bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resolvin E1 improves efferocytosis and rescues severe aplastic anemia in mice
Authors: Grazda Rachel , Seyfried Allison N. , Maddipatti Krishna Rao , Fredman Gabrielle , MacNamara Katherine C. 
Published: February 2023

AbstractCurrent treatments for severe aplastic anemia (SAA) rely on hematopoietic stem cell (HSC) transplantation and immunosuppressive therapies, however these treatments are not always effective. While immune-mediated destruction and inflammation are known drivers of SAA, the underlying mechanisms that lead to persistent inflammation are unknown. Using an established mouse model of SAA, we observed a significant increase in apoptotic cells within the bone marrow (BM) and demonstrate impaired efferocytosis in SAA mice, as compared to radiation controls. Single-cell transcriptomic analysis revealed heterogeneity among BM monocytes and unique populations emerged during SAA characterized by increased inflammatory signatures and significantly increased expression ofSirpaandCd47. CD47, a “don’t eat me” signal, was increased on both live and apoptotic BM cells, concurrent with markedly increased expression of signal regulatory protein alpha (SIRPα) on monocytes. Functionally, SIRPα blockade improved cell clearance and reduced accumulation of CD47-positive apoptotic cells. Lipidomic analysis revealed a reduction in the precursors of specialized pro-resolving lipid mediators (SPMs) and increased prostaglandins in the BM during SAA, indicative of impaired inflammation resolution. Specifically, 18-HEPE, a precursor of E-series resolvins, was significantly reduced in SAA-induced mice relative to radiation controls. Treatment of SAA mice with Resolvin E1 (RvE1) improved efferocytic function, BM cellularity, platelet output, and survival. Our data suggest that impaired efferocytosis and inflammation resolution contributes to SAA progression and demonstrate that SPMs, such as RvE1, offer new and/or complementary treatments for SAA that do not rely on immune suppression.Key Points–IFNγ impairs efferocytosis in SAA, correlating with increased SIRPahimonocytes and increased CD47 expression–Pro-inflammatory and pro-resolving lipid mediators are imbalanced in SAA, and RvE1 treatment improved efferocytosis and disease outcomes
Prolongedin-vivotracking of vitreous fluid and its early diagnostic imaging biomarkers for cancer growth
Authors: Goswami Mayank , Shakya Snehlata , Zhang Pengfei 
Published: February 2023

AbstractPurposeEstimation of a correlation between cells in vitreous humour and growth in glioblastoma xenografts.MethodsStreams of cells in vitreous humor are observed in optical coherence tomography (OCT) imaging data of animal (NSGS and Athymic Nude-Foxn1nu) eyes (34 in total) subjected to xenograft growth study, in-vivo. The cancer disease model is studied with and without nanodrug-based treatment protocols.ResultsThe presence of CD8+ and CD4+ is reported inside the tumor using the same data earlier. The transition of these cells is shown to take place from the optic nerve via the vitreous into the nerve fiber layer (NFL) at tumor locations and xenograft -related injuries. Functional analysis of dense temporal imaging series (varying from 28 to more than 100 days) reveals a mild correlation between the volumetric growth of the tumor with the density of these cells, quantitatively and qualitatively.The cross-correlation analysis indicates imaging assisted photodynamic treatment protocol perform relatively better if started with certain delay. Doxorubicin treatment to Nu/Nu Male and NSGS female transforms mild weak negative correlation into mild weak positive correlation.ConclusionsThe plots indicate that the mix of the cells in vitreous humor are effectively dominated by immunosuppressor cytotoxic component.Translational RelevanceWe propose that the vitreous cell density can be used as imaging biomarker helpful for clinicians in early diagnosis and treatment planning of similar disease models. The limitation of this work is that high resolution OCT systems and data-dependent image segmentation methods are required.
Identifying Promising Sequences For Protein Engineering Using A Deep Transformer Protein Language Model
Authors: Frisby Trevor S. , Langmead Christopher James 
Published: February 2023

ABSTRACTProtein engineers aim to discover and design novel sequences with targeted, desirable properties. Given the near limitless size of the protein sequence landscape, it is no surprise that these desirable sequences are often a relative rarity. This makes identifying such sequences a costly and time-consuming endeavor. In this work, we show how to use a deep Transformer Protein Language Model to identify sequences that have the mostpromise. Specifically, we use the model’s self-attention map to calculate a PROMISE SCORE that weights the relative importance of a given sequence according to predicted interactions with a specified binding partner. This PROMISE SCORE can then be used to identify strong binders worthy of further study and experimentation. We use the PROMISE SCORE within two protein engineering contexts— Nanobody (Nb) discovery and protein optimization. With Nb discovery, we show how the PROMISE SCORE provides an effective way to select lead sequences from Nb repertoires. With protein optimization, we show how to use the PROMISE SCORE to select site-specific mutagenesis experiments that identify a high percentage of improved sequences. In both cases, we also show how the self-attention map used to calculate the PROMISE SCORE can indicate which regions of a protein are involved in intermolecular interactions that drive the targeted property. Finally, we describe how to fine-tune the Transformer Protein Language Model to learn a predictive model for the targeted property, and discuss the capabilities and limitations of fine-tuning with and without knowledge transfer within the context of protein engineering.
Vacuum Insulated Probe Heated ElectroSpray Ionization source (VIP-HESI) enhances micro flow rate chromatography signals in the Bruker timsTOF mass spectrometer
Authors: Midha Mukul K. , Kapil Charu , Maes Michal , Baxter David H. , Morrone Seamus R. , Prokop Timothy J. , Moritz Robert L. 
Published: February 2023

AbstractBy far the largest contribution to ion detectability in liquid chromatography-driven mass spectrometry-based proteomics is the efficient generation of peptide ions by the electrospray source. To maximize the transfer of peptides from liquid to a gaseous phase to allow molecular ions to enter the mass spectrometer at micro-spray flow rates, an efficient electrospray process is required. Here we describe superior performance of new Vacuum-Insulated-Probe-Heated-ElectroSpray-Ionization source (VIP-HESI) coupled with micro-spray flow rate chromatography and Bruker timsTOF PRO mass spectrometer. VIP-HESI significantly improves chromatography signals in comparison to nano-spray ionization using the CaptiveSpray source and provides increased protein detection with higher quantitative precision, enhancing reproducibility of sample injection amounts. Protein quantitation of human K562 lymphoblast samples displayed excellent chromatographic retention time reproducibility (<10% coefficient-of-variation (CV)) with no signal degradation over extended periods of time, and a mouse plasma proteome analysis identified 12% more plasma protein groups allowing large-scale analysis to proceed with confidence (1,267 proteins at 0.4% CV). We show that Slice-PASEF mode with VIP-HESI setup is sensitive in identifying low amounts of peptide without losing quantitative precision. We demonstrate that VIP-HESI coupled with micro-flow-rate chromatography achieves higher depth of coverage and run-to-run reproducibility for a broad range of proteomic applications.
Predicting Brain Amyloid Positivity from T1 weighted brain MRI and MRI-derived Gray Matter, White Matter and CSF maps using Transfer Learning on 3D CNNs*
Authors: Chattopadhyay Tamoghna , Ozarkar Saket S. , Buwa Ketaki , Thomopoulos Sophia I. , Thompson Paul M. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: February 2023

AbstractAbnormal β-amyloid (Aβ) accumulation in the brain is an early indicator of Alzheimer’s disease and practical tests could help identify patients who could respond to treatment, now that promising anti-amyloid drugs are available. Even so, Aβ positivity (Aβ+) is assessed using PET or CSF assays, both highly invasive procedures. Here, we investigate how well Aβ+ can be predicted from T1 weighted brain MRI and gray matter, white matter and cerebrospinal fluid segmentations from T1-weighted brain MRI (T1w), a less invasive alternative. We used 3D convolutional neural networks to predict Aβ+ based on 3D brain MRI data, from 762 elderly subjects (mean age: 75.1 yrs. ±7.6SD; 394F/368M; 459 healthy controls, 67 with MCI and 236 with dementia) scanned as part of the Alzheimer’s Disease Neuroimaging Initiative. We also tested whether the accuracy increases when using transfer learning from the larger UK Biobank dataset. Overall, the 3D CNN predicted Aβ+ with 76% balanced accuracy from T1w scans. The closest performance to this was using white matter maps alone when the model was pre-trained on an age prediction in the UK Biobank. The performance of individual tissue maps was less than the T1w, but transfer learning helped increase the accuracy. Although tests on more diverse data are warranted, deep learned models from standard MRI show initial promise for Aβ+ estimation, before considering more invasive procedures.Clinical RelevanceEarly detection of Aβ positivity from less invasive MRI images, could offer a screening test prior to more invasive testing procedures.
Electroacupuncture prevents astrocyte atrophy to alleviate depression
Authors: Lin Si-Si , Zhou Bin , Chen Bin-Jie , Jiang Ruo-Tian , Li Baoman , Illes Peter , Semyanov Alexey , Tang Yong , Verkhratsky Alexei 
Published: February 2023

AbstractAstrocyte atrophy is the main histopathological hallmark of the major depressive disorder (MDD) in humans and in animal models of depression. Here we show that electroacupuncture prevents astrocyte atrophy in the prefrontal cortex and alleviates depressive-like behaviour in mice subjected to the chronic unpredictable mild stress (CUMS). Treatment of mice with CUMS induced depressive-like phenotypes as confirmed by sucrose preference test, tail suspension test, and forced swim test. These behavioural changes were paralleled with morphological atrophy of astrocytes in the prefrontal cortex, revealed by analysis of 3D reconstructions of confocal Z-stack images of mCherry expressing astrocytes. This morphological atrophy was accompanied with a decrease in expression of cytoskeletal linker Ezrin, associated with formation of astrocytic leaflets, which form astroglial synaptic cradle. Electroacupuncture at the acupoint ST36 as well as treatment with anti-depressant fluoxetine prevented depressive-like behaviours, astrocytic atrophy and down-regulation of astrocytic ezrin. In conclusion, our data further strengthen the notion of a primary role of astrocytic atrophy in depression and reveal astrocytes as cellular target for electroacupuncture in treatment of depressive disorders.
Kif6 regulates cilia motility and polarity in brain ependymal cells
Authors: Takagishi Maki , Yue Yang , Gray Ryan S. , Verhey Kristen J. , Wallingford John B. 
Published: February 2023

AbstractEpendymal cells, lining brain ventricular walls, display tufts of cilia that beat in concert promoting laminar Cerebrospinal fluid (CSF) flow within brain ventricles. The ciliary axonemes of multiciliated ependymal cells display a 9+2 microtubule array common to motile cilia. Dyneins and kinesins are ATPase microtubule motor proteins that promote the rhythmic beating of cilia axonemes. Despite common consensus about the importance of axonemal dynein motor proteins, little is known about how Kinesin motors contribute to cilia motility. Here, we define the function of Kinesin family member 6 (Kif6) using a mutation that lacks a highly conserved C-terminal tail domain (Kif6p.G555fs) and which displays progressive hydrocephalus in mice. An analogous mutation was isolated in a proband displaying macrocephaly, hypotonia, and seizures implicating an evolutionarily conserved function for Kif6 in neurodevelopment. We find that loss of Kif6 function caused decreased ependymal cilia motility and subsequently decreased fluid flow on the surface of brain ventricular walls. Kif6 protein was localized at ependymal cilia and displayed processive motor movement (676 nm/s) on microtubulesin vitro. Loss of the Kif6 C-terminal tail domain did not affect the initial ciliogenesisin vivo, but did result in defects in cilia orientation, the formation of robust apical actin networks, and stabilization of basal bodies at the apical surface. This suggests a novel role for the Kif6 motor in maintenance of ciliary homeostasis of ependymal cells.Summary statementWe found that Kif6 is localized to the axonemes of ependymal cells. In vitro analysis shows that Kif6 moves on microtubules and that its loss mice decrease cilia motility and cilia-driven flow, resulting in hydrocephalus.
Visual perception and workload of office workers in various acoustic conditions
Authors: Kamińska Joanna , Radosz Jan , Kapica Łukasz 
Published: February 2023

AbstractNoise in the office work environment can negatively affect workers’ cognitive performance, number of errors made and comfort. The aim of the study was to determine the effects of various types of acoustic conditions in the mental work environment on visual perception (eye-tracking parameters) and workload. Method: In the experiment a group of 39 people aged 20 to 34 was asked to perform two eye-tracking tests (Perceptiveness and Speed Tests (PTs) and to read the text of a fictional biography, and then to answer questions about the reading). Mental workload was evaluated in each condition using NASA TLX questionnaire. The tests were performed in various acoustic conditions: variant W1 – no presentation of acoustic stimuli, variant W2 – sounds of office equipment, variant W3 – sounds of office equipment with quiet conversation in native language, variant W4 – sounds of office equipment with loud conversation in native language, variant W5 – filtered pink noise. In variants from W2 to W5 the equivalent sound level A was 55 dB. Results: The assessment of work efficiency in the reading test indicates the existence of statistically significant differences. The most errors were made during mental work with the audible sounds of office equipment with a loud conversation (Variant W4) and during mental work performed with audible filtered pink noise (W5). While reading the text, different acoustic conditions do not differentiate statistically significantly visual perception described by eye-tracking parameters. In turn, in the PTs test, statistically significant differences between the variants were found in the Digit test (average blink duration) and the Fraction test (average blink duration, average fixation duration and saccades frequency parameters). In conclusion, visual perception depends on the type of noise. Acoustic factors aggect workers’ cognitive functions, mostly in more difficult tasks.
Divergent phenotypes in germline versus conditional mutant mouse models of Sifrim-Hitz-Weiss Syndrome
Authors: Larrigan Sarah , Joshi Shrilaxmi , Mattar Pierre 
Published: February 2023

AbstractChromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), however, their functions during brain development are not fully understood. Here, we focused on Sifrim-Hitz-Weiss Syndrome (SIHIWES) – a brain overgrowth/intellectual disability disorder caused by mutations in theCHD4chromodomain helicase gene. We utilized mouse genetics to excise theChd4ATPase/helicase domain – either in the germline, or conditionally in the developing telencephalon. Conditional heterozygotes exhibited little change in cortical size and cellular composition, and had only subtle behavioral phenotypes. Telencephalon-specific conditional knockouts had marked reductions in cortical growth, reduced numbers of upper-layer neurons, and exhibited alterations in anxiety and repetitive behaviors. Despite the fact that germline heterozygotes exhibited comparable growth defects, they were unaffected in these behaviors, but instead exhibited female-specific alterations in learning and memory. These data reveal unexpected phenotypic divergence arising from differences in the spatiotemporal deployment of loss-of-function manipulations, underscoring the importance of context in chromatin remodeller function during neurodevelopment.Graphical Abstract.
Linking genotypic and phenotypic changes in theE. coliLong-Term Evolution Experiment using metabolomics
Authors: Favate John S. , Skalenko Kyle S. , Chiles Eric , Su Xiaoyang , Yadavalli Srujana S. , Shah Premal 
Published: February 2023

1AbstractChanges in an organism’s environment, genome, or gene expression patterns can lead to changes in its metabolism. The metabolic phenotype can be under selection and contributes to adaptation. However, the networked and convoluted nature of an organism’s metabolism makes relating mutations, metabolic changes, and effects on fitness challenging. To overcome this challenge, we use the Long-Term Evolution Experiment (LTEE) withE. colias a model to understand how mutations can eventually affect metabolism and perhaps fitness. We used mass-spectrometry to broadly survey the metabolomes of the ancestral strains and all 12 evolved lines. We combined this metabolic data with mutation and expression data to suggest how mutations that alter specific reaction pathways, such as the biosynthesis of nicotinamide adenine dinucleotide, might increase fitness in the system. Our work provides a better understanding of how mutations might affect fitness through the metabolic changes in the LTEE and thus provides a major step in developing a complete genotype-phenotype map for this experimental system.
Maternal dietary deficiencies in one-carbon metabolism during early neurodevelopment result in larger damage volume, reduced neurodegeneration and neuroinflammation and changes in choline metabolites after ischemic stroke in middle-aged offspring
Authors: Hurley Lauren , Jauhal Jesse , Ille Sharadyn , Pull Kasey , Malysheva Olga V. , Jadavji Nafisa M. 
Published: February 2023

AbstractMaternal diet pregnancy and lactation is vital to the early life neuro programming of offspring. One-carbon (1C) metabolism, which includes folic acid and choline, plays a vital role in closure of the neural tube and other neurodevelopment. However, the impact of maternal dietary deficiencies on offspring neurological function following ischemic stroke later in life remains undefined. Stroke is one of the leading causes of death globally, and its prevalence is expected to increase in younger age groups as the incidence of various risk factors for stroke increases. Furthermore, our group has shown that dietary deficiencies in 1C metabolism result in worse stroke outcome. Our study aimed to investigate the role of maternal dietary deficiencies in folic acid and choline on ischemic stroke outcome in middle-aged male and female mice. Female mice were maintained on either a control or deficient diets prior to and during pregnancy and lactation. When female and male offspring were 10-months of age, ischemic stroke was induced via photothrombosis targeting the sensorimotor cortex. Stroke outcome was assessed by measuring motor function in living animals and ischemic damage volume, neurodegeneration, neuroinflammation, and choline metabolism in the brain postmortem. No significant difference was observed between maternal dietary groups in offspring motor function; however, males and females differed in their motor function. Maternal diet significantly impacted ischemic damage volume. Male and female offspring from deficient mothers showed significantly reduced neurodegeneration and neuroinflammation within the ischemic damage region. We also report changes in plasma 1C metabolites as a result of maternal diet and sex after ischemic stroke in offspring. Our data indicates that maternal dietary deficiencies do not impact offspring motor outcome following ischemic stroke, but do play a role in other ischemic stroke outcomes such as ischemic damage volume and plasma 1C metabolites in middle-aged adult offspring. Furthermore, our data indicates that sex of mice plays an important role in stroke outcome during middle-age.
Comprehensive comparison of female germ cell developmentin vitroandin vivoidentifies epigenetic gene regulation crucial for oocyte development and embryonic competence
Authors: Aizawa Eishi , Ozonov Evgeniy A. , Kawamura Yumiko K. , Dumeau Charles-Etienne , Nagaoka So , Saitou Mitinori , Peters Antoine H. F. M. , Wutz Anton 
Published: February 2023

SummaryGerm cells are the origin of new individuals. Hence, specifying germ cell identity is crucial for reproduction. The recent establishment ofin vitroculture systems for generating oocytes from mouse pluripotent stem cells provides a basis for progress in studies of oogenesis and reproductive technology. However, currently the developmental competence ofin vitrogenerated oocytes is low compared toin vivogrown oocytes. The causes underlying poor oocyte quality remain to be determined. By reconstituting germ cell development in culture from different developmental starting points within gametogenesis, we show that the differentiation of primordial germ cells (PGCs) and primordial germ cell-like cells (PGCLCs) to growing oocytes (GROs), as well as the subsequent growth of follicles are critical culture steps for specifying competence of fully-grown oocytes (FGOs) for preimplantation development. A systematic comparison of transcriptomes of single oocytes having undergone differentin vitroculture trajectories identifies genes normally upregulated during oocyte growth to be susceptible for mis-regulation duringin vitrooogenesis. Many of such genes have been described as targets of Polycomb repressive complexes (PRCs). Deregulation of Polycomb repression therefore likely perturbs the accumulation of cytoplasmic factors and/or setting of chromatin states in FGOs that are required for embryonic development after fertilization. Conversely,in vitroderived oocytes often displayed failure of zygotic genome activation (ZGA) and abnormal acquisition of 5-hydroxymethylcytosine (5hmC) on maternal chromosomes after activation. In addition, subcellular delocalization of pyruvate dehydrogenase (PDH) and of STELLA were observed suggesting new molecular markers for defective oocyte development. Our study identifies epigenetic regulation at an early stage of oogenesis as crucial for developmental competence and suggests specificin vitroculture steps as targets for improving oocyte quality.HighlightsSingle cell transcriptomics and functional assessment of oocyte development from pluripotent stem cells in culture in a stage-specific manner provides a comprehensive resource for comparisons to oogenesisin vivo.Culture steps for growth and differentiation of reconstituted follicles are critical for defining embryonic competence ofin vitrogenerated oocytes.Zygotic genome activation failure and epigenetic impairment are hallmarks of in vitro-generated oocytes that fail to develop after activation or fertilization.Computational analysis of gene expression changes and chromatin modification patterns identifies specific gene sets that indicate that Polycomb mediated repression is vulnerable duringin vitrofolliculogenesis.