bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human subcutaneous adipose tissue variability is driven by VEGFA, ACTA2, adipocyte density, and ancestral history of the patient
Authors: DeBari Megan K , Johnston Elizabeth K , Scott Jacqueline V , Ilzuka Erica , Sun Wenhuan , Webster-Wood Victoria A , Abbott Rosalyn D 
Published: June 2023

AbstractAdipose tissue is a dynamic regulatory organ that has profound effects on the overall health of patients. Unfortunately, inconsistencies in human adipose tissues are extensive and multifactorial including large variability in cellular sizes, lipid content, inflammation, extracellular matrix components, mechanics, and cytokines secreted. Given the high human variability, and since much of what is known about adipose tissue is from animal models, we sought to establish correlations and patterns between biological, mechanical, and epidemiological properties of human adipose tissues. To do this, twenty-six independent variables were cataloged for twenty patients that included patient demographics and factors that drive health, obesity, and fibrosis. A factorial analysis for mixed data (FAMD) was used to analyze patterns in the dataset (with BMI > 25) and a correlation matrix was used to identify interactions between quantitative variables. Vascular endothelial growth factor A (VEGFA) and actin alpha 2, smooth muscle (ACTA2) gene expression were the highest loading in the first two dimensions of the FAMD. The number of adipocytes was also a key driver of patient-related differences, where a decrease in the density of adipocytes was associated with aging. Aging was also correlated with a decrease in overall lipid percentage of subcutaneous tissue (with lipid deposition being favored extracellularly), an increase in transforming growth factor-β1 (TGFβ1), and an increase in M1 macrophage polarization. An important finding was that self-identified race contributed to variance between patients in this study, where Black patients had significantly lower gene expression levels of TGFβ1 and ACTA2. This finding supports the urgent need to account for patient ancestry in biomedical research to develop better therapeutic strategies for all patients. Another important finding was that TGFβ induced factor homeobox 1 (TGIF1), an understudied signaling molecule, is highly correlated with leptin signaling and was correlated with metabolic inflammation. Finally, this study revealed an interesting gene expression pattern where M1 and M2 macrophage markers were correlated with each other, and leptin, in patients with a BMI > 25. This finding supports growing evidence that macrophage polarization in obesity involves a complex, interconnecting network system rather than a full switch in activation patterns from M2 to M1 with increasing body mass. Overall, this study reinforces key findings in animal studies and identifies important areas for future research, where human and animal studies are divergent. Understanding key drivers of human patient variability is required to unravel the complex metabolic health of unique patients.
Single-chain fluorescent integrators for mapping G-protein-coupled receptor agonists
Authors: Kroning Kayla , Gannot Noam , Li Xingyu , Zhou Guanwei , Sescil Jennifer , Putansu Aubrey , Shen Jiaqi , Wilson Avery , Fiel Hailey , Li Peng , Wang Wenjing 
Published: June 2023

AbstractGPCRs transduce the effects of many neuromodulators including dopamine, serotonin, epinephrine, acetylcholine, and opioids. The localization of synthetic or endogenous GPCR agonists impacts their action on specific neuronal pathways. In this paper, we show a series of single-protein chain integrator sensors to determine GPCR agonist localization in the whole brain. We previously engineered integrator sensors for the mu and kappa opioid receptor agonists called M- and K-SPOTIT, respectively. Here, we show a new integrator sensor design platform called SPOTall that we used to engineer sensors for the beta-2-adrenergic receptor (B2AR), the dopamine receptor D1, and the cholinergic receptor muscarinic 2 agonists. For multiplexed imaging of SPOTIT and SPOTall, we engineered a red version of the SPOTIT sensors. Finally, we used M-SPOTIT and B2AR-SPOTall to detect morphine, isoproterenol, and epinephrine in the mouse brain. The SPOTIT and SPOTall sensor design platform can be used to design a variety of GPCR integrator sensors for unbiased agonist detection of many synthetic and endogenous neuromodulators across the whole brain.
Temperature-dependent twist of double-stranded RNA probed by magnetic tweezers experiments and molecular dynamics simulations
Authors: Dohnalová Hana , Seifert Mona , Matoušková Eva , Papini Flávia S. , Lipfert Jan , Dulin David , Lankaš Filip 
Published: June 2023

AbstractRNA plays critical roles in the transmission and regulation of genetic information and is increasingly used in biomedical and biotechnological applications. Functional RNAs contain extended double-stranded regions and the structure of double-stranded RNA (dsRNA) has been revealed at high-resolution. However, the dependence of the properties of the RNA double helix on environmental effects, notably temperature, is still poorly understood. Here, we use single-molecule magnetic tweezers measurements to determine the dependence of the dsRNA twist on temperature. We find that dsRNA unwinds with increasing temperature, even more than DNA, with ΔTwRNA= −14.4 ± 0.7 º/(°C·kbp), compared to ΔTwDNA= −11.0 ± 1.2 º/(°C·kbp). All-atom molecular dynamics (MD) simulations using a range of nucleic acid force fields, ion parameters, and water models correctly predict that dsRNA unwinds with rising temperature, but significantly underestimate the magnitude of the effect. These MD data, together with additional MD simulations involving DNA and DNA-RNA hybrid duplexes, reveal a linear correlation between twist temperature decrease and the helical rise, in line with DNA but at variance with RNA experimental data. We speculate that this discrepancy might be caused by some unknown bias in the RNA force fields tested, or by as yet undiscovered transient alternative structures in the RNA duplex. Our results provide a baseline to model more complex RNA assemblies and to test and develop new parameterizations for RNA simulations. They may also inspire physical models of temperature-dependent dsRNA structure.
An abundant future for quagga mussels in deep European lakes
Authors: Kraemer Benjamin M. , Boudet Salomé , Burlakova Lyubov E. , Haltiner Linda , Ibelings Bas W. , Karatayev Alexander Y. , Karatayev Vadim , Rossbacher Silvan , Stöckli Raphael , Straile Dietmar , Piet Spaak 
Published: June 2023

AbstractQuagga mussels have expanded their range across the northern hemisphere in recent decades owing to their dispersal abilities, prolific reproduction rates, and broad ecological tolerances. Their remarkable capacity to filter particulates from the water column has had profound effects on inland aquatic ecosystems. In the North American Great Lakes, quagga mussel populations have increased inexorably since the late 1980’s, but it remains unclear whether quagga mussels will follow a similar trajectory in Europe where they have appeared more recently. Here we apply knowledge from a 33-year quagga population monitoring effort in the North American lakes to predict future quagga populations in deep European lakes, where quaggas are quickly becoming a conspicuous part of the underwater landscape. We predict that quagga mussel biomass in Lakes Biel, Constance, and Geneva may increase by a factor of 9 – 20 by 2045. Like in North America, this increase may be characterized by a shift to larger individuals and deeper depths as the population matures. If realized, this rapid expansion of quagga mussels would likely drive the largest aquatic ecosystem change in deep European lakes since the eutrophication period of the mid-20thcentury.
Single-cell sequencing of individual retinal organoids reveals determinants of cell fate heterogeneity
Authors: Tresenrider Amy , Sridhar Akshayalakshmi , Eldred Kiara C. , Cuschieri Sophia , Hoffer Dawn , Trapnell Cole , Reh Thomas A. 
Published: June 2023

SummaryWith a critical need for more completein vitromodels of human development and disease, organoids hold immense potential. Their complex cellular composition makes single-cell sequencing of great utility; however, the limitation of current technologies to a handful of treatment conditions restricts their use in screens or studies of organoid heterogeneity. Here, we apply sci-Plex, a single-cell combinatorial indexing (sci)-based RNA-seq multiplexing method to retinal organoids. We demonstrate that sci-Plex and 10x methods produce highly concordant cell class compositions and then expand sci-Plex to analyze the cell class composition of 410 organoids upon modulation of critical developmental pathways. Leveraging individual organoid data, we develop a method to measure organoid heterogeneity, and we identify that activation of Wnt signaling early in retinal organoid cultures increases retinal cell classes up to six weeks later. Our data show sci-Plex’s potential to dramatically scale-up the analysis of treatment conditions on relevant human models.
A new pipeline SPICE identifies novel JUN-IKZF1 composite elements
Authors: Li Peng , Pulugulla Sree H. , Das Sonali , Oh Jangsuk , Spolski Rosanne , Lin Jian-Xin , Leonard Warren J. 
Published: June 2023

AbstractTranscription factor partners can cooperatively bind to DNA composite elements to augment gene transcription. Here, we report a novel protein-DNA binding screening pipeline, termed Spacing Preference Identification of Composite Elements (SPICE), that can systematically predict protein binding partners and DNA motif spacing preferences. Using SPICE, we successfully identified known composite elements, such as AP1-IRF composite elements (AICEs) and STAT5 tetramers, and also uncovered several novel binding partners, including JUN-IKZF1 composite elements. One such novel interaction was identified at CNS9, an upstream conserved noncoding region in the humanIL10gene, which harbors a non-canonical IKZF1 binding site. We confirmed cooperative binding of JUN and IKZF1 and showed that the activity of anIL10-luciferase reporter construct in primary B and T cells depended on both this site and the AP1 binding site within this composite element. Overall, our findings reveal an unappreciated global association of IKZF1 and AP1 and establish SPICE as a valuable new pipeline for predicting novel transcription binding complexes.
Heat stress disrupts acid-base homeostasis independent of symbiosis in the model cnidarianExaiptasia diaphana
Authors: Allen-Waller Luella , Jones Katelyn G. , Martynek Marcelina P. , Brown Kristen T. , Barott Katie L. 
Published: June 2023

ABSTRACTHeat stress threatens the survival of symbiotic cnidarians by causing their photosymbiosis to break down in a process known as bleaching. The direct effects of temperature on cnidarian host physiology remain difficult to describe because heat stress depresses symbiont performance, leading to host stress and starvation. The symbiotic sea anemoneExaiptasia diaphanaprovides an opportune system in which to disentangle direct vs. indirect effects of heat stress on the host, since it can survive indefinitely without symbionts. Here, we tested the hypothesis that heat stress directly influences cnidarian physiology by comparing symbiotic and aposymbiotic individuals of a clonal strain ofE. diaphana. We exposed anemones to a range of temperatures (ambient, +2°C, +4°C, +6°C) for 15-18 days, then measured their symbiont population densities, autotrophic carbon assimilation and translocation, photosynthesis, respiration, and host intracellular pH (pHi). Anemones with initially high symbiont densities experienced dose-dependent symbiont loss with increasing temperature, resulting in a corresponding decline in host photosynthate accumulation. In contrast, anemones with low initial symbiont densities did not lose symbionts or assimilate less photosynthate as temperature increased, similar to the response of aposymbiotic anemones. Interestingly, pHidecreased in anemones at higher temperatures regardless of symbiont presence, cell density, or photosynthate translocation, indicating that heat stress disrupts cnidarian acid-base homeostasis independent of symbiosis dysfunction, and that acid-base regulation may be a critical point of vulnerability for hosts of this vital mutualism.Summary StatementWarming oceans threaten marine invertebrates. We found that heat disrupts acid-base homeostasis in a model symbiotic sea anemone regardless of symbiont presence or function, highlighting bleaching-independent effects of climate change.
Scalable projected Light Sheet Microscopy for high-resolution imaging of living and cleared samples
Authors: Chen Yannan , Chauhan Shradha , Gong Cheng , Dayton Hannah , Xu Cong , Cruz Estanislao Daniel De La , Datta Malika S. , Leong Kam W. , Dietrich Lars E.P. , Tomer Raju 
Published: June 2023

AbstractLight sheet fluorescence microscopy (LSFM) is a widely used imaging technique for living and large cleared samples. However, high-performance LSFM systems are often prohibitively expensive and not easily scalable for high-throughput applications. Here, we introduce a cost-effective, scalable, and versatile high-resolution imaging framework, called projected Light Sheet Microscopy (pLSM), which repurposes readily available off-the-shelf consumer-grade components and an over-the-network control architecture to achieve high-resolution imaging of living and cleared samples. We extensively characterize the pLSM framework and showcase its capabilities through high-resolution, multi-color imaging and quantitative analysis of mouse and post-mortem human brain samples cleared using various techniques. Moreover, we show the applicability of pLSM for high-throughput molecular phenotyping of human induced pluripotent cells (iPSC)-derived brain and vessel organoids. Additionally, we utilized pLSM for comprehensive live imaging of bacterial pellicle biofilms at the air-liquid interface, uncovering their intricate layered architecture and diverse cellular dynamics across different depths. Overall, the pLSM framework has the potential to further democratize LSFM by making high-resolution light sheet microscopy more accessible and scalable.
Systematic disease-agnostic identification of therapeutically actionable targets using the genetics of human plasma proteins
Authors: Karim Mohd Anisul , Ariano Bruno , Schwartzentruber Jeremy , Roldan-Romero Juan Maria , Mountjoy Edward , Hayhurst James , Buniello Annalisa , Mohammed Elmutaz Shaikho Elhaj , Carmona Miguel , Holmes Michael V , Robins Chloe , Surendran Praveen , Haddad Stephen , Scott Robert A , Leach Andrew R. , Ochoa David , Maranville Joseph , McDonagh Ellen M. , Dunham Ian , Ghoussaini Maya 
Published: June 2023

AbstractProteome-wide Mendelian randomization (MR) has emerged as a promising approach in uncovering novel therapeutic targets. However, genetic colocalization analysis has revealed that a third of MR associations lacked a shared causal signal between the protein and disease outcome, raising questions about the effectiveness of this approach. The impact of proteome-wide MR, stratified by cis-trans status, in the presence or absence of genetic colocalization, on therapeutic target identification remains largely unknown.In this study, we conducted genome-wide MR and cis/trans-genetic colocalization analyses using proteomic and complex trait genome-wide association studies. Using two different gold-standard datasets, we found that the enrichment of target-disease pairs supported by MR increased with more p-value stringent thresholds MR p-value, with the evidence of enrichment limited to colocalizing cis-MR associations.Using a phenome-wide proteogenetic colocalization approach, we identified 235 unique targets associated with 168 binary traits at high confidence (at colocalization posterior probability of shared signal > 0.8 and 5% FDR-corrected MR p-value). The majority of the target-trait pairs did not overlap with existing drug targets, highlighting opportunities to investigate novel therapeutic hypotheses. 42% of these non-overlapping target-trait pairs were supported by GWAS, interacting protein partners, animal models, and Mendelian disease evidence. These high confidence target-trait pairs assisted with causal gene identification and helped uncover translationally informative novel biology, especially from trans-colocalizing signals, such as the association of lower intestinal alkaline phosphatase with a higher risk of inflammatory bowel disease inFUT2non-secretors.Beyond target identification, we used MR of colocalizing signals to infer therapeutic directions and flag potential safety concerns. For example, we found that most genetically predicted therapeutic targets for inflammatory bowel disease could potentially worsen allergic disease phenotypes, except forTNFRSF6Bwhere we observed directionally consistent associations for both phenotypes.Our results are publicly available to download or browse in a web application enabling others to use proteogenomic evidence to appraise therapeutic targets.
The periaqueductal grey in chronic low back pain: dysregulated metabolites and function
Authors: Sirucek Laura , De Schoenmacker Iara , Gorrell Lindsay , Lütolf Robin , Langenfeld Anke , Baechler Mirjam , Wirth Brigitte , Hubli Michèle , Zölch Niklaus , Schweinhardt Petra 
Published: June 2023

AbstractMechanisms underlying chronic pain are insufficiently understood. Preclinical evidence suggests a potential contribution of excitatory glutamatergic and inhibitory GABAergic imbalances in pain-relevant brain areas, such as a lower excitatory/inhibitory tone in the brainstem periaqueductal grey (PAG). This cross-sectional magnetic resonance spectroscopy (MRS) study investigated whether a lower excitatory/inhibitory tone is also observed in the PAG of patients with non-specific chronic low back pain (CLBP) and whether this would relate to altered psychophysical measures of descending pain modulation and experimental pressure pain sensitivity. Specifically, the ratio between pooled glutamate and glutamine and GABA levels (Glx/GABA), Glx and GABA in the PAG were compared between CLBP patients and pain-free controls. Further, associations of Glx/GABA with conditioned pain modulation (CPM) effects and pressure pain thresholds (PPTs) were assessed.MRS was acquired on a 3T Philipps MR system using a point-resolved spectroscopy sequence optimized with very selective saturation pulses (OVERPRESS) and voxel-based flip angle calibration in a 1.1 mL volume of interest. Data from 41 CLBP patients (median [interquartile range]: 54 years [41 - 65], 22 females) and 29 age- and sex-matched controls (47 years [34 - 67], 17 females) fulfilled MRS quality criteria. CPM and PPTs were assessed at the lower back as most painful area and the non-dominant hand as pain-free control area. The CPM paradigm consisted of PPTs applied before, during (parallel CPM effect) and after a cold water bath and an ambient temperature water bath as control paradigm to identify ‘true’ CPM effects.In the PAG of CLBP patients, a lower Glx/GABA ratio, i.e. a lower excitatory/inhibitory tone, was observed (P= 0.002,partial η2= 0.14) driven by decreased Glx (P= 0.012,partial η2= 0.11) and increased GABA (P= 0.038,d= 0.46). CLBP patients showed disrupted associations between Glx/GABA and PPTs compared to controls in both areas (lower back:P= 0.004,partial η2= 0.12; hand:P= 0.002,partial η2= 0.16). In controls, lower Glx/GABA was associated with lower PPTs (lower back:r= 0.48,P= 0.009, hand:r= 0.53,P= 0.003), but this link was missing in CLBP patients (r’s> -0.23,P’s> 0.150). Additionally, CLBP patients with more severe clinical pain showed smaller CPM effects at the hand (rho= 0.54,P= 0.003).These findings suggest a dysfunction of the PAG in patients with CLBP and might indicate altered descending inhibition of deep tissue afferents.
Use of Point-of-care Haemoglobin Tests to Diagnose Childhood Anaemia in Low-and Middle-Income Countries: A Systematic Review
Authors: Brehm Rebecca , South Annabelle , George Elizabeth C 
Published: June 2023

ABSTRACTObjectivesAnaemia is a major cause of mortality and transfusion in children in Low- and Middle-Income Countries (LMICs), however current diagnostics are slow, costly, and frequently unavailable. Point-of-care haemoglobin tests (POC(Hb)Ts) could improve patient outcomes and use of resources by providing rapid and affordable results. We systematically reviewed the literature to investigate what, where and how POC(Hb)Ts are being used by health facilities in LMICs to diagnose childhood anaemia, and to explore challenges to their use.MethodsWe searched a total of nine databases and trial registries up to 10thJune 2022 using the concepts: anaemia, POC(Hb)T, LMIC and clinical setting. Adults ≥21 years and literature published >15 years ago were excluded. A single reviewer conducted screening, data extraction and quality assessment (of diagnostic studies) using QUADAS-2. Outcomes including POC(Hb)T used, location, setting, challenges and diagnostic accuracy were synthesised.ResultsOf 626 records screened, 41 studies were included. Evidence is available on the use of 15 POC(Hb)Ts in hospitals (n=28, 68%), health centres (n=9, 22%) and clinics/units (n=10, 24%) across 16 LMICs. HemoCue (HemoCue AB, Ängelholm, Sweden) was the most used test (n=31, 76%). Key challenges reported were overestimation of haemoglobin concentration, clinically unacceptable limits of agreement, errors/difficulty in sampling, environmental factors, cost, inter-observer variability, and supply of consumables. Five POC(Hb)Ts (33%) could not detect haemoglobin levels below 4g/dl. Diagnostic accuracy varied, with sensitivity and specificity to detect anaemia ranging from 24.2-92.2% and 70-96.7%, respectively.ConclusionsPOC(Hb)Ts have been successfully utilised in health facilities in LMICs to diagnose childhood anaemia. However, limited evidence is available, and challenges exist that must be addressed before wider implementation. Further research is required to confirm accuracy, clinical benefits, and cost-effectiveness.