bluuebunny/crossref_metadata_2025_split huggingface dataset:
The nonlinear meccano of hyperactivity in Alzheimer
Authors: Bonifazi Giulio , Luchena Celia , Gaminde-Blasco Adhara , Ortiz-Sanz Carolina , Capetillo-Zarate Estibaliz , Matute Carlos , Alberdi Elena , De Pittà Maurizio 
Published: October 2023

AbstractThe pathophysiological process of Alzheimer’s disease (AD) is believed to begin many years before the formal diagnosis of AD dementia. This protracted preclinical phase offers a crucial window for potential therapeutic interventions, yet its comprehensive characterization remains elusive. Accumulating evidence suggests that amyloid-β (Aβ) may mediate neuronal hyperactivity in circuit dysfunction in the early stages of AD. At the same time, neural activity can also facilitate Aβ accumulation through intricate feed-forward interactions, complicating elucidating the conditions governing Aβ-dependent hyperactivity and its diagnostic utility. In this study, we use biophysical modeling to shed light on such conditions. Our analysis reveals that the inherently nonlinear nature of the underlying molecular interactions can give rise to various modes of hyperactivity emergence. This diversity in the mechanisms of hyperactivity may ultimately account for a spectrum of AD manifestations.
Pial collaterals develop through mosaic colonization of capillaries by arterial and microvascular endothelial cells
Authors: Perovic Tijana , Hollfinger Irene , Mayer Stefanie , Lips Janet , Dopatka Monika , Harms Christoph , Gerhardt Holger 
Published: October 2023

AbstractCollaterals are unique blood vessels present in many healthy tissues that cross-connect distal-end arterioles of adjacent arterial trees, thus providing alternate routes of perfusion. Stroke patients with superior pial collateral flow respond better to treatments and present with an overall improved prognostic outcome. However, how pial collaterals develop in the embryo and how they reactivate upon stroke remains unclear. Here, using lineage tracing in combination with three-dimensional imaging, we demonstrate that mouse embryos employ a novel mechanism to build pial collaterals, distinct from their outward remodeling following stroke. Endothelial cells (ECs) of arterial and microvascular origin invade already existing pre-collateral vascular structures in a process which we termed mosaic colonization. Arterialization of these pre-collateral vascular segments happens concurrently with mosaic colonization. Despite having a smaller proliferative capacity, embryonic arterial cells represent the majority of cells that migrate to form nascent collaterals; embryonic microvascular cells, despite their higher proliferative potential, form only about a quarter of collateral endothelial cells. Moreover, postnatal collateral growth relies much more on self-replenishment of arterial cells than on microvascular contribution. Following ischemic injury, pial collateral outward remodeling relies on local cell proliferation rather than recruitment of non-arterial cells. Together, these findings establish distinct cellular mechanisms underlying pial collateral development and ischemic remodeling, raising the prospect for future research to identify novel, collateral-specific therapeutic strategies for ischemic stroke.
A feasibility study of smartphone sensors to assess the effect of acute high altitude (3,800 m) exposure on cognition and motor function in healthy participants
Authors: Goldman Oliver G. , Dubowitz Gerald , Anderson David 
Published: October 2023

ABSTRACTAcute exposure to hypoxia at attitude has neurologic effects. Some subjects develop severe neurologic symptoms, including Parkinsonism, when hypoxic at high altitude as part of an Acute Mountain Sickness syndrome. Digital health technologies can provide continuous monitoring and objective, real-world measures of movement disorders, but only limited validation data of wearable sensors is available in the high-altitude setting. This equipment validation and feasibility study assessed smartphone microphone and accelerometer function at sea level and 12470 feet (3,800 m) to assess their potential value to predict and prevent neurologic features of acute mountain sickness. A feasibility study of standardized assessments of motor, speech and cognitive tasks was performed in 3 normal subjects at sea level and at altitude. All subjects were hypoxic at altitude with O2saturations ranging from 77-81%. Shaker table (range of frequencies) and high-fidelity speaker (range of frequencies) controls confirmed high correlation of observed and expected measurements for microphone and accelerometer under all conditions. The feasibility study demonstrated that under conditions of hypoxia at attitude, fine motor skills are impaired; visual short-term memory is not impaired but has longer response time; gait and balance is impaired, and a postural tremor develops with frequencies below 10 Hz. Future studies could use these wearable sensors to further assess effects at altitude of more severe hypoxia with applications in the high-altitude environment for Parkinson’s Disease patients, with further opportunity for aviation and military use.
The single-molecule accessibility landscape of newly replicated mammalian chromatin
Authors: Ostrowski Megan S , Yang Marty G , McNally Colin P , Abdulhay Nour J , Wang Simai , Nora Elphège P , Goodarzi Hani , Ramani Vijay 
Published: October 2023

ABSTRACTThe higher-order structure of newly replicated (i.e.‘nascent’) chromatin fibers remains poorly-resolved, limiting our understanding of how epigenomes are maintained across cell divisions. To address this, we presentReplication-AwareSingle-moleculeAccessibilityMapping (RASAM), a long-read sequencing method that nondestructively measures genome-wide replication-status and protein-DNA interactions simultaneously on intact chromatin templates. We report that individual human and mouse nascent chromatin fibers are ‘hyperaccessible’ compared to steady-state chromatin. This hyperaccessibility occurs at two, coupled length-scales: first, individual nucleosome core particles on nascent DNA exist as a mixture of partially-unwrapped nucleosomes and other subnucleosomal species; second, newly-replicated chromatin fibers are significantly enriched for irregularly-spaced nucleosomes on individual DNA molecules. Focusing on specificcis-regulatory elements (e.g.transcription factor binding sites; active transcription start sites [TSSs]), we discover unique modes by which nascent chromatin hyperaccessibility is resolved at the single-molecule level: at CCCTC-binding factor (CTCF) binding sites, CTCF and nascent nucleosomes compete for motifs on nascent chromatin fibers, resulting in quantitatively-reduced CTCF occupancy and motif accessibility post-replication; at active TSSs, high levels of steady-state chromatin accessibility are preserved, implying that nucleosome free regions (NFRs) are rapidly re-established behind the fork. Our study introduces a new paradigm for studying higher-order chromatin fiber organization behind the replication fork. More broadly, we uncover a unique organization of newly replicated chromatin that must be reset by active processes, providing a substrate for epigenetic reprogramming.
Identification of a binding site for bupropion inGloeobacter violaceusligand-gated ion channel
Authors: Pirayesh Elham , Do Hoa Quynh , Ferreira Garren , Pandhare Akash , Gallardo Zackary Ryan , Jansen Michaela 
Published: October 2023

ABSTRACTBupropion is an atypical antidepressant and smoking cessation drug which causes adverse effects such as insomnia, irritability, and anxiety. Bupropion inhibits dopamine and norepinephrine reuptake transporters and eukaryotic cation-conducting pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT3A) receptors, at clinically relevant concentrations. However, the binding sites and binding mechanisms of bupropion are still elusive. To further understand the inhibition of pLGICs by bupropion, in this work, using a prokaryotic homologue of pLGICs as a model, we examined the inhibitory potency of bupropion inGloeobacter violaceusligand-gated ion channel (GLIC), a proton-gated ion channel. Bupropion inhibited proton-induced currents in GLIC with an inhibitory potency of 14.9 ± 2.0 μM, comparable to clinically attainable concentrations previously shown to also modulate eukaryotic pLGICs. Using single amino acid substitutions in GLIC and two-electrode voltage-clamp recordings, we further determined a binding site for bupropion in the lower third of the first transmembrane segment M1 at residue T214. The sidechain of M1 T214 together with additional residues of M1 and also of M3 of the adjacent subunit have previously been shown to contribute to binding of other lipophilic molecules like allopregnanolone and pregnanolone.SIGNIFICANCEGLIC,Gloeobacterligand-gated ion channel, has been extensively used as a model to identify and understand binding sites and mechanisms for cholesterol, neurosteroids, and anesthetics interacting with neurotransmitter-gated ion channels, such as, GABAAreceptors and nicotinic acetylcholine receptors. Recently, increasing evidence has revealed that another neurotransmitter-gated ion channel, the serotonin type 3A receptor, binds to an atypical antidepressant, bupropion, at clinically relevant concentrations. Our work here proposes a binding site for bupropion in GLIC and suggests a new approach to characterize binding mechanisms of bupropion in other neurotransmitter-gated ion channels.
β-catenin-mediated activation of Wnt target genes utilizes a biomolecular condensate-dependent mechanism
Authors: Stewart Richard A. , Goodman Lauren B. , Tran Jeannine J. , Zientko John P. , Sabu Malavika , Jeon Ung Seop , Cadigan Kenneth M. 
Published: October 2023

AbstractThe Wnt/β-catenin signaling pathway plays numerous, essential roles in animal development and tissue/stem cell maintenance. The activation of genes regulated by Wnt/β-catenin signaling requires the nuclear accumulation of β-catenin, a transcriptional co-activator. β-catenin is recruited to many Wnt-regulated enhancers through direct binding to T-cell factor/Lymphoid enhancer factor (TCF/LEF) family transcription factors. β-catenin has previously been reported to form phase-separated biomolecular condensates (BMCs), which was implicated as a component of β-catenin’s mechanism of action. This function required aromatic amino acid residues in the intrinsically disordered regions (IDRs) at the N- and C-termini of the protein. In this report, we further explore a role for β-catenin BMCs in Wnt target gene regulation. We find that β-catenin BMCs are miscible with LEF1 BMCsin vitro. We characterized a panel of β-catenin mutants with different combinations of aromatic residue mutations in human cell culture andDrosophila melanogaster. Our data support a model in which aromatic residues across both IDRs contribute to BMC formationin vitroand signaling activityin vivo. Although different Wnt targets have different sensitivities to loss of β-catenin’s aromatic residues, the activation of every target examined was compromised by aromatic substitution. These mutants are not defective in nuclear import, and residues in the N-terminal IDR with no previously known role in signaling are clearly required for the activation of various Wnt readouts. Consistent with this, deletion of the N-terminal IDR results in a loss of signaling activity, which can be rescued by the addition of heterologous IDRs enriched in aromatic residues. Overall, our work supports a model in which the ability of β-catenin to form biomolecular condensates in the nucleus is tightly linked to its function as a transcriptional co-regulator.
How to measure the controllability of an infectious disease?
Authors: Parag Kris V 
Published: October 2023

AbstractQuantifying how difficult it is to control an emerging infectious disease is crucial to public health decision-making, providing valuable evidence on if targeted interventions e.g., quarantine and isolation, can contain spread or when population-wide controls e.g., lockdowns, are warranted. The disease reproduction number,R, or growth rate,r, are universally assumed to measure controllability becauseR=1 andr=0 define when infections stop growing and hence the state of critical stability. Outbreaks with largerRorrare therefore interpreted as less controllable and requiring more stringent interventions. We prove this common interpretation is impractical and incomplete. We identify a positive feedback loop among infections intrinsically underlying disease transmission and evaluate controllability from how interventions disrupt this loop. The epidemic gain and delay margins, which respectively define how much we can scale infections (this scaling is known as gain) or delay interventions on this loop before stability is lost, provide rigorous measures of controllability. Outbreaks with smaller margins necessitate more control effort. Using these margins, we quantify how presymptomatic spread, surveillance limitations, variant dynamics and superspreading shape controllability and demonstrate thatRandronly measure controllability when interventions do not alter timings between the infections and are implemented without delay. Our margins are easily computed, interpreted and reflect complex relationships among interventions, their implementation and epidemiological dynamics.
Vibration of effects resulting from network geometry in mixed-treatment comparisons: a case study on network meta-analyses of antidepressants in major depressive disorder
Authors: Vinatier Constant , Palpacuer Clement , Scanff Alexandre , Naudet Florian 
Published: October 2023

AbstractObjectiveIt is frequent to find overlapping network meta-analyses (NMAs) on the same topic with differences in terms of both treatments included and effect estimates. We aimed to evaluate the impact on effect estimates of selecting different treatment combinations (i.e. network geometries) for inclusion in NMAs.DesignMultiverse analysis, covering all possible NMAs on different combinations of treatments.SettingData from a previously published NMA exploring the comparative effectiveness of 22 treatments (21 antidepressants and a placebo) for the treatment of acute major depressive disorder.ParticipantsCipriani et al (2018) explored a dataset of 116 477 patients included in 522 randomized controlled trials.Main outcome measuresFor each possible network geometry, we performed a NMA to estimate comparative effectiveness on treatment response and treatment discontinuation for the treatments included (231 between-treatment comparisons). The distribution of effect estimates of between-treatment comparisons across NMAs was computed, and the direction, magnitude, and statistical significance of the 1stand 99thpercentiles were compared.Results4 116 254 different NMAs concerned treatment response. Among possible network geometries, 172/ 231 (74%) pairwise comparisons exhibited opposite effects between the 1stand 99thpercentiles, 57/231 (25%) comparisons exhibited statistically significant results in opposite directions, 118 of 231 (51%) comparisons derived non-robust results in terms of statistical significance at 5% risk and 56/231 (24%) treatment pairs obtained robust results across meta-analyses. Comparisons based on indirect evidence only were associated with greater variability in effect estimates. Comparisons with small absolute values observed in the complete NMA more frequently obtained statistically significant results in opposite directions. Similar results were observed for treatment discontinuation.ConclusionIn this case study we observed that the selection of treatments to be included in a NMA could have considerable consequences on treatment effect estimations.Registrationhttps://osf.io/mb5dy
Surrogate virus neutralisation test based on nanoluciferase-tagged antigens to quantify inhibitory antibodies against SARS-CoV-2 and characterise Omicron-specific reactivity
Authors: Schoefbaenker M , Neddermeyer R , Guenther T , Mueller MM , Romberg ML , Classen N , Hennies MT , Hrincius ER , Ludwig S , Kuehn JE , Lorentzen EU 
Published: October 2023

ABSTRACTVirus-specific antibodies are important determinants of protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While regarded as the gold standard for detecting functional antibodies, conventional virus neutralisation tests (VNT) or pseudotyped virus neutralisation tests (pVNT) require biosafety level 2 or 3 facilities. Alternatively, the virus-free surrogate virus neutralisation test (sVNT) quantifies inhibitory antibodies that prevent the spike protein from binding to its receptor, human angiotensin-converting enzyme 2 (hACE2).We evaluated secreted nanoluciferase (NLuc)-tagged spike (S) protein fragments as diagnostic antigens in the sVNT in the framework of a vaccination study. First, spike fragments of different lengths were tested for their suitability as diagnostic antigens in a capture enzyme immunoassay (EIA) using unprocessed culture supernatants of transfected cells, identifying the receptor binding domain (RBD) of S as the optimal construct. The sensitivity of the in-house sVNT relying on the NLuc-labelled RBD equalled or surpassed a commercial sVNT (cPass, GenScript Diagnostics) and an in-house pVNT four weeks after the first vaccination (98% vs. 94% and 72%, respectively), reaching 100% in all assays four weeks after the second and third vaccinations. Additionally, serum reactivity with spike constructs of Omicron BA.1 was tested. Compared with a capture EIA, the in-house sVNT and pVNT displayed superior discrimination between wild-type- and variant-specific reactivity of sera. Differences in reactivity were most pronounced after the first and second vaccinations, whereas the third vaccination resulted in robust, cross-reactive detection of Omicron constructs.In conclusion, assays utilising NLuc-labelled protein fragments permit the quantification and functional assessment of SARS-CoV-2-specific antibodies and the detection of variant-specific differences in reactivity. Potential applications include monitoring therapy and vaccine efficacy and follow-up of prolonged disease courses in high-risk groups. Designed as straightforward, highly flexible modular systems, these tests can be readily adapted to further emerging viral variants.
Widespread drastic reduction of brain myelin content upon prolonged endurance exercise
Authors: Ramos-Cabrer Pedro , Cabrera-Zubizarreta Alberto , Padró Daniel , Matute-González Mario , Rodríguez-Antigüedad Alfredo , Matute Carlos 
Published: October 2023

AbstractRecent evidence suggests that myelin lipids may act as glial energy reserves when glucose is lacking, a hypothesis yet to be solidly proven. Hereby, we examined the effects of running a marathon on the myelin content by MRI. Our findings show that marathon runners undergo widespread robust myelin decrease at completion of the effort. This reduction involves white and gray matter, and includes primary motor and sensory cortical areas and pathways, as well as the entire corpus callosum and internal capsule. Notably, myelin levels partially recover within two weeks after the marathon. These results reveal that myelin use and replenishment is an unprecedented form of metabolic plasticity aimed to maintain brain function during extreme conditions.One-Sentence SummaryBrain myelin usage during strenuous exercise and recovery thereafter
Chromosome-scale Genome Assembly of Lewis Flax (Linum lewisiiPursh.)
Authors: Innes Peter A. , Smart Brian C. , Barham Joseph A.M. , Hulke Brent S. , Kane Nolan C. 
Published: October 2023

ABSTRACTLinum lewisii, a perennial blue flax native to North America, holds potential as a sustainable perennial crop for oilseed production due to its ecological adaptability, upright harvestable structure, nutritious seeds, and low insect and disease issues. Its native distribution spans a large geographic range, from the Pacific Coast to the Mississippi River, and from Alaska to Baja California. Tolerant to cold and drought conditions, this species is also important for native ecosystem rehabilitation. Its enhancement of soil health, support for pollinators, and carbon sequestration underscore its agricultural relevance.This study presents a high-quality, chromosome-scale assembly of theL. lewisii(2n = 2x = 18) genome, derived from PacBio HiFi and Dovetail Omni-C sequencing of the “Maple Grove” variety. The initial assembly contained 642,903,787 base pairs across 2,924 scaffolds. Following HiRise scaffolding, the final assembly contained 643,041,835 base pairs, across 1,713 scaffolds, yielding an N50 contig length of 66,209,717 base pairs. Annotation of the assembly revealed 38,808 genes, including 37,599 protein-coding genes and 7,108 putative transposable elements. Analysis of synteny with other flax species revealed a striking number of chromosomal rearrangements. We also found an intriguing absence of the single-copyTSS1gene in theL. lewisiigenome, potentially linked to its transition from heterostyly to homostyly.Taken together, these findings represent a significant advancement in our understanding of theLinumgenus and provide a resource for future domestication efforts and basic research on Lewis flax.
Regulatory Role of PKR in Systemic Inflammation-Triggered Neuroinflammation and its Modulation of Glucose Metabolism and Cognitive Functions in Cholinergic Neurons
Authors: Cheng Wai-Yin , Lee Xin-Zin , Lai Michael Siu-Lun , Ho Yuen-Shan , Chang Raymond Chuen-Chung 
Published: October 2023

AbstractSystemic inflammation may promote neuroinflammation and neurodegeneration. The double-stranded RNA-dependent protein kinase (PKR) is a key signaling molecule that regulates immune responses. This study aims to examine the role of PKR in regulating systemic inflammation-induced neuroinflammation and cognitive dysfunctions using a laparotomy mouse model. In the first part, wild-type C57BL/6J and C57BL/6-Tg(CD68-EGFP)1Drg/J mice were assigned to undergo either laparotomy with sevoflurane anesthesia or sevoflurane alone to examine effects of systemic inflammation on neuroinflammation and cognition. In the second part, PKR-/-mice were used to study the role of PKR in modulating laparotomy-induced systemic inflammation, neuroinflammation, and cognition. For the third part, PKR was inhibited selectively in cholinergic neurons of ChAT-IRES-Cre-eGFP mice via intracerebroventricular injection of rAAV-DIO-PKR-K296R. This examined the effects of inhibiting PKR in cholinergic neurons on glucose metabolism and cognition in the laparotomy model. Our study revealed that genetic deletion of PKR in mice potently attenuated the laparotomy-induced peripheral and neural inflammation and cognitive deficits. Furthermore, inhibiting PKR in the cholinergic neurons rescued the laparotomy-induced brain glucose hypometabolism and cognitive impairment. Our results demonstrated the critical role of PKR in regulating neuroinflammation and cognitive dysfunctions in a peripheral inflammation model. PKR could be a pharmacological target for treating systemic inflammation-induced neuroinflammation and cognitive dysfunctions.