bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of collective load transport on the individual walking
Authors: Sghaier N. , Pasquaretta C. , Turpin N A. , Moretto P. 
Published: November 2023

AbstractCollective handling is a collaborative strategy that involves two or more people in carrying out load transport. Different positions can be adopted, depending on the handle locations of the transported load, external constraints and the capacities of the carriers. The most adopted collective transport in our daily life is stretcher type transport. However, very little research has focused on the kinematic modifications caused by this type of transport. This research aims to evaluate and quantify the modifications of the locomotor pattern of stretcher transport. Our results highlighted a modification of walking parameters (step length, duration of the walking cycle, speed of execution, etc.), an increase in energy cost but above all a modification of the walking pattern with a reduction in joint range of motion. These results could be used to establish new recommendations for musculoskeletal disorders.
Protein-lipid interactions drive presynaptic assembly upstream of cell adhesion molecules
Authors: Frankel Elisa B. , Tiroumalechetty Araven , Henry Parise S. , Su Zhaoqian , Wu Yinghao , Kurshan Peri T. 
Published: November 2023

ABSTRACTTextbook models of synaptogenesis position cell adhesion molecules such as neurexin as initiators of synapse assembly. Here we discover a mechanism for presynaptic assembly that occurs prior to neurexin recruitment, while supporting a role for neurexin in synapse maintenance. We find that the cytosolic active zone scaffold SYD-1 interacts with membrane phospholipids to promote active zone protein clustering at the plasma membrane, and subsequently recruits neurexin to stabilize those clusters. Employing molecular dynamics simulations to model intrinsic interactions between SYD-1 and lipid bilayers followed byin vivotests of these predictions, we find that PIP2-interacting residues in SYD-1’s C2 and PDZ domains are redundantly necessary for proper active zone assembly. Finally, we propose that the uncharacterized yet evolutionarily conserved short γ isoform of neurexin represents a minimal neurexin sequence that can stabilize previously assembled presynaptic clusters, potentially a core function of this critical protein.
Multiple Guidance Mechanisms Control Axon Growth to Generate Precise T-shaped Bifurcation during Dorsal Funiculus Development in the Spinal Cord
Authors: Curran Bridget M , Nickerson Kelsey R , Yung Andrea R , Goodrich Lisa V , Jaworski Alexander , Tessier-Lavigne Marc , Ma Le 
Published: November 2023

AbstractThe dorsal funiculus in the spinal cord relays somatosensory information to the brain. It is made of T-shaped bifurcation of dorsal root ganglion (DRG) sensory axons. Our previous study has shown that Slit signaling is required for proper guidance during bifurcation, but loss of Slit does not affect all DRG axons. Here, we examined the role of the extracellular molecule Netrin-1 (Ntn1). Using wholemount staining with tissue clearing, we showed that mice lacking Ntn1 have axons escaping from the dorsal funiculus at the time of bifurcation. Genetic labeling confirmed that these misprojecting axons come from DRG neurons. Single axon analysis showed that loss of Ntn1 does not affect bifurcation but rather alters turning angles. To distinguish their guidance functions, we examined mice with triple deletion of Ntn1, Slit1, and Slit2 and found a completely disorganized dorsal funiculus. Comparing mice with different genotypes using immunolabeling and single axon tracing revealed additive guidance errors, demonstrating the independent roles of Ntn1 and Slit. Moreover, the same defects were observed in embryos lacking their cognate receptors. Thesein vivostudies thus demonstrate the presence of multi-factorial guidance mechanisms that ensure proper formation of a common branched axonal structure during spinal cord development.
Minimum changes in sleep, physical activity, and nutrition associated with clinically important reductions in all-cause mortality risk: a prospective cohort study
Authors: Stamatakis Emmanuel , Koemel Nicholas A. , Biswas Raaj K. , Ahmadi Matthew N. , Allman-Farinelli Margaret , Trost Stewart G. , Eroglu Elif I. , Cruz Borja del Pozo , Bin Yu Sun , Postnova Svetlana , Simpson Stephen , Duncan Mitch , Dumuid Dorothea , Fontana Luigi , Brown Helen , Maher Carol , Cistulli Peter A. 
Published: November 2023

ABSTRACTBackgroundSleep, physical activity, and nutrition (SPAN) are crucial modifiable factors for health, yet most research has examined them independently rather than exploring their combined and incremental impact on disease risk and mortality.ObjectiveTo determine the collective associations of SPAN exposures and establish clinically relevant targets for reducing all-cause mortality risk.MethodsThis study included 59,078 UK Biobank participants with valid wearable tracker and nutrition data (Median age [IQR]: 64.0 [7.8] years; 45.4% male). Sleep duration (hours/day) and moderate to vigorous physical activity duration (MVPA; mins/day) were calculated using a machine learning based wearable data schema. A 10-item diet quality score (DQS) assessed the consumption of vegetables, fruits, fish, dairy, whole grains, and vegetable oils, as well as lower intakes of refined grains, processed meats, unprocessed red meats, and sugar-sweetened beverages using a food frequency questionnaire. The DQS assigned values from 0-10 for each component, totalling 100 points, with higher values indicating higher diet quality. Associations with all-cause mortality were explored using Cox proportional hazard models with combinations of SPAN exposure tertiles.ResultsDuring the median 8.1-year follow-up period, 2,458 deaths occurred. MVPA exhibited the strongest overall effect on mortality risk, followed by sleep (with a U- shaped relationship), and diet quality. Compared to the referent group of combined SPAN exposure (lowest tertiles for all three behaviours), the optimal SPAN combination involving moderate sleep duration (7.2-8.0 hours/day), high MVPA (42-103 mins/day), and high DQS (57.5-72.5) was associated with a hazard ratio (HR) of 0.45 (95% CI: 0.37, 0.53). Relative to the 5th percentile of sleep (5.5 hours/day), physical activity (7.3 mins/day), and nutrition (36.9 DQS), a minimum increase of 15 mins/day of sleep, 1.6 min/day MVPA, and 5 DQS points was associated with a 10% reduction in all-cause mortality risk (HR: 0.90; 95% CI: 0.88, 0.93). Additionally, compared to the referent group, an additional 75 mins/day of sleep, 12.5 min/day MVPA, and 25 DQS points was associated with a 50% reduction in all-cause mortality risk (HR: 0.50; 95%CI: 0.44, 0.58).ConclusionThese findings underscore the importance of combined incremental lifestyle modifications in reducing the risk of all-cause mortality.
16p11.2 Microduplication is Associated with Lobule-Specific Abnormalities in Cerebellar Structure and Function
Authors: Hayes Cessily , Halverson Hunter , Keeran Krisha , Tison Krislen , Jacobo Kamilla , Karki Asriya , Herring Isaias , Tunuguntla Swetha , Pace Martha , Doan Binh , Wen Hsiang , Klomp Annette , Lauffer Marisol , Gaine Marie E. , Parker Krystal , Williams Aislinn J. 
Published: November 2023

ABSTRACTThe 16p11.2 microduplication (16p11.2dp/+) is associated with several neuropsychiatric disorders including schizophrenia, autism spectrum disorder, bipolar disorder, intellectual disability, and attention deficit/hyperactivity disorder (ADHD). Cerebellar abnormalities have been increasingly implicated in these neuropsychiatric disorders, including those conferred by 16p11.2 microduplication. In 16p11.2dp/+mouse models, the cerebellum is a site of transcriptional dysregulation, and cerebellar microcephaly has been reported in humans with 16p11.2 microduplication. Despite mounting evidence indicating a role for the cerebellum in neuropsychiatric disorders associated with this CNV, cerebellar cellular structure and cerebellar-dependent behavior in mice with 16p11.2 microduplication remain uncharacterized. To address this, we histologically labeled Purkinje cells (PCs) and molecular layer interneurons (MLIs) in a mouse model of 16p11.2 microduplication. We did not find any structural differences in cerebellar lobule IV/V, nor did we observe impairments in gait or motor coordination, behaviors that are associated with lobule IV/V. In contrast, we discovered a significant increase in calbindin/parvalbumin-positive PCs mislocalized to the granule layer of cerebellar lobule VI in 16p11.2dp/+mice compared to wild-type (WT) littermates. Additionally, we found a significant decrease in parvalbumin-positive MLIs without a decrease in total DAPI-positive cell counts in lobule VI of 16p11.2dp/+mice compared to WT littermates. Cerebellar lobule VI is associated with delay eyeblink conditioning, and 16p11.2dp/+mice are impaired in cerebellum-dependent associative learning on this task. Specifically, 16p11.2dp/+mice showed deficits in both conditioned response (CR) percentage and CR onset latency relative to WT mice. These results suggest that lobule VI–specific alterations to PC localization and MLI parvalbumin expression in 16p11.2dp/+mice impair both cerebellar learning and adaptive timing of cerebellar-driven, conditioned responses. Thus, we have identified novel structural and functional alterations in the cerebellum that are associated with 16p11.2 microduplication. Importantly, individuals with schizophrenia and ADHD also show CR acquisition deficits in delay eyeblink conditioning. Together, these data suggest that the behavioral impairments in 16p11.2dp/+mice resemble impairments seen in neuropsychiatric disorders linked to 16p11.2 microduplication in humans. Further investigation of cerebellar cortex neurons in 16p11.2dp/+mice may provide insights into the pathogenesis of neuropsychiatric disorders linked to this copy number variant.
Detecting Protein-DNA Binding in Single Molecules using Antibody Guided Methylation
Authors: Thatavarty Apoorva , Sagy Naor , Erdos Michael R , Lee Isac , Simpson Jared T , Timp Winston , Collins Francis S , Bar Daniel Z 
Published: November 2023

AbstractCharacterization of DNA binding sites for specific proteins is of fundamental importance in molecular biology. It is commonly addressed experimentally by chromatin immunoprecipitation and sequencing (ChIP-seq) of bulk samples (103-107cells). We have developed an alternative method that uses a Chromatin Antibody-mediated Methylating Protein (ChAMP) composed of a GpC methyltransferase fused to protein G. By tethering ChAMP to a primary antibody directed against the DNA-binding protein of interest, and selectively switching on its enzymatic activityin situ, we generated distinct and identifiable methylation patterns adjacent to the protein binding sites. This method is compatible with methods of single-cell methylation-detection and single molecule methylation identification. Indeed, as every binding event generates multiple nearby methylations, we were able to confidently detect protein binding in long single molecules.Abstract FigureGraphical abstract(i) ChAMP is added to fix and permeabilized cells, where it binds (ii) any antibody, and upon the addition of SAM, methylates nearby GpC sites, to be detected by sequencing (iii-iv).
Transcriptional inhibition after irradiation occurs preferentially at highly expressed genes in a manner dependent on cell cycle progression
Authors: Chen Zulong , Wang Xin , Gao Xinlei , Arslanovic Nina , Chen Kaifu , Tyler Jessica 
Published: November 2023

AbstractIn response to DNA double strand damage, ongoing transcription is inhibited to facilitate accurate DNA repair while transcriptional recovery occurs after DNA repair is complete. However, the mechanisms at play and identity of the transcripts being regulated in this manner are unclear. In contrast to the situation following UV damage, we found that transcriptional recovery after ionizing radiation (IR) occurs in a manner independent of the HIRA histone chaperone. Sequencing of the nascent transcripts identified a programmed transcriptional response, where certain transcripts and pathways are rapidly downregulated after IR, while other transcripts and pathways are upregulated. Specifically, most of the loss of nascent transcripts occurring after IR is due to inhibition of transcriptional initiation of the highly transcribed histone genes and the rDNA. To identify factors responsible for transcriptional inhibition after IR in an unbiased manner, we performed a whole genome gRNA library CRISPR / Cas9 screen. Many of the top hits in our screen were factors required for protein neddylation. However, at short times after inhibition of neddylation, transcriptional inhibition still occurred after IR, even though neddylation was effectively inhibited. Persistent inhibition of neddylation blocked transcriptional inhibition after IR, and it also leads to cell cycle arrest. Indeed, we uncovered that many inhibitors and conditions that lead to cell cycle arrest in G1or G2phase also prevent transcriptional inhibition after IR. As such, it appears that transcriptional inhibition after IR occurs preferentially at highly expressed genes in cycling cells.
Volume Electron Microscopy Reveals Unique Laminar Synaptic Characteristics in the Human Entorhinal Cortex
Authors: Plaza-Alonso Sergio , Cano-Astorga Nicolás , DeFelipe Javier , Alonso-Nanclares Lidia 
Published: November 2023

AbstractThe entorhinal cortex (EC) plays a pivotal role in memory function and spatial navigation, connecting the hippocampus with the neocortex. The EC integrates a wide range of cortical and subcortical inputs, but its synaptic organization in the human brain is largely unknown. We used volume electron microscopy to perform a 3D analysis of the microanatomical features of synapses in all layers of the medial EC (MEC) from the human brain. Using this technology, 12,974 synapses were fully 3D reconstructed at the ultrastructural level. The MEC presented a distinct set of synaptic features, differentiating this region from other human cortical areas. Furthermore, ultrastructural synaptic characteristics within the MEC was predominantly similar, although layers I and VI exhibited several synaptic characteristics that were distinct from other layers. The present study constitutes an extensive description of the synaptic characteristics of the neuropil of all layers of the EC, a crucial step to better understand the connectivity of this cortical region, in both health and disease.
Localized oxygen control in a microfluidic osteochondral interface model recapitulates bone-cartilage crosstalk during osteoarthritis
Authors: Ong Louis Jun Ye , Sun Antonia Rujia , Wang Zhongzheng , Lee Jayden , Pradasadam Indira , Toh Yi-Chin 
Published: November 2023

AbstractOsteoarthritis (OA) is characterized by the dysregulation of the osteochondral interface between bone and cartilage.In vitromodels that accurately mimic this interface hold great potential for understanding OA pathophysiology and screening therapeutic agents. Presently, research efforts have focused on emulating heterogeneity in structural and mechanical attributes of the extracellular matrix (ECM) at the osteochondral interface. However, the precise simulation of differential oxygen gradients experienced by chondrocytes and osteoblasts in vivo remains a substantial obstacle for modeling osteo-chondral interactions effectively. To overcome this limitation, we show that micropatterned granular hydrogels, which are small microgel particles swelled in liquid culture media to create a shear-yielding jammed-packed solid, can be used to control the delivery of oxygen scavenging agents in a simple and scalable manner. Hypoxic granular hydrogels formulated with Oxyrase™ could maintain <1% oxygen concentration in a conventional cell culture incubator. Primary human chondrocytes maintained in the hypoxic hydrogels expressed a more anabolic phenotype similar to those cultured in a hypoxic incubator. The granular hydrogels can be readily patterned in a microfluidic device to generate a localized hypoxic environment, mimicking the differential oxygen levels at the osteochondral tissue interface (i.e. osteoblast at 20% and chondrocyte at 2% oxygen). Using this microfluidic coculture model, we paired healthy human chondrocytes with osteoblasts isolated from non-sclerotic and sclerotic subchondral bone to investigate how oxygen environment modulates osteoblast-chondrocyte crosstalk during OA. In a differential oxygen environment, the osteoblast-chondrocyte co-culture model showed sclerotic osteoblasts inducing chondrocyte collagen expression changes through increased MMP13 and ADAM15 production, unlike in a uniform normoxic oxygen environment, where the change was driven by altered collagen gene expression favoring Type I over Type II collagen. Furthermore, differential oxygen conditions enabled the identification of extensive transcriptional alterations induced by sclerotic osteoblasts, which involved inflammatory NF-κβ, TGF-β/BMP, and IGF signaling pathways, that was otherwise not detectable in a uniform normoxic co-culture. The microfluidic model with localized oxygen variations effectively mimics physiologically relevant osteoblast-chondrocyte crosstalk, providing valuable insights into OA pathophysiology.
Grasp Orientation in Ambiguous Settings is Sensitive to Prior Object Motion
Authors: Maffitt Natalie J , Cairns Emma G , Wozna Julia , Soteropoulos Demetris S , Kraskov Alexander 
Published: November 2023

AbstractThe wrist posture chosen to grasp an object is normally consistent, determined by the optimal, most efficient strategy learnt from previous experience. Yet in certain settings, despite object properties remaining constant and intention the same, the action chosen by an individual can vary with a lack of clear preference for one posture over another. This is referred to as motor ambiguity. Here, we investigate the influence of preceding dynamically changing visual information on participants’ choice between two possible wrist postures when grasping an object at various orientations. By presenting an initial orientation prior to the grasping of an ambiguous orientation, we found that subjects become biased to select a grasp for the ambiguous target that would be most congruent with the initial, determinate orientation. However, when object motion is observed between the initial and target positions, the bias is reversed, i.e. subjects choose the alternate wrist posture. Furthermore, the bias strength was found to be independent of the motion magnitude, and persists even when greater decision time is allowed. We provide evidence that this bias effect is not a perceptual phenomenon, and suggest it is potentially a behavioural manifestation of inhibitory circuits that delay decisions in conditions of motor ambiguity.
14-3-3 binding motif phosphorylation disrupts Hdac4 organized condensates to stimulate cardiac reprogramming
Authors: Liu Liu , Lei Ienglam , Tian Shuo , Gao Wenbin , Guo Yijing , Li Zhaokai , Sabry Ziad , Tang Paul , Chen Y. Eugene , Wang Zhong 
Published: November 2023

AbstractCell fate conversion is associated with extensive epigenetic and post translational modifications (PTMs) and architectural changes of sub-organelles and organelles, yet how these events are interconnected remains unknown. We report here the identification of a phosphorylation code in 14-3-3 binding motifs (PC14-3-3) that greatly stimulates induced cardiomyocyte (iCM) formation from fibroblasts. PC14-3-3 was identified in pivotal functional proteins for iCM reprogramming, including transcription factors and epigenetic factors. Akt1 kinase and PP2A phosphatase were a key writer and eraser of the PC14-3-3 code, respectively. PC14-3-3 activation induces iCM formation with the presence of only Tbx5. In contrast, PC14-3-3 inhibition by mutagenesis or inhibitor-mediated code removal abolished reprogramming. We discovered that key PC14-3-3 embedded factors, such as Hdac4, Mef2c, Nrip1, and Foxo1, formed Hdac4 organized inhibitory nuclear condensates. Notably, PC14-3-3 activation disrupted Hdac4 condensates to promote cardiac gene expression. Our study suggests that sub-organelle dynamics regulated by a post-translational modification code could be a general mechanism for stimulating cell reprogramming and organ regeneration.HighlightsA PC14-3-3 (phosphorylation code in 14-3-3 binding motifs) is identified in pivotal functional proteins, such as HDAC4 and Mef2c, that stimulates iCM formation.Akt1 kinase and PP2A phosphatase are a key writer and a key eraser of the PC14-3-3 code, respectively, and PC14-3-3 code activation can replace Mef2c and Gata4 in cardiac reprogramming.PC14-3-3 activation disrupts Hdac4 organized condensates which results in releasing multiple 14-3-3 motif embedded proteins from the condensates to stimulate cardiac reprogramming.Sub-organelle dynamics and function regulated by a post-translational modification code could be a general mechanism in stimulating cell reprogramming and organ regeneration.Graphic abstract
Assessing Tumor Microenvironment Characteristics and Stratifying EPR with a Nanobubble Companion Nanoparticle via Contrast-Enhanced Ultrasound Imaging
Authors: Cooley Michaela B. , Wegierak Dana , Perera Reshani , Abenojar Eric C. , Nittayacharn Pinunta A. , Berg Felipe M. , Kim Youjoung , Kolios Michael C. , Exner Agata A. 
Published: November 2023

AbstractThe tumor microenvironment is characterized by dysfunctional endothelial cells, resulting in heightened vascular permeability. Many nanoparticle-based drug delivery systems attempt to use this enhanced permeability combined with impaired lymphatic drainage (a concept known as the ‘enhanced permeability and retention effect’ or EPR effect) as the primary strategy for drug delivery, but this has not proven to be as clinically effective as anticipated. The specific mechanisms behind the inconsistent clinical outcomes of nanotherapeutics have not been clearly articulated, and the field has been hampered by a lack of accessible tools to study EPR-associated phenomena in clinically relevant scenarios. While medical imaging has tremendous potential to contribute to this area, it has not been broadly explored. This work examines, for the first time, the use of multiparametric dynamic contrast-enhanced ultrasound (CEUS) with a novel nanoscale contrast agent to examine tumor microenvironment characteristics noninvasively and in real-time. We demonstrate that CEUS imaging can: (1) evaluate tumor microenvironment features and (2) be used to help predict the distribution of doxorubicin-loaded liposomes in the tumor parenchyma. CEUS using nanobubbles (NBs) was carried out in two tumor types of high (LS174T) and low (U87) vascular permeability, and time-intensity curve (TIC) parameters were evaluated in both models prior to injection of doxorubicin liposomes. Consistently, LS174T tumors showed significantly different TIC parameters, including area under the rising curve (2.7x), time to peak intensity (1.9x) and decorrelation time (DT, 1.9x) compared to U87 tumors. Importantly, the DT parameter successfully predicted tumoral nanoparticle distribution (r = 0.86 ± 0.13). Ultimately, substantial differences in NB-CEUS generated parameters between LS174T and U87 tumors suggest that this method may be useful in determining tumor vascular permeability and could be used as a biomarker for identifying tumor characteristics and predicting sensitivity to nanoparticle-based therapies. These findings could ultimately be applied to predicting treatment efficacy and to evaluating EPR in other diseases with pathologically permeable vasculature.