bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new murineRpl5(uL18) mutation provides a unique model of variably penetrant Diamond Blackfan Anemia
Authors: Yu Lei , Lemay Philippe , Ludlow Alexander , Guyot Marie-Claude , Jones Morgan , Mohamed Fatma F. , Saroya Ghazi-Abdullah , Panaretos Christopher , Schneider Emily , Wang Yu , Myers Greggory , Khoriaty Rami , Li Qing , Franceschi Renny , Engel James Douglas , Kaartinen Vesa , Rothstein Thomas L. , Justice Monica J. , Kibar Zoha , Singh Sharon A. 
Published: February 2021

AbstractRibosome dysfunction is implicated in multiple abnormal developmental and disease states in humans. Heterozygous germline mutations in genes encoding ribosomal proteins (RPs) are found in the majority of individuals with Diamond Blackfan anemia (DBA) while somatic mutations have been implicated in a variety of cancers and other disorders. Ribosomal protein-deficient animal models show variable phenotypes and penetrance, similar to human DBA patients. The spontaneous anemia remission observed in some DBA patients occurs via unknown mechanism(s) and has not been previously described in animal models. Here we characterized a novel ENU mouse mutant (Skax23m1Jus) with growth and skeletal defects, cardiac malformations and increased mortality. Following genetic mapping and whole exome sequencing, we identified an intronicRpl5mutation, which segregated with all affected mice. This mutation was associated with decreased ribosome generation, consistent withRpl5haploinsufficiency.Rpl5Skax23-Jusmutant animals had a profound delay in erythroid maturation and increased mortality at embryonic day E12.5, which improved by E14.5. Surviving mutant animals had a macrocytic anemia at birth as well as evidence of ventricular septal defect (VSD). Surviving adult and aged mice exhibited no hematopoietic defect or VSD. We propose that this novelRpl5Skax23-Jusmutant mouse will be useful to study the factors influencing the variable penetrance and anemia remission that are observed in DBA.
Ade novoparadigm for male infertility
Authors: Oud MS , Smits RM , Smith HE , Mastrorosa FK , Holt GS , Houston BJ , de Vries PF , Alobaidi BKS , Batty LE , Ismail H , Greenwood J , Sheth H , Mikulasova A , Astuti GDN , Gilissen C , McEleny K , Turner H , Coxhead J , Cockell S , Braat DDM , Fleischer K , D’Hauwers KWM , Schaafsma E ,   GEMINI Consortium, Nagirnaja L , Conrad DF , Friedrich C , Kliesch S , Aston KI , Riera-Escamilla A , Krausz C , Gonzaga-Jauregui C , Santibanez-Koref M , Elliott DJ , Vissers LELM , Tüttelmann F , O’Bryan MK , Ramos L , Xavier MJ , van der Heijden GW , Veltman JA 
Published: February 2021

IntroductionDe novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness1. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00×10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01×10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing2. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.
Circulating miRNAs associated with bone mineral density in healthy adult baboons
Authors: Quillen Ellen. E. , Foster Jaydee , Sheldrake Anne , Stainback Maggie , Bredbenner Todd L. 
Published: February 2021

AbstractMicroRNAs (miRNAs) regulate gene expression post-transcriptionally and circulate in the blood, making them attractive biomarkers of disease state for tissues like bone that are challenging to interrogate directly. Here we report on five miRNAs – miR-197-3p, miR-320a, miR-320b, miR-331-5p, and miR-423-5p – that are associated with bone mineral density (BMD) in 147 healthy adult baboons. These baboons range in age from 15 to 25 years (45 to 75 human equivalent years) and were 65% female with a broad range of BMDs including a minority of osteopenic individuals. miRNAs were generated via RNA sequencing from buffy coats collected at necropsy and areal BMD evaluated via DXA of the lumbar vertebrae post-mortem. Differential expression analysis controlled for the underlying pedigree structure of these animals to account for genetic variation which may be driving miRNA abundance and BMD values. While many of these miRNAs have been associated with risk of human osteoporosis, this finding is of interest because the cohort represent a model of normal aging and bone metabolism rather than a disease cohort. The replication of miRNA associations with osteoporosis or other bone metabolic disorders in animals with healthy BMD suggests an overlap in normal variation and disease states. We suggest that these miRNAs are involved in the regulation of cellular proliferation, apoptosis, and protein composition in the extracellular matrix throughout life. However, age-related dysregulation of these systems may lead to disease causing associations of the miRNAs among individuals with clinically defined disease.
Flor yeasts rewire the central carbon metabolism during wine alcoholic fermentation
Authors: Peltier Emilien , Vion Charlotte , Saada Omar Abou , Friedrich Anne , Schacherer Joseph , Marullo Philippe 
Published: February 2021

AbstractThe identification of natural allelic variations controlling quantitative traits could contribute to decipher metabolic adaptation mechanisms within different populations of the same species. Such variations could result from man-mediated selection pressures and participate to the domestication. In this study, the genetic causes of the phenotypic variability of the central carbon metabolismSaccharomyces cerevisiaewere investigated in the context of the enological fermentation. Carbon dioxide and glycerol production as well as malic acid consumption modulate the fermentation yield revealing a high level of genetic complexity. Their genetic determinism was found out by a multi environment QTL mapping approach allowing the identification of 14 quantitative trait loci from which 8 of them were validated down to the gene level by genetic engineering. Most of the validated genes had allelic variations involving flor yeast specific alleles. Those alleles were brought in the offspring by one parental strain that is closely related to the flor yeast genetic group while the second parental strain is part of the wine group. The causative genes identified are functionally linked to quantitative proteomic variations that would explain divergent metabolic features of wine and flor yeasts involving the tricarboxylic acid cycle (TCA), the glyoxylate shunt and the homeostasis of proton and redox cofactors. Overall, this work led to the identification of genetic factors that are hallmarks of adaptive divergence between flor yeast and wine yeast in the wine biotope. These alleles can also be used in the context of yeast selection to improve oenological traits linked to fermentation yield.
G9a and Sirtuin6 epigenetically modulate host cholesterol accumulation to facilitate mycobacterial survival
Authors: Prakhar Praveen , Bhatt Bharat , Mukherjee Tanushree , Lohia Gaurav Kumar , Kolthur-Seetharam Ullas , Sundaresan Nagalingam Ravi , Rajmani R.S. , Balaji Kithiganahalli Narayanaswamy 
Published: February 2021

AbstractCholesterol derived from the host milieu forms a critical factor for mycobacterial pathogenesis. However, the molecular circuitry co-opted byMycobacterium tuberculosis(Mtb) to accumulate cholesterol in host cells remains obscure. Here, we report that a functional amalgamation of WNT-responsive histone modifiers G9a (H3K9 methyltransferase) and Sirt6 (H3K9 deacetylase) orchestrate cholesterol build-up inin-vitroandin-vivomodels of Mtb infection. Mechanistically, G9a, along with SREBP2, drives the expression of cholesterol biosynthesis and uptake genes; while Sirt6 represses the genes involved in cholesterol efflux. The accumulated cholesterol promotes the expression of antioxidant genes leading to reduced oxidative stress, thereby supporting Mtb survival. In corroboration, loss-of-function of G9ain vitroandin vivoby pharmacological inhibition; or utilization of BMDMs derived fromSirt6KO mice orin vivoinfection inSirt6heterozygous mice; hampers host cholesterol accumulation and restricts Mtb burden. These findings shed light on the novel roles of G9a and Sirt6 during Mtb infection and highlight the previously unknown contribution of host cholesterol in potentiating anti-oxidative responses for aiding Mtb survival.
Post-transcriptional dysregulation in autism, schizophrenia and bipolar disorder
Authors: Wang Yuanyuan , Liu Liya , Lin Mingyan 
Published: February 2021

AbstractPost-transcriptional gene regulation (PTGR) contributes to numerous aspects of RNA metabolism. While multiple regulators of PTGR have been associated with the occurrence and development of psychiatric disorders, a systematic investigation of the role of PTGR in the context of neuropsychiatric disorders is still lacking. In this work, we developed a new transcriptome -based algorithm to estimate PTGR and applied it to an RNA-Seq dataset of 2160 brain samples from individuals with autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BD) and controls. The results showed that the contribution of PTGR abnormality to gene differential expression between three common psychiatric disorders and controls was about 30% of that of transcriptional gene regulation (TGR) abnormality. Besides, aberrant PTGR tended to decrease RNA stability in SCZ/BD, while increase RNA stability in ASD, implicating contrasting pathologies among diseases. The abnormal alteration of PTGR in SCZ/BD converged on the inhibition of neurogenesis and neural differentiation, whereas dysregulation of PTGR in ASD induced enhanced activity of apoptosis. This suggested that heterogeneity in disease mechanism and clinical manifestation across different psychiatric disorders may be partially attributed to the diverse role of PTGR. Intriguingly, we identified a promising RBP (RNA bind protein) ELAVL3 (ELAV-Like Protein 3) that have a profound role in all three psychiatric disorders. Our systematic study expands the understanding of the link between PTGR and psychiatric disorders and also open a new avenue for deciphering the pathogenesis of psychiatric disorders.
Beyond Carbon Pricing: Tax Reform is Climate Policy
Authors: Green Jessica F. 
Published: February 2021

AbstractThe incrementalism of carbon pricing, which includes carbon taxes and emissions trading, has led us astray. It has been proffered as a key component of climate policy, yet evidence clearly shows that its effects are marginal. It provides limited emissions reductions and has provoked considerable political controversy in key large‐emitting countries. More importantly, pricing carbon means viewing climate change as a market failure, rather than as a problem of societal transformation. But rapid decarbonization will require more than market corrections; it demands strong state intervention to reorganize the economy. In this maximalist view, the state must create public goods, rather than merely prevent public bads. This article seeks to expand our collective political imagination about climate policy, moving beyond mundane fights about the appropriate design of carbon pricing. Instead, we need to think bigger. Aggressive climate policy begins with a reassertion of state sovereignty. Multinational corporations use ‘offshore’ tax havens to avoid paying taxes. By closing loopholes on corporate tax evasion, states reaffirm one of their fundamental functions: taxation. This reform would repatriate billions of dollars in missing capital, and help create the political conditions for meaningful action on decarbonization. Tax reform, not just carbon pricing, is climate policy too.
Estimating peptide half‐life in serum from tunable, sequence‐related physicochemical properties
Authors: Cavaco Marco , Valle Javier , Flores Isabel , Andreu David , A. R. B. Castanho Miguel 
Published: February 2021

AbstractProteolytic instability is a critical limitation for peptide‐based products. Although significant efforts are devoted to stabilize sequences against proteases/peptidases in plasma/serum, such approaches tend to be rather empirical, unspecific, time‐consuming, and frequently not cost‐effective. A more rational and potentially rewarding alternative is to identify the chemical grounds of susceptibility to enzymatic degradation of peptides so that proteolytic resistance can be tuned by manipulation of key chemical properties. In this regard, we conducted a meta‐analysis of literature published over the last decade reporting experimental data on the lifetimes of peptides exposed to proteolytic conditions. Our initial database contained 579 entries and was curated with regard to amino acid sequence, chemical modification, terminal half‐life (t1/2) or other stability readouts, type of stability assay, and biological application of the study. Although the majority of entries in the database corresponded to (slightly or substantially) modified peptides, we chose to focus on unmodified ones, as we aimed to decipher intrinsic characteristics of peptide proteolytic susceptibility. Specifically, we developed a multivariable regression model to unravel those peptide properties with most impact on proteolytic stability and thus potential t1/2 predicting ability. Model validation was done by two different approaches. First, a library of peptides spanning a large interval of properties that modulate stability was synthesized and their t1/2 in human serum were experimentally determined. Second, the t1/2 of 21 selected peptides approved for clinical use or in clinical trials were recorded and matched with the model‐estimated values. With both approaches, good correlation between experimental and predicted t1/2 data was observed.
Temporal changes in the relative abundance of anadromous Arctic charr, brown trout, and Atlantic salmon in northern Europe: Do they reflect changing climates?
Authors: Svenning Martin‐A. , Falkegård Morten , Dempson J. Brian , Power Michael , Bårdsen Bård‐Jørgen , Guðbergsson Gudni , Fauchald Per 
Published: February 2021

AbstractWarming temperatures resulting from climate change may alter the distribution and abundance of many freshwater fish species, especially those in northern latitudes. Owing to interspecific differences in temperature adaptations and tolerances, warming may lead to changes in the fish community as a result of shifts in the abundance of co‐existing species.We investigated how increased temperatures have potentially affected the abundance and catch composition of anadromous salmonids in northern Europe. We used national angling catch statistics over a period of several decades (1993–2018) as a proxy of relative annual abundance of adult Atlantic salmon (Salmo salar), brown trout (Salmo trutta), and Arctic charr (Salvelinus alpinus) in water courses in Iceland and in northern Norway. These are the only locations in the world where the three species coexist naturally as anadromous forms, and where they are distributed across latitudinal gradients characterised by varying temperatures.Interpolated data on average annual air temperatures proximate to the study rivers increased 1–1.7°C in northern Norway and 1.0–1.5°C in Iceland during the 26‐year study period.While the overall total number of fish caught has remained relatively stable during the period of study, gradual climate warming has been accompanied by a marked change in the catch composition of the three species in both countries. Increased temperatures were related to a decreased proportion of Arctic charr and an increased proportion of brown trout, while no temperature effect was found for Atlantic salmon. Controlling for the difference between fluvial and lacustrine systems, brown trout has begun to replace Arctic charr in all regions, whereas the relative catch of Atlantic salmon has been stable.Interpretation of angling data can facilitate understanding of longer‐term trends in catch data and provide insights into possible underlying changes in fish species and alert managers to shifts in abundance that might be mitigated by management actions. However, care must be taken to avoid the confounding effects that changes in fisheries management measures, angler preferences, and effort might have on the metrics of relative change used to make inferences about long‐term trends.
Integrated analysis of gait parameters and gene expression profiles in a murine model of subarachnoid hemorrhage
Authors: Zheng Zhi Yuan , Lu Gang , Xiong Zhi Qiang , Leung Chi Kwan , Su Xian Wei , Li Tu , Poon Wai Sang , Chan Wai Yee , Wong George Kwok Chu 
Published: February 2021

AbstractGait analysis has been widely used to examine the behavioral presentation of numerous neurological disorders. Thorough murine model evaluation of the subarachnoid hemorrhage (SAH)‐associated gait deficits is missing. This study measures gait deficits using a clinically relevant murine model of SAH to examine associations between gait variability and SAH‐associated gene expressions. A total of 159 dynamic and static gait parameters from the endovascular perforation murine model for simulating clinical human SAH were determined using the CatWalk system. Eighty gait parameters and the mRNA expression levels of 35 of the 88 SAH‐associated genes were differentially regulated in the diseased models. Totals of 42 and 38 gait parameters correlated with the 35 SAH‐associated genes positively and negatively with Pearson's correlation coefficients of >0.7 and <−0.7, respectively. p‐SP1453 expression in the motor cortex in SAH animal models displays a significant correlation with a subset of gait parameters associated with muscular strength and coordination of limb movements. Our data highlights a strong correlation between gait variability and SAH‐associated gene expression. p‐SP1453 expression could act as a biomarker to monitor SAH pathological development and a therapeutic target for SAH.
Prenylflavonoids isolated from Macaranga tanarius stimulate odontoblast differentiation of human dental pulp stem cells and tooth root formation via the mitogen‐activated protein kinase and protein kinase B pathways
Authors: Nam S. H. , Yamano A. , Kim J. A. , Lim J. , Baek S. H. , Kim J. E. , Kwon T.G. , Saito Y. , Teruya T. , Choi S. Y. , Kim Y. K. , Bae Y. C. , Shin H. I. , Woo J. T. , Park E. K. 
Published: February 2021

AbstractAimTo identify odontogenesis‐promoting compounds and examine the molecular mechanism underlying enhanced odontoblast differentiation and tooth formation.MethodologyFive different nymphaeols, nymphaeol B (NB), isonymphaeol B (INB), nymphaeol A (NA), 3’‐geranyl‐naringenin (GN) and nymphaeol C (NC) were isolated from the fruit of Macaranga tanarius. The cytotoxic effect of nymphaeols on human DPSCs was observed using a 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. The effect of nymphaeols on odontoblast differentiation was analysed with Alizarin Red S staining and odontoblast marker expression was assessed using real‐time polymerase chain reaction and Western blot analysis. The molecular mechanism was investigated with Western blot analysis. In order to examine the effect of INB on dentine formation in the developing tooth germ, INB‐soaked beads were placed under the tooth bud explants in the collagen gel; thereafter, the tooth bud explant‐bead complexes were implanted into the sub‐renal capsules for 3 weeks. Tooth root formation was analysed using micro‐computed tomography and histological analysis. Data are presented as mean ± standard error (SEM) values of three independent experiments, and results are compared using a two‐tailed Student's t‐test. The data were considered to have statistical significance when the P‐value was less than 0.05.ResultsThree of the compounds, NB, INB, and GN, did not exert a cytotoxic effect on human DPSCs. However, INB was most effective in promoting the deposition of calcium minerals in vitro (P < 0.001) and induced the expression of odontogenic marker genes (P < 0.05). Moreover, this compound strongly induced the phosphorylation of mitogen‐activated protein (MAP) kinases and protein kinase B (AKT) (P < 0.05). The inhibition of p38 MAP, c‐Jun N‐terminal kinase (JNK), and AKT substantially suppressed the INB‐induced odontoblast differentiation (P < 0.001). In addition, isonymphaeol B significantly induced the formation of dentine and elongation of the tooth root in vivo (P < 0.05).ConclusionsPrenylflavonoids, including INB, exerted stimulatory effects on odontoblast differentiation and tooth root and dentine formation via the MAP kinase and AKT signalling pathways. These results suggest that nymphaeols could stimulate the repair processes for dentine defects or injuries.
Effects of enzymatic treatment conditions on dietary fibre content of wheat bran and use of cellulase‐treated bran in cookie
Authors: Nguyen Si Nhat , Vien Man Dat , Le Thi Thu Trang , Tran Thi Thu Tra , Ton Nu Minh Nguyet , Le Van Viet Man 
Published: February 2021

SummaryA commercial cellulase preparation (Viscozyme Cassava C) was employed to process wheat bran to improve the ratio of insoluble to soluble dietary fibre. The effects of initial moisture content, enzyme dosage, and incubation time on the content of soluble and insoluble fibre during the enzymatic treatment were investigated. The appropriate conditions for the cellulase treatment were initial moisture content of 0.75 g water g−1 dry matter, enzyme dosage of 9 U g−1 dry matter and incubation time of 120 min under which the ratio of insoluble to soluble fibre of wheat bran was lowered by 42%. Untreated and cellulase‐treated wheat bran was incorporated into cookies at levels of 0%, 20%, 30%, 40% and 50%. Cookie with 50% cellulase‐treated bran showed 21% lower ratio of insoluble to soluble fibre as well as 14% lower hardness and 13% higher overall acceptability than sample with the same amount of untreated bran.