bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive Noise Reduction in Single-Cell Data with the RECODE Platform
Authors: Imoto Yusuke 
Published: April 2024

AbstractSingle-cell sequencing generates vast amounts of genomic and epigenomic data from thousands of individual cells and can reveal insights into biological principles at the single-cell resolution. However, challenges such as technical noise (dropout) and batch effects hinder obtaining high-resolution structures that are essential for tasks such as the identification of rare cell types and dataset comparison across different cultures. Here, I introduceintegrative RECODE (iRECODE), a comprehensive method for noise reduction that is based on the RECODE platform, which targets the technical noise in single-cell RNA-sequencing data using high-dimensional statistics. I show iRECODE effectively mitigates both technical and batch noise with high accuracy and low computational cost. Additionally, the application of RECODE extended to other single-cell sequencing data types including single-cell Hi-C and spatial transcriptomics data and the recent enhancements in RECODE have markedly improved its accuracy and computational efficiency. Thus, the RECODE platform presents a robust solution for mitigating noise in single-cell sequencing, offering promise for advancing our understanding of biological phenomena beyond transcriptomics, encompassing epigenomic and spatial transcriptomic domains.
Luminance invariant encoding in primary visual cortex
Authors: O’Shea Ronan , Nauhaus Ian , Wei Xue-Xin , Priebe Nicholas J. 
Published: April 2024

AbstractThe retina maintains sensitivity over a large range of luminance intensities by switching between rod and cone photoreceptors. This luminance adaptation has been shown to alter the receptive fields and interneuronal correlations of retinal ganglion cells (RGCs). While these adaptations allow the retina to encode visual information across environmental conditions, they present a challenge to downstream processing areas for which it is important that representations are invariant to light level. We measured the effects of scotopic versus photopic luminance adaptation on thalamic and cortical activity by tracking neuronal populations across light levels. While changes in the output of the retina are evident in the lateral geniculate nucleus (LGN), the representation in primary visual cortex (V1) is largely invariant to the changes in luminance. We show that an invariant V1 code can emerge through the integration of parallel functional pathways at the geniculocortical synapse.
Dietary stress induced macrophage metabolic reprogramming, a determinant of animal growth
Authors: Mahanta Anusree , Najar Sajad Ahmad , Hariharan Nivedita , Goyal Manisha , Subramanian Ramaswamy , Giangrande Angela , Palakodeti Dasaradhi , Mukherjee Tina 
Published: April 2024

AbstractNutrient sensing and signaling play pivotal roles in animal growth. However, under dietary stress, this system falters, leading to growth defects. While immune cells are increasingly recognized as key nutrient sensors, their impact on animal growth remains poorly understood. In this study, we investigate howDrosophilalarval macrophages respond to excessive dietary sugar and identify a reconfiguration of their metabolic state. They undergo a glycolytic shift, intensify TCA activity, and elevate TAG synthesis. While typical of sugarinduced nutrient stress, these changes interestingly exert contrasting effects on animal growth: glycolysis and increased TCA activity inhibit growth, while the lipogenic shift promotes it. However, the lipogenic response is insufficient to counteract the metabolic events suppressing growth, resulting in an overall reduction in adult fly size under high sugar conditions. Stimulating a pro-lipogenic immune state facilitates growth recovery, suggesting a growth paradigm governed by immune-metabolic transitions. This study unveils the unexpected influence of macrophage metabolic reprogramming on organismal growth homeostasis duringDrosophiladevelopment, highlighting immune cell states as central determinants of growth, particularly under dietary stress.
Effects of SGLT2 Ablation or Inhibition on Corticosterone Secretion in High-Fat-Fed Mice: Exploring a Nexus with Cytokine Levels
Authors: Brisnovali Niki F. , Franco Isabelle , Abdelgawwad Amira , Tsou Hio Lam Phoebe , Cao Thong Huy , Riva Antonio , Rutter Guy A. , Akalestou Elina 
Published: April 2024

AbstractDespite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing Type 2 Diabetes (T2D). Sodium-glucose co-transporter type 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive. To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high fat diet-fed control, chronically dapagliflozin-treated mice and total-body SGLT2/Slc5a2knockout mice. SGLT2 null mice exhibited superior glucose tolerance and insulin sensitivity compared to control or dapagliflozin-treated mice, independent of glycosuria and body weight. Moreover, SGLT2 null mice demonstrated physiological regulation of corticosterone secretion, with lowered morning levels compared to control mice. Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly interleukin 6 (IL-6). Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 increased SGLT2 expression in kidney HK2 cells suggesting a role for cytokines in the effects of hyperglycemia. Collectively, our study elucidates a potential interplay between SGLT2 activity, immune modulation, and metabolic homeostasis.Graphical AbstractArticle HighlightsThe role of Sodium-glucose co-transporter type 2 (SGLT2) in immunity regulation remains elusive, despite extensive research in SGLT2 inhibitors.We sought to discern the effects of SGLT2 inhibition or deletion on metabolic and immune profiles in high-fat-fed mice, focussing on corticosterone regulation and cytokine alterations.SGLT2 null mice exhibit enhanced insulin sensitivity, alongside physiologically regulated corticosterone levels and significant alterations in inflammatory cytokines, and we identified changes in protein expression suggestive of antioxidant modulation.Our findings emphasize the interplay between immune responses and metabolic regulation mediated by SGLT2 activity.
Revealing the Prevalence of Suboptimal Cells and Organs in Reference Cell Atlases: An Imperative for Enhanced Quality Control
Authors: Montserrat-Ayuso Tomàs , Esteve-Codina Anna 
Published: April 2024

AbstractThe advent of droplet-based single-cell RNA-sequencing (scRNA-seq) has dramatically increased data throughput, enabling the release of a diverse array of tissue cell atlases to the public. However, we will show that prominent initiatives such as the Human Cell Atlas, Tabula Muris, and Tabula Sapiens contain a significant amount of contamination products (frequently affecting the whole organ) in their data portals due to suboptimal quality filtering. Our work addresses a critical gap by advocating for more stringent quality filtering, highlighting the imperative for a shift from existing standards, which currently lean towards greater permissiveness. We will show the importance of incorporating cell intronic fraction in quality control -or MALAT1 expression otherwise- showcasing its informative nature and potential to elevate cell atlas data reliability. In summary, here, we unveil the hidden intronic landscape of every tissue and highlight the importance of more rigorous single-cell RNA-sequencing quality assessment in cell atlases to enhance their applicability in diverse downstream analyses.
Polygenic hazard score models for the prediction of Alzheimer’s free survival using the lasso for Cox’s proportional hazards model
Authors: Hahn Georg , Prokopenko Dmitry , Hecker Julian , Lutz Sharon M. , Mullin Kristina ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Tanzi Rudolph E. , DeSantis Stacia , Lange Christoph 
Published: April 2024

AbstractThe prediction of the susceptibility of an individual to a certain disease is an important and timely research area. An established technique is to estimate the risk of an individual with the help of an integrated risk model, that is a polygenic risk score with added epidemiological covariates. However, integrated risk models do not capture any time dependence, and may provide a point estimate of the relative risk with respect to a reference population. The aim of this work is twofold. First, we explore and advocate the idea of predicting the time dependent hazard and survival (defined as disease free time) of an individual for the onset of a disease. This provides a practitioner with a much more differentiated view of the absolute survival as a function of time. Second, to compute the time dependent risk of an individual, we use published methodology to fit a Cox’s proportional hazard model to data from a genetic SNP study of time to Alzheimer’s disease (AD) onset, using the lasso to incorporate further epidemiological variables such as sex, APOE (apolipoprotein E, a genetic risk factor for AD) status, ten leading principal components, and selected genomic loci. We apply the lasso for Cox’s proportional hazards to a dataset of 6792 AD patients (composed of 4102 cases and 2690 controls) and 87 covariates. We demonstrate that fitting a lasso model for Cox’s proportional hazards allows one to obtain more accurate survival curves than with state-of-the-art (likelihood-based) methods. Moreover, the methodology allows one to obtain personalized survival curves for a patient, thus giving a much more differentiated view of the expected progression of a disease than the view offered by integrated risk models. The runtime to compute personalized survival curves is under a minute for the entire dataset of AD patients, thus enabling it to handle datasets with 60, 000 to 100, 000 subjects in less than one hour.
Knockout of Dectin-1 does not modify disease onset or progression in a MATR3 S85C knock-in mouse model of ALS
Authors: You Justin , Maksimovic Katarina , Chen Karin , Lee Jooyun , Schoeppe Anneka , Santos Jhune Rizsan , Youssef Mohieldin M. M. , Salter Michael W. , Park Jeehye 
Published: April 2024

AbstractMicroglia have been increasingly implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Dectin-1, encoded by theClec7agene, is highly upregulated in a specific microglial response state called disease-associated microglia (DAM) in various neurodegenerative conditions. However, the role of Dectin-1 in ALS is undetermined. Here, we show thatClec7amRNA upregulation occurs in central nervous system (CNS) regions that exhibit neurodegeneration in a MATR3 S85C knock-in mouse model (Matr3S85C/S85C) of ALS. Furthermore, a significant increase in the number of Dectin-1+microglia coincides with the onset of motor deficits, and this number increases with disease severity. We demonstrate that the knockout of Dectin-1 does not affect survival, motor function, neurodegeneration, or microglial responses inMatr3S85C/S85Cmice. These findings suggest that Dectin-1 does not play a role in modifying ALS onset or progression but could potentially serve as a valuable biomarker for ALS severity.Subject areasPhysiology; Molecular biology; Neuroscience; ImmunologyHighlightsClec7aupregulation is confined to central nervous system regions that exhibit overt neurodegeneration in a MATR3 S85C knock-in mouse model of ALSThe appearance of Dectin-1+microglia coincides with the onset of motor deficits, and its number increases with disease progressionKnockout of Dectin-1 does not modify survival, motor deficits, neurodegeneration, or microglial responses in MATR3 S85C knock-in mice
Altered visual cortex excitatory/inhibitory ratio following transient congenital visual deprivation in humans
Authors: Pant Rashi , Pitchaimuthu Kabilan , Ossandón José , Shareef Idris , Lingareddy Sunitha , Finsterbusch Jürgen , Kekunnaya Ramesh , Röder Brigitte 
Published: April 2024

ABSTRACTNon-human animal models have indicated that the ratio of excitation to inhibition (E/I) in neural circuits is experience dependent and changes across development. Here, we assessed 3T Magnetic Resonance Spectroscopy (MRS) and electroencephalography (EEG) markers of cortical E/I ratio in ten individuals who had been treated for dense bilateral congenital cataracts, after an average of 12 years of blindness, to test for dependence of the E/I ratio in humans on early visual experience. First, participants underwent MRS scanning at rest with their eyes opened and eyes closed, to obtain visual cortex Gamma-Aminobutyric Acid (GABA+) concentration, Glutamate/Glutamine (Glx) concentration and the concentration ratio of Glx/GABA+, as measures of inhibition, excitation, and E/I ratio respectively. Subsequently, EEG was recorded to assess aperiodic activity (1-20 Hz) as a neurophysiological measure of the cortical E/I ratio, during rest with eyes open and eyes closed, and during flickering stimulation. Across conditions, congenital cataract-reversal individuals demonstrated a significantly lower visual cortex Glx/GABA+ ratio, and a higher intercept and steeper aperiodic slope at occipital electrodes, compared to age-matched sighted controls. In the congenital cataract-reversal group, a lower Glx/GABA+ ratio was associated with better visual acuity, and Glx concentration correlated positively with the aperiodic intercept in the conditions with visual input. We speculate that these findings result from an increased E/I ratio of the visual cortex as a consequence of congenital blindness, which might require commensurately increased inhibition in order to balance the additional excitation from restored visual input. The lower E/I ratio in congenital cataract-reversal individuals would thus be a consequence of homeostatic plasticity.
Flexible integration of natural stimuli by auditory cortical neurons
Authors: Ang Grace Wan Yu , Clopath Claudia , Kozlov Andriy S. 
Published: April 2024

ABSTRACTNeurons have rich input-output functions for processing and combining their inputs. Although many experiments characterize these functions by directly activating synaptic inputs on dendritesin vitro, the integration of spatiotemporal inputs representing real-world stimuli is less well studied. Using ethologically relevant stimuli, we study neuronal integration in relation to Boolean AND and OR operations thought to be important for pattern recognition. We recorded single-unit responses in the mouse auditory cortex to pairs of ultrasonic mouse vocalization (USV) syllables. We observed a range of integration responses, spanning the sublinear to supralinear regimes, with many responses resembling the MAX-like function, an instantiation of the OR operation. Integration was more MAX-like for strongly activating features, and more AND-like for spectrally distinct inputs. Importantly, single neurons could implement more than one integration function, in contrast to artificial networks which typically fix activation functions across all units and inputs. To understand the mechanism underlying the flexibility and heterogeneity in neuronal integration, we modelled how dendritic properties could influence the integration of inputs with complex spectrotemporal structure. Our results link nonlinear integration in dendrites to single-neuron computations for pattern recognition.Significance statementSensory neurons compute over their inputs, combining them in ways to achieve selectivity and invariance for pattern recognition. Using real-world stimuli, we show that single cortical neurons are flexible, being capable of implementing more than one computation, unlike artificial neural-network units with fixed activation functions. We investigate this flexibility by modeling how synaptic activation patterns of real-world stimuli affect dendritic integration and the resultant neuronal computation. Our work bridges the gap between biophysical mechanisms and computation, linking neuronal input integration to pattern recognition.
ITGB6 inhibition stimulates anti-tumor responses in immunocompetent mouse models of head & neck squamous cell carcinoma and pancreatic adenocarcinoma
Authors: MacDonald William J. , Srinivasan Praveen R. , Pinho-Schwermann Maximilian , Zhang Shengliang , Tajiknia Vida , Purcell Connor , Strandberg Jillian , El-Deiry Wafik S. 
Published: April 2024

AbstractITGB6, the gene encoding the β6 subunit of integrin αvβ6, is a potent prognostic marker across multiple cancer types. As a major activator of latent TGFβ, αvβ6, and consequently, ITGB6, has considerable therapeutic implications due to the immunosuppressive effect that activated TGFβ has on the tumor microenvironment. The present study identifies ITGB6 as a potent target for inducing an immune-mediated anti-tumor response. ITGB6 is highly upregulated in various squamous cell carcinomas and pancreatic adenocarcinomas, allowing it to disrupt tumor-immune cell signaling, while avoiding the widespread side-effects of systemic TGFβ inhibition. Genetic knockout of ITGB6 in heterotopically injected head and neck squamous cell carcinoma and pancreatic adenocarcinoma cell lines showed markedly reduced tumor progression in immunocompetent mice. Additionally, co-cultures of human squamous cell carcinoma cell lines and human T-cells showed increased T-cell killing upon cancer cell ITGB6 inhibition. Colony formation experiments give further evidence that the reduction in tumor growth observed upon ITGB6 inhibitionin vivois through immunological clearance of cancer cells and not merely through intrinsic factors. Analysis of The Cancer Genome Atlas (TCGA) revealed not only the high prognostic value of ITGB6 on overall survival but also that high ITGB6 expression in patients is often associated with an inferior response to α-PD-1 and α-PD-L1 immune checkpoint blockade. The potent anti-tumor immune response observed bothin vitroandin vivoupon ITGB6 inhibition, combined with our analysis of RNA-seq data from immune checkpoint blockade-treated patients, encourages the development of ITGB6 blockade and immunotherapy combination regimes. Further pre-clinical studies will serve to facilitate the translation of our findings into therapeutic clinical trials of combination therapies for treating immunotherapy-resistant cancers.Visual Abstract
Proteome profiling of cerebrospinal fluid using machine learning shows a unique protein signature associated with APOE4 genotype
Authors: Shvetcov Artur , Thomson Shannon , Cho Ann-Na , Wilkins Heather M. , Reed Joanne H. , Swerdlow Russell H. , Brown David A. ,   the Alzheimer’s Disease Neuroimaging Initiative, Finney Caitlin A. 
Published: April 2024

AbstractINTRODUCTIONProteome changes associated with APOE4 variant carriage that are independent of Alzheimer’s disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment.METHODSClinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning.RESULTSWe found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells.DISCUSSIONAPOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers’ vulnerability to cognitive decline and AD.
High Variability in Nicotine Analog Contents, Misleading Labeling, and Artificial Sweetener in New E-Cigarette Products Marketed as “FDA-Exempt”
Authors: Erythropel Hanno C. , Jabba Sairam V. , Silinski Peter , Anastas Paul T. , Krishnan-Sarin Suchitra , Zimmerman Julie B. , Jordt Sven E. 
Published: April 2024

ABSTRACTThe recent introduction of electronic cigarette products containing a synthetic nicotine analog, 6-methyl nicotine (6MN), challenges FDA’s tobacco regulatory authority. A similar strategy is pursued by vendors of recently introduced e-cigarette liquids containing nicotinamide (NA), marketed as ‘Nixotine’ or ‘Nixamide’. Compared to nicotine, 6MN is pharmacologically more potent at nicotinic receptors, and more toxic, raising concerns about increased addictiveness and adverse effects.Here, combinations of gas chromatography, high performance liquid chromatography and mass spectrometry were used to determine nicotine analogs, flavor and sweetener contents of e-cigarette liquids of the brands “SpreeBar” and ECBlend “Nixotine” products. All SpreeBar products, labelled as containing 5% 6-methyl nicotine, contained only 0.61-0.64% 6-methylnicotine, while “Nixotine” samples contained 7-46% less of the declared nicotinamide contents. Although “Nixotine” product labels did not list 6MN as an ingredient, small amounts of 6-methyl nicotine were detected. All ‘SpreeBar’ samples contained the artificial sweetener neotame (0.20-0.86μg/mg).Results identified significant discrepancies between declared and measured constituents of e-cigarette products containing nicotine alternatives. The discrepancy is misleading for consumers and raises concerns about production errors. ‘SpreeBar’ products also contained neotame, a high-intensity sweetener with high heat stability, likely increasing appeal to young and first-time users. Novel e-cigarette products with misleading labels containing nicotine analogs instead of nicotine on the US market is concerning and should be urgently addressed by lawmakers and regulators.
Impact of Diagnostic Stewardship on Ordering Trends and Pathogen Yield from mNGS Studies
Authors: Shean Ryan C. , Garrett Elizabeth , Malleis James , Lieberman Joshua A. , Bradley Benjamin T. 
Published: April 2024

BackgroundGiven the cost and unclear clinical impact of metagenomic next-generation sequencing (mNGS), laboratory stewardship may improve utilization. This study examines mNGS results from two academic medical centers employing different stewardship approaches.Methods80 mNGS orders (54 CSF and 26 plasma) were identified from 2019 to 2021 at the University of Washington (UW), which requires director-level approval for mNGS orders, and the University of Utah (Utah), which does not restrict ordering. The impact of mNGS results and the relationship to traditional microbiology orders were retrospectively evaluated.Results19% (10/54) CSF and 65% (17/26) plasma studies detected at least one organism. Compared to CSF results, plasma results were more frequently clinically significant (23% vs 7%) and led to more novel diagnoses (15% vs 0%). Results affecting antibiotic management were more common for plasma than CSF (32% vs. 2%). Stewardship practices were not associated with statistically significant differences in results or antimicrobial management. The number and cost of traditional microbiology tests at UW was greater than Utah for CSF mNGS testing (UW: 46 tests, $6237; Utah: 26 tests, $2812; p<0.05) but similar for plasma mNGS (UW: 31 tests, $3975; Utah: 21 tests, $2715; p=0.14). mNGS testing accounted for 30-50% of the total microbiology costs.ConclusionsImproving the diagnostic performance of mNGS by stewardship remains challenging due to low positivity rates and difficulties assessing clinical impact. From a fiscal perspective, stewardship efforts should focus on reducing testing in low-yield populations given the high costs of mNGS relative to overall microbiology testing expenditures.