bluuebunny/crossref_metadata_2025_split huggingface dataset:
Crystal structure of β-arrestin 2 in complex with an atypical chemokine receptor phosphopeptide reveals an alternative active conformation
Authors: Min Kyungjin , Yoon Hye-Jin , Park Ji Young , Baidya Mithu , Dwivedi Hemlata , Maharana Jagannath , Chung Ka Young , Shukla Arun K. , Lee Hyung Ho 
Published: September 2019

Abstractβ-arrestins (βarrs) critically regulate signaling and trafficking of G protein-coupled receptors (GPCRs), the largest family of drug targets in the human genome, and there are two isoforms of βarrs: βarr1 and βarr2. Most GPCRs interact with both the heterotrimeric G-proteins and βarrs, inducing distinct downstream signal transduction. However, certain chemokine receptors lack functional G-protein coupling, but they can efficiently recruit βarrs upon agonist-stimulation, and they are referred to as atypical chemokine receptors (ACKRs). Receptor phosphorylation is a key determinant for the binding of βarrs, and understanding the intricate details of receptor-βarr interaction is the next frontier in GPCR structural biology. To date, the high-resolution structures of active βarr1 have been revealed, but the activation mechanism of βarr2 by a phosphorylated GPCR remains elusive. Here, we present a 1.95 Å crystal structure of βarr2 in complex with a phosphopeptide (C7pp) derived from the carboxyl-terminus of ACKR3, also known as CXCR7. The structure of C7pp-bound βarr2 reveals key differences from the previously determined active conformation of βarr1. One of the key differences is that C7pp-bound βarr2 shows a relatively small inter-domain rotation. An antibody-fragment-based conformational sensor and hydrogen/deuterium exchange experiments further corroborate structural features and suggest that the determined structure is an alternative active conformation of βarr2.
Mathematical deconvolution of CAR T-cell proliferation and exhaustion from real-time killing assay data
Authors: Sahoo Prativa , Yang Xin , Abler Daniel , Maestrini Davide , Adhikarla Vikram , Frankhouser David , Cho Heyrim , Machuca Vanessa , Wang Dongrui , Barish Michael , Gutova Margarita , Branciamore Sergio , Brown Christine E. , Rockne Russell C. 
Published: September 2019

AbstractChimeric antigen receptor (CAR) T-cell therapy has shown promise in the treatment of hematological cancers and is currently being investigated for solid tumors including high-grade glioma brain tumors. There is a desperate need to quantitatively study the factors that contribute to the efficacy of CAR T-cell therapy in solid tumors. In this work we use a mathematical model of predator-prey dynamics to explore the kinetics of CAR T-cell killing in glioma: the Chimeric Antigen Receptor t-cell treatment Response in GliOma (CARRGO) model. The model includes rates of cancer cell proliferation, CAR T-cell killing, CAR T-cell proliferation and exhaustion, and CAR T-cell persistence. We use patient-derived and engineered cancer cell lines with an in vitro real-time cell analyzer to parameterize the CARRGO model. We observe that CAR T-cell dose correlates inversely with the killing rate and correlates directly with the net rate of proliferation and exhaustion. This suggests that at a lower dose of CAR T-cells, individual T-cells kill more cancer cells but become more exhausted as compared to higher doses. Furthermore, the exhaustion rate was observed to increase significantly with tumor growth rate and was dependent on level of antigen expression. The CARRGO model highlights nonlinear dynamics involved in CAR T-cell therapy and provides novel insights into the kinetics of CAR T-cell killing. The model suggests that CAR T-cell treatment may be tailored to individual tumor characteristics including tumor growth rate and antigen level to maximize therapeutic benefit.Statement of SignificanceWe utilize a mathematical model to deconvolute the nonlinear contributions of CAR T-cell proliferation and exhaustion to predict therapeutic efficacy and dependence on CAR T-cell dose and target antigen levels.
The First Publicly Available Annotated Genome for Cannabis plants
Authors: Jenkins Conor , Orsburn Ben 
Published: September 2019

AbstractRecently we have seen a relaxation of the historic restrictions on the use and subsequent research on the Cannabis plants in North America. We have recently described a pipeline for the creation of annotated protein databases using a combination of genomic and proteomic data and the application of this method toward the analysis of the proteomes of Cannabis plants. In parallel with our work, we approached the National Center for Biotechnology Information (NCBI) to align and annotate publicly deposited genomic files for these plants. In September of 2019, this project was completed. The result, NCBI Cannabis sativa Annotation Release 100 is now live and publicly available. The annotated genome allows, for the first time, the use of classical genetics and proteomics tools for the interrogation of these plants. Furthermore, the presence of an annotated genome within the NCBI Genome browser now permits any researcher with a web browser to manually examine or BLAST genetic sequences, vastly reducing the resources required to create primers to amplify genes from the plants or microbial contaminants that may affect them. We describe this new resource and some points of obvious value to the scientific community as well as the integration into the Cannabis Proteome Draft Map Project.Significance StatementUntil recently laws in North America have restricted nearly all research on Cannabis plants. Until recent research from our lab, only a few hundred genes and proteins from the plant had been annotated for putative function. The construction of a publicly available annotated genome for this plant allows, for the first time, the use of traditional genomic and proteomic tools for the investigation of these plants. We evaluate herein the first fully annotated publicly available genome for Cannabis plants and the integration of this resource into www.CannabisDraftmap.org
A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery
Authors: Tang Shaogeng , Kim Peter S. 
Published: September 2019

AbstractImmune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC′ and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1’s affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 Å and 1.2 Å resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC′ and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC′ loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors.Significance StatementImmune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has transformed the treatment of cancer. Small-molecule PD-1 drugs have the potential to offer increased efficacy, safety, and global access. Despite substantial efforts such small-molecule drugs have been out of reach. We identify a prominent pocket on the ligand-binding surface of human PD-1 that appears to be an attractive small-molecule drug target. The pocket forms when PD-1 is bound to one of its ligands, PD-L2. Our high-resolution crystal structure of the human PD-1/PD-L2 complex facilitates virtual drug-screening efforts and opens additional avenues for the design and discovery of small-molecule PD-1 inhibitors. Our work provides a strategy that may enable discovery of small-molecule inhibitors of other “undruggable” protein-protein interactions.
Group-Level Analysis of Induced Electric Field in Deep Brain Regions by Different TMS Coils
Authors: Gomez-Tames Jose , Hamasaka Atsushi , Hirata Akimasa , Laakso Ilkka , Lu Mai , Ueno Shoogo 
Published: September 2019

AbstractDeep transcranial magnetic stimulation (dTMS) is a non-invasive technique used in treating depression. In this study, we computationally evaluate group-level dosage during dTMS with the aim of characterizing targeted deep brain regions to overcome the limitation of using individualized head models to characterize coil performance in a population.We use an inter-subject registration method adapted to deep brain regions that enable projection of computed electric fields (EFs) from individual realistic head models (n= 18) to the average space of deep brain regions. The computational results showed consistent group-level hotspots of the EF in deep brain region with intensities between 20%-50% of the maximum EF in the cortex. Large co-activation in other brain regions was confirmed while half-value penetration depth from the cortical surface was smaller than 2 cm. The halo figure-8 assembly and halo circular assembly coils induced the highest EFs for caudate, putamen, and hippocampus.Generalized induced EF maps of deep regions show target regions despite inter-individual difference. This is the first study that visualizes generalized target regions during dTMS and provides a method for making informed decisions during dTMS interventions in clinical practice.
Structural studies of the Tudor domain from the Bombyx homolog of Drosophila PAPI: Implication to piRNA biogenesis
Authors: Hubbard Paul A. , Pan Xinlei , McNally Randall , Kirino Yohei , Murali Ramachandran 
Published: September 2019

ABSTRACTPIWI proteins and their associated PIWI-interacting RNAs (piRNAs) play crucial roles in proper gametogenesis in animal gonads. Partner of PIWIs (PAPI) is one of the important piRNA biogenesis factors. PAPI contains a Tudor domain and tandem KH domains. The tudor domain specifically recognizes symmetrical-dimethylarginines (sDMAs) on PIWI proteins. BmPAPI, a Bombyx mori homolog of PAPI, is localized at the outer membrane of mitochondria and supports exonucleolytic trimming of piRNA precursors to form mature 3’-end of piRNAs. To understand the structural basis of piRNA processing by BmPAPI, we present crystal structures of the apo- and sDMA-liganded Tudor domain of BmPAPI.
Enriching human interactome with functional mutations to detect high-impact network modules underlying complex diseases
Authors: Cui Hongzhu , Srinivasan Suhas , Korkin Dmitry 
Published: September 2019

AbstractProgress in high-throughput -omics technologies moves us one step closer to the datacalypse in life sciences. In spite of the already generated volumes of data, our knowledge of the molecular mechanisms underlying complex genetic diseases remains limited. Increasing evidence shows that biological networks are essential, albeit not sufficient, for the better understanding of these mechanisms. The identification of disease-specific functional modules in the human interactome can provide a more focused insight into the mechanistic nature of the disease. However, carving a disease network module from the whole interactome is a difficult task. In this paper, we propose a computational framework, DIMSUM, which enables the integration of genome-wide association studies (GWAS), functional effects of mutations, and protein-protein interaction (PPI) network to improve disease module detection. Specifically, our approach incorporates and propagates the functional impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on PPIs to implicate the genes that are most likely influenced by the disruptive mutations, and to identify the module with the greatest impact. Comparison against state-of-the-art seed-based module detection methods shows that our approach could yield modules that are biologically more relevant and have stronger association with the studied disease. We expect for our method to become a part of the common toolbox for disease module analysis, facilitating discovery of new disease markers.
Genome sequence and characterisation of coliphage vB_Eco_SLUR29
Authors: Besler Ibrahim , Sazinas Pavelas , Harrison Christian , Gannon Lucy , Redgwell Tamsin , Michniewski Slawomir , Hooton Steven P. , Hobman Jon L. , Millard Andrew 
Published: September 2019

AbstractBacteriophage that infect Escherichia coli are relatively easily isolated, with greater than 600 coliphage genomes sequenced to date. Despite this there is still much to be discovered about the diversity of coliphage genomes. Within this study we isolated a coliphage from cattle slurry collected from a farm in rural England. Transmission electron microscopy identified the phage as member of the Siphoviridae family. Phylogenetic analysis and comparative genomics further placed it within the subfamily Tunavirinae and forms part of a new genus. Characterisation of the lytic properties reveals that it is rapidly able to lyse its host when infected at high multiplicity of infection, but not at low multiplicity of infection.
CO2 per se activates carbon dioxide receptors
Authors: Xu Pingxi , Wen Xiaolan , Leal Walter S. 
Published: September 2019

SUMMARYCarbon dioxide has been used in traps for more than six decades to monitor mosquito populations and help make informed vector management decisions. CO2 is sensed by gustatory receptors (GRs) housed in neurons in the maxillary palps. CO2-sensitive GRs have been identified from the vinegar fly and mosquitoes, but it remains to be resolved whether these receptors respond to CO2 or bicarbonate. As opposed to the vinegar fly, mosquitoes have three GR subunits, but it is assumed that subunits GR1 and GR3 form functional receptors. In our attempt to identify the chemical species that bind these receptors, we discovered that GR2 and GR3 are essential for receptor function and that GR1 appears to function as a modulator. While Xenopus oocytes coexpressing Culex quinquefasciatus subunits CquiGR1/3 and CquiGR1/2 were not activated, CquiGR2/3 gave robust responses to sodium bicarbonate. Interestingly, CquiGR1/2/3- coexpressing oocytes gave significantly lower responses. That the tertiary combination is markedly less sensitive than the GR2/GR3 combination was also observed with orthologs from the yellow fever and the malaria mosquito. By comparing responses of CquiGR2/CquiGR3- coexpressing oocytes to sodium bicarbonate samples (with or without acidification) and measuring the concentration of aqueous CO2, we showed that there is a direct correlation between dissolved CO2 and receptor response. We then concluded that subunits GR2 and GR3 are essential for these carbon dioxide-sensitive receptors and that they are activated by CO2 per se, not bicarbonate.
Maximizing Dissimilarity in Resting State detects Heterogeneous Subtypes in Healthy population associated with High Substance-Use and Problems in Antisocial Personality
Authors: Kashyap Rajan , Bhattacharjee Sagarika , Thomas Yeo B.T. , Annabel Chen SH 
Published: September 2019

AbstractPatterns in resting-state fMRI (rs-fMRI) are widely used to characterize the trait effects of brain function. In this aspect, multiple rs-fMRI scans from single subjects can provide interesting clues about the rs-fMRI patterns, though scan-to-scan variability pose challenges. Therefore, rs-fMRI’s are either concatenated or the functional connectivity is averaged. This leads to loss of information. Here, we use an alternative way to extract the rs-fMRI features that are common across all the scans by applying Common-and-Orthogonal-Basis-Extraction (COBE) technique. To address this, we employed rs-fMRI of 788 subjects from the human connectome project and estimated the common-COBE-component of each subject from the four rs-fMRI runs. Since the common-COBE-component are specific to a subject, the pattern was used to classify the subjects based on the similarity/dissimilarity of the features. The subset of subjects (n=107) with maximal-COBE-Dissimilarity (MCD) was extracted and the remaining subjects (n = 681) formed the COBE-similarity (CS) group. The distribution of weights of the common-COBE-component for the two groups across rs-fMRI networks and subcortical regions was evaluated. We found the weights in the default mode network to be lower in the MCD compared to the CS. We compared the scores of 69 behavioral measures and found 6 behaviors related to the use of marijuana, illicit drugs, alcohol, and tobacco; and including a measure of antisocial personality to differentiate the two groups. Gender differences were also significant. Altogether findings suggested that subtypes exist even in healthy control population and comparison studies (Case vs Control) need to be mindful of it.
Mentoring as meaningful professional development
Authors: Walters William , Robinson Daniel Bruce , Walters Jared 
Published: September 2019

PurposeWithin teacher education, many experienced in-service teachers routinely mentor pre-service teachers during teaching practicums. Notwithstanding the benefits pre-service teachers are meant to experience from these mentor–protégé relationships and experiences, recent research has demonstrated that mentors, too, may experience some (oftentimes unintended) potential benefits. The purpose of this paper is to further investigate such potential benefits within a Canadian secondary school physical education (PE) context.Design/methodology/approachThe researchers employed a qualitative case study methodology. The three primary data sources included field observations/notes, journals and interviews. More specifically, over a ten-week period, the researchers made 26 field visits, observing two mentors’ interactions with five protégés before, during, and after PE class instruction; collected the two mentors’ ten journal entries, all made in response to researcher-provided writing prompts; and interviewed the two mentors, both individually and together.FindingsThe mentor teachers viewed the mentor–protégé relationship/experience as meaningful professional development, recognizing that it approximated a professional learning community. Relatedly, the mentor teachers experienced professional growth with respect to their own teaching identity and teaching practice.Research limitations/implicationsThis research could inform those who structure and/or coordinate mentoring research within teacher education programs so that they might place a more purposeful focus upon the potential and/or idealized outcomes for mentors (as well as for protégés). Given the single case study methodology, this research may lack generalizability to other educational contexts.Originality/valueThis research adds to the emerging body of research that investigates how mentoring may provide benefits to mentors. More specifically, this research suggests benefits to mentors relate, especially, to their own teaching identity and practice.
Industrial revolution 4.0: implication to libraries and librarians
Authors: Hussain Abid 
Published: September 2019

Purpose
Industry 4.0 is a term for the so-called Fourth Industrial revolutions. It is the technological integration of cyber-physical systems (CPS) in the process of production. CPS enables internet-based process networking with all participants in the process of value creation. The industrial revolution is actually changing how we live, work and communicate. Many trades have highly been affected by 4IR, libraries are one of them. The libraries of twenty-first century are shifting their paradigms from traditional setup to modern information networking. As people and machines are connecting to each other at enormous speed, artificial intelligence, mobile computing, machine learning and automation of every trade have become a need of the day. Automation and artificial intelligence are change agents in 4IR that will make certain groups of employees redundant, replacing them with new workers with the needed skills or with machines that do the job cheaper. This paper aims to shed light on how the 4IR will “shape the future of education, gender, work and library services”. The purpose of this paper is to highlight the challenges being faced by the library and librarians in the age of Industrial 4.0 revolution in contemporary society. The purpose of this study is to review the past literature on Industrial Revolutions 4.0 in education and interlink them with Library services.

Design/methodology/approach
The current study performs a systematic and content-centric review of literature relevant to library services. The literature of this study is based on a six-stage approach to identify the design principles and technology trends of 4IR in education and Library services.

Findings
Industry 4.0 Revolution is the current trend of revolutionary technology, which has affected many services in this age of globalization. Similar, Library services have highly been affected by 4IR. An effort has been made to highlight the vari-ous challenges being faced by libraries and librarians in this age of information. Some solutions have been presented to the library professionals to overcome this technology to boost its services up to the entire satisfaction of the patrons.

Research limitations/implications
The strategic approach in this study can serve the academicians and practitioners in the field of librarianship as a stepping stone to develop a successful transition from traditional manufacturing into the industry 4.0.

Originality/value
The study is among the first to identify the challenges being faced by libraries and librarians in this age of Industrial revolutions.
Compound and heterozygous mutations of KCNQ1 in long QT syndrome with familial history of unexplained sudden death: Identified by analysis of whole exome sequencing and predisposing genes
Authors: Lin Yubi , Zhao Ting , He Siqi , Huang Jiana , Liu Qianru , Yang Zhe , Qin Jiading , Yu Nan , Lu Hongyun , Lin Xiufang 
Published: September 2019

AbstractIntroductionLong QT syndrome (LQTS) increases the risk of life‐threatening arrhythmia in young individuals with structurally normal hearts. Sixteen genes such as the KCNQ1, KCNH2, and SCN5A have been reported for association with LQTS.Case presentationWe identified the compound heterozygous mutations in the KCNQ1 gene at c. G527A (p.W176X) and c.G1765A (p.G589S) predicted as “damaging.” The in‐silico analysis showed that when compared to the characteristics of mRNA and protein of wild‐type KCNQ1, the mRNA of c.G527A mutation was significantly different in the centroid secondary structure. The subunit coded by W176X would lose the transmembrane domains S3–S6 and helices A‐D. The protein secondary structure of G589S was slightly shortened in helix structure; the protein physics‐chemical parameters of W176X and G589S significantly and slightly changed, respectively.ConclusionsThe compound heterozygous mutations of W176X and G589S coexisting in KCNQ1 gene of homologous chromosomes, resulting in more severe phenotype, are the likely pathogenic and genetic risks of LQTS and USD in this Chinese family.