bluuebunny/crossref_metadata_2025 huggingface dataset:
The Bilateral Remote Ischaemic Conditioning in Children (BRICC) trial: a two-centre, double-blind, randomised controlled trial in young children undergoing cardiac surgery
Authors: Drury Nigel E , van Doorn Carin , Woolley Rebecca L , Amos-Hirst Rebecca J , Bi Rehana , Spencer Collette M , Morris Kevin P , Montgomerie James , Stickley John , Crucean Adrian , Gill Alicia , Hill Matt , Weber Ralf J.M. , Najdekr Lukas , Jankevics Andris , Southam Andrew D. , Lloyd Gavin R. , Jaber Osama , Kassai Imre , Pelella Guiseppe , Khan Natasha E , Botha Phil , Barron David J , Madhani Melanie , Dunn Warwick B , Ives Natalie J , Kirchhof Paulus , Jones Timothy J
Published: April 2023

Background and Aims

Previous trials evaluating remote ischaemic preconditioning in children undergoing cardiac surgery showed mixed results. We sought to determine whether adequately delivered bilateral preconditioning is cardioprotective in young children, with or without cyanosis, undergoing surgery.

Methods

Prospective, double-blind, randomised controlled trial at two UK centres. Children aged 3-36 months undergoing tetralogy of Fallot repair or ventricular septal defect closure were randomised in a 1:1 ratio to receive either bilateral preconditioning or sham intervention. Participants were followed up until hospital discharge or 30 days. The primary outcome was area under the curve for high-sensitivity troponin-T in the first 24 hours after surgery, analysed by intention-to-treat. Right atrial biopsies were obtained in selected patients. Trial registration:ISRCTN12923441.

Results

Between 24 October 2016 and 8 December 2020, 120 eligible children were randomised to receive either bilateral preconditioning (n=60) or sham intervention (n=60). Participants had a median age of 7 months and 42 (35%) were female. The primary outcome, area under the curve for hs-troponin-T was higher in the preconditioning group (mean: 70.0±50.9µg/L/hr, n=56) than in controls (mean: 55.6±30.1µg/L/hr, n=58), p=0.04. Sub-group analyses did not show a differential treatment effect by oxygen saturations (pinteraction=0.25) but showed evidence of differential treatment effect by underlying defect (pinteraction=0.04). Myocardial metabolism, quantified in atrial biopsies, and secondary outcomes were not different between randomised groups.

Conclusions

Bilateral remote ischemic preconditioning does not attenuate myocardial injury in children undergoing surgical repair for congenital heart defects, and there was evidence of potential harm in unstented tetralogy of Fallot.
Molecular insight into the mechanism of action of some beneficial flavonoids for the treatment of Parkinson’s Disease
Authors: Biswas Sima , Mitra Anindita , Roy Sreekanya , Ghosh Rita , Bagchi Angshuman
Published: April 2023

Parkinson’s Disease (PD) is a severe neurodegenerative disorder. It is characterized by the declination of dopaminergic (DA) neurons of substantia nigra pars compacta in the mid brain. Decrease in dopamine level in substantia nigra is a major event in PD. Mutation in Parkin protein is responsible for the onset of Autosomal Recessive Juvenile Parkinson’s (ARJP) Disease. Till date, there is no available treatment of PD without any side-effects. Therefore, the focus has been shifted to identifying natural product inhibitors for the treatment of the disorder. Flavonoids, a class of natural products, have proven neuroprotective effects. Some of the flavonoids have their abilities to influence the activities of central nervous system. Therefore, many studies are being conducted to analyze their activities to lower the progression of neurodegenerative diseases. This study was conducted to identify the flavonoids to be used as potential drugs for PD. From the literature, we picked up the flavonoids active on the nervous systems of human beings. We employed a literature mining approach to build a Structure Activity Relationship (SAR) to measure their efficacies. We performed molecular docking simulations using the flavonoids as the ligands and computed their binding free energy values. Our study would therefore point towards future drug- designing endeavours to come up with plausible therapeutics against PD onset.
BEERS2: RNA-Seq simulation through high fidelityin silicomodeling
Authors: Brooks Thomas G. , Lahens Nicholas F. , Mrčela Antonijo , Sarantopoulou Dimitra , Nayak Soumyashant , Naik Amruta , Sengupta Shaon , Choi Peter S. , Grant Gregory R.
Published: April 2023

Simulation of RNA-seq reads is critical in the assessment, comparison, benchmarking, and development of bioinformatics tools. Yet the field of RNA-seq simulators has progressed little in the last decade. To address this need we have developed BEERS2, which combines a flexible and highly configurable design with detailed simulation of the entire library preparation and sequencing pipeline. BEERS2 takes input transcripts (typically fully-length mRNA transcripts with polyA tails) from either customizable input or from CAMPAREE simulated RNA samples. It produces realistic reads of these transcripts as FASTQ, SAM, or BAM formats with the SAM or BAM formats containing the true alignment to the reference genome. It also produces true transcript-level quantification values. BEERS2 combines a flexible and highly configurable design with detailed simulation of the entire library preparation and sequencing pipeline and is designed to include the effects of polyA selection and RiboZero for ribosomal depletion, hexamer priming sequence biases, GC-content biases in PCR amplification, barcode read errors, and errors during PCR amplification. These characteristics combine to make BEERS2 the most complete simulation of RNA-seq to date. Finally, we demonstrate the use of BEERS2 by measuring the effect of several settings on the popular Salmon pseudoalignment algorithm.
Inosine Induces Stemness Features in CAR T cells and Enhances Potency
Authors: Klysz Dorota D. , Fowler Carley , Malipatlolla Meena , Stuani Lucille , Freitas Katherine A. , Meier Stefanie , Daniel Bence , Sandor Katalin , Xu Peng , Huang Jing , Labanieh Louai , Leruste Amaury , Bashti Malek , Keerthi Vimal , Mata-Alcazar Janette , Gkitsas Nikolaos , Guerrero Justin A. , Fisher Chris , Patel Sunny , Asano Kyle , Patel Shabnum , Davis Kara L. , Satpathy Ansuman T. , Feldman Steven A. , Sotillo Elena , Mackall Crystal L.
Published: April 2023

Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.

Statement of Significance

Adenosine is well known to inhibit T cell function and substantial effort has focused on inhibiting adenosine generation and signaling. Here, we show that exhausted T cells are suppressed by adenosine, which is only modestly impacted by inhibiting adenosine generation or signaling. In contrast, metabolism of adenosine to inosine augmented T cell function and culture of T cells with inosine induced multi-level reprogramming leading to stemness and improved anti-tumor potency. We demonstrate the feasibility of introducing inosine during GMP cell manufacturing as a novel strategy to generate enhanced CAR-T cells.
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

The 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

Healthcare-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

Dimensionality 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

The 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

With 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

The 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

Background and purpose

Psychological 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 approach

We 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 results

Female 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 implications

Our 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

Objective

Epileptic 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.

Methods

Consecutive 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.

Results

Spindle 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.

Interpretation

These 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

In 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

Norovirus 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.
Simultaneous photoactivation and high-speed structural tracking reveal diffusion-dominated motion in the endoplasmic reticulum
Authors: Dora Matteo , Obara Christopher J. , Abel Tim , Lippincott-Schwarz Jennifer , Holcman David
Published: April 2023

The endoplasmic reticulum (ER) is a structurally complex, membrane-enclosed compartment that stretches from the nuclear envelope to the extreme periphery of eukaryotic cells. The organelle is crucial for numerous distinct cellular processes, but how these processes are spatially regulated within the structure is unclear. Traditional imaging-based approaches to understanding protein dynamics within the organelle are limited by the convoluted structure and rapid movement of molecular components. Here, we introduce a combinatorial imaging and machine learning-assisted image analysis approach to track the motion of photoactivated proteins within the ER of live cells. We find that simultaneous knowledge of the underlying ER structure is required to accurately analyze fluorescently-tagged protein redistribution, and after appropriate structural calibration we see all proteins assayed show signatures of Brownian diffusion-dominated motion over micron spatial scales. Remarkably, we find that in some cells the ER structure can be explored in a highly asymmetric manner, likely as a result of uneven connectivity within the organelle. This remains true independently of the size or folding state of the fluorescently-tagged molecules, suggesting a potential role for ER connectivity in driving spatially regulated biology in eukaryotes.
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

In 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 implementation

AtlasXplore 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

Abstract

Studying 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

T 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

Deletions 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.
Clinical features and outcomes of hospitalised patients with COVID-19 and Parkinsonian disorders: a multicentre UK-based study
Authors: Sorrell Lexy , Leta Valentina , Barnett Anton , Stevens Kara , King Angela , Inches Jemma , Kobylecki Christopher , Walker Richard , Chaudhuri K Ray , Martin Hannah , Rideout Jane , Sneyd J Robert , Campbell Sarah , Carroll Camille
Published: April 2023

Background

Parkinson’s disease has been identified as a risk factor for severe Coronavirus disease 2019 (COVID-19) outcomes. However, whether the significant high risk of death from COVID-19 in people with Parkinson’s disease is specific to the disease itself or driven by other concomitant and known risk factors such as comorbidities, age, and frailty remains unclear.

Objective

To investigate clinical profiles and outcomes of people with Parkinson’s disease and atypical parkinsonian syndromes who tested positive for COVID-19 in the hospital setting in a multicentre UK-based study.

Methods

A retrospective cohort study of Parkinson’s disease patients with a positive COVID-19 test admitted to hospital between February 2020 and July 2021. An online survey was used to collect data from clinical care records, recording patient, Parkinson’s disease and COVID-19 characteristics. Associations with time-to-mortality and severe outcomes were analysed using either the Cox proportional hazards model or logistic regression models, as appropriate.

Results

Data from 552 admissions were collected: 365 (66%) male; median (inter-quartile range) age 80 (74-85) years. The 34-day mortality rate was 38.4%; male sex, increased age and frailty, Parkinson’s dementia syndrome, requirement for respiratory support and no vaccination were associated with increased mortality risk. Community-acquired COVID-19 and co-morbid chronic neurological disorder were associated with increased odds of requiring respiratory support. Hospital-acquired COVID-19 and delirium were associated with requiring an increase in care level post-discharge.

Conclusions

This first, multicentre, UK-based study on people with Parkinson’s disease or atypical parkinsonian syndromes, hospitalised with COVID-19, adds and expands previous findings on clinical profiles and outcomes in this population.
Genetic associations of risk behaviours and educational attainment
Authors: Spano Michelle Arellano , Morris Tim , Davies Neil M , Hughes Amanda
Published: April 2023

Risk behaviours such as alcohol use, smoking, and physical inactivity are common in adolescence and persist into adulthood. People who engage in more risk behaviour are more likely to have lower educational attainment. Genome-wide association studies show that participation in risk behaviours and level of education are both heritable and have a highly polygenic architecture, suggesting an important role of many variants across the genome. The extent to which risk behaviours and educational attainment have shared genetic overlap is unknown, yet knowledge of this could help understand how these traits co-occur and influence each other. In the ALSPAC cohort, we used genome-based restricted maximum likelihood (GREML) to estimate the genetic covariance between risk behaviours and educational achievement. We found a strong genetic component of educational achievement and a modest genetic component of the risk behaviours. Whereby children who have a higher genetic liability for education also have a lower genetic liability for risky behaviours.
Depressive symptoms are associated with DNA methylation age acceleration in a cross-sectional analysis of adults over age 50 in the United States
Authors: Wang Herong , Bakulski Kelly M. , Blostein Freida , Porath Brittany R. , Dou John , Tejera Cesar Higgins , Ware Erin B.
Published: April 2023

Background

Major depressive disorder affects mental well-being and accelerates DNA methylation age, a marker of biological aging. Subclinical depressive symptoms and DNA methylation aging have not been explored.

Objective

To assess the cross-sectional association between depressive symptoms and accelerated DNA methylation aging among United States adults over age 50.

Methods

We included 3,793 participants from the 2016 wave of the Health and Retirement Study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale and operationalized as high versus low/no. Blood DNA methylation GrimAge was regressed on chronologic age to obtain acceleration. Multiple linear regression assessed the relationship between high depressive symptoms and GrimAge acceleration, controlling for demographic factors, health behaviors, and cell type proportions. We investigated sex and race/ethnicity stratified associations.

Results

Participants were 42% male, 14% had high depressive symptoms, 44% had accelerated GrimAge, and were mean age 70 years. In our fully adjusted model, those with high depressive symptoms had 0.40 (95%CI: 0.06, 0.73) years accelerated GrimAge, compared to those with low/no depressive symptoms. The association between depressive symptoms and GrimAge acceleration was larger in male participants (P= 0.04).

Conclusion

Higher depressive symptoms were associated with accelerated DNA methylation age among older adults.
The evaluation of the quality of life in survivors of critical illness after discharge from Intensive Care Unit (ICU): A prospective cohort study
Authors: Papageorgiou Dimitrios , Triantafyllou Christos , Stavropoulou Areti , Kelesi Martha , Kaba Evridiki , Evgenikos Konstantinos , Liveri Athanasia , Stroumpouki Theodora
Published: April 2023

Introduction

Admission to the Intensive Care Unit (ICU) constitutes a substantial psychophysical burden for both patients and their relatives. Individuals who are critically ill and receive care in the ICU frequently exhibit numerous physical and mental issues stemming from the primary ailment, its complications, and subsequent treatments. This study aimed to assess the quality of life (QoL) for ICU patients in the first and third month after ICU discharge and identify any issues arising from their ICU hospitalization.

Material and methods

This was a prospective cohort study. The study participants were adult medical or surgical patients admitted to Intensive Care Units (ICUs) in three public hospitals in the region of Attica in Greece, from August 2020 to December 2021. The short form (SF)-36 was used to measure QoL. Data collection was performed through telephone interviews during the first and third month after ICU discharge.

Results

The study included 43 patients, 34 men and nine women. The mean age was 59.63±13.06 years. The average value of the two main categories in the 1st month was: Physical health: 53.72 ± 15.92, and Mental health: 69.03 ± 26.02, while in the 3rdmonth, it was 62.42 ± 20.45 and 72.81 ± 16.47, respectively. The duration of mechanical ventilation, high-flow oxygen therapy, and spontaneous breathing in days seemed to be correlated with the “Physical Functioning”, “Pain”, and “Limitation of the role due to Physical health” subscales of SF-36, respectively (p-value <0.05). The total length of hospitalization seemed to have a statistically significant negative correlation with “Physical Function” and “Physical Health” subscales (p-value<0.05).

Conclusions

An improvement in patients’ QoL was demonstrated three months after discharge from the ICU. Factors such as gender, cause of ICU admission, occurrence or non-occurrence of cardiac arrest, the performance of a tracheostomy, and type of ventilation support should always be considered when assessing the quality of life after ICU hospitalization.
Neural stem and progenitor cells support and protect adult hippocampal function via vascular endothelial growth factor secretion
Authors: Denninger Jiyeon K. , Miller Lisa N. , Walters Ashley E. , Hosawi Manal , Sebring Gwendolyn , Rieskamp Joshua D. , Ding Tianli , Rindani Raina , Chen Kelly S. , Senthilvelan Sakthi , Volk Abigail , Zhao Fangli , Askwith Candice , Kirby Elizabeth D.
Published: April 2023

Adult neural stem and progenitor cells (NSPCs) reside in the dentate gyrus (DG) of the hippocampus throughout the lifespan of most mammalian species. In addition to generating new neurons, NSPCs may alter their niche via secretion of growth factors and cytokines. We recently showed that adult DG NSPCs secrete vascular endothelial growth factor (VEGF), which is critical for maintaining adult neurogenesis. Here, we asked whether NSPC-derived VEGF alters hippocampal function independent of adult neurogenesis. We found that loss of NSPC-derived VEGF acutely impaired hippocampal memory, caused neuronal hyperexcitability and exacerbated excitotoxic injury. We also found that NSPCs generate substantial proportions of total DG VEGF and VEGF disperses broadly throughout the DG, both of which help explain how this anatomically-restricted cell population could modulate function broadly. These findings suggest that NSPCs actively support and protect DG function via secreted VEGF, thereby providing a non-neurogenic functional dimension to endogenous NSPCs.
Chromosome-Level Genome Assembly and Circadian Gene Repertoire of the Patagonia blennieEleginops maclovinus- the closest ancestral proxy of Antarctic cryonotothenioids
Authors: Cheng C.-H. Christina , Rivera-Colón Angel G. , Minhas Bushra Fazal , Wilson Loralee , Rayamajhi Niraj , Vargas-Chacoff Luis , Catchen Julian M.
Published: April 2023

The basal S. American notothenioidEleginops maclovinus(Patagonia blennie) occupies a uniquely important phylogenetic position in Notothenioidei as the singular closest sister species to the Antarctic cryonotothenioid fishes. Its genome and the traits encoded therein would be nearest representatives of the temperate ancestor from which the Antarctic clade arose, providing an ancestral reference for deducing polar derived changes. In this study, we generated a gene- and chromosome-complete assembly ofE. maclovinusgenome using long read sequencing and HiC scaffolding. We compared its genome architecture with the more basally divergentCottoperca gobioand the derived genomes of nine cryonotothenioids representing all five Antarctic families. We additionally curated its repertoire of circadian rhythm genes, ascertained their functionality by transcriptome sequencing, and compared its pattern of gene retention withC. gobioand the derived cryonotothenioids. Both analyses foundE. maclovinusto share greater conservation with the Antarctic clade, solidifying its evolutionary status as direct sister and best suited ancestral proxy of cryonotothenioids. The high quality genome ofE. maclovinuswill facilitate inquiries into cold derived traits in temperate to polar evolution, as well as inform on the paths of readaptation to non-freezing habitats in various secondarily temperate cryonotothenioids through comparative genomic analyses.
Chemical screens in aging-relevant human motor neurons identify MAP4Ks as therapeutic targets for amyotrophic lateral sclerosis
Authors: Liu Meng-Lu , Ma Shuaipeng , Tai Wenjiao , Zhong Xiaoling , Ni Haoqi , Zou Yuhua , Wang Jingcheng , Zhang Chun-Li
Published: April 2023

Effective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.
Whole Body PBPK Model of Nasal Naloxone Administration to Measure Repeat Dosing Requirements During Fentanyl Overdose
Authors: Baird Austin , White Steven A. , Das Rishi , Tatum Nathan , Bisgaard Erika K
Published: April 2023

Opioid use in the United States and abroad is an endemic part of culture with yearly increases in overdose rates and deaths. As rates of overdose incidence increases, the use of the safe and effective reversal agent, naloxone, in the form of a nasal rescue spray is being fielded and used by emergency medical technicians (EMTs) at a greater and greater rate. Despite advances in deployment of these rescue products, deaths are continuing to increase. There is evidence that repeated dosing of a naloxone nasal spray (such as Narcan) is becoming more common due to the amount and type of opiate being abused. Despite the benefits of naloxone related to opioid reversals, we lack repeated dosing guidelines as a function of opiate and amount the patient has taken. Goal directed dosing is promising, where respiratory markers are being used as an indication of the patient recovery but require time and understanding by the EMT. We construct a whole-body model of the pharmacokinetics and dynamics of an opiate, fentanyl on respiratory depression. We then construct a model of nasal deposition and administration of naloxone to investigate repeat dosing requirements for large overdoses. We demonstrate that naloxone is highly effective at reversing respiratory symptoms of the patient and recommend dosing requirements as a function of opiate amount administered. By designing the model to include circulation and respiration we investigate physiological markers that may be used in goal directed therapy rescue treatments.