bluuebunny/crossref_metadata_2025_split huggingface dataset:
Weight loss improves skeletal muscle mitochondrial energy efficiency
Authors: Ferrara Patrick J. , Lang Marisa J. , Johnson Jordan M. , Watanabe Shinya , McLaughlin Kelsey L. , Maschek J. Alan , Verkerke Anthony R.P. , Siripoksup Piyarat , Chaix Amandine , Cox James E. , Fisher-Wellman Kelsey H. , Funai Katsuhiko 
Published: December 2022

AbstractWeight loss is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight-regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype male C57BL6/N mice were fed with high-fat diet for 10 wks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 wks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.
Strong postmating reproductive isolation inMimulussectionEunanus
Authors: Farnitano Matthew C. , Sweigart Andrea L. 
Published: December 2022

ABSTRACTPostmating reproductive isolation can help maintain species boundaries when premating barriers to reproduction are incomplete. The strength and identity of postmating reproductive barriers are highly variable among diverging species, leading to questions about their genetic basis and evolutionary drivers. These questions have been tackled in model systems but are less often addressed with broader phylogenetic resolution. In this study we analyze patterns of genetic divergence alongside direct measures of postmating reproductive barriers in an overlooked group of sympatric species within the model monkeyflower genus,Mimulus. Within thisMimulus brevipesspecies group, we find substantial divergence among species, including a cryptic genetic lineage. However, rampant gene discordance and ancient signals of introgression suggest a complex history of divergence. In addition, we find multiple strong postmating barriers, including postmating prezygotic isolation, hybrid seed inviability, and hybrid male sterility, leading to complete or substantial postmating isolation in all species pairs. Hybrid seed inviability appears linked to differences in seed size, providing a window into possible developmental mechanisms underlying this reproductive barrier. While geographic proximity and incomplete mating isolation may have allowed gene flow within this group in the distant past, strong postmating reproductive barriers today are likely to prevent any ongoing hybridization. By producing foundational information about reproductive isolation and genomic divergence in this understudied group, we add new diversity and phylogenetic resolution to our understanding of the mechanisms of plant speciation.
Seasonal and daily patterns in known dissolved metabolites in the northwestern Sargasso Sea
Authors: Longnecker Krista , Kido Soule Melissa C. , Swarr Gretchen J. , Parsons Rachel , Liu Shuting , Johnson Winifred M. , Widner Brittany , Curry Ruth , Carlson Craig A. , Kujawinski Elizabeth B. 
Published: December 2022

AbstractOrganic carbon in seawater plays a significant role in the global carbon cycle. The concentration and composition of dissolved organic carbon, operationally defined in this project as organic carbon that passes through a 0.2 µm filter, reflect the activity of the biological community and chemical reactions that occur in seawater. From 2016 to 2019, we repeatedly sampled the oligotrophic northwest Sargasso Sea in the vicinity of the Bermuda Atlantic Time-series Study site (BATS) to quantitatively follow known compounds within the pool of dissolved organic matter in the upper 1000 meters of the water column. Dissolved metabolite concentrations revealed patterns with depth and time with most metabolites showing surface enrichment and lower concentrations with increasing depth. Select metabolites displayed seasonal patterns throughout the year, and this seasonality was repeated in each of the years sampled. Concentrations of vitamins, including pantothenic acid (vitamin B5) and riboflavin (vitamin B2), increased annually during winter periods when mixed layer depths were deepest. During diel sampling, light-sensitive riboflavin decreased significantly during daylight hours. Metabolite concentrations over time at BATS showed less variability compared to a previous sample set collected over a broad latitudinal range in the western Atlantic Ocean. The metabolites examined in this study are all components of central carbon metabolism. By examining these metabolites at finer resolution and in a relatively long time series, we have insights into microbial biogeochemical activity, data which are fundamental to understanding the chemical response of marine systems to future changes in climate.
Dynamic readout of the Hh gradient in the Drosophila wing disc reveals pattern-specific tradeoffs between robustness and precision
Authors: Reyes Rosalío , Lander Arthur D. , Nahmad Marcos 
Published: December 2022

AbstractHow patterning by morphogen gradients determine tradeoffs between robustness and precision is unclear. Gradients that exhibit self-enhanced ligand degradation provide robustness to perturbations in morphogen production rates. However, increased robustness achieved through this mechanism is traded off for lower precision to noise. Here we use a hypotheses-driven theoretical approach to show that Hedge-hog (Hh) signaling would confer the same robustness to all target genes established by the steady-state gradient, but when a dynamical interpretation of patterning is used, robustness is maintained for steady-state outputs, but is traded off for higher precision in outputs set prior to steady-state. As predicted by our model, the widths ofdecapentaplegic (dpp), andcollier (col), two target genes established by the Hh gradient in theDrosophilawing disc, exhibit differential robustness to Hh dosage. Particularly, higher robustness in thecolpattern is ensured by Hh-dependent upregulation of its receptor Patched, an evolutionary-conserved property of Hh signaling that results in self-promoted Hh degradation. In contrast,dppexpression that is determined by the transient overshoot gradient, is insensitive to self-enhanced ligand degradation and exhibits less robustness, in exchange for a more precise boundary. Our work reveals of how morphogen gradients can establish tunable patterning properties in a target-specific manner.
VCP acts downstream of tTAFs to downregulate mono-ubiquitinated H2A and promote spermatocyte differentiation inDrosophila
Authors: Butsch Tyler J. , Dubuisson Olga , Johnson Alyssa E. , Bohnert K. Adam 
Published: December 2022

ABSTRACTValosin-containing protein (VCP) binds and extracts ubiquitinated cargo to regulate protein homeostasis. While VCP has been studied primarily in aging and disease contexts, it also affects germline development. However, the precise molecular functions of VCP in the germline, particularly in males, are poorly understood. Using theDrosophilamale germline as a model system, we find that VCP translocates from the cytosol to the nucleus as germ cells transition into the meiotic spermatocyte stage. Importantly, nuclear translocation of VCP appears to be one critical event stimulated by testis-specific TBP-associated factors (tTAFs) to drive spermatocyte differentiation. LiketTAFmutants, spermatocyte gene expression fails to properly activate inVCP-RNAi testes, and germ cells arrest in early meiosis. At a molecular level, VCP activity supports spermatocyte gene expression by downregulating a repressive histone modification, mono-ubiquitinated H2A (H2Aub), at this developmental transition. Remarkably, experimentally blocking H2Aub inVCP-RNAi testes is sufficient to overcome the meiotic-arrest phenotype and to promote development through meiosis. Collectively, our data highlight VCP as a novel downstream effector of tTAFs that downregulates H2Aub to facilitate meiotic progression.SUMMARY STATEMENTVCP promotes the downregulation of mono-ubiquitinated H2A (H2Aub), potentially by driving H2A turnover. VCP-dependent downregulation of H2Aub occurs downstream of testis-specific TBP-associated factors and supports spermatocyte gene expression and differentiation.
Tumor cell intrinsic RIG-I activation co-opts the host microenvironment to drive immune mediated tumor rejection
Authors: Fraile-Bethencourt Eugenia , Khou Sokchea , Baris Adrian , Ruhl Rebecca , Anand Sudarshan 
Published: December 2022

AbstractTargeting cytosolic nucleic acid sensors is a potent approach to drive type I interferon responses and anti-tumor immunity. Recent evidence suggests that activation of retinoic acid inducible gene-I (RIG-I) using synthetic hairpin RNA agonists decreases tumor progression in multiple preclinical models. However, the role of tumor cell intrinsic RIG-I in shaping tumor cell fates and the host immune microenvironment remains unclear. Here, we show that RIG-I expression is correlated with better overall survival and a distinct immune gene signature in specific human cancers including colorectal cancer. Activation of RIG-I in breast and colorectal cancer cells is sufficient to drive tumor cell death in vitro and significantly delay tumor growth in vivo in multiple preclinical models. Importantly, the efficacy of tumor cell RIG-I activation is lost in immune deficient mice suggesting the requirement of immune responses for this effect. We observe that tumor cell intrinsic RIG-I activation elicits a robust cellular and molecular immune response. We show that tumor cell RIG-I activation also leads to induction of specific immune checkpoints including PD-L1. Using a publicly available database, we found that RIG-I expression serves as an excellent prognostic marker for responders to checkpoint immunotherapy, particularly PD-L1/PD-1 across cancers. Finally, combination of tumor cell intrinsic RIG-I activation with anti-PD-L1 led to a synergistic decrease in tumor growth in a colorectal tumor model. Our findings suggest that tumor cell intrinsic RIG-I can be targeted to enhance anti-tumor immune responses and highlights a potential strategy for anti-cancer vaccines that can invigorate the immune system.
Who removes seeds in a heavily urbanized area?
Authors: Hueso-Olaya Dayana , Rocha-Ortega Maya , Coronel-Arellano Helí , Palacino-Rodríguez Fredy , Córdoba-Aguilar Alex 
Published: December 2022

AbstractIn urban landscapes, granivores play a key ecosystem service: they contribute to the establishment of plants and thereby increase the probability of vegetal community recovery. It is therefore a priority to determine how and by whom seeds are removed, which seeds are removed and where they are removed. Our objective here was to determine the removal patterns in three core zones of an urban reserve, three urban parks, and three peri-urban parks, all in and around Mexico City. We performed a selective exclusion experiment with treatments for each type of seed consumer (ants, birds, and rodents) and seeds of nine plant species. Ants were the most important granivores in terms of seed removal (especially small seeds), followed by rodents and birds. Seeds of the native plantsPassiflora subpeltata, Pittocaulon praecoxandOpuntia joconostlehad higher removal rates than other exotic and cosmopolitan species. The urban reserve had higher rates of seed predation compared to the urban and peri-urban parks. Thus, ants are pivotal in keeping seed removal and vegetation communities. We propose a series of measures to promote the ecosystem function of seed removal and increase plant diversity in these different urban patches.
Formation and growth of co-culture tumour spheroids: new compartment-based mathematical models and experiments
Authors: Murphy Ryan J. , Gunasingh Gency , Haass Nikolas K. , Simpson Matthew J. 
Published: December 2022

AbstractCo-culture tumour spheroid experiments are routinely performed to investigate cancer progression and test anti-cancer therapies. Therefore, methods to quantitatively characterise and interpret coculture spheroid growth are of great interest. However, co-culture spheroid growth is complex. Multiple biological processes occur on overlapping timescales and different cell types within the spheroid may have different characteristics, such as differing proliferation rates or responses to nutrient availability. At present there is no standard, widely-accepted mathematical model of such complex spatio-temporal growth processes. Typical approaches to analyse these experiments focus on the late-time temporal evolution of spheroid size and overlook early-time spheroid formation, spheroid structure and geometry. Here, using a range of ordinary differential equation-based mathematical models and parameter estimation, we interpret new co-culture experimental data. We provide new biological insights about spheroid formation, growth, and structure. As part of this analysis we connect Greenspan’s seminal mathematical model to co-culture data for the first time. Furthermore, we generalise a class of compartment-based spheroid mathematical models that have previously been restricted to one population so they can be applied to multiple populations. As special cases of the general model, we explore multiple natural two population extensions to Greenspan’s seminal model and reveal biological mechanisms that can describe the internal dynamics of growing co-culture spheroids and those that cannot. This mathematical and statistical modelling-based framework is well-suited to analyse spheroids grown with multiple different cell types and the new class of mathematical models provide opportunities for further mathematical and biological insights.
Progressive spreading of DNA methylation in the GSTP1 promoter CpG island across transitions from precursors to invasive prostate cancer
Authors: Gupta Harshath , Inoue Hitoshi , Nakai Yasutomo , Nakayama Masashi , Jones Tracy , Hicks Jessica , Kumar Balasubramanian , Gurel Meltem , Nelson William G. , De Marzo Angelo M. , Yegnasubramanian Srinivasan 
Published: December 2022

AbstractGlutathione S-transferase pi 1 (GSTP1) is lowly expressed in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy lesions (PIA). GSTP1 becomes silenced in prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma (CaP) via cytosine-phospho-guanine (CpG) island promoter hypermethylation. However,GSTP1methylation patterns in PIA and PIN, and their relationship to patterns in CaP are poorly understood. We used bisulfite genomic sequencing to examine patterns ofGSTP1promoter CpG island methylation in laser capture microdissected benign, PIA, PIN, and CaP regions from 32 subjects that underwent radical prostatectomy. We analyzed 908 sequence clones across 24 normal epithelium, 37 PIA, 18 PIN, and 23 CaP regions, allowing assessment of 34,863 CpG sites with allelic phasing. Normal and PIA lesions were mostly unmethylated with 0.52 and 1.3% of total CpG sites methylated, respectively. PIN and CaP lesions had greater methylation with 24% and 51% of total CpG sites methylated, respectively. The degree ofGSTP1methylation showed progression from PIA ≪ PIN < CaP. PIN lesions showed more partial methylation compared to CaP lesions. Partially methylated lesions were enriched for methylation changes at AP1 and SP1 transcription factor binding sites. These results demonstrate that methylation density in theGSTP1CpG island in PIN was intermediate relative to that in normal prostate epithelium/PIA and CaP lesions. These results are consistent with gradual spreading of DNA methylation centered at the SP1/AP1 transcription factor binding sites in precursor lesions, with subsequent spreading of methylation across the entire CpG island in transition to CaP.
Comparative analysis of chloroplast genome between wild and cultivatedRehmannia glutinosa Libosch
Authors: Yang Hao , Sasaki Yohei , Lian Conglong , Zhang Liping , Wang Lili , Yang Jingfan , Xue Shujuan , Chen Suiqing 
Published: December 2022

ABSTRACTRehmanniaeradix, as a tonic Chinese medicine, has a good therapeutic effect on cardiovascular and cerebrovascular diseases and central nervous system diseases, and has a good development prospect in the international market.R.glutinosaLibosch has a large number of source varieties, and the wild and cultivated varieties are different types ofR.glutinosaLibosch. There has been a lot of controversy in the formulation of scientific names for wild and cultivated types ofR.glutinosaLibosch. In order to learn more about the genetic information of wildR.glutinosaLibosch and explore the phylogenetic relationship between wildR.glutinosaLibosch and cultivatedR.glutinosaLibosch. In the current study, we constructed and annotated a complete circular chloroplast genome of wildR.glutinosaLibosch. The chloroplast genome of wildR.glutinosa Libosch. is 153,678 bp in length, including two inverted repeat (IR) regions of 25,759 bp, separated by a large single copy (LSC) region of 84,544 bp and a small single copy (SSC) region of 17,616 bp. The GC content of whole chloroplast genome is 37.9%. The genome contains 133 different genes, including 88 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Among them, 23 genes contained introns, 50 SSR loci and 49 long repeats were found by Microsatellite scan, and codon use showed obvious A, T base preference. Nine variation regions were screened by mVISTA analysis and combined with DnaSP analysis, and psaJ-rpl33 was finally identified as a region with high variation, which could be used as a candidate DNA barcode for later interspecific identification ofR.glutinosaLibosch.. Neighbor-joining method phylogenomic analysis showed that wildR.glutinosa Libosch. formed a monophyletic group, and was sister to other groups ofR.glutinosa Libosch.The results of this study revealed the chloroplast genome information of wildR.glutinosa Liboschin detail, and found the genetic information difference between wild and cultivatedR.glutinosa Libosch. which laid the foundation for the variety identification, genetic engineering, biosynthesis and other studies.
The structural basis of itch receptor MRGPRX1 activation
Authors: Gan Bing , Yu Leiye , Yang Haifeng , Jiao Haizhan , Pang Bin , Chen Yian , Wang Chen , Lv Rui , Hu Hongli , Cao Zhijian , Ren Ruobing 
Published: December 2022

AbstractMas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are four primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 angstrom via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over opioid receptor. According to the structure analysis, we revealed that MRGPRX1 shares common features of the Gq-mediated receptor activation mechanism of MRGPRX family members. However, the variable residues in orthosteric pocket of MRGPRX1 exhibits the unique agonist recognition pattern, which may facilitate to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.
Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease susceptibility and age-of-onset
Authors: Williams Alexander T , Chen Jing , Coley Kayesha , Batini Chiara , Izquierdo Abril , Packer Richard , Abner Erik , Shepherd David J , Free Robert C , Hollox Edward J , Brunskill Nigel J , Ntalla Ioanna , Reeve Nicola , Brightling Christopher E , Venn Laura , Adams Emma , Bee Catherine , Wallace Susan , Pareek Manish , Hansell Anna L , Esko Tõnu ,   Estonian Biobank Research Team, Hennah William , Rao Balasubramanya S , Dudbridge Frank , Wain Louise V , Shrine Nick , Tobin Martin D , John Catherine 
Published: December 2022

AbstractThyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Electronic health records were used to undertake the largest genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identified 158 novel signals, more than doubling the number of known associations with TSH, and implicating 112 putative causal genes, of which 78 were not previously implicated. For the first time, we demonstrate that a polygenic score for TSH was associated with TSH levels in all ancestries in UK Biobank, and strongly predicted age of onset of hypothyroidism and hyperthyroidism in European ancestry participants. We developed pathway-specific genetic risk scores for TSH levels and used these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.
To test or not to test? A new behavioral epidemiology framework for COVID-19
Authors: Sarkar Jayanta 
Published: December 2022

AbstractRecent clinical research finds that rapid transmission of SARS-CoV-2 is facilitated by substantial undocumented asymptomatic infections. Asymptomatic infections have implications for behavioral response to voluntary testing. The paper argues that a substantial proportion of SARS-CoV-2 infections are hidden due to rational test avoidance behavior, especially among those without perceptible disease symptoms. However, if perception of disease threat is prevalence dependent, testing compliance increases in response to reported infection prevalence rate in the population. This behavior, in turn, affects infection and mortality dynamics. This paper proposes an analytical framework that explicitly incorporates prevalence-dependent testing behavior in a standard epidemiological model, generating distinctive equilibrium epidemiological outcomes with significant policy implications. Numerical simulations show that failure to consider endogenous testing behavior among asymptomatic individuals leads to over- and underestimation of infection rates at the peaks and troughs, respectively, thereby distorting the disease containment policies. The results underscore the importance of augmenting testing capacity as an effective mitigation policy for COVID-19 and similar infectious diseases.JEL CodesI12, I18