bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADP release can explain spatially-dependent kinesin binding times
Authors: Nguyen Trini , Narayanareddy Babu Janakaloti , Gross Steven P. , Miles Christopher E. 
Published: November 2023

AbstractThe self-organization of cells relies on the profound complexity of protein-protein interactions. Challenges in directly observing these events have hindered progress toward understanding their diverse behaviors. One notable example is the interaction between molecular motors and cytoskeletal systems that combine to perform a variety of cellular functions. In this work, we leverage theory and experiments to identify and quantify the rate-limiting mechanism of the initial association between a cargo-bound kinesin motor and a microtubule track. Recent advances in optical tweezers provide binding times for several lengths of kinesin motors trapped at varying distances from a microtubule, empowering the investigation of competing models. We first explore a diffusion-limited model of binding. Through Brownian dynamics simulations and simulation-based inference, we find this simple diffusion model fails to explain the experimental binding times, but an extended model that accounts for the ADP state of the molecular motor agrees closely with the data, even under the scrutiny of penalizing for additional model complexity. We provide quantification of both kinetic rates and biophysical parameters underlying the proposed binding process. Our model suggests that most but not every motor binding event is limited by their ADP state. Lastly, we predict how these association rates can be modulated in distinct ways through variation of environmental concentrations and spatial distances.Significance StatementCytoskeletal-motor assemblies self-organize to achieve cellular functions ranging from delivering intracellular cargoes to generating forces in mitosis. Advancements in single-molecule experiments have revealed immense detail about motor detachment and stepping, but relatively little regarding the attachment process. With newly available spatially parameterized motor binding times from an optical trap, the evaluation of mechanistic models for binding becomes possible. We find that a model limited by both diffusive search and ADP-release best explains the data. The coupled chemo-mechanical nature of this interaction is more malleable than either separately, possibly explaining the rich diversity and regulation observed in cells. More broadly, our study provides a timely vignette on leveraging computations with experiments to understand how geometry and other complexities shape protein-protein interactions.
Environmental enrichment and physical exercise prevent stress-induced behavioral and blood-brain barrier alterationsviaFgf2
Authors: Paton Sam E.J. , Solano José L. , Collignon Adeline , Richer Émanuelle , Coulombe-Rozon François , Dion-Albert Laurence , Binder Luisa Bandeira , Dudek Katarzyna Anna , Cadoret Alice ,   Signature Consortium, Lebel Manon , Ménard Caroline 
Published: November 2023

SummaryChronic stress can promote loss of blood-brain barrier (BBB) integrity leading to passage of circulating inflammatory mediators in mood-regulating brain areas and establishment of depressive behaviors. Conversely, neurovascular adaptations favoring resilience to stress exposure remain undetermined. Here, we report that environmental enrichment dampens stress-induced loss of endothelial tight junction protein Claudin-5 (Cldn5) along with anxiety- and depression-like behaviors in mice via an increase in fibroblast growth factor 2 (Fgf2). Treatment of mouse and human endothelial cells with Fgf2 preceding an immune challenge with the proinflammatory cytokine TNFα, elevated after chronic stress and in depression, reduces BBB dysfunction, and altered cell signaling. Coping with voluntary physical exercise also protects the BBB from stress deleterious effects by increasing Fgf2 preventing Cldn5 loss, exacerbated inflammation, and social avoidance. Circulating FGF2 level is linked with depression severity and symptomatology in humans supporting involvement of this growth factor in mood disorders and stress-induced BBB changes.
Generation and characterization of a multi-functional panel of monoclonal antibodies for SARS-CoV-2 research and treatment
Authors: Patterson Lila D. , Dubansky Benjamin D. , Dubansky Brooke H. , Stone Shannon , Kumar Mukesh , Rice Charles D. 
Published: November 2023

ABSTRACTThe Coronavirus disease 2019 (COVID19) pandemic caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is an ongoing threat to global public health. To this end, intense efforts are underway to develop reagents to aid in diagnostics, enhance preventative measures, and provide therapeutics for managing COVID-19. The recent emergence of SARS-CoV-2 Omicron variants with enhanced transmissibility, altered antigenicity, and significant escape of existing monoclonal antibodies and vaccines underlines the importance of the continued development of such agents. The SARS-CoV-2 spike protein and its receptor binding domain (RBD) are critical to viral attachment and host cell entry and are primary targets for antibodies elicited from both vaccination and natural infection. In this study, mice were immunized with two synthetic peptides (Pep 1 and Pep 2) within the RBD of the original Wuhan SARS-CoV-2, as well as the whole RBD as a recombinant protein (rRBD). Hybridomas were generated and a panel of three monoclonal antibodies, mAb CU-P1-1 against Pep 1, mAb CU-P2-20 against Pep 2, and mAb CU-28-24 against rRBD, were generated and further characterized. These mAbs were shown by ELISA to be specific for each immunogen/antigen. Monoclonal antibody CU-P1-1 has limited applicability other than in ELISA approaches and basic immunoblotting. Monoclonal antibody CU-P2-20 is shown to be favorable for ELISA, immunoblotting, and immunohistochemistry (IHC), however, not live virus neutralization. In contrast, mAb CU-28-24 is most effective at live virus neutralization as well as ELISA and IHC. Moreover, mAb CU-28-24 was active against rRBD proteins from Omicron variants B.2 and B.4/B5 as determined by ELISA, suggesting this mAb may neutralize live virus of these variants. Each of the immunoglobulin genes has been sequenced using Next Generation Sequencing, which allows the expression of respective recombinant proteins, thereby eliminating the need for long-term hybridoma maintenance. The synthetic peptides and hybridomas/mAbs are under the intellectual property management of the Clemson University Research Foundation, and the three CDRs have been submitted as an invention disclosure for further patenting and commercialization.
Rho/ROCK activity tunes cell compartment segregation and differentiation in nephron-forming niches
Authors: Viola John M. , Liu Jiageng , Huang Aria , Grindel Samuel H. , Prahl Louis S. , Hughes Alex J. 
Published: November 2023

AbstractControlling the time and place of nephron formationin vitrowould improve nephron density and connectivity in next-generation kidney replacement tissues. Recent developments in kidney organoid technology have paved the way to achieving self-sustaining nephrogenic nichesin vitro. The physical and geometric structure of the niche are key control parameters in tissue engineering approaches. However, their relationship to nephron differentiation is unclear. Here we investigate the relationship between niche geometry, cell compartment mixing, and nephron differentiation by targeting the Rho/ROCK pathway, a master regulator of the actin cytoskeleton. We find that the ROCK inhibitor Y-27632 increases mixing between nephron progenitor and stromal compartments in native mouse embryonic kidney niches, and also increases nephrogenesis. Similar increases are also seen in reductionist mouse primary cell and human induced pluripotent stem cell (iPSC)-derived organoids perturbed by Y-27632, dependent on the presence of stromal cells. Our data indicate that niche organization is a determinant of nephron formation rate, bringing renewed focus to the spatial context of cell-cell interactions in kidney tissue engineering efforts.
Plasticity-led and mutation-led evolutions are different modes of the same developmental gene regulatory network
Authors: Ng Eden Tian Hwa , Kinjo Akira R. 
Published: November 2023

ABSTRACTThe standard theory of evolution proposes that mutations cause heritable variations, which are naturally selected, leading to evolution. However, this mutation-led evolution (MLE) is being questioned by an alternative theory called plasticity-led evolution (PLE). PLE suggests that an environmental change induces adaptive phenotypes, which are later genetically accommodated. According to PLE, developmental systems should be able to respond to environmental changes adaptively. However, developmental systems are known to be robust against environmental and mutational perturbations. Thus, we expect a transition from a robust state to a plastic one. To test this hypothesis, we constructed a gene regulatory network (GRN) model that integrates developmental processes, hierarchical regulation, and environmental cues. We then simulated its evolution over different magnitudes of environmental changes. Our findings indicate that this GRN model exhibits PLE under large environmental changes and MLE under small environmental changes. Furthermore, we observed that the GRN model is susceptible to environmental or genetic fluctuations under large environmental changes but is robust under small environmental changes. This indicates a breakdown of robustness due to large environmental changes. Before the breakdown of robustness, the distribution of phenotypes is biased and aligned to the environmental changes, which would facilitate rapid adaptation should a large environmental change occur. These observations suggest that the evolutionary transition from mutation-led to plasticity-led evolution is due to a developmental transition from robust to susceptible regimes over increasing magnitudes of environmental change. Thus, the GRN model can reconcile these conflicting theories of evolution.
The potential effect of romosozumab on perioperative management for instrumentation surgery
Authors: Ishikawa Koji , Tani Soji , Toyone Tomoaki , Tsuchiya Koki , Towatari Tomoko , Oshita Yusuke , Yamamura Ryo , Nagai Takashi , Shirahata Toshiyuki , Inagaki Katsunori , Kudo Yoshifumi 
Published: November 2023

AbstractBackgroundAge-related changes in bone health increase the risk for complications in elderly patients undergoing orthopedic surgery. Osteoporosis is a key therapeutic target that needs to be addressed to ensure successful instrumentation surgery. The effectiveness of pharmacological interventions in orthopedic surgery, particularly the new drug romosozumab, is still unknown. We aim to evaluate the effect of 3-month romosozumab treatment on biomechanical parameters related to spinal instrumentation surgery, using the Quantitative Computed Tomography (QCT)-based Finite Element Method (FEM).MethodsThis open-labeled, prospective study included 81 patients aged 60 to 90 years, who met the osteoporosis criteria and were scheduled for either romosozumab or eldecalcitol treatment. Patients were assessed using blood samples, dual-energy absorptiometry (DXA), and QCT. Biomechanical parameters were evaluated using FEM at baseline and 3 months post-treatment. The primary endpoints were biomechanical parameters at 3 months, while secondary endpoints included changes in regional volumetric bone mineral density around the pedicle (P-vBMD) and vertebral body (V-vBMD).ResultsRomosozumab treatment led to significant gains in P-vBMD, and V-vBMD compared to eldecalcitol at 3 months. Notably, the romosozumab group showed greater improvements in all biomechanical parameters estimated by FEM at 3 months compared to the eldecalcitol group.ConclusionRomosozumab significantly increased the regional vBMD as well as biomechanical parameters, potentially offering clinical benefits in reducing post-operative complications in patients with osteoporosis undergoing orthopedic instrumentation surgery. This study highlights the novel advantages of romosozumab treatment and advocates further research on its effectiveness in perioperative management.
Neuronal PAS domain 1 identifies a major subpopulation of wakefulness-promoting GABAergic neurons in basal forebrain
Authors: Troppoli Timothy A. , Yang Chun , Katsuki Fumi , Uygun David S. , Lin Ilyan , Aguilar David , Spratt Tristan , Basheer Radhika , McNally James M. , Chan C. Savio , McKenna James T. , Brown Ritchie E. 
Published: November 2023

ABSTRACTHere we describe a novel group of basal forebrain (BF) neurons expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+neurons was high, 5-6 times that of neighboring cholinergic, parvalbumin or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+neurons to brain regions involved in sleep-wake control, motivated behaviors and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area and olfactory bulb. Chemogenetic activation of BF Npas1+neurons in the light (inactive) period increased the amount of wakefulness and the latency to sleep for 2-3 hr, due to an increase in long wake bouts and short NREM sleep bouts. Non-REM slow-wave (0-1.5 Hz) and sigma (9-15 Hz) power, as well as sleep spindle density, amplitude and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+neurons in stress responsiveness, the anatomical projections of BF Npas1+neurons and the effect of activating them suggest a possible role for BF Npas1+neurons in motivationally-driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia and other neuropsychiatric conditions involving BF.SIGNIFICANCE STATEMENTWe characterize a group of basal forebrain (BF) neurons in the mouse expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. BF Npas1+neurons are a major subset of GABAergic neurons distinct and more numerous than cholinergic, parvalbumin or glutamate neurons. BF Npas1+neurons target brain areas involved in arousal, motivation and olfaction. Activation of BF Npas1+neurons in the light (inactive) period increased wakefulness and the latency to sleep due to increased long wake bouts. Non-REM sleep slow waves and spindles were reduced reminiscent of findings in several neuropsychiatric disorders. Identification of this major subpopulation of BF GABAergic wake-promoting neurons will allow studies of their role in insomnia, dementia and other conditions involving BF.
Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer’s disease
Authors: Younes Kyan , Smith Viktorija , Johns Emily , Carlson Mackenzie L. , Winer Joseph , He Zihuai , Henderson Victor W. , Greicius Michael D. , Young Christina B. , Mormino Elizabeth C. ,   Alzheimer’s Disease Neuroimaging Initiative Researchers
Published: November 2023

AbstractUnderstanding psychiatric symptoms in Alzheimer’s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is unknown. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored.This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory, and composite scores for memory, executive function, and language; using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define “asymmetry-extreme” groups (individuals with laterality indices greater than two standard deviations from the mean).858 individuals (age=73.9±7.7 years, 434(50%) females) were included, comprising 438 cognitively unimpaired (CU) (53.4%) and 420 impaired (CI) participants (48.9%). In the full cohort analysis, right temporal tau was associated with worse behavior (B(SE)=7.19 (2.9),p-value=0.01) and left temporal tau was associated with worse language (B(SE)=1.4(0.2),p-value<0.0001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, four patterns of tau PET uptake were observed: anterior temporal, typical AD, typical AD with frontal involvement, and posterior.Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Behavioral and socioemotional measures are needed to understand right-sided asymmetry in AD.
Epidemiological Surveillance of Amyotrophic Lateral Sclerosis: A Review
Authors: Wolfson Christina , Gauvin Danielle E. , Ishola Foluso , Oskoui Maryam , Atabe Boris 
Published: November 2023

AbstractBackgroundRegistries and clinical databases are important tools to systematically record and collect information about individuals with rare diseases and to monitor disease patterns in populations. Through a review of the published literature on strategies used for surveillance of Amyotrophic Lateral Sclerosis (ALS), our objective was to better delineate the varied approaches used to monitor ALS at a population level. Further, we sought to determine the potential of registries to enhance knowledge on the epidemiology of ALS using a case study comparing epidemiological outputs from registries in the United States, United Kingdom, and Italy.SummaryWe searched Medline, Embase, Global Health, PsycInfo, Cochrane Library, and CINAHL identifying articles published between January 1st, 2010, and May 12th, 2021. Studies describing population registries, cohorts of individuals with ALS, or large-scale studies aimed at systematically identifying people with ALS, were eligible for inclusion. 1,447 publications were found, of which 141 were selected for full text review, and 41 of those were selected for data extraction. We identified ALS registries and pertinent databases in 4 continents (North America, Europe, Asia, and Oceania). Stated objectives of the registries/databases shaped their framework, methodology, and follow-up. The US National Registry demonstrates substantial research outputs and methodological strengths, producing many descriptive epidemiological outputs (n=5 studies) and several methodological papers (n=12 studies). The UK and Italy overall each produced a similar number of studies (albeit with fewer methodological papers), across several different registries and regions.Key MessagesDue to challenges inherent to the surveillance of rare diseases, registries are a vital tool in determining and assessing the global impact of ALS. Nevertheless, the development and implementation of registries is not feasible everywhere in the world. There are advantages and drawbacks to structuring registries at a national or regional level, often dictated by funding availability, resources and health care infrastructure, and research objectives. To fully assess the epidemiological burden of ALS globally, collaborative initiatives are needed to fill gaps in knowledge, and there is a critical need to harmonize and optimize the development, collection, and sharing of data across registries.
Estimating cancer risk in carriers of Lynch syndrome variants in UK Biobank
Authors: Fummey Eilidh , Navarro Pau , Plazzer John-Paul , Frayling Ian M , Knott Sara , Tenesa Albert 
Published: November 2023

BackgroundLynch syndrome (LS) is an inherited cancer predisposition syndrome caused by genetic variants affecting DNA mismatch repair (MMR) genesMLH1,MSH2,MSH6, andPMS2. Cancer risk in LS is estimated from cohorts of individuals ascertained by family history of cancer, which is known to upwardly bias estimates.MethodsThe InSiGHT Database classifies MMR gene variants by pathogenicity through expert panel review of published evidence. 830 carriers of pathogenic or likely pathogenic (path_MMR) MMR gene variants from InSiGHT were identified in 454,756 UK Biobank participants using whole exome sequence. Nelson-Aalen survival analysis was used to estimate cumulative incidence of colorectal, endometrial, and breast cancer.ResultsCumulative incidence of colorectal and endometrial cancer by age 70 was elevated inpath_MMRcarriers compared to non-carriers (colorectal: 11.8% (95% CI: 9.5 - 14.6) vs. 1.7% (1.6 - 1.7), endometrial: 13.4% (10.2 - 17.6) vs. 1.0% (0.9 - 1.0)), but the magnitude of this increase differed between genes. Cumulative breast cancer incidence by age 70 was not elevated inpath_MMRcarriers compared to non-carriers (8.9% (6.3 - 12.4) vs. 7.5% (7.4 - 7.6)). Cumulative cancer incidence estimates in UK Biobank were similar to estimates from the Prospective Lynch Syndrome Database for all genes and cancers, except there was no evidence for elevated endometrial cancer risk in carriers of pathogenicPMS2variants in UK Biobank.ConclusionThese results can be used to inform the management of incidentally identified cases of LS. For example, they support the application of existing colorectal cancer surveillance strategies for LS in incidentally identified cases.