bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-read nanopore sequencing reveals novel common genetic structural variants in Prader-Willi syndrome and associated psychosis
Authors: Deest Maximilian , Brändl Björn , Rohrandt Christian , Eberlein Christian , Bleich Stefan , Müller Franz-Josef , Frieling Helge 
Published: July 2022

AbstractPrader-Willi syndrome (PWS) is associated with severe hyperphagia, a specific behavioral phenotype and a high risk for developing psychotic episodes. Despite intense research, how genes within the PWS locus contribute to the phenotype remains elusive. In this study, we sequenced the whole genomes of 20 individuals with PWS using long-read nanopore sequencing by Oxford Nanopore Technologies (ONT). We demonstrate that ONT sequencing can resolve the PWS locus by determining the genetic subtype of PWS. Furthermore, we identified several novel structural variants (SV, >30bp) common in all PWS individuals. We are the first to show that the opioid system and the nociceptin/orphanin FQ system may be affected in PWS due to SVs in OPRM1 and OPRL1. Furthermore, we demonstrate that individuals with PWS, especially those with psychosis, exhibit a high burden of SVs in loci with known associations with bipolar disorder, schizophrenia and autism spectrum disorder. Our results challenge the current hypothesis that the PWS phenotype can be mainly explained by the loss of paternally expressed genes on chr15q11.2-13.
Development of a Diagnosis Grading System for Patients Undergoing Intrauterine Inseminations: A Machine-learning Perspective
Authors: Jin Changbo , Zong Jiaqi , Xue Shuya 
Published: July 2022

AbstractObjectiveTo develop an innovative, non-invasive and objective grading system for enhancing clinicians’ assessment of intrauterine insemination (IUI) patients.DesignPatients who had undergone IUI treatments previously were divided into pregnant (N=4618) and non-pregnant(N=20974) groups. An evaluation index method was developed using collected clinical data from the two groups, particularly on indications of considerable differences between the two groups. The weight of each indicator was determined using random forest machine learning, and the indicators and patients’ conditions were classified using an entropy-based feature discretization technique. The indices for each indicator were further divided into five grades, from A to E, and given five points to one point, respectively. Effectiveness of the system was tested using the ten-fold cross-validation method.SettingReproductive medicine center, Shanghai, ChinaPatientsInfertile couples who had undergone IUI treatment.InterventionNone.Main Outcome MeasuresWeight of each indicator and grades of infertile patients.ResultsFrom the 25,592 medical records of infertile couples who had IUI, 4618 women were pregnant subsequently, with a mean age of 28.69±3.34 years. From the collected records, 18 indicators (e.g., body mass indices [BMI], endometrial thicknesses, couples’ ages, IUI cycle days, and semen situations) were selected to construct our diagnosis scoring system. Among the 18 indicators, BMI (weight, 12.49%), endometrial thickness (11.99%), female age (11.88%), semen density (10.41%), semen volume (8.92%), cycle day (7.38%) and male age (6.96%) were closely related to the pregnancy rates. Among patients with the final scores for > 75.29 individually, the pregnancy rates for them was > 56.35%. The system’s stability was 95.1% (95%CI,94.5%-95.7%) according to cross-validation data.ConclusionThis quick and objective machine learning-based approach can be used to simplify and enhance the decision-making process among clinicians, especially to advise and to select patients for better IUI outcomes.
Identification of splicing defects caused by novel exonic mutations in LEF1 in Sudanese B- chronic lymphocytic leukemia patients: computational approach
Authors: Elmageed Eltayeb Elkhazin Ali Abd , Gameel Fatelrhman Mahdi , Idris Abeer Babiker , Dawoud Enas dk. , Hamid Mukhtar Hajir Sir Elkhatim , Mohieldein Abdelmarouf Hassan , Mutlu Mehmet Burak , Mohmmed Ali Ismail A. Elrhman , Gassoum Alsadig , Hassan Mohamed A. 
Published: July 2022

AbstractBackgroundLymphocyte enhancer factor-1 (LEF-1) is a member of the LEF-1/TCF family of transcription factors that are critically involved in canonical Wnt/β-catenin Signaling to regulate B Lymphocyte proliferation and survival. Alteration of LEF1 expression and function leads to leukemogenesis as well as other several neoplasms.Aimsto identify mutations in exons two and three of the LEF1 among B-CLL Sudanese patients. Also, to functionally analyze the detected SNPs using different in silico tools.Materials and methodsImmuno-phenotype for the detection of B cells CD5 and CD19 markers was performed on 128 B-CLL Sudanese patients by using a flow cytometry technique. DNA extraction, conventional PCR, and Sanger sequencing were applied to the LEF1 gene. Also, we performed a mutational analysis for identified SNPs using bioinformatics tools.ResultsA positive CD5 & CD19 expression was found in B-CLL patients. No mutation was observed in exon two. While four mutations were observed in exon three; two of them were not reported in previous studies. Interestingly, splicing analysis predicted that these mutations could lead to splicing defects in LEF1 pre-mRNA due to their potential effects on splicing regulatory elements (i.e. ESE).Conclusionthe two mutations Pro134Pro and Ile135Asn (novel mutation) were detected in all enrolled CLL patients and they could be used as diagnostic and/or prognostic markers for CLL. Therefore, further in vitro and in vivo functional studies with a large sample size are required to verify the splicing effect of the detected mutations in LEF1 pre-mRNA.
Pelvis perturbations in various directions while standing in staggered stance elicit concurrent responses in both the sagittal and frontal plane
Authors: van Mierlo Michelle , Ormiston Jean A. , Vlutters Mark , van Asseldonk Edwin H.F. , van der Kooij Herman 
Published: July 2022

AbstractWalking very slowly increases the time spent in the double support phase, which could be resembled by the staggered stance posture. Maintaining balance in this posture is important in order to continue walking safely. We therefore aimed to increase the understanding of balance recovery in staggered stance. We studied balance responses on joint- and muscle level to pelvis perturbations in various directions while standing in this posture. Ten healthy individuals participated in this study. We used one motor beside and one behind the participant to apply perturbations in mediolateral (ML), anteroposterior (AP) and diagonal directions, with a magnitude of 3, 6, 9 and 12% of the participant’s body weight. Meanwhile motion capture, ground reaction forces and moments, and electromyography of the muscles around the ankles and hips were recorded. The perturbations caused movements of the centre of mass (CoM) and centre of pressure (CoP) in the direction of the perturbation. Furthermore, these were often accompanied by motions in a direction different from the perturbation direction. After ML perturbations and diagonal perturbations transverse to the line between both feet, large and significant CoM and CoP deviations were present in the sagittal plane. Also, stronger responses on joint and muscle level were present after these perturbations, compared to AP and diagonal perturbations collinear with the line between both feet. The hip, knee and ankle joints significantly responded to all perturbation directions, but in different manners and modes of cooperation. To conclude, standing in a staggered stance posture makes individuals more vulnerable to perturbations in ML direction and transverse to the line between both feet, requiring larger responses on joint level as well as contributions in the sagittal plane.
Fine-mapping and comparative genomic analysis reveal the gene composition at theSandZself-incompatibility loci in grasses
Authors: Rohner Marius , Manzanares Chloé , Yates Steven , Thorogood Daniel , Copetti Dario , Lübberstedt Thomas , Asp Torben , Studer Bruno 
Published: July 2022

AbstractSelf-incompatibility (SI) is a genetic mechanism of hermaphroditic plants to prevent inbreeding after self-pollination. Allogamous Poaceae species exhibit a unique gametophytic SI system controlled by two multi-allelic and independent loci,SandZ.Despite intense research efforts in the last decades, the genes that determine the initial recognition mechanism are yet to be identified. Here, we report the fine-mapping of theZ-locus in perennial ryegrass (Lolium perenneL.) and provide evidence that the pollen and stigma components are determined by two genes encoding DUF247 domain proteins (ZDUF247-IandZDUF247-II) and the genesZ, respectively. The pollen and stigma determinants are located side-by-side and were genetically linked in 10,245 individuals of two independent mapping populations segregating forZ. Moreover, they exhibited high allelic diversity as well as tissue-specific gene expression, matching expected characteristics of SI determinants known from other systems. Revisiting theS-locus using the latest high-quality whole-genome assemblies revealed a similar gene composition and structure as found forZ, supporting the hypothesis of a duplicated origin of the two-locus SI system of grasses. Ultimately, comparative genomic analyses across a wide range of self-compatible and self-incompatible Poaceae species revealed that the absence of a functional copy of at least one of the six putative SI determinants is accompanied by a self-compatible phenotype. Our study provides new insights into the origin and evolution of the unique gametophytic SI system in one of the largest and economically most important plant families.
Supply-driven evolution explains the locking-in of structures that open new evolutionary possibilities, such as higher hierarchies of organization
Authors: Xue Julian Z. , Chindelevich Leonid , Guichard Frédéric 
Published: July 2022

AbstractMany well-documented macro-evolutionary phenomena, such as increases in organization hierarchy, or sudden and episodic creation of new taxa, still challenge current evolutionary theories. Here we show a new mechanism that can explain them. We begin by showing how the order of mutations can alter evolutionary trajectories. We present a framework integrating both mutation and environmental biases and show that mutation bias can strongly outweigh any environmental bias, a regime we call “supply-driven” evolution. We then show how a common type of mutation bias, where detrimental mutations are more common than beneficial mutations, can drive the locking-in of structural hierarchies such as eukaryotism or multicellularity, independently from the environment. Finally, we generalize this result to show how any mutation (or sets of mutations) that creates the possibility of new phenotypes can persist for a very long period of time. That is, innovations that make possible a large range of new phenotypes can become frozen in time. By becoming frozen, these novel structures can no longer change, which means a range of phenotypes also become impossible. This opening and closing of phenotypic space is a new mechanism of macro-evolution.
The C-terminal tail of CSNAP attenuates the CSN complex
Authors: Füzesi-Levi Maria G. , Ben-Nissan Gili , Listov Dina , Hayouka Zvi , Fleishman Sarel , Sharon Michal 
Published: July 2022

AbstractProtein degradation is one of the essential mechanisms that enables reshaping of the proteome landscape in response to various stimuli. The largest E3 ubiquitin ligase family that targets proteins to degradation by catalyzing ubiquitnation is the cullin-RING ligases (CRL). Many of the proteins that are regulated by CRLs are central to tumorigenesis and tumour progression, and dysregulation of the CRL family is frequently associated with cancer. The CRL family comprises ∼300 complexes all of which are regulated by the COP9 signalosome complex (CSN). Therefore, the CSN is considered an attractive target for therapeutic intervention. Research efforts for targeted CSN inhibition have been directed towards inhibition of the complex enzymatic subunit, CSN5. Here, we have taken a fresh approach focusing on CSNAP, the smallest CSN subunit. Our results show that the C-terminal region of CSNAP is tightly packed within the CSN complex, in a groove formed by CSN3 and CSN8. We show that a 16 amino acid C-terminal peptide, derived from this CSN interacting region, can displace the endogenous CSNAP subunit from the complex. This, in turn, leads to a CSNAP null phenotype that attenuates CSN activity and consequently CRLs function. Overall, our findings emphasize the potential of a CSNAP-based peptide for CSN inhibition as a new therapeutic avenue.
Porous microneedle patch with sustained exosome delivery repairs severe spinal cord injury
Authors: Fang Ao , Wang Yifan , Guan Naiyu , Lin Lingmin , Guo Binjie , Cai Wanxiong , Chen Xiangfeng , Ye Jingjia , Abdelrahman Zeinab , Li Xiaodan , Zuo Yanming , Zheng Hanyu , Wu Zhonghan , Jin Shuang , Xu Kan , Gu Xiaosong , Yu Bin , Wang Xuhua 
Published: July 2022

1.AbstractMesenchymal stem cell-derived exosome (MSC-EXO) transplantation has been suggested as an efficacious treatment to suppress spinal cord injury (SCI)-triggered neuroinflammation. However, an ethically acceptable method to continuously deliver MSC-EXOs to acute spinal lesions, without damaging nearby tissues/axons, has never been achieved. In this study, we fabricated a device comprising a patch containing MSCs and a microneedle array (MN-MSC patch) to treat severe SCI. When topically applied to an acute spinal lesion beneath the spinal dura, the soft microneedle (MN) array with reasonable mechanical strength avoided damaging the nearby spinal tissues, and the porous microstructure of MNs facilitated highly efficient MSC-EXO delivery. With the capacity for sustained delivery of MSC-EXOs, the MN-MSC patch was evaluated in a contusive rat SCI model. The MSCs encapsulated in the patch could survive for at least 7 days, encompassing the optimal time window for downregulating SCI-triggered neuroinflammation. As a result, MN-MSC patch treatment led to reduced cavity and scar tissue formation, greater angiogenesis, and improved survival of nearby tissues/axons. Remarkably, rats treated by this method achieved superior muscle control and exhibited robust hindlimb locomotion functional recovery. Conclusively, the MN-MSC patch device proposed here overcomes the current dilemma between treatment efficacy and ethical issues in treating acute SCI.
Development of immortalized rhesus macaque kidney cells supporting infection with a panel of viruses
Authors: Reiter Stefanie , Gärtner Sabine , Pöhlmann Stefan , Winkler Michael 
Published: July 2022

AbstractNon-human primate (NHP)-based model systems are important for biomedical research, due to the close phylogenetic relationship and physiologic similarities of NHP and humans. In infection research, NHP models are used to model various viral diseases including Ebola, influenza, AIDS and Zika. However, only a small number of NHP cell lines are available and generation of additional cell lines could help to refine these models.We immortalized rhesus macaque kidney cells by lentiviral transduction with a vector encoding telomerase reverse transcriptase (TERT). Expression of kidney markers on these cells was analyzed by flow cytometry and quantitative real-time PCR (qRT-PCR) was employed to determine functionality of the interferon (IFN) system. Finally, we assessed susceptibility and permissiveness for virus infection by the use of pseudotyped particles and replication-competent viruses.We report the generation of three TERT-immortalized cell lines derived from rhesus macaque kidney. The cell lines expressed the podocyte marker podoplanin and expressed MX1 upon stimulation with IFN or viral infection. Further, the cell lines were susceptible to entry driven by the glycoproteins of vesicular stomatitis virus, influenza A virus, Ebola virus, Nipah virus and Lassa virus. Finally, these cells supported growth of Zika virus (ZIKV) and the primate simplexviruses Cercopithecine alphaherpesvirus 2 (CeHV2) and Papiine alphaherpesvirus 2 (PaHV2).We developed IFN-responsive rhesus macaque kidney cell lines that allowed entry driven by diverse viral glycoproteins and were permissive to infection with Zika virus and primate simplexviruses. These cell lines will be useful for efforts to analyze viral infections of the kidney in macaque models.
Erythrocyte signalling is critical for Plasmodium falciparum invasion
Authors: Ming Yong James Jia , Gao Xiaohong , Prakash Prem , Lai Soak Kuan , Chen Ming Wei , Long Neo Jason Jun , Lescar Julien , Li Hoi Yeung , Preiser Peter R. 
Published: July 2022

AbstractSuccessful Plasmodium falciparum merozoite invasion requires the activation of red blood cell (RBC) signalling pathways. The binding of parasite ligand reticulocyte binding protein homologue 5 (RH5) to its host receptor Basigin is essential for merozoite invasion and triggers a Ca2+ influx in RBCs. Here we observed that RH5-bound RBCs form a multimeric protein complex containing Basigin, CD44 and β2-adrenergic receptor (β2AR), suggesting that RH5-Basigin interaction is functionally associated with the host cAMP signalling pathway. Interestingly, we detected a characteristic rise in cAMP levels in the RBC upon RH5-Basigin interaction, which can be blocked by G protein and cAMP-synthesising adenylyl cyclase (AC) inhibitors. Furthermore, we demonstrated that RBC L-type Ca2+ channel inhibitor and cAMP signalling inhibitors are able to block merozoite invasion. Checkerboard invasion inhibition assay containing different combinations of signalling inhibitors also exhibited a drastic amplification of inhibition levels, indicating that these signalling proteins are functioning in a common signalling cascade to activate the L-type Ca2+ channels. Taken together, this study provides new insights into the role of a host cAMP-Ca2+ signalling pathway during merozoite invasion and sheds new light on antimalarial therapeutic strategies to tackle the high infection rate and growing threat of drug resistant parasites.Key PointsA pre-existing Basigin-associated membrane protein complex undergoes increased protein assembly upon RH5 binding on the RBC surface.Plasmodium falciparum merozoite exploits host cAMP signalling to initiate Ca2+ influx in the RBC.
Genetic analysis of global faba bean germplasm maps agronomic traits and identifies strong selection signatures for geographical origin
Authors: Skovbjerg Cathrine Kiel , Angra Deepti , Robertson-Shersby-Harvie Tom , Kreplak Jonathan , Ecke Wolfgang , Windhorst Alex , Nielsen Linda Kærgaard , Schiemann Andrea , Knudsen Jens , Gutierrez Natalia , Tagkouli Vasiliki , Fechete Lavinia Ioana , Janss Luc , Stougaard Jens , Warsame Ahmed , Alves Sheila , Khazaei Hamid , Link Wolfgang , Torres Ana Maria , O’Sullivan Donal Martin , Andersen Stig Uggerhøj 
Published: July 2022

AbstractFaba bean (Vicia faba L.) is a high-protein grain legume crop with great potential for further cultivation. However, little is known about the genetics underlying trait diversity. In this study, we use 21,345 high-quality SNP markers to genetically characterise 2,678 faba bean genotypes. We perform genome-wide association studies of key agronomic traits using a Seven-parent-MAGIC population and detect 238 significant marker-trait associations linked to 12 traits of agronomic importance, with 65 of these being stable across multiple environments. Using a non-redundant diversity panel of 685 accessions from 52 countries, we identify 3 subpopulations differentiated by geographical origin and 33 genomic regions subject to strong diversifying selection between subpopulations. We find that SNP markers associated with the differentiation of northern and southern accessions were able to explain a significant proportion of agronomic trait variance in the Seven-parent-MAGIC population, suggesting that some of these traits have played an important role in breeding. Altogether, our findings point to genomic regions associated with important agronomic traits and selection in faba bean, which can be used for breeding purposes.Key MessageWe identified marker-trait associations for key faba bean agronomic traits and genomic signatures of selection within a global germplasm collection.
Deletion induced splicing in RIC3 drives nicotinic acetylcholine receptor regulation with implications for endoplasmic reticulum stress in human astrocytes
Authors: Yadav Navneesh , Thelma B. K. 
Published: July 2022

ABSTRACTNicotinic acetylcholine receptor (nAChR) dysregulation in astrocytes is reported in neurodegenerative disorders. Modulation of nAChRs through agonists confers protection to astrocytes from stress but regulation of chaperones is unclear. Resistance to inhibitors of cholinesterase 3 (RIC3) is a potential chaperone of nAChRs but poorly studied in humans. We characterized RIC3 in astrocytes derived from an isogenic wild-type and a Cas9 edited ‘del’ human iPSC line harboring a 25bp homozygous deletion in exon2. Altered RIC3 transcript ratio due to deletion induced splicing and an unexpected gain of α7nAChR expression were observed in ‘del’ astrocytes. Transcriptome analysis showed higher expression of neurotransmitter/G-protein coupled receptors mediated by cAMP and calcium/calmodulin-dependent kinase signaling. Functional implications of these observations were examined using tunicamycin induced ER stress. Wild-type astrocyte stress model showed cell cycle arrest, RIC3 upregulation, reduction in α7nAChR surface levels but increased α4nAChR surface expression. Conversely, tunicamycin treated ‘del’ astrocytes showed a comparatively higher α4nAChR surface expression and upsurged cAMP signaling. In addition, reduced expression of stress markers CHOP, phospho-PERK and lowered XBP1 splicing in western blot and qPCR, validated by proteome-based pathway analysis indicated lowered disease severity. These findings indicate i) a complex RNA regulatory mechanism via exonic deletion induced splicing; ii) RIC-3 as a disordered protein having contrasting effects on co-expressed nAChR subtypes under basal/stress conditions; and iii) RIC3 as a potential drug target against ER stress in astrocytes for nicotine related brain disorders. Furthermore, cellular rescue mechanism through deletion induced exon skipping possibly opens up ASO based therapies for tauopathies.
A unique H2B acetylation signature marks active enhancers and predicts their target genes
Authors: Narita Takeo , Higashijima Yoshiki , Kilic Sinan , Liebner Tim , Walter Jonas , Choudhary Chunaram 
Published: July 2022

AbstractChromatin features are widely used for genome-scale mapping of enhancers. However, discriminating active enhancers from other cis-regulatory elements, predicting enhancer strength, and identifying their target genes remains challenging. Here we establish histone H2B N-terminus multisite lysine acetylation (H2BNTac) as a genuine signature of active enhancers. H2BNTac prominently marks candidate active enhancers and their target promoters and discriminates them from ubiquitously active promoters. Two mechanisms afford the distinct H2BNTac specificity. (1) Unlike H3K27ac, H2BNTac is specifically catalyzed by CBP/p300. (2) H2A-H2B, but not H3-H4, are rapidly exchanged through transcription-induced nucleosome remodeling. H2BNTac-positive candidate enhancers show a high validation rate in orthogonal enhancer activity assays, and a vast majority of endogenously active enhancers are marked by H2BNTac and H3K27ac. Notably, H2BNTac intensity predicts enhancer strength and outperforms the current state-of-the-art models in predicting enhancer target genes. These findings have broad implications for generating fine-grained enhancer maps and modeling enhancer-dependent gene regulation.