bluuebunny/crossref_metadata_2025_split huggingface dataset:
Global PPPs and the Choice of Law Challenge
Authors: Lin Tan Yock 
Published: April 2020

Abstract
Positing the public-private partnership as an important optional legal structure in the delivery of infrastructural services in the Belt and Road Initiative (BRI), this exploratory article discusses the crucial, but formidable, problems of risks in management or governance. It considers whether traditional common law conflict of laws as applied in Singapore courts can contribute principles that recognize shared expectations and commitment or foster solidarity, mutuality, and trust—values regarded as essential to their effective resolution. Arguing that traditional conflicts distinctions between State and non-State law as well as between public and private law are unhelpful in this respect, it concludes that modern critical developments contain promising prospects for developing such principles. These principles will predicate a role for foreign State substantive public policies and, if there is relevant ‘relational distance’, implement them in BRI choice-of-law disputes, thereby reconciling private efficiency and public accountability beyond borders.
On the Stabilization of the Betti Numbers of the Moduli Space of Sheaves on ℙ2
Authors: Mandal Sayanta 
Published: April 2020

AbstractLet $r \geq 2$ be an integer, and let $a$ be an integer coprime to $r$. We show that if $c_2 \geq n + \left \lfloor \frac{r-1}{2r}a^2 + \frac{1}{2}(r^2 + 1) \right \rfloor $, then the $2n$th Betti numbers of the moduli space $M_{\mathbb{P}^2,H}(r,aH,c_2)$ stabilize where $H = c_1(\mathcal{O}_{\mathbb{P}^2}(1))$.
The Unified Medical Language System SPECIALIST Lexicon and Lexical Tools: Development and applications
Authors: Lu Chris J , Payne Amanda , Mork James G 
Published: April 2020

Abstract
Natural language processing (NLP) plays a vital role in modern medical informatics. It converts narrative text or unstructured data into knowledge by analyzing and extracting concepts. A comprehensive lexical system is the foundation to the success of NLP applications and an essential component at the beginning of the NLP pipeline. The SPECIALIST Lexicon and Lexical Tools, distributed by the National Library of Medicine as one of the Unified Medical Language System Knowledge Sources, provides an underlying resource for many NLP applications. This article reports recent developments of 3 key components in the Lexicon. The core NLP operation of Unified Medical Language System concept mapping is used to illustrate the importance of these developments. Our objective is to provide generic, broad coverage and a robust lexical system for NLP applications. A novel multiword approach and other planned developments are proposed.
Infectious Complications Following CD19 Chimeric Antigen Receptor T-cell Therapy for Children, Adolescents, and Young Adults
Authors: Vora Surabhi B , Waghmare Alpana , Englund Janet A , Qu Pingping , Gardner Rebecca A , Hill Joshua A 
Published: April 2020

Abstract

Background
Infectious complications of chimeric antigen receptor (CAR) T-cell immunotherapy in children and young adults have not been well described.

Methods
Medical records of patients ≤26 years old receiving CD19 CAR T-cell infusion (CTI) at a single institution between 2014 and 2017 were reviewed. The number of infections per 100 days-at-risk (infection density) in the 90 days preceding and 0–28 and 29–90 days after CTI was calculated. Poisson regression and Cox analyses were utilized to identify risk factors for infections.

Results
Eighty-three patients received CTI during the study period. Most patients (98%) had refractory or relapsed acute lymphoblastic leukemia (ALL). Infections occurred in 54% of patients in the 90 days before CTI (infection density, 1.23) and in 40% of patients in the first 28 days following CTI (infection density, 2.89). Infection density decreased to 0.55 in the 29–90 days post-CTI. Most infections were bacteremias (39%) or respiratory viral infections (43%). Pre-CTI risk factors associated with infection included prior hematopoietic cell transplantation (HCT), immunoglobulin G (IgG) level &lt;400 mg/dL, and lymphodepletion other than cyclophosphamide plus fludarabine; post-CTI risk factors included higher-severity CRS and IgG &lt;400 mg/dL.

Conclusions
Infection rates in children and young adults receiving CD19 CAR T-cell therapy increase in the first month and then decline. Understanding types and timing of infections and contributing risk factors may help inform prophylactic and monitoring strategies. Specific attention should be given to patients with prior HCT, severe hypogammaglobulinemia, and severe CRS.
Updates in Pediatric Malignant Gliomas
Authors: Gonçalves Fabrício Guimarães , Alves César Augusto Pinheiro Ferreira , Vossough Arastoo 
Published: April 2020

Abstract
Malignant gliomas constitute a smaller portion of brain tumors in children compared with adults. Nevertheless, they can be devastating tumors with poor prognosis. Recent advances and improved understanding of the genetic and molecular characterization of pediatric brain tumors, including those of malignant gliomas, have led to the reclassification of many pediatric brain tumors and new entities have been defined. In this paper, we will present some of the more recent characterization and pertinent changes in pediatric high-grade gliomas, along with the conventional and advanced imaging features associated with these entities. Implications of the recent changes in pediatric malignant glioma classifications will also be discussed.
Integrative and Conjugative Elements (ICE) and Associated Cargo Genes within and across Hundreds of Bacterial Genera
Authors: Kaufman James H , Terrizzano Ignacio , Nayar Gowri , Seabolt Ed , Agarwal Akshay , Slizovskiy Ilya B , Noyes Noelle 
Published: April 2020

AbstractHorizontal gene transfer mediated by integrative and conjugative elements (ICE) is considered an important evolutionary mechanism of bacteria. It allows organisms to quickly evolve new phenotypic properties including antimicrobial resistance (AMR) and virulence. The rate of ICE-mediated cargo gene exchange has not yet been comprehensively studied within and between bacterial taxa. In this paper we report a big data analysis of ICE and associated cargo genes across over 200,000 bacterial genomes representing 1,345 genera. Our results reveal that half of bacterial genomes contain one or more known ICE features (“ICE genomes”), and that the associated genetic cargo may play an important role in the spread of AMR genes within and between bacterial genera. We identify 43 AMR genes that appear only in ICE genomes and never in non-ICE genomes. A further set of 95 AMR genes are found >5x more often in ICE versus non-ICE genomes. In contrast, only 29 AMR genes are observed more frequently (at least 5:1) in non-ICE genomes compared to ICE genomes. Analysis of NCBI antibiotic susceptibility assay data reveals that ICE genomes are also over-represented amongst phenotypically resistant isolates, suggesting that ICE processes are critical for both genotypic and phenotypic AMR. These results, as well as the underlying big data resource, are important foundational tools for understanding bacterial evolution, particularly in relation to important bacterial phenotypes such as AMR.
State-dependent regulation of cortical processing speed via gain modulation
Authors: Wyrick David , Mazzucato Luca 
Published: April 2020

AbstractTo thrive in dynamic environments, animals must be capable of rapidly and flexibly adapting behavioral responses to a changing context and internal state. Examples of behavioral flexibility include faster stimulus responses when attentive and slower responses when distracted. Contextual or state-dependent modulations may occur early in the cortical hierarchy and may be implemented via top-down projections from cortico-cortical or neuromodulatory pathways. However, the computational mechanisms mediating the effects of such projections are not known. Here, we introduce a theoretical framework to classify the effects of cell-type specific top-down perturbations on the information processing speed of cortical circuits. Our theory demonstrates that perturbation effects on stimulus processing can be predicted by intrinsic gain modulation, which controls the timescale of the circuit dynamics. Our theory leads to counter-intuitive effects such as improved performance with increased input variance. We tested the model predictions using large-scale electrophysiological recordings from the visual hierarchy in freely running mice, where we found that a decrease in single-cell intrinsic gain during locomotion led to an acceleration of visual processing. Our results establish a novel theory of cell-type specific perturbations, applicable to top-down modulation as well as optogenetic and pharmacological manipulations. Our theory links connectivity, dynamics, and information processing via gain modulation.
Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases: A Mendelian Randomization Study
Authors: Levin Michael G. , Klarin Derek , Assimes Themistocles L. , Freiberg Matthew S. , Ingelsson Erik , Lynch Julie , Natarajan Pradeep , O’Donnell Christopher , Rader Daniel J. , Tsao Philip S. , Chang Kyong-Mi , Voight Benjamin F. , Damrauer Scott M. 
Published: April 2020

ABSTRACTImportanceSmoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood.ObjectiveTo determine the effect of smoking on risk of coronary artery disease, peripheral artery disease, and large-artery stroke.DesignMendelian randomization study using summary statistics from genome-wide associations of smoking (up to 462,690 individuals), coronary artery disease (up to 60,801 cases, 123,504 controls), peripheral artery disease (up to 24,009 cases, 150,983 controls), and large-artery stroke (up to 4,373 cases, 406,111 controls)SettingPopulation-based study of primarily European-ancestry individualsParticipantsParticipants in genome-wide association studies of smoking, coronary artery disease, peripheral artery disease, and stroke.ExposuresGenetic liability to smoking defined by lifetime smoking index: an integrated measure of smoking status, age at initiation, age at cessation, number of cigarettes smoked per day, and declining effect of smoking on health outcomes).Main Outcome MeasureRisk of coronary artery disease, peripheral artery disease, and large-artery stroke.ResultsGenetic liability to smoking was associated with increased risk of PAD (OR 2.13; 95% CI 1.78-2.56; P = 3.6 × 10−16), CAD (OR 1.48; 95% CI 1.25-1.75; P = 4.4 × 10−6), and stroke (OR 1.4; 95% CI 1.02-1.92; P = 0.036). Risk of PAD in smokers was greater than risk of large-artery stroke (pdifference= 0.025) or CAD (pdifference= 0.0041). The effect of smoking on ASCVD remained independent from the effects of smoking on traditional cardiovascular risk factors.Conclusions and RelevanceGenetic liability to smoking is a strong, causal risk factor for CAD, PAD, and stroke, although the effect of smoking is strongest for PAD. The effect of smoking is independent of traditional cardiovascular risk factors.
HAPPI GWAS: Holistic Analysis with Pre and Post Integration GWAS
Authors: Slaten Marianne L. , Chan Yen On , Shrestha Vivek , Lipka Alexander E. , Angelovici Ruthie 
Published: April 2020

AbstractMotivationAdvanced publicly available sequencing data from large populations have enabled in-formative genome-wide association studies (GWAS) that associate SNPs with phenotypic traits of interest. Many publicly available tools able to perform GWAS have been developed in response to increased demand. However, these tools lack a comprehensive pipeline that includes both pre-GWAS analysis such as outlier removal, data transformation, and calculation of Best Linear Unbiased Predictions (BLUPs) or Best Linear Unbiased Estimates (BLUEs). In addition, post-GWAS analysis such as haploblock analysis and candidate gene identification are lacking.ResultsHere, we present HAPPI GWAS, an open-source GWAS tool able to perform pre-GWAS, GWAS, and post-GWAS analysis in an automated pipeline using the command-line interface.AvailabilityHAPPI GWAS is written in R for any Unix-like operating systems and is available on GitHub (https://github.com/Angelovici-Lab/HAPPI.GWAS.git).Contactangelovicir@missouri.edu
Polygenic scores for height in admixed populations
Authors: Bitarello Bárbara D. , Mathieson Iain 
Published: April 2020

AbstractPolygenic risk scores (PRS) use the results of genome-wide association studies (GWAS) to predict quantitative phenotypes or disease risk at an individual level. This provides a potential route to the use of genetic data in personalized medical care. However, a major barrier to the use of PRS is that the majority of GWAS come from cohorts of European ancestry. The predictive power of PRS constructed from these studies is substantially lower in non-European ancestry cohorts, although the reasons for this are unclear. To address this question, we investigate the performance of PRS for height in cohorts with admixed African and European ancestry, allowing us to evaluate ancestry-related differences in PRS predictive accuracy while controlling for environment and cohort differences. We first show that that the predictive accuracy of height PRS increases linearly with European ancestry and is largely explained by European ancestry segments of the admixed genomes. We show that differences in allele frequencies, recombination rate, and marginal effect sizes across ancestries all contribute to the decrease in predictive power, but none of these effects explain the decrease on its own. Finally, we demonstrate that prediction for admixed individuals can be improved by using a linear combination of PRS that includes ancestry-specific effect sizes, although this approach is at present limited by the small size of non-European ancestry discovery cohorts.
Repeated parallel losses of inflexed stamens in Moraceae: phylogenomics and generic revision of the tribe Moreae and the reinstatement of the tribe Olmedieae (Moraceae)
Authors: Gardner Elliot M. , Garner Mira , Cowan Robyn , Dodsworth Steven , Epitawalage Niroshini , Arifiani Deby , Sahromi S. , Baker William J. , Forest Felix , Maurin Olivier , Zerega Nyree J.C. , Monro Alexandre , Hipp Andrew L. 
Published: April 2020

AbstractWe present a densely-sampled phylogenomic study of the mulberry tribe (Moreae, Moraceae), an economically important clade with a global distribution, revealing multiple losses of inflexed stamens, a character traditionally used to circumscribe Moreae. Inflexed stamens facilitate ballistic pollen release and are associated with wind pollination, and the results presented here suggest that losses of this character state may have evolved repeatedly in Moraceae. Neither Moreae nor several of its major genera (Morus,Streblus,Trophis) were found to be monophyletic. A revised system for a monophyletic Moreae is presented, including the reinstatement of the generaAmpalis, Maillardia, Taxotrophis,andParatrophis, and the recognition of the new genusAfromorus, based onMorussubgenusAfromorus.Pseudostreblusis reinstated and transferred to the Parartocarpeae, andSloetiopsisis reinstated and transferred to the Dorstenieae. The tribe Olmediae is reinstated, replacing the Castilleae, owing to the reinstatement of the type genusOlmedia,and its exclusion from Moreae.Strebluss.s. is excluded from Moreae and transferred to the Olmediae, which is characterized primarily by involucrate inflorescences without regard to stamen position. Eight new combinations are made.
Functional characterization of germline variants in theTMEM127tumor suppressor reveals novel insights into its membrane topology and trafficking
Authors: Flores Shahida K. , Deng Yilun , Cheng Ziming , Zhang Xingyu , Tao Sifan , Saliba Afaf , Chu Irene , Wang Exing , Aguiar Ricardo C. T. , Dahia Patricia L. M. 
Published: April 2020

ABSTRACTPurposeTo better understand the function of the transmembrane protein TMEM127, a poorly known tumor suppressor gene associated with pheochromocytomas, paragangliomas and renal carcinomas, we evaluated patient-derived germline variants.MethodsSubcellular localization and steady-state levels of 21 tumor-associated, transiently expressedTMEM127variants were compared to the wild-type protein using immunofluorescence and immunoblot analysis, respectively, in cells genetically modified to lack endogenous TMEM127. Membrane topology and endocytic mechanisms were also assessed.ResultsWe identified three subgroups of mutations and determined that 15 of the 21 variants (71%), including 9 of 15 missense variants (60%), are pathogenic or likely pathogenic, through loss of membrane binding ability, stability and/or internalization capability. Investigation into an N-terminal cluster of missense variants uncovered a previously unrecognized transmembrane domain, indicating that TMEM127 is a four-, not a three-, transmembrane domain-containing protein. Additionally, a C-terminal variant with predominant plasma membrane localization revealed an atypical, extended acidic, dileucine-based motif required for TMEM127 internalization through clathrin-mediated endocytosis.ConclusionWe characterized the functional deficits of several germlineTMEM127variants and identified novel structure-function features of TMEM127, namely, a fourth transmembrane domain and an endocytic motif. These findings will assist inTMEM127variant interpretation and will help guide future studies investigating the cellular role of TMEM127.
Increased capillary stalling is associated with endothelial glycocalyx loss in subcortical vascular dementia
Authors: Yoon Jin-Hui , Shin Paul , Joo Jongyoon , Kim Gaon S. , Oh Wang-Yuhl , Jeong Yong 
Published: April 2020

AbstractProper regulation and patency of cerebral microcirculation is crucial for maintaining a healthy brain. Capillary stalling, i.e., the brief interruption of microcirculation mainly by leukocytes, has been observed in several diseases and contributes to disease pathogenesis or progression. However, the underpinning mechanism for leukocyte capillary plugging remains elusive. Therefore, we investigated the mechanism of capillary stalling in mice during the development of subcortical vascular dementia (SVaD), the most common type of vascular dementia characterized by impaired microcirculation and associated pathological features. Longitudinal optical coherence tomography angiography showed increased number of stalled segments as the disease progressed, while two-photon microscopy indicated a less extensive endothelial glycocalyx (EG) in the stalled segments. We also found that increased gliosis and blood-brain barrier leakage were correlated with the increased number of stalled segments. Based on the above, we conclude that EG potentially mediates capillary stalling and can be a therapeutic target of SVaD.
Determining the interaction status and evolutionary fate of duplicated homomeric proteins
Authors: Mallik Saurav , Tawfik Dan S 
Published: April 2020

AbstractOligomeric proteins are central to life. Duplication and divergence of their genes is a key evolutionary driver, also because duplications can yield very different outcomes. Given a homomeric ancestor, duplication can yield two paralogs that form two distinct homomeric complexes, or a heteromeric complex comprising both paralogs. Alternatively, one paralog remains a homomer while the other acquires a new partner. However, so far, conflicting trends have been noted with respect to which fate dominates, primarily because different methods and criteria are being used to assign the interaction status of paralogs. Here, we systematically analyzed allSaccharomyces cerevisiaeandEscherichia colioligomeric complexes that include paralogous proteins. We found that the proportions of homo-hetero duplication fates strongly depend on a variety of factors, yet that nonetheless, rigorous filtering gives a consistent picture. InE. coliabout 50%, of the paralogous pairs appear to have retained the ancestral homomeric interaction, whereas inS. cerevisiaeonly ∼10% retained a homomeric state. This difference was also observed when unique complexes were counted instead of paralogous gene pairs. We further show that this difference is accounted for by multiple cases of heteromeric yeast complexes that share common ancestry with homomeric bacterial complexes. Our analysis settles contradicting trends and conflicting previous analyses, and provides a systematic and rigorous pipeline for delineating the fate of duplicated oligomers in any organism for which protein-protein interaction data are available.
Multiple Myeloma: Combination Therapy of BET Proteolysis Targeting Chimeric Molecule with CDK9 Inhibitor
Authors: Lim Su-Lin , Xu Liang , Han Bing-Chen , Shyamsunder Pavithra , Chng Wee-Joo , Koeffler H. Phillip 
Published: April 2020

AbstractCyclin Dependent Kinase 9 (CDK9) associates with Bromodomain and Extra-Terminal Domain (BET) proteins to promote transcriptional elongation by phosphorylation of serine 2 of RNAP II C-terminal domain. We examined the therapeutic potential of selective CDK9 inhibitors (AZD 4573 and MC180295) against human multiple myeloma cellsin vitro.Short-hairpin RNA silencing of CDK9 in Multiple Myeloma (MM) cell lines reduced cell viability compared to control cells showing the dependency of MM cells on CDK9. In order to explore synergy with the CDK9 inhibitor, proteolysis targeting chimeric molecule (PROTAC) ARV 825 was added. This latter drug causes ubiquitination of BET proteins resulting in their rapid and efficient degradation. Combination treatment of MM cells with ARV 825 and AZD 4573 markedly reduced their protein expression of BRD 2, BRD 4, MYC and phosphorylated RNA pol II as compared to each single agent alone. Combination treatment synergistically inhibited multiple myeloma cells bothin vitroandin vivowith insignificant weight loss. The combination also resulted in marked increase of apoptotic cells at low dose compared to single agent alone. Taken together, our studies show for the first time that the combination of a BET PROTAC (ARV 825) plus AZD 4573 (CDK9 inhibitor) is effective against MM cells.
Deep evolutionary origin of gamete-directed zygote activation by KNOX/BELL transcription factors in green plants
Authors: Hisanaga Tetsuya , Fujimoto Shota , Cui Yihui , Sato Katsutoshi , Sano Ryosuke , Yamaoka Shohei , Kohchi Takayuki , Berger Frédéric , Nakajima Keiji 
Published: April 2020

AbstractKNOX and BELL transcription factors regulate distinct steps of diploid development in the green lineages. In the green alga Chlamydomonas reinhardtii, KNOX and BELL proteins are inherited by gametes of the opposite mating types, and heterodimerize in zygotes to activate diploid development. By contrast, in land plants such as Physcomitrella and Arabidopsis, KNOX and BELL proteins function in meristem maintenance and organogenesis during the later stages of diploid development. However, whether the contrasting functions of KNOX and BELL were acquired independently in algae and land plants is currently unknown. Here we show that in the basal land plant species Marchantia polymorpha, gamete-expressed KNOX and BELL are required to initiate zygotic development by promoting nuclear fusion in a manner strikingly similar to that of C. reinhardtii. Our results indicate that zygote activation is the ancestral role of KNOX/BELL transcription factors, which shifted toward meristem maintenance as land plants evolved.