bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Orientationally Averaged Version of the Rotne-Prager-Yamakawa Tensor Provides A Fast But Still Accurate Treatment Of Hydrodynamic Interactions In Brownian Dynamics Simulations Of Biological Macromolecules
Authors: Tworek John W. , Elcock Adrian H. 
Published: April 2023

AbstractThe Brownian dynamics (BD) simulation technique is widely used to model the diffusive and conformational dynamics of complex systems comprising biological macromolecules. For the diffusive properties of macromolecules to be described correctly by BD simulations, it is necessary to include hydrodynamic interactions (HI). When modeled at the Rotne-Prager-Yamakawa (RPY) level of theory, for example, the translational and rotational diffusion coefficients of isolated macromolecules can be accurately reproduced; when HIs are neglected, however, diffusion coefficients can be underestimated by an order of magnitude or more. The principal drawback to the inclusion of HIs in BD simulations is their computational expense, and several previous studies have sought to accelerate their modeling by developing fast approximations for the calculation of the correlated random displacements. Here we explore the use of an alternative way to accelerate calculation of HIs, i.e., by replacing the full RPY tensor with an orientationally averaged (OA) version which retains the distance dependence of the HIs but averages out their orientational dependence. We seek here to determine whether such an approximation can be justified in application to the modeling of typical proteins and RNAs. We show that the use of an OA RPY tensor allows translational diffusion of macromolecules to be modeled with very high accuracy at the cost of rotational diffusion being underestimated by ∼25%. We show that this finding is independent of the type of macromolecule simulated and the level of structural resolution employed in the models. We also show, however, that these results are critically dependent on the inclusion of a non-zero term that describes the divergence of the diffusion tensor: when this term is omitted from simulations that use the OA RPY model, unfolded macromolecules undergo rapid collapse. Our results indicate that the orientationally averaged RPY tensor is likely to be a useful, fast approximate way of including HIs in BD simulations of intermediate-scale systems.
Ultraviolet-C mediated inactivation ofCandida auris, a rapid emerging health threat
Authors: Koutras Carolina , Wade Richard L. 
Published: April 2023

AbstractHealthcare-associated infections (HAIs), particularly those caused by multidrug-resistant organisms (MDROs), pose significant challenges to patient safety.Candida auris(C. auris), an emerging MDRO fungus, has been acknowledged as an urgent threat by the Centers for Disease Control and Prevention (CDC) due to its high mortality and difficulty in prevention, diagnosis, and treatment. In this study, we investigated the efficacy of 254 nm ultraviolet-C light (UV-C) in inactivatingC. aurison hard surfaces. A mobile UV-C tower equipped with high-performance bulbs was used, and within 7 minutes of continuous exposure, ≥ 99.97% (≥ 3.86 log10) inactivation of C. auris was achieved in a patient-room sized test chamber. Our findings suggest that UV-C can serve as an effective infection control measure for preventingC. aurisand other MDRO HAIs in healthcare settings. Implementation of UV-C disinfection protocols can contribute to enhanced patient safety and combat the growing threat of MDRO pathogens.
Model-based dimensionality reduction for single-cell RNA-seq using generalized bilinear models
Authors: Nicol Phillip B. , Miller Jeffrey W. 
Published: April 2023

AbstractDimensionality reduction is a critical step in the analysis of single-cell RNA-seq (scRNA-seq) data. The standard approach is to apply a transformation to the count matrix followed by principal components analysis (PCA). However, this approach can induce spurious heterogeneity and mask true biological variability. An alternative approach is to directly model the counts, but existing methods tend to be computationally intractable on large datasets and do not quantify uncertainty in the low-dimensional representation. To address these problems, we develop scGBM, a novel method for model-based dimensionality reduction of scRNA-seq data using a Poisson bilinear model. We introduce a fast estimation algorithm to fit the model using iteratively reweighted singular value decompositions, enabling the method to scale to datasets with millions of cells. Furthermore, scGBM quantifies the uncertainty in each cell’s latent position and leverages these uncertainties to assess the confidence associated with a given cell clustering. On real and simulated single-cell data, we find that scGBM produces low-dimensional embeddings that better capture relevant biological information while removing unwanted variation.
Accounting for sex differences variability in the design of sex-adapted cancer treatments
Authors: Yang Wei , Rubin Joshua B 
Published: April 2023

AbstractThe significant sex differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. We hypothesized that one barrier to translation is that sex differences in cancer phenotypes resemble sex differences in height: highly overlapping, but distinct, male and female population distributions that vary continuously between female- and male-biased extremes. A consequence of this variance is that sex-specific treatments are rendered unrealistic, and our translational goal should be adaptation of treatment to the unique mix of sex-biased mechanisms that are present in each patient. To develop a tool that could advance this goal, we applied a Bayesian Nearest Neighbor (BNN) analysis to 8370 cancer transcriptomes from 26 different adult and 4 different pediatric cancer types to establish patient-specific Transcriptomic Sex Indices (TSI). TSI precisely partitions an individual patient’s whole transcriptome into female- and male-biased components such that cancer type, patient sex, and transcriptomics, provide a novel and patient-specific mechanistic identifier that can be used for sex-adapted, precision cancer treatment planning.
Impact of glacier retreat on biodiversity and plant–insect interaction dynamics
Authors: Tu Bao Ngan , Khelidj Nora , Losapio Gianalberto 
Published: April 2023

ABSTRACTWith the retreat and extinction of glaciers worldwide, new areas are exposed for colonization by diverse plants and associated insects. Yet, glacier retreat is also followed by the loss of plants and insects from local communities, causing changes in species diversity, species composition and plant–insect interactions. However, the impact of glacier retreat and extinction on pollination networks remains poorly understood. An integrative understanding of pollination network dynamics following glacier retreat is therefore of major importance to biodiversity maintenance and ecosystem functioning and services. Here, we addressed how glacier retreat affects directly and indirectly through biodiversity the frequency, complexity, and diversity of plant–insect interactions. After reconstructing the geochronology of glaciers (Mont Miné glacier, Swiss Alps), we surveyed plant–insect interactions and analyzed network dynamics. We observed sharp changes in the diversity of both plant and insect communities. We found an increase in the frequency of their interactions following glacier retreat, but an ultimate decrease with glacier extinction. Yet, after controlling for the effects of flower diversity, interaction frequency showed a regular, ‘universal’ pattern. Accordingly, the complexity of pollination networks and interaction diversity tended to change at constant rates with glacier retreat. Our results indicate that, in the long-term, glacier retreat decreases biodiversity and influence the stability of ecological networks. The good news is that increasing flower diversity would counteract these impacts by increasing interaction diversity and complexity. Supporting plant and flower diversity may therefore be a key strategy for halting the erosion of ecological networks while increasing ecosystem functioning.
Histone methylation has a direct metabolic role in human cells
Authors: Perez Marcos Francisco , Sarkies Peter 
Published: April 2023

ABSTRACTThe N-terminal tails of eukaryotic histones are frequently post-translationally modified. The role of these modifications in transcriptional regulation is well-documented. However, the extent to which the enzymatic process of histone post-translational modification itself contributes to metabolic regulation is less clear. Here we investigated the metabolic role of histone methylation using metabolomics, proteomics and RNA-seq data from cancer cell lines, primary tumour samples and healthy tissue samples. In cancer the transcription of histone methyltransferases was inversely correlated to the activity of NNMT, an enzyme previously characterised as a methyl sink that disposes of excess methyl groups carried by the universal methyl donor S-adenosyl methionine (SAM or AdoMet). In healthy tissues histone methylation was inversely correlated to the levels of an alternative methyl sink, PEMT. These associations affected the levels of multiple histone marks on chromatin genome-wide but had no detectable impact on transcriptional regulation. We show that histone methyltransferases with a variety of different associations to transcription are co-regulated by the Retinoblastoma (Rb) tumour suppressor in human cells. Total HMT expression is increased in Rb-mutant cancers, and this leads toNNMTdownregulation. Together, our results suggest a direct metabolic role for histone methylation in SAM homeostasis, independent of transcriptional regulation.
Sex-dependent effect of inflammatory pain on negative affective states is prevented by kappa opioid receptors blockade in the nucleus accumbens shell
Authors: Lorente J.D. , Cuitavi J. , Rullo L. , Candeletti S. , Romualdi P. , Hipólito L 
Published: April 2023

AbstractBackground and purposePsychological disorders, such as anxiety and anhedonia are pain comorbidities, however how pain affects male and female individuals and through which mechanism is not well understood. Previous research show pain-induced alterations in the dynorphinergic pathway in the mesocorticolimbic system (MCLS) together with a relationship between corticotropin-releasing system and dynorphin release in the MCLS. Here, we analyse the sex and time course-dependent effects of pain on negative affect. Additionally, we study the implication of dynorphinergic and corticotropin releasing factor involvement in these pain related behaviours.Experimental approachWe used behavioural pharmacology and biochemical tools to characterize negative affective states induced by inflammatory pain in male and female rats, and the alterations in dynorphinergic and corticotropin systems in the MCLS.Key resultsFemale rats showed a persistent anxiety-like together with a reversible anhedonia-like behaviours derived from inflammatory pain. Additionally, we found alterations of in both dynorphin and corticotropin releasing factor in NAc and amygdala that suggest sex-dependent dynamic adaptations. Finally blockade on the kappa opioid receptor in the NAc confirmed its role in pain-induced anxiety-like behaviour in female rats.Conclusions and implicationsOur results show sex and time dependent anxiety- and anhedonia-like behaviours induced by the presence of pain in female rats. Furthermore, we replicated previous data pointing to the KOR/dyn recruitment in the NAc as key neurological substrate mediating these behaviours. This research encourages the study the mechanisms underlying these behaviours, to better understand the emotional dimension of pain.
Preliminary evidence of a relationship between sleep spindles and treatment response in epileptic encephalopathy
Authors: McLaren John R. , Luo Yancheng , Kwon Hunki , Shi Wen , Kramer Mark A. , Chu Catherine J. 
Published: April 2023

AbstractObjectiveEpileptic encephalopathy with spike wave activation in sleep (EE-SWAS) is a challenging neurodevelopmental disease characterized by abundant epileptiform spikes during non-rapid eye movement (NREM) sleep accompanied by cognitive dysfunction. The mechanism of cognitive dysfunction is unknown, but treatment with high-dose diazepam may improve symptoms. Spike rate does not predict treatment response, but spikes may disrupt sleep spindles. We hypothesized that in patients with EE-SWAS: 1) spikes and spindles would be anticorrelated, 2) high-dose diazepam would increase spindles and decrease spikes, and 3) spindle response would be greater in those with cognitive improvement.MethodsConsecutive EE-SWAS patients treated with high-dose diazepam that met criteria were included. Using a validated automated spindle detector, spindle rate, duration, and percentage were computed in pre- and post-treatment NREM sleep. Spikes were quantified using a validated automated spike detector. Cognitive response was determined from chart review.ResultsSpindle rate was anticorrelated with spike rate in the channel with the maximal spike rate (p=0.002) and averaged across all channels (p=0.0005). Spindle rate, duration, and percentage each increased, and spike rate decreased, after high-dose diazepam treatment (p≤2e-5, all tests). Spindle rate, duration, and percentage (p≤0.004, all tests) were increased in patients with cognitive improvement after treatment, but not those without. Changes in spike rate did not distinguish between groups.InterpretationThese findings confirm thalamocortical disruption in EE-SWAS, identify a mechanism through which benzodiazepines may support cognitive recovery, and introduce sleep spindles as a promising mechanistic biomarker to detect treatment response in severe epileptic encephalopathies.
Investigating Neural Dysfunction with Abnormal Protein Deposition in Alzheimer’s Disease Through Magnetic Resonance Spectroscopic Imaging, Plasma Biomarkers, and Positron Emission Tomography
Authors: Matsuoka Kiwamu , Hirata Kosei , Kokubo Naomi , Maeda Takamasa , Tagai Kenji , Endo Hironobu , Takahata Keisuke , Shinotoh Hitoshi , Ono Maiko , Seki Chie , Tatebe Harutsugu , Kawamura Kazunori , Zhang Ming-Rong , Shimada Hitoshi , Tokuda Takahiko , Higuchi Makoto , Takado Yuhei 
Published: April 2023

AbstractIn Alzheimer’s disease (AD), aggregated abnormal proteins induce neuronal dysfunction. Despite the evidence supporting the association between tau proteins and brain atrophy, further studies are needed to explore their link to neuronal dysfunction in the human brain. To clarify the relationship between neuronal dysfunction and abnormal proteins in AD-affected brains, we conducted magnetic resonance spectroscopic imaging (MRSI) and assessed the neurofilament light chain plasma levels (NfL). We evaluated tau and amyloid-β depositions using standardized uptake value ratios (SUVRs) of florzolotau (18F) for tau and11C-PiB for amyloid-β positron emission tomography in the same patients. Heatmaps were generated to visualize Z scores of glutamate to creatine (Glu/Cr) and N-acetylaspartate to creatine (NAA/Cr) ratios using data from healthy controls. In AD brains, Z score maps revealed reduced Glu/Cr and NAA/Cr ratios in the gray matter, particularly in the right dorsolateral prefrontal cortex (rDLPFC) and posterior cingulate cortex (PCC). Glu/Cr ratios were negatively correlated with florzolotau (18F) SUVRs in the PCC, and plasma NfL levels were elevated and negatively correlated with Glu/Cr (P = 0.040, r = −0.50) and NAA/Cr ratios (P = 0.003, r = −0.68) in the rDLPFC. This suggests that the abnormal tau proteins in AD-affected brains play a role in diminishing glutamate levels. Furthermore, neuronal dysfunction markers including Glu/tCr and NAA/tCr could potentially indicate favorable clinical outcomes. Using MRSI provided spatial information about neural dysfunction in AD, enabling the identification of vulnerabilities in the rDLPFC and PCC within the AD’s pathological context.
Norovirus NS3 protein induces apoptosis through translation repression and dysregulation of BCL-2 pro-survival proteins
Authors: Aktepe Turgut E , Deerain Joshua M , Hyde Jennifer L. , Fritzlar Svenja , Pearson Jaclyn , White Peter A. , Mackenzie Jason M. 
Published: April 2023

ABSTRACTNorovirus infection is characterised by a rapid onset of disease and the development of debilitating symptoms including projectile vomiting and diffuse diarrhoea. Vaccines and antivirals are sorely lacking and developments in these areas are hampered by the lack of an adequate cell culture system to investigate human norovirus replication and pathogenesis. Herein, we describe how the model norovirus, Mouse norovirus (MNV), produces a viral protein, NS3, with the functional capacity to attenuate host protein translation which invokes the activation cell death via apoptosis. We show that this function of NS3 is conserved between human and mouse viruses and map the protein domain attributable to this function. Our study highlights a critical viral protein that mediates crucial activities during replication, potentially identifying NS3 as a worthy target for antiviral drug development.
AtlasXplore: a web platform for visualizing and sharing spatial epigenome data
Authors: Barnett Joshua , Sotudeh Noori , Rao Poorvi , Silverman Jonah , Jafar Tamara , Wang Liya 
Published: April 2023

AbstractIn recent years, a growing number of spatial epigenome datasets have been generated, presenting rich opportunities for studying the regulation mechanisms in solid tissue sections. However, visual exploration of these datasets requires extensive computational processing of raw data, presenting a challenge for researchers without advanced computational skills to fully explore and analyze such datasets. Here we introduce AtlasXplore™, a web-based platform that enables scientists to interactively navigate a growing collection of spatial epigenome data using an expanding set of tools.Availability and implementationAtlasXplore is freely available athttps://web.atlasxomics.com
Response to photic stimulation as a measure of cortical excitability in epilepsy patients
Authors: Vranic-Peters Michaela J. , O’brien Patrick , Seneviratne Udaya , Reynolds Ashley , Lai Alan , Grayden David , Cook Mark , Peterson Andre 
Published: April 2023

AbstractStudying states and state transitions in the brain is challenging due to nonlinear, complex dynamics. In this research, we analyse the brain’s response to non-invasive perturbations. Perturbation techniques offer a powerful method for studying complex dynamics, though their translation to human brain data is under-explored. This method involves applying small inputs, in this case via photic stimulation, to a system and measuring its response. Sensitivity to perturbations can forewarn a state transition. Therefore, biomarkers of the brain’s perturbation response or ‘cortical excitability’ could be used to indicate seizure transitions. However, perturbing the brain often involves invasive intracranial surgeries or expensive equipment such as transcranial magnetic stimulation (TMS) which is only accessible to a minority of patient groups, or animal model studies. Photic stimulation is a widely used diagnostic technique in epilepsy that can be used as a non-invasive perturbation paradigm to probe brain dynamics during routine electroencephalography (EEG) studies in humans. This involves changing the frequency of strobing light, sometimes triggering a photo-paroxysmal response (PPR), which is an electrographic event that can be studied as a state transition to a seizure state. We investigate alterations in the response to these perturbations in patients with genetic generalised epilepsy (GGE), with (n= 10) and without (n= 10) PPR, and patients with psychogenic non-epileptic seizures (PNES;n= 10), compared to resting controls (n= 10). Metrics of EEG time-series data were evaluated as biomarkers of the perturbation response including variance, autocorrelation, and phase-based synchrony measures. We observed considerable differences in all group biomarker distributions during stimulation compared to controls. In particular, variance and autocorrelation demonstrated greater changes in epochs close to PPR transitions compared to earlier stimulation epochs. Comparison of PPR and spontaneous seizure morphology found them indistinguishable, suggesting PPR is a valid proxy for seizure dynamics. Also, as expected, posterior channels demonstrated the greatest change in synchrony measures, possibly reflecting underlying PPR pathophysiologic mechanisms. We clearly demonstrate observable changes at a group level in cortical excitability in epilepsy patients as a response to perturbation in EEG data. Our work re-frames photic stimulation as a non-invasive perturbation paradigm capable of inducing measurable changes to brain dynamics.
Loss of thymocyte competition underlies the tumor suppressive functions of the E2a transcription factor in T lymphocyte acute lymphoblastic leukemia
Authors: Parriott Geoffrey , Hegermiller Emma , Morman Rosemary E. , Frank Cameron , Saygin Caner , Stock Wendy , Bartom Elizabeth T. , Kee Barbara L. 
Published: April 2023

ABSTRACTT lymphocyte acute lymphoblastic leukemia (T-ALL) is frequently associated with increased expression of the E protein transcription factor inhibitors TAL1 and LYL1. In mouse models, ectopic expression of Tal1 or Lyl1 in T cell progenitors or inactivation of E2a, is sufficient to predispose mice to develop T-ALL. How E2a suppresses thymocyte transformation is currently unknown. Here, we show that early deletion ofE2a, prior to the DN3 stage, was required for robust leukemogenesis and was associated with alterations in thymus cellularity, T cell differentiation, and gene expression in immature CD4+CD8+ thymocytes. Introduction of wild-type thymocytes into mice with early deletion ofE2aprevented leukemogenesis, or delayed disease onset, and impacted the expression of multiple genes associated with transformation and genome instability. Our data indicate that E2a suppresses leukemogenesis by promoting T cell development and enforcing inter-thymocyte competition, a mechanism that is emerging as a safeguard against thymocyte transformation. These studies have implications for understanding how multiple essential regulators of T cell development suppress T-ALL and support the hypothesis that thymus cellularity is a determinant of leukemogenesis.
SurVIndel2: improving CNVs calling from next-generation sequencing using novel hidden information
Authors: Rajaby Ramesh , Sung Wing-Kin 
Published: April 2023

AbstractDeletions and tandem duplications (commonly called CNVs) represent the majority of structural variations. They can be identified using short reads, but because they frequently occur in repetitive regions, existing methods fail to detect most of them. This is because CNVs in repetitive regions often do not produce the evidence needed by existing short reads-based callers (split reads, discordant pairs or read depth change). Here, we introduce a new CNV short reads-based caller named SurVIndel2. SurVindel2 builds on statistical techniques we previously developed, but also employs a novel type of evidence, hidden split reads, that can uncover many CNVs missed by existing algorithms. We use public benchmarks to show that SurVIndel2 outperforms other popular callers, both on human and non-human datasets. Then, we demonstrate the practical utility of the method by generating a catalogue of CNVs for the 1000g project that contains hundreds of thousands of CNVs missing from the most recent public catalogue. We also show that SurVIndel2 is able to complement small indels predicted by Google DeepVariant, and the two software used in tandem produce a remarkably complete catalogue of variants in an individual. Finally, we characterise how the limitations of current sequencing technologies contribute significantly to the missing CNVs.