bluuebunny/crossref_metadata_2025_split huggingface dataset:
Burden and risk factors for Achilles tendinopathy in the military population from 2006 to 2015. A retrospective cohort study
Authors: Sullivan Christopher K , Janney Cory F. , Fraser John J. 
Published: March 2023

ABSTRACTBackgroundAnkle-foot conditions are ubiquitous in the US Military. The objective of this study was to evaluate the burden and associated factors of Achilles tendinopathy (AT).MethodsThe Defense Medical Epidemiology Database was used to identify all diagnosed AT in military personnel from 2006 to 2015. Prevalence of AT was calculated and compared by year, service branch, and military rank. Unadjusted and adjusted assessment of injury risk were calculated.ResultsOfficers incurred 37,939 episodes at a prevalence of 17.65 per 1000 (male officers: 18.20 per 1000; female officers: 14.80 per 1000). Among enlisted personnel, there were 116,122 episodes of AT that occurred in 12.22 per 1000 (male enlisted: 12.07 per 1000; female enlisted: 13.22 per 1000). All officer specialties had significantly higher risk of AT episodes compared to the ground and naval gunfire officers (PR: 1.04-1.43), with aviation demonstrating a significant protective effect (PR: 0.65). Among enlisted specialties, maritime/naval specialties had reduced risk (PR: 0.82), with all specialties (except aviation) having increased risk of AT compared to infantry (PR: 1.07-1.71). There were multiple associated factors identified, to include sex, age, rank, military occupation, and service branch.ConclusionsAT was ubiquitous in the US military, with a progressive increase in prevalence during the study epoch. There were multiple associated factors identified, to include sex, age, rank, military occupation, and service branch. These findings highlight both the need for prophylactic interventions and identification of the populations with the greatest need.
Condensate-driven interfacial forces reposition DNA loci and measure chromatin viscoelasticity
Authors: Strom Amy R. , Kim Yoonji , Zhao Hongbo , Orlovsky Natalia , Chang Yi-Che , Košmrlj Andrej , Storm Cornelis , Brangwynne Clifford P. 
Published: March 2023

SummaryBiomolecular condensates assemble in living cells through phase separation and related phase transitions. An underappreciated feature of these dynamic molecular assemblies is that they form interfaces with cellular structures, including membranes, cytoskeleton, DNA and RNA, and other membraneless compartments. These interfaces are expected to give rise to capillary forces, but there are few ways of quantifying and harnessing these forces in living cells. Here, we introduce VECTOR (ViscoElasticChromatinTethering andORganization), which uses light-inducible biomolecular condensates to generate capillary forces at targeted DNA loci. VECTOR can be utilized to programmably reposition genomic loci on a timescale of seconds to minutes, quantitatively revealing local heterogeneity in the viscoelastic material properties of chromatin. These synthetic condensates are built from components that naturally form liquid-like structures in living cells, highlighting the potential role for native condensates to generate forces and do work to reorganize the genome and impact chromatin architecture.
Topology recapitulates ontogeny of dendritic arbors
Authors: Liao Maijia , Bird Alex D. , Cuntz Hermann , Howard Jonathon 
Published: March 2023

AbstractBranching of dendrites and axons allows neurons to make synaptic contacts with large numbers of other neurons, facilitating the high connectivity of the nervous system. Neurons have geometric properties, such as the lengths and diameters of their branches, that change systematically throughout the arbor in ways that are thought to minimize construction costs and to optimize the transmission of electrical signals and the intracellular transport of materials. In this work, we investigated whether neuronal arbors also have topological properties that reflect the growth and/or functional properties of their dendritic arbors. In our efforts to uncover possible topological rules, we discovered a function that depends only on the topology of bifurcating trees such as dendritic arbors:the tip-support distribution, which is the average number of branches that supportndendrite tips. We found that for many, but not all, neurons from a wide range of invertebrate and vertebrate species,the tip-support distributionfollows a power law with slopes ranging from -1.4 and -1.8 on a log-log plot. The slope is invariant under iterative trimming of terminal branches and under random ablation of internal branches. We found that power laws with similar slopes emerge from a variety of iterative growth processes including the Galton-Watson (GW) process, where the power-law behavior occurs after the percolation threshold. Through simulation, we show the slope of the power-law increases with the branching probability of a GW process, which corresponds to a more regular tree. Furthermore, the inclusion of postsynaptic spines and other terminal processes on branches causes a characteristic deviation of thetip-support distributionfrom a power law. Therefore, the tip-support function is a topological property that reflects the underlying branching morphogenesis of dendritic trees.
Haplotype phasing ofCYP2D6: an allelic ratio method using Agena MassARRAY data
Authors: Thamilselvan Megana , Mather Cheryl , Wang Yabing , Aitchison Katherine J. 
Published: March 2023

AbstractPharmacogenomics aims to use the genetic information of an individual to personalize drug prescribing. There is evidence that pharmacogenomic testing before prescription may prevent adverse drug reactions, increase efficacy, and reduce cost of treatment.CYP2D6is a key pharmacogene of relevance to multiple therapeutic areas. Indeed, there are prescribing guidelines available for medications based on CYP2D6 enzyme activity as deduced fromCYP2D6genetic data. The Agena MassARRAY system is a cost-effective method of detecting genetic variation that has been clinically applied to other genes. However, its clinical application toCYP2D6has to date been limited by weaknesses such as the inability to determine which haplotype was present in more than one copy for individuals with more than two copies of theCYP2D6gene. We report application of a new protocol forCYP2D6haplotype phasing of data generated from the Agena MassARRAY system. For samples with more than two copies of theCYP2D6gene for which the prior consensus data specified which one was present in more than one copy, our protocol was able to conductCYP2D6haplotype phasing resulting in 100% concordance with the prior data. In addition, for three reference samples known to have more than two copies ofCYP2D6but for which the exact number ofCYP2D6genes was unknown, our protocol was able to resolve the number for two out of the three of these, and estimate the likely number for the third. In addition, we demonstrate that our method is applicable toCYP2D6hybrid tandem configurations.
Activation of prefrontal parvalbumin interneurons ameliorates treatment-resistant working memory deficit even under continuous antipsychotic treatment in a mouse model of schizophrenia
Authors: Arime Yosefu , Saitoh Yoshito , Ishikawa Mikiko , Kamiyoshihara Chikako , Uchida Yasuo , Fujii Kazuki , Takao Keizo , Akiyama Kazufumi , Ohkawa Noriaki 
Published: March 2023

AbstractBACKGROUNDOne of the critical unmet medical needs in schizophrenia is a remedy for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. In addition, despite the patients with schizophrenia cannot stop taking antipsychotics due to a high rate of discontinuation-induced relapse, previous studies using animal models of schizophrenia have not considered these clinical situations.METHODSHere, we employ multi-dimensional approaches, including histological analysis in the prelimbic cortex, LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotic drugs, in vivo calcium imaging and behavioral analyses of mice using chemogenetic manipulation, to investigate neural mechanisms and potential therapeutic interventions for working memory deficit in a mouse model with chronic phencyclidine (PCP) administration that resembles the schizophrenia symptomatology.RESULTSChronic PCP administration led to abnormalities in excitatory and inhibitory synapses, including dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons, in layer 2–3 of the prelimbic cortex. Continuous olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60–80%) in the striatum, did not affect these synaptic abnormalities and working memory deficit in the PCP-treated mice. We found that the selective prelimbic PV activation, using hM3D(Gq)-DREADD system confirmed by in vivo calcium imaging, restored working memory deficit, even under continuous olanzapine treatment.CONCLUSIONSOur study raises a possibility that intervention in prefrontal PV neurons leads to an add-on therapy to antipsychotics targeting amelioration of treatment-resistant cognitive deficits in schizophrenia.
Radiobiological analysis of the response of prostate cancer to different fractionations
Authors: Pardo-Montero Juan , González-Crespo Isabel , Gómez-Caamaño Antonio , Gago-Arias Araceli 
Published: March 2023

AbstractPurposeTo investigate the response of prostate cancer to different radiotherapy schedules, including hypofractionation, and to evaluate potential departures from the linear-quadratic (LQ) response. To obtain best-fitting parameters for low (LR), intermediate (IR), and high risk (HR) prostate cancer.Methods and MaterialsWe have constructed a dataset of dose-response containing 87 entries (35 LR, 32 IR, 20 HR), with doses per fraction ranging from 1.8 to 10 Gy. These data were fitted to tumor control probability models based on the LQ model, linear-quadratic-linear (LQL), and a modification of the LQ (LQmod) accounting for increasing radiosensitivity at large doses. Fits were performed with the maximum likelihood expectation methodology, and the Akaike-Information-Criterion (AIC) was used to compare models.ResultsThe AIC shows that the LQ model is superior to the LQL and LQmod for all risks, except for IR where the LQL outperforms the other models. The analysis shows a low α/β for all risks: 2.01 Gy for LR (95% confidence interval 1.74-2.26), 3.44 Gy for IR (2.99-4.02), and 2.78 Gy for HR (1.43-4.18). Best-fits do not show proliferation for LR, and only moderate proliferation for IR/HR.ConclusionsIn general, the LQ model describes the response of prostate cancer better than the alternative models. Only for IR the LQL outperforms the LQ. This study confirms a lowα/βfor all risks, with doses per fraction ranging from <2 Gy up to 10 Gy.
An analogue of the Prolactin Releasing Peptide reduces obesity and promotes adult neurogenesis
Authors: Jörgensen Sara K. M. , Karnošová Alena , Mazzaferro Simone , Rowley Oliver , Chen Hsiao-Jou Cortina , Robbins Sarah J. , Christofides Sarah , Merkle Florian T. , Maletínská Lenka , Petrik David 
Published: March 2023

AbstractHypothalamic Adult Neurogenesis (hAN) has been implicated in regulating energy homeostasis. Adult-generated neurons and adult Neural Stem Cells (aNSCs) in the hypothalamus control food intake and body weight. Conversely, Diet Induced Obesity (DIO) by High Fat Diets (HFD) exerts adverse influence on hAN. However, the effects of anti-obesity compounds on hAN are not known. To address this, we administered a lipidized analogue of an anti-obesity neuropeptide, Prolactin Releasing Peptide (PrRP), so-called LiPR. In the HFD context, LiPR rescued survival of adult-born hypothalamic neurons and increased the number of aNSCs by reducing their activation. In addition, LiPR rescued reduction of immature hippocampal neurons and modulated calcium dynamics in iPSC-derived human neurons. These results show for the first time that anti-obesity neuropeptides influence adult neurogenesis and suggest that the neurogenic process can serve as a target of anti-obesity pharmacotherapy.
How is Emotional Evidence from Multiple Sources Used in Perceptual Decision Making?
Authors: Ngai Hilary H.T. , Hsiao Janet H. , Luhmann Christian , Mohanty Aprajita , Jin Jingwen 
Published: March 2023

AbstractJudging the emotional nature of a scene requires us to deliberately integrate pieces of evidence with varying intensity of emotion. Our existing knowledge about emotion-related perceptual decision making is largely based on paradigms using single stimulus and, when involving multiple stimuli, rapid decisions. Consequently, it remains unclear how we sample and integrate multiple pieces of emotional evidence deliberately to form an overall judgment. Findings from non-emotion rapid decision-making studies show humans down-sample and downweight extreme evidence. However, deliberate decision making may rely on a different attention mode than in rapid decision making; and extreme emotional stimuli are inherently salient. Given these critical differences, it is imperative to directly examine the deliberate decision-making process about multiple emotional stimuli. In the current study, human participants (N=33) viewed arrays of faces with expressions ranging from extremely fearful to extremely happy freely with their eye movement tracked. They then decided whether the faces were more fearful or happier on average. In contrast to conclusions drawn from non-emotion and rapid decision-making studies, eye movement measures revealed that participants attentionally sampled extreme emotional evidence more than less extreme evidence. Computational modeling results showed that even though participants exhibited biased attention distribution, they weighted various emotional evidence equally. These findings provide novel insights into how people sample and integrate multiple pieces of emotional evidence, contribute to a more comprehensive understanding of emotion-related decision making, and shed light on the mechanisms of pathological affective decisions.
Release of Histone H3K4-reading transcription factors from chromosomes in mitosis is independent of adjacent H3 phosphorylation
Authors: Harris Rebecca J. , Heer Maninder , Levasseur Mark D. , Cartwright Tyrell N. , Weston Bethany , Mitchell Jennifer L. , Coxhead Jonathan M. , Gaughan Luke , Prendergast Lisa , Rico Daniel , Higgins Jonathan M.G. 
Published: March 2023

ABSTRACTHistone modifications influence the recruitment of reader proteins to chromosomes to regulate events including transcription and cell division. The idea of a histone code, where particular combinations of modifications specify unique downstream functions, is widely accepted and can be demonstratedin vitro. For example, on synthetic peptides, phosphorylation of Histone H3 at threonine-3 (H3T3ph) prevents the binding of reader proteins that recognise trimethylation of the adjacent lysine-4 (H3K4me3), including the TAF3 component of TFIID. To study these combinatorial effects in cells, we analyzed the genome-wide distribution of H3T3ph and H3K4me3 during mitosis. We find that H3K4me3 hinders adjacent H3T3ph deposition in cells, and that the PHD domain of TAF3 can bind H3K4me3 in mitotic chromatin despite the presence of H3T3ph. Unlikein vitro, H3K4 readers are displaced from chromosomes in mitosis in Haspin-depleted cells lacking H3T3ph. H3T3ph is therefore unlikely to be responsible for transcriptional downregulation during cell division.
Pptc7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy
Authors: Niemi Natalie M. , Serrano Lia R. , Muehlbauer Laura K. , Balnis Catie , Kozul Keri-Lyn , Rashan Edrees H. , Shishkova Evgenia , Schueler Kathryn L. , Keller Mark P. , Attie Alan D. , Pagan Julia , Coon Joshua J. , Pagliarini David J. 
Published: March 2023

AbstractPptc7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lackingPptc7exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss ofPptc7in adult mice causes marked reduction in mitochondrial mass concomitant with elevation of the mitophagy receptors Bnip3 and Nix. Consistently,Pptc7-/-mouse embryonic fibroblasts (MEFs) exhibit a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs— including multiple sites on Bnip3 and Nix. These data suggest thatPptc7deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that Pptc7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for Pptc7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
Liver-specific Inflammatory Signatures Predict Clinically Significant Liver Damage
Authors: Chua Conan , Mahamed Deeqa , Nkongolo Shirin , Mehrotra Aman , Wong David K.H. , Chung Raymond T. , Feld Jordan J. , Janssen Harry L.A. , Gehring Adam J. 
Published: March 2023

ABSTRACTBackground and AimsInflammation drives progression of chronic liver disease. However, the triggers of inflammation remain undefined during chronic hepatitis B (CHB) because hepatic flares are spontaneous and difficult to capture. We used nucleoside analogue (NA) withdrawal to investigate early inflammatory events because liver damage after stopping therapy occurs in a predictable time frame. 11 CHB patients underwent 192 weeks of NA therapy before a protocol defined stop. Liver fine-needle aspirates (FNAs) were collected at baseline and 4-weeks post-withdrawal and analyzed using flow cytometry and single-cell RNA sequencing (scRNA-seq). Intrahepatic mononuclear cells (IHMCs) from uninfected livers were used to validate transcriptomic findings. At 4 weeks post NA-withdrawal, HBV DNA rebounded but alanine aminotransferase (ALT) levels remained normal, 7/11 patients developed ALT elevations (>2xULN) at later timepoints. There were no changes in cell frequencies between baseline and viral rebound. ScRNA-seq revealed upregulation of IFN stimulated genes (ISGs) and pro-inflammatory cytokineMIFupon viral rebound. In vitro experiments confirmed the type I IFN-dependent ISG profile whereasMIFwas induced primarily by IL-12. MIF exposure further amplified inflammatory cytokine production by myeloid cells. Our data show that innate immune activation is detectable in the liver before clinically-significant liver damage is detectable in the serum.
Cryo-EM-guided engineering of T-box-tRNA modules with enhanced selectivity and sensitivity in translational regulation
Authors: Jia Xinyu , Zhang Chong , Luo Bingnan , Frandsen Jane K. , Watkins Andrew M. , Li Kaiyu , Zhang Minghua , Wei Xiawei , Yang Yang , Henkin Tina M. , Su Zhaoming 
Published: March 2023

AbstractRiboswitches are non-coding RNA elements that play vital roles in regulating gene expression. Their specific ligand-dependent structural reorganization facilitates their use as templates for design of engineered RNA switches for therapeutics, nanotechnology and synthetic biology. T-box riboswitches bind tRNAs to sense aminoacylation and control gene expression via transcription attenuation or translation inhibition. Here we determine the cryo-EM structure of the wild-typeMycobacterium smegmatis ileST-box in complex with its cognate tRNAIle. This structure shows a very flexible antisequestrator region that tolerates both 3’-OH and 2’,3’-cyclic phosphate modification at the 3’ end of tRNAIle. Elongation of one helical turn (11-base pair) in both the tRNA acceptor arm and T-box Stem III maintains T-box-tRNA complex formation and increases the selectivity for tRNA 3’ end modification. Moreover, elongation of Stem III results in ∼6-fold tighter binding to tRNA, which leads to increased sensitivity of downstream translational regulation indicated by precedent translation. Our results demonstrate that cryo-EM can guide RNA engineering to design improved riboswitch modules for translational regulation, and potentially a variety of additional functions.
Automatic Detection of Cell-cycle Stages using Recurrent Neural Networks
Authors: Jose Abin , Roy Rijo , Moreno-Andrés Daniel , Stegmaier Johannes 
Published: March 2023

AbstractMitosis is the process by which eukaryotic cells divide to produce two similar daughter cells with identical genetic material. Research into the process of mitosis is therefore of critical importance both for the basic understanding of cell biology and for the clinical approach to manifold pathologies resulting from its malfunctioning, including cancer. In this paper, we propose an approach to study mitotic progression automatically using deep learning. We used neural networks to predict different mitosis stages. We extracted video sequences of cells undergoing division and trained a Recurrent Neural Network (RNN) to extract image features. The use of RNN enabled better extraction of features. The RNN-based approach gave better performance compared to classifier based feature extraction methods which do not use time information. Evaluation of precision, recall, and F-score indicates the superiority of the proposed model compared to the baseline. To study the loss in performance due to confusion between adjacent classes, we plotted the confusion matrix as well, to quantify the amount of misclassification. In addition, we visualized the feature space to understand why RNNs are better at classifying the mitosis stages than other classifier models, which indicated the formation of strong clusters for the different classes, clearly confirming the advantage of the proposed RNN-based approach.
PS4: a Next-Generation Dataset for Protein Single Sequence Secondary Structure Prediction
Authors: Peracha Omar 
Published: March 2023

AbstractProtein secondary structure prediction is a subproblem of protein folding. A lightweight algorithm capable of accurately predicting secondary structure from only the protein residue sequence could provide a useful input for tertiary structure prediction, alleviating the reliance on MSA typically seen in today’s best-performing models. Unfortunately, existing datasets for secondary structure prediction are small, creating a bottleneck. We present PS4, a dataset of 18,731 non-redundant protein chains and their respective secondary structure labels. Each chain is identified, and the dataset is also non-redundant against other secondary structure datasets commonly seen in the literature. We perform ablation studies by training secondary structure prediction algorithms on the PS4 training set, and obtain state-of-the-art accuracy on the CB513 test set in zero shots.
Super-resolution microscopy reveals the nanoscale organization of the DEK protein cancer biomarker
Authors: Pierzynska-Mach Agnieszka , Diaspro Alberto , Cella Zanacchi Francesca 
Published: March 2023

AbstractThe chromatin architectural factor DEK is involved in regulating the chromatin organization and is highly overexpressed in numerous forms of cancer. DEK is traditionally described as uniformly distributed within the nucleus by diffraction-limited microscopy studies, but super-resolution advent highlighted the formation of cluster-like DEK structures. Still, a characterization of the DEK protein cellular distribution and its role in cancer and cell proliferation is missing. In this work, we used single-molecule localization microscopy (SMLM) to investigate the nanoscale characteristics of DEK organization in normal-like and aggressive types of breast cancer cell lines, characterizing the number of localizations per cluster, as well as areas and density of clusters. We show how the cluster features correlate with the breast cell type and how the chromatin decompaction influences the DEK clusters in both cell lines. Our results suggest that the DEK density and nano-organization are preserved and are not influenced by protein overexpression itself or by chromatin compaction changes.