and negative—younger species more likely to go extinct (Caninae)—trends. Combining subfamilies into a family-level analysis yields weak evidence for ADE or strong support for age-independent extinction, depending on the period analyzed. Within ecologically defined species pools, hypercarnivores show strong evidence for positive ADE, whereas non-hypercarnivores show signals akin to age-independent extinction. Phylogenetic pools with more hypercarnivores tended to show evidence of positive ADE, while those with fewer tended toward negative ADE. These findings emphasize that the choice of species pool significantly influences observed age-dependent extinction dynamics and that ecology impacts the regime of age-dependent extinction.
A striosomal accumbens pathway drives compulsive seeking behaviors through an aversive Esr1+ hypothalamic-habenula circuit
Authors: Contesse Thomas , Bektash Buse Yel , Graziano Marta , Forastieri Chiara , Contestabile Alessandro , Hahne Salome , Jung Felix , Nikolakopoulou Ifigeneia , Cao Xiao , Skara Vasiliki , Mantas Ioannis , Giatrellis Sarantis , Carlén Marie , Sandberg Rickard , Calvigioni Daniela , Meletis Konstantinos 
Published: October 2024

ABSTRACTThe lateral hypothalamic area (LHA) integrates external stimuli with internal states to drive the choice between competing innate or value-driven motivated behaviors. Projections from the LHA to the lateral habenula (LHb) shape internal states, with excitatory estrogen receptor 1-expressing (Esr1+) LHA-LHb neurons driving aversive responses and sustained negative states. Here, we identify and functionally characterize a specific projection from the nucleus accumbens (ACB) that targets Esr1+ LHA-LHb neurons. Using cell-type-specific tracing of monosynaptic inputs, single-nucleus RNA sequencing, and neuroanatomical mapping, we demonstrate that the Esr1+ LHA-LHb pathway receives a major input from a striosomal Tac1+/Tshz1+/Oprm1+ ACB neuron subtype. Intersectional cell-type-specific and input-output defined optogenetic manipulation of this ACB-LHA-LHb pathway revealed its role in signaling aversion after repeated activation, with the negative behavioral state being dependent on recruitment of Esr1+ LHA-LHb neurons. Importantly, we found that activation of the D1+ ACB-LHA pathway drives reward-independent compulsive-like seeking behaviors, expressed as compulsive digging or poking behaviors. We found that these complex yet stereotyped behaviors compete with highly motivated states and can override the need for natural rewards or social stimuli. Our findings reveal a discrete striosomal Tac1+ ACB projection targeting the aversive Esr1+ LHA-LHb pathway as a key circuit that promotes compulsive seeking behaviors over goal-directed actions.
Peripherally administered TNF inhibitor is not protective against α-synuclein-induced dopaminergic neuronal death in rats
Authors: Christiansen Josefine R. , Ferreira Sara A. , Szymkowski David E. , Jakobsson Johan , Tansey Malú Gámez , Romero-Ramos Marina 
Published: October 2024

ABSTRACTThe underlying cause of neuronal loss in Parkinson’s disease (PD) remains unknown, but evidence implicates neuroinflammation in PD pathobiology. The pro-inflammatory cytokine soluble tumor necrosis factor (TNF) seems to play an important role and thus has been proposed as a therapeutic target for modulation of the neuroinflammatory processes in PD. In this regard, dominant-negative TNF (DN-TNF) agents are promising antagonists that selectively inhibit soluble TNF signaling, while preserving the beneficial effects of transmembrane TNF. Previous studies have tested the protective potential of DN-TNF-based therapy in toxin-based PD models. Here we test for the first time the protective potential of a DN-TNF therapeutic against α-synuclein-driven neurodegeneration in the viral vector-based PD rat model. To do so, we administered the DN-TNF agent XPro1595 subcutaneously for a period of 12 weeks. In contrast to previous studies using different PD models, neuroprotection was not achieved by systemic XPro1595 treatment. α-synuclein-induced loss of nigrostriatal neurons, accumulation of pathological inclusions and microgliosis was detected in both XPro1595- and saline-treated animals. XPro1595 treatment increased the percentage of the hypertrophic/ameboid Iba1+ cells in SN and reduced the striatal MHCII+ microglia in the striatum of α-synuclein-overexpressing animals. However, the treatment did not prevent the MHCII upregulation seen in the SN of the model, nor the increase of CD68+ phagocytic cells. Therefore, despite an apparently positive immune effect, this did not suffice to protect against viral vector-derived α-synuclein-induced neurotoxicity. Further studies are warranted to better elucidate the therapeutic potential of soluble TNF inhibitors in PD.
Improved protein binder design using beta-pairing targeted RFdiffusion
Authors: Sappington Isaac , Toul Martin , Lee David S. , Robinson Stephanie A. , Goreshnik Inna , McCurdy Clara , Chan Tung Ching , Buchholz Nic , Huang Buwei , Vafeados Dionne , Garcia-Sanchez Mariana , Roullier Nicole , Glögl Matthias , Kim Christopher J. , Watson Joseph L. , Torres Susana Vázquez , Verschueren Koen H. G. , Verstraete Kenneth , Hinck Cynthia S. , Benard-Valle Melisa , Coventry Brian , Sims Jeremiah Nelson , Ahn Green , Wang Xinru , Hinck Andrew P. , Jenkins Timothy P. , Ruohola-Baker Hannele , Banik Steven M. , Savvides Savvas N. , Baker David 
Published: October 2024

AbstractDespite recent advances in the computational design of protein binders, designing proteins that bind with high affinity to polar protein targets remains an outstanding problem. Here we show that RFdiffusion can be conditioned to efficiently generate protein scaffolds that form geometrically matched extended beta-sheets with target protein edge beta-strands in which polar groups on the target are nearly perfectly complemented with hydrogen bonding groups on the design. We use this approach to design binders against a set of therapeutically relevant polar targets (KIT, PDGFRɑ, ALK-2, ALK-3, FCRL5, and NRP1) and find that beta-strand-targeted design yields higher affinities and success rates than unconditioned RFdiffusion. All by all binding experiments show that the designs have affinities ranging from 137 pM to mid nM for their targets and essentially no off target binding despite the sharing of beta-strand interactions, likely reflecting the precise customization of interacting beta-strand geometry and additional designed binder-target interactions. A co-crystal structure of one such design in complex with the KIT receptor is nearly identical to the computational design model confirming the accuracy of the design approach. The ability to robustly generate binders displaying high affinity and specificity to polar interaction surfaces with exposed beta-strands considerably increases the range and capabilities of computational binder design.
Thrombolysis exacerbates cerebrovascular injury after ischemic stroke via a VEGF-B dependent effect on adipose lipolysis
Authors: Nilsson Ingrid , Su Enming J. , Fredriksson Linda , Sahlgren Benjamin Heller , Bagoly Zsuzsa , Moessinger Christine , Stefanitsch Christina , Ning Frank Chenfei , Zeitelhofer Manuel , Muhl Lars , Lawrence Anna-Lisa E. , Scotney Pierre D. , Lu Li , Samén Erik , Ho Heidi , Keep Richard F. , Medcalf Robert L. , Lawrence Daniel A. , Eriksson Ulf 
Published: October 2024

SummaryCerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.
HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signaturesin vitro
Authors: Haage Verena , Tuddenham John F. , Bautista Alex , White Charles C. , Garcia Frankie , Patel Ronak , Comandante-Lou Natacha , Marshe Victoria , Soni Rajesh Kumar , Sims Peter A. , Menon Vilas , Sproul Andrew A. , De Jager Philip L. 
Published: October 2024

AbstractDisease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes1. Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans2–6; however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate7,8. Here, we present a pharmacological approach to mimic human DAMin vitroby exposing different human microglia models to selected histone deacetylase (HDAC) inhibitors. We also provide an initial functional characterization of our model system, showing a specific increase of amyloid beta phagocytosis along with a reduction of MCP-1 secretion. Additionally, we report an increase inMITFexpression, a transcription factor previously described to drive expression towards the DAM phenotype. We further identifyCADM1,LIPAandSCINas DAM- marker genes shared across various proposed DAM signatures and in our model systems. Overall, our strategy for targeted microglial polarization bears great potential to further explore human DAM function and biology.
Neuronal correlates of sleep in honey bees
Authors: Moguilner Sebastian , Tiraboschi Ettore , Fantoni Giacomo , Strelevitz Heather , Soleimani Hamid , Del Torre Luca , Hasson Uri , Haase Albrecht 
Published: October 2024

AbstractHoney beesApis melliferafollow the day-night cycle for their foraging activity, entering rest periods during dark. To date, studies of bee sleep have focused mostly on behavioural markers; it is not known if these resting states manifest reduced information processing at the level of brain networks, a defining signature of sleep. We used two-photon calcium imaging of the antennal lobes (AL) in head-fixed bees to analyse brain activity in motion/rest epochs during the nocturnal period. The neuronal activity data during these epochs were then computationally described, and machine learning was applied to determine whether a classifier could distinguish the two states after motion correction. Out-of-sample classification accuracy reached up to 93%. The feature importance analysis suggested network features to be decisive. Accordingly, the glomerular connectivity was found to be significantly increased in the rest-state patterns. A full simulation of the AL using a leaky spiking neural network revealed that such a transition in network connectivity could be achieved by weakly correlated input noise and a reduction of synaptic conductance of the inhibitive local neurons (LNs) which couple the AL network nodes. The difference in the AL response maps between awake- and sleep-like states generated by the simulation showed a decreased specificity of the odour code in the sleep state, suggesting reduced information processing during sleep. Since LNs in the bee brain are GABAergic, this suggests that the GABAergic system plays a central role in sleep regulation in bees as in many higher species including humans. Such conservation of sleep mechanisms throughout evolution indicates that bees can serve as a model for studying these mechanisms on the level of individual neurons.