bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacogenomics of Coronary Artery Response to Intravenous Gamma Globulin in Kawasaki Disease
Authors: Shrestha Sadeep , Wiener Howard W , Chowdhury Sabrina , Kajimoto Hidemi , Srinivasasainagendra Vinodh , Mamaeva Olga A , Brahmbhatt Ujval N , Ledee Dolena , Lau Yung , Padilla Luz A , Chen Jake , Dahdah Nagib , Tiwari Hemant K , Portman Michael A 
Published: February 2024

ABSTRACTBackgroundKawasaki disease (KD) is a multisystem inflammatory illness of infants and young children that can result in acute vasculitis. The pathological walls of afflicted coronary arteries show propensity for forming thrombosis and aneurysms. The mechanism of coronary artery aneurysms (CAA) despite intravenous gamma globulin (IVIG) treatment is not known.MethodsWe performed a Whole Genome Sequencing (WGS) association analysis in a racially diverse cohort of KD patients treated with IVIG, both using AHA guidelines. We defined coronary aneurysm (CAA) (N = 234) as coronary z>2.5 and large coronary aneurysm (CAA/L) (N = 92) as z>5.0. We conducted logistic regression models to examine the association of genetic variants with CAA/L during acute KD and with persistence >6 weeks using an additive model between cases and 238 controls with no CAA. We adjusted for age, gender and three principal components of genetic ancestry. We performed functional mapping and annotation (FUMA) analysis and further assessed the predictive risk score of genomic risk loci using the area under the receiver operating characteristic curve (AUC).ResultsThe top significant variants associated with CAA/L were in the intergenic regions (rs62154092 p<6.32E-08 most significant). Variants inSMAT4, LOC100127,PTPRD, TCAF2andKLRC2were the most significant non-intergenic SNPs. FUMA identified 12 genomic risk loci with eQTL or chromatin interactions mapped to 48 genes. Of theseNDUFA5has been implicated in KD CAA andMICUandZMAT4has potential functional implications. Genetic risk score using these 12 genomic risk loci yielded an AUC of 0.86.ConclusionsThis pharmacogenomics study provides insights into the pathogenesis of CAA/L in IVIG-treated KD patients. We have identified multiple novel SNPs associated with CAA/L and related genes with potential functional implications. The study shows that genomics can help define the cause of CAA/L to guide management and improve risk stratification of KD patients.
Thyroid hormone receptor beta (THRB) dependent regulation of diurnal hepatic lipid metabolism in adult male mice
Authors: de Assis Leonardo Vinicius Monteiro , Harder Lisbeth , Inderhees Julica , Jöhren Olaf , Mittag Jens , Oster Henrik 
Published: February 2024

ABSTRACTThyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRBKO) mice under normal chow conditions revealed a markedly modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri- and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosis-promoting conditionsin vitro. Integration of transcriptome profiles from THRBKOmice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THR(B) manipulation in fatty liver diseases.
Moth resonant mechanics are tuned to wingbeat frequency and energetic demands
Authors: Wold Ethan S. , Aiello Brett , Harris Manon , Sikandar Usama Bin , Lynch James , Gravish Nick , Sponberg Simon 
Published: February 2024

AbstractAn insect’s wingbeat frequency is a critical determinant of its flight performance and varies by multiple orders of magnitude across Insecta. Despite potential energetic and kine-matic benefits for an insect that matches its wingbeat frequency to its resonant frequency, recent work has shown that moths may operate off of their resonant peak. We hypothesized that across species, wingbeat frequency scales with resonance frequency to maintain favorable energetics, but with an offset in species that use frequency modulation as a means of flight control. The moth superfamily Bombycoidea is ideal for testing this hypothesis because their wingbeat frequencies vary across species by an order of magnitude, despite similar morphology and actuation. We used materials testing, high-speed videography, and a “spring-wing” model of resonant aerodynamics to determine how components of an insect’s flight apparatus (thoracic properties, wing inertia, muscle strain, and aerodynamics) vary with wingbeat frequency. We find that the resonant frequency of a moth correlates with wingbeat frequency, but resonance curve shape (described by the Weis-Fogh number) and peak location vary within the clade in a way that corresponds to frequency-dependent biomechanical demands. Our results demonstrate that a suite of adaptations in muscle, exoskeleton and wing drive variation in resonant mechanics, reflecting potential constraints on matching wingbeat and resonant frequencies.
Simulated Microgravity Enhances Adipocyte Maturation and Glucose Uptake via Increased Cortical Actin Remodeling
Authors: Anvari Golnaz , Struss Michael , Bellas Evangelia 
Published: February 2024

AbstractAdipose tissue (AT) regulates whole-body metabolism and is subject to various forces during movement, exercise, and during rest. Adipocytes are mechanically responsive cells, yet little is known about how the lack of mechanical loading may affect adipocytes and their function. To model the lack of mechanical loading, we exposed engineered AT constructs to simulated microgravity (sµg) conditions for 28 days. We found sµg enhanced lipid accumulation (lipogenesis) and lipid mobilization (lipolysis). Adipocyte maturation involves a phenotypic switch from actin stress fiber disruption and cortical actin formation. Sµg exposure increased cortical actin formation through mechanoresponsive signaling pathways involving Ras homolog family member A (RhoA) and Rho Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1) downstream targets, cofilin and actin-related protein 2/3 (ARP2/3). Adipocytes cultured in sµg have increased glucose transporter type 4 (GLUT4) translocation to the cell membrane and insulin-stimulated glucose uptake, independent of the canonical Akt pathway. GLUT4 translocation to the cell membrane and insulin-stimulated glucose uptake was limited when we inhibited new formation of branched cortical actin using an ARP2/3 inhibitor, CK-666. This study demonstrated that sµg enhances adipocyte maturation via increased lipogenesis and lipolysis and cortical actin remodeling which further enhanced glucose uptake. Therefore, targeting these mechanosensitive pathways pharmacologically or simulating microgravity on earth as a non-pharmacological modality are novel approaches to improving adipocyte function and AT metabolism and possibly for treating related comorbidities such as type 2 diabetes and obesity.
Microphysiological Modeling of Vascular Adipose Tissue for Multi-Throughput Applications
Authors: Struss Michael , Bellas Evangelia 
Published: February 2024

SummaryAdipose tissue (AT) is a highly vascularized endocrine organ which regulates whole-body metabolic homeostasis. Key AT functions which rely on vascularization include insulin-stimulated glucose uptake and lipolysis (lipid mobilization to supply energy). Most in vitro AT models do not include the vasculature, and while microphysiological systems (MPS) incorporate spatial organization of cells, 3D environments, and perfusion by external pumps, they are too large to fit traditional cultureware. Thus, we developed a novel miniaturized vascularized adipose tissue (µAT) platform compatible with traditional 24 well plates. Using this µAT platform, we quantified vascular permeability and adipocyte function by insulin-stimulated glucose uptake and lipolysis assays. Shear flow decreased vascular permeability and increased insulin-stimulated glucose uptake. Treatment with forskolin, an adenyl cyclase agonist, increased lipolysis, and decreased vascular permeability. This µAT platform allows for the facile screening of compounds in a physiologically relevant system where both adipocyte and vascular function can be evaluated.
Caspase prime-side active-site characterization with non-hydrolyzable peptides assists in the design of a caspase-7-selective irreversible probe
Authors: Solania Angelo , Xu Janice H. , Wolan Dennis W. 
Published: February 2024

AbstractLimited structural information and biochemical studies are available that demonstrate how the prime side of cysteine protease active sites, such as for human caspases, are used for substrate recognition and how these binding regions can be exploited in the design of inhibitors and probes. Reported small molecules that interact with, and are optimized for, the prime side of caspase active sites are limited to methylketone leaving groups and other nonpeptidic inhibitor moieties, such as aza-Michael acceptors. We present the design, synthesis, and co-complex x-ray structures of the first prime-side elongated non-hydrolyzable peptidomimetic ketomethylene inhibitors designed to interrogate the S4-S4’ active-site binding pockets of the executioner caspases-3 and -7. In addition to our structures depicting the first examples of an active-site cysteine in complex with a P1 residue trapped in a non-covalent tetrahedral intermediate, we elucidated prime-side binding interactions for pockets S1’ through S4’ with our biologically relevant peptide Ac-DEVD-Propionate-AAA. Despite the substantial homology among the caspase active sites, we identified a key difference in the prime-side architecture within binding distance to the P2’ inhibitor alanine whereby caspase-3 F128 is substituted for caspase-7 Y151. We exploited this prime-side difference in side chains and their reactivities in the design of non-hydrolyzable ketomethylene-based probes bearing a C-terminal tyrosine-reactive 4-phenyl-1,2,4-triazole-3,5-dione moiety. Our probe selectively labels caspase-7 over caspase-3 and we posit that further characterization of protease active-site prime sides with similar non-hydrolyzable molecules will yield additional tool-like compounds that will assist in establishing the non-redundant roles of caspase family members and other cysteine proteases.
Microbiota-Short Chain Fatty Acid Relationships Underlie Clinical Heterogeneity and Identify Key Microbial Targets in Irritable Bowel Syndrome (IBS)
Authors: Shin Andrea , Xing Yue , Waseem Mohammed Rayyan , Siwiec Robert , James-Stevenson Toyia , Rogers Nicholas , Bohm Matthew , Wo John , Lockett Carolyn , Gupta Anita , Kadariya Jhalka , Toh Evelyn , Anderson Rachel , Xu Huiping , Gao Xiang 
Published: February 2024

ABSTRACTBackgroundIdentifying microbial targets in irritable bowel syndrome (IBS) and other disorders of gut-brain interaction (DGBI) is challenging due to the dynamic nature of microbiota-metabolite-host interactions. SCFA are key microbial metabolites that modulate intestinal homeostasis and may influence IBS pathophysiology. We aimed to assess microbial features associated with short chain fatty acids (SCFA) and determine if features varied across IBS subtypes and endophenotypes. Among 96 participants who were screened, 71 completed the study. We conducted in-depth investigations of stool microbial metagenomes, stool SCFA, and measurable IBS traits (stool bile acids, colonic transit, stool form) in 41 patients with IBS (IBS with constipation [IBS-C] IBS with diarrhea [IBS-D]) and 17 healthy controls. We used partial canonical correspondence analyses (pCCA), conditioned on transit, to quantify microbe-SCFA associations across clinical groups. To explore relationships between microbially-derived SCFA and IBS traits, we compared gut microbiome-encoded potential for substrate utilization across groups and within a subset of participants selected by their stool characteristics as well as stool microbiomes of patients with and without clinical bile acid malabsorption.ResultsOverall stool microbiome composition and individual taxa abundances differed between clinical groups. Microbes-SCFA associations differed across groups and revealed key taxa includingDoreasp. CAG:317 andBifidobacterium pseudocatenulatumin IBS-D andAkkermansia muciniphilaandPrevotella copriin IBS-C that that may drive subtype-specific microbially-mediated mechanisms. Strongest microbe-SCFA associations were observed in IBS-D and several SCFA-producing species surprisingly demonstrated inverse correlations with SCFA. Fewer bacterial taxa were associated with acetate to butyrate ratios in IBS compared to health. In participants selected by stool form, we demonstrated differential abundances of microbial genes/pathways for SCFA metabolism and degradation of carbohydrates and mucin across groups. SCFA-producing taxa were reduced in IBS-D patients with BAM.ConclusionKeystone taxa responsible for SCFA production differ according to IBS subtype and traits and the IBS microbiome is characterized by reduced functional redundancy. Differences in microbial substrate preferences are also linked to bowel functions. Focusing on taxa that drive SCFA profiles and stool form may be a rational strategy for identifying relevant microbial targets in IBS and other DGBI.
Leveraging Machine Learning-Guided Molecular Simulations Coupled with Experimental Data to Decipher Membrane Binding Mechanisms of Aminosterols
Authors: Muscat Stefano , Errico Silvia , Danani Andrea , Chiti Fabrizio , Grasso Gianvito 
Published: February 2024

AbstractUnderstanding the molecular mechanisms of the interactions between specific compounds and cellular membranes is essential for numerous biotechnological applications, including targeted drug delivery, elucidation of drug mechanism of action, pathogen identification, and novel antibiotic development. However, the estimation of the free energy landscape associated with solute binding to realistic biological systems is still a challenging task. In this work, we leverage the Time-lagged Independent Component Analysis (TICA) in combination with neural networks (NN) through the Deep-TICA approach for determining the free energy associated with the membrane insertion processes of two natural aminosterol compounds, trodusquemine (TRO) and squalamine (SQ). These compounds are particularly noteworthy because they interact with the outer layer of neuron membranes protecting them from the toxic action of misfolded proteins involved in neurodegenerative disorders, both in their monomeric and oligomeric forms. We demonstrate how this strategy could be used to generate an effective collective variable for describing solute absorption in the membrane and for estimating free energy landscape of translocation via On-the-fly probability enhanced sampling (OPES) method. In this context, the computational protocol allowed an exhaustive characterization of the aminosterols entry pathway into a neuron-like lipid bilayer. Furthermore, it provided accurate prediction of membrane binding affinities, in close agreement with the experimental binding data obtained by using fluorescently-labelled aminosterols and large unilamellar vesicles (LUVs). The findings contribute significantly to our comprehension of aminosterol entry pathways and aminosterol-lipid membrane interactions. Finally, the deployed computational methods in this study further demonstrate considerable potential for investigating membrane binding processes.
A range expanding ecosystem engineer influences historical and expanded habitats via the same causal pathways
Authors: Roy Michael S. , Johnson David Samuel , Byrnes Jarrett E. K. 
Published: February 2024

ABSTRACTSpecies are shifting their ranges in response to climate change. There remain many unknowns about relative impacts of range-expanding ecosystem engineers between historical and expanded habitats, however. The mud fiddler crabMinuca pugnax(=Uca pugnax) is shifting its range northward likely due to increased warming in the Gulf of Maine. A burrowing crab,M. pugnaxaffects ecosystem functioning in salt marshes south of Cape Cod, Massachusetts with unknown effects in expanded marsh habitats over 150km to the north. We therefore studied theM. pugnaxrange expansion to determine the extent that range expanding ecosystem engineers are influencing ecosystem functioning expanded rangesrelative tohistorical habitats. We installed in 2017 and 2018 a series of crab-inclusion cages at both the UMass Boston Nantucket Field Station (historical range) and the Plum Island Estuary Long Term Ecological Research site (PIE-LTER, expanded range). For each site, year, and block, we measured in the beginning and end of the three-month experiment metrics of sediment strength, primary production, and decomposition. We developed and tested causal models using structural equation modeling (SEM) to determine direct and indirect effects of fiddler crabs on ecosystem functions. Despite site, year, and block variability, local environment influenced burrow density, which directly affected sediment strength and indirectly affected primary production in both ranges. Overall, understanding range-expanding ecosystem engineers in historical ranges was predictive for how they influence expanded habitats, despite inter-site heterogeneity. Therefore, it is critical to study relative impacts of range-expanding ecosystem engineers to understand total impacts of global range shifts.
Seedless: On-the-fly pulse calculation for NMR experiments
Authors: Buchanan Charles , Bhole Gaurav , Karunanithy Gogulan , Casablancas-Antràs Virginia , Poh Adeline , Davis Benjamin G. , Jones Jonathan A. , Baldwin Andrew J. 
Published: February 2024

AbstractAll NMR experiments require sequences of RF ‘pulses’ to manipulate nuclear spins. Signal is lost due to non-uniform excitation of nuclear spins resonating at different energies (chemical shifts) and inhomogeneity in the RF actually generated by hardware over the sample volume. Here, we present Seedless, a tool to calculate NMR pulses that compensate for these effects to enhance control of magnetisation and boost signal. The calculations take only a few seconds using an optimised GRadient Ascent Pulse Engineering (GRAPE) implementation, allowing pulses to be generated ‘on-the-fly’, optimised for individual samples and spectrometers. Each calculated pulse requires bands of chemical shift to be identified, over which one of 4 transforms will be performed, selected from a set that covers all commonly used applications: a universal rotation (e.g. 90° about the x axis), including as a special case an identity operation (return spins in the same state as they started), state-to-state (e.g. Z->Y), an XYcite (Z->XY plane), or a novel type, a suppression, that leaves spins minimally perturbed at all times during the pulse. Using imaging experiments we demonstrate our pulses effectively increase the size of the coil volume and effectively increase signal-to-noise in all experiments. We illustrate the approach by devising ultra-broadband pulses (300 ppm excitation pulse for19F 1D spectra), a15N HSQC with 58% increased S/N (950 MHz spectrometer + cryoprobe), triple resonance biomolecular NMR experiments such as HNCACO with 55% increased S/N (600 MHz spectrometer + RT probe), and a highly efficient pulse sequence for water suppression. The 8 optimised pulse sequences presented required 54 bespoke pulses all calculated on-the-fly. Seedless provides a means to enhance sensitivity in all pulse sequences in a manner that can be tailored to all samples/hardware being used.
Investigating low frequency somatic mutations inArabidopsiswith Duplex Sequencing
Authors: Waneka Gus , Pate Braden , Monroe J. Grey , Sloan Daniel B. 
Published: February 2024

ABSTRACTMutations are the source of novel genetic diversity but can also lead to disease and maladaptation. The conventional view is that mutations occur randomly with respect to their environment-specific fitness consequences. However, intragenomic mutation rates can vary dramatically due to transcription coupled repair and based on local epigenomic modifications, which are non-uniformly distributed across genomes. One sequence feature associated with decreased mutation is higher expression level, which can vary depending on environmental cues. To understand whether the association between expression level and mutation rate creates a systematic relationship with environment-specific fitness effects, we perturbed expression through a heat treatment inArabidopsis thaliana. We quantified gene expression to identify differentially expressed genes, which we then targeted for mutation detection using Duplex Sequencing. This approach provided a highly accurate measurement of the frequency of rare somatic mutations in vegetative plant tissues, which has been a recent source of uncertainty in plant mutation research. We included mutant lines lacking mismatch repair (MMR) and base excision repair (BER) capabilities to understand how repair mechanisms may drive biased mutation accumulation. We found wild type (WT) and BER mutant mutation frequencies to be very low (mean variant frequency 1.8×10-8and 2.6×10-8, respectively), while MMR mutant frequencies were significantly elevated (1.13×10-6). These results show that somatic variant frequencies are extremely low in WT plants, indicating that larger datasets will be needed to address the fundamental evolutionary question as to whether environmental change leads to gene-specific changes in mutation rate.SIGNIFICANCEAccurately measuring mutations in plants grown under different environments is important for understanding the determinants of mutation rate variation across a genome. Given the low rate ofde novomutation in plant germlines, such measurements can take years to obtain, hindering tests of mutation accumulation under varying environmental conditions. We implemented highly accurate Duplex Sequencing to study somatic mutations in plants grown in two different temperatures. In contrast to plants with deficiencies in DNA mismatch repair machinery, we found extremely low mutation frequencies in wild type plants. These findings help resolve recent uncertainties about the somatic mutation rate in plant tissues and indicate that larger datasets will be necessary to understand the interaction between mutation and environment in plant genomes.