bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nuplazid suppresses esophageal squamous cell carcinoma growth in vitro and in vivo by targeting PAK4
Authors: Wei Yaxing , Wu Wenjie , Jiang Yanan , Zhou Hao , Yu Yin , Zhao Lili , Wu Xiangyu , Lu Xuebo , Yuan Qiang , Wang Zitong , Dong Zigang , He Luyun , Zhao Jimin , Liu Kangdong 
Published: December 2021

Abstract
Background
Due to the high recurrence and low 5-year survival rates of esophageal squamous cell carcinoma (ESCC) after treatment, the discovery of novel drugs for recurrence chemoprevention is of particular importance.

Methods
We screened the FDA-approved drug library and found that Nuplazid, an atypical antipsychotic that acts as an effective 5-HT 2 A receptor inverse agonist, could potentially exert anticancer effects in vitro and in vivo on ESCC.

Results
Pull-down results indicated that Nuplazid binds with p21-activated kinase 4 (PAK4), and a kinase assay showed that Nuplazid strongly suppressed PAK4 kinase activity. Moreover, Nuplazid exhibited inhibitory effects on ESCC in vivo.

Conclusions
Our findings indicate that Nuplazid can suppress ESCC progression through targeting PAK4.
Phenome-wide association study (PheWAS) of colorectal cancer risk SNP effects on health outcomes in UK Biobank
Authors: Zhang Xiaomeng , Li Xue , He Yazhou , Law Philip J. , Farrington Susan M. , Campbell Harry , Tomlinson Ian P. M. , Houlston Richard S. , Dunlop Malcolm G. , Timofeeva Maria , Theodoratou Evropi 
Published: December 2021

AbstractBackgroundAssociations between colorectal cancer (CRC) and other health outcomes have been reported, but these may be subject to biases, or due to limitations of observational studies.MethodsWe set out to determine whether genetic predisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and tree-structured phenotypic model (TreeWAS), we studied 334,385 unrelated White British individuals (excluding CRC patients) from the UK Biobank cohort. We generated a polygenic risk score (PRS) from CRC genome-wide association studies as a measure of CRC risk. We performed sensitivity analyses to test the robustness of the results and searched the Danish Disease Trajectory Browser (DTB) to replicate the observed associations.ResultsEight PheWAS phenotypes and 21 TreeWAS nodes were associated with CRC genetic predisposition by PheWAS and TreeWAS, respectively. The PheWAS detected associations were from neoplasms and digestive system disease group (e.g. benign neoplasm of colon, anal and rectal polyp and diverticular disease). The results from the TreeWAS corroborated the results from the PheWAS. These results were replicated in the observational data within the DTB.ConclusionsWe show that benign colorectal neoplasms share genetic aetiology with CRC using PheWAS and TreeWAS methods. Additionally, CRC genetic predisposition is associated with diverticular disease.
The role of Ubiquitination in Apoptosis and Necroptosis
Authors: Roberts Jamie Z. , Crawford Nyree , Longley Daniel B. 
Published: December 2021

AbstractCell death pathways have evolved to maintain tissue homoeostasis and eliminate potentially harmful cells from within an organism, such as cells with damaged DNA that could lead to cancer. Apoptosis, known to eliminate cells in a predominantly non-inflammatory manner, is controlled by two main branches, the intrinsic and extrinsic apoptotic pathways. While the intrinsic pathway is regulated by the Bcl-2 family members, the extrinsic pathway is controlled by the Death receptors, members of the tumour necrosis factor (TNF) receptor superfamily. Death receptors can also activate a pro-inflammatory type of cell death, necroptosis, when Caspase-8 is inhibited. Apoptotic pathways are known to be tightly regulated by post-translational modifications, especially by ubiquitination. This review discusses research on ubiquitination-mediated regulation of apoptotic signalling. Additionally, the emerging importance of ubiquitination in regulating necroptosis is discussed.
Sea-ice derived meltwater stratification slows the biological carbon pump: results from continuous observations
Authors: von Appen Wilken-Jon , Waite Anya M. , Bergmann Melanie , Bienhold Christina , Boebel Olaf , Bracher Astrid , Cisewski Boris , Hagemann Jonas , Hoppema Mario , Iversen Morten H. , Konrad Christian , Krumpen Thomas , Lochthofen Normen , Metfies Katja , Niehoff Barbara , Nöthig Eva-Maria , Purser Autun , Salter Ian , Schaber Matthias , Scholz Daniel , Soltwedel Thomas , Torres-Valdes Sinhue , Wekerle Claudia , Wenzhöfer Frank , Wietz Matthias , Boetius Antje 
Published: December 2021

AbstractThe ocean moderates the world’s climate through absorption of heat and carbon, but how much carbon the ocean will continue to absorb remains unknown. The North Atlantic Ocean west (Baffin Bay/Labrador Sea) and east (Fram Strait/Greenland Sea) of Greenland features the most intense absorption of anthropogenic carbon globally; the biological carbon pump (BCP) contributes substantially. As Arctic sea-ice melts, the BCP changes, impacting global climate and other critical ocean attributes (e.g. biodiversity). Full understanding requires year-round observations across a range of ice conditions. Here we present such observations: autonomously collected Eulerian continuous 24-month time-series in Fram Strait. We show that, compared to ice-unaffected conditions, sea-ice derived meltwater stratification slows the BCP by 4 months, a shift from an export to a retention system, with measurable impacts on benthic communities. This has implications for ecosystem dynamics in the future warmer Arctic where the seasonal ice zone is expected to expand.
Artificial intelligence-aided clinical annotation of a large multi-cancer genomic dataset
Authors: Kehl Kenneth L. , Xu Wenxin , Gusev Alexander , Bakouny Ziad , Choueiri Toni K. , Riaz Irbaz Bin , Elmarakeby Haitham , Van Allen Eliezer M. , Schrag Deborah 
Published: December 2021

AbstractTo accelerate cancer research that correlates biomarkers with clinical endpoints, methods are needed to ascertain outcomes from electronic health records at scale. Here, we train deep natural language processing (NLP) models to extract outcomes for participants with any of 7 solid tumors in a precision oncology study. Outcomes are extracted from 305,151 imaging reports for 13,130 patients and 233,517 oncologist notes for 13,511 patients, including patients with 6 additional cancer types. NLP models recapitulate outcome annotation from these documents, including the presence of cancer, progression/worsening, response/improvement, and metastases, with excellent discrimination (AUROC > 0.90). Models generalize to cancers excluded from training and yield outcomes correlated with survival. Among patients receiving checkpoint inhibitors, we confirm that high tumor mutation burden is associated with superior progression-free survival ascertained using NLP. Here, we show that deep NLP can accelerate annotation of molecular cancer datasets with clinically meaningful endpoints to facilitate discovery.
Destructiveness of pyroclastic surges controlled by turbulent fluctuations
Authors: Brosch Ermanno , Lube Gert , Cerminara Matteo , Esposti-Ongaro Tomaso , Breard Eric C. P. , Dufek Josef , Sovilla Betty , Fullard Luke 
Published: December 2021

AbstractPyroclastic surges are lethal hazards from volcanoes that exhibit enormous destructiveness through dynamic pressures of 100–102kPa inside flows capable of obliterating reinforced buildings. However, to date, there are no measurements inside these currents to quantify the dynamics of this important hazard process. Here we show, through large-scale experiments and the first field measurement of pressure inside pyroclastic surges, that dynamic pressure energy is mostly carried by large-scale coherent turbulent structures and gravity waves. These perpetuate as low-frequency high-pressure pulses downcurrent, form maxima in the flow energy spectra and drive a turbulent energy cascade. The pressure maxima exceed mean values, which are traditionally estimated for hazard assessments, manifold. The frequency of the most energetic coherent turbulent structures is bounded by a critical Strouhal number of ~0.3, allowing quantitative predictions. This explains the destructiveness of real-world flows through the development of c. 1–20 successive high-pressure pulses per minute. This discovery, which is also applicable to powder snow avalanches, necessitates a re-evaluation of hazard models that aim to forecast and mitigate volcanic hazard impacts globally.
The economy of chromosomal distances in bacterial gene regulation
Authors: Cakir Eda , Lesne Annick , Hütt Marc-Thorsten 
Published: December 2021

AbstractIn the transcriptional regulatory network (TRN) of a bacterium, the nodes are genes and a directed edge represents the action of a transcription factor (TF), encoded by the source gene, on the target gene. It is a condensed representation of a large number of biological observations and facts. Nonrandom features of the network are structural evidence of requirements for a reliable systemic function. For the bacterium Escherichia coli we here investigate the (Euclidean) distances covered by the edges in the TRN when its nodes are embedded in the real space of the circular chromosome. Our work is motivated by ’wiring economy’ research in Computational Neuroscience and starts from two contradictory hypotheses: (1) TFs are predominantly employed for long-distance regulation, while local regulation is exerted by chromosomal structure, locally coordinated by the action of structural proteins. Hence long distances should often occur. (2) A large distance between the regulator gene and its target requires a higher expression level of the regulator gene due to longer reaching times and ensuing increased degradation (proteolysis) of the TF and hence will be evolutionarily reduced. Our analysis supports the latter hypothesis.
Fractional Chern insulators in magic-angle twisted bilayer graphene
Authors: Xie Yonglong , Pierce Andrew T. , Park Jeong Min , Parker Daniel E. , Khalaf Eslam , Ledwith Patrick , Cao Yuan , Lee Seung Hwan , Chen Shaowen , Forrester Patrick R. , Watanabe Kenji , Taniguchi Takashi , Vishwanath Ashvin , Jarillo-Herrero Pablo , Yacoby Amir 
Published: December 2021

AbstractFractional Chern insulators (FCIs) are lattice analogues of fractional quantum Hall states that may provide a new avenue towards manipulating non-Abelian excitations. Early theoretical studies1–7have predicted their existence in systems with flat Chern bands and highlighted the critical role of a particular quantum geometry. However, FCI states have been observed only in Bernal-stacked bilayer graphene (BLG) aligned with hexagonal boron nitride (hBN)8, in which a very large magnetic field is responsible for the existence of the Chern bands, precluding the realization of FCIs at zero field. By contrast, magic-angle twisted BLG9–12supports flat Chern bands at zero magnetic field13–17, and therefore offers a promising route towards stabilizing zero-field FCIs. Here we report the observation of eight FCI states at low magnetic field in magic-angle twisted BLG enabled by high-resolution local compressibility measurements. The first of these states emerge at 5 T, and their appearance is accompanied by the simultaneous disappearance of nearby topologically trivial charge density wave states. We demonstrate that, unlike the case of the BLG/hBN platform, the principal role of the weak magnetic field is merely to redistribute the Berry curvature of the native Chern bands and thereby realize a quantum geometry favourable for the emergence of FCIs. Our findings strongly suggest that FCIs may be realized at zero magnetic field and pave the way for the exploration and manipulation of anyonic excitations in flat moiré Chern bands.
Tritiation of aryl thianthrenium salts with a molecular palladium catalyst
Authors: Zhao Da , Petzold Roland , Yan Jiyao , Muri Dieter , Ritter Tobias 
Published: December 2021

AbstractTritium labelling is a critical tool for investigating the pharmacokinetic and pharmacodynamic properties of drugs, autoradiography, receptor binding and receptor occupancy studies1. Tritium gas is the preferred source of tritium for the preparation of labelled molecules because it is available in high isotopic purity2. The introduction of tritium labels from tritium gas is commonly achieved by heterogeneous transition-metal-catalysed tritiation of aryl (pseudo)halides. However, heterogeneous catalysts such as palladium supported on carbon operate through a reaction mechanism that also results in the reduction of other functional groups that are prominently featured in pharmaceuticals3. Homogeneous palladium catalysts can react chemoselectively with aryl (pseudo)halides but have not been used for hydrogenolysis reactions because, after required oxidative addition, they cannot split dihydrogen4. Here we report a homogenous hydrogenolysis reaction with a well defined, molecular palladium catalyst. We show how the thianthrene leaving group—which can be introduced selectively into pharmaceuticals by late-stage C–H functionalization5—differs in its coordinating ability to relevant palladium(II) catalysts from conventional leaving groups to enable the previously unrealized catalysis with dihydrogen. This distinct reactivity combined with the chemoselectivity of a well defined molecular palladium catalyst enables the tritiation of small-molecule pharmaceuticals that contain functionality that may otherwise not be tolerated by heterogeneous catalysts. The tritiation reaction does not require an inert atmosphere or dry conditions and is therefore practical and robust to execute, and could have an immediate impact in the discovery and development of pharmaceuticals.
Direct limits for scalar field dark matter from a gravitational-wave detector
Authors: Vermeulen Sander M. , Relton Philip , Grote Hartmut , Raymond Vivien , Affeldt Christoph , Bergamin Fabio , Bisht Aparna , Brinkmann Marc , Danzmann Karsten , Doravari Suresh , Kringel Volker , Lough James , Lück Harald , Mehmet Moritz , Mukund Nikhil , Nadji Séverin , Schreiber Emil , Sorazu Borja , Strain Kenneth A. , Vahlbruch Henning , Weinert Michael , Willke Benno , Wittel Holger 
Published: December 2021

AbstractThe nature of dark matter remains unknown to date, although several candidate particles are being considered in a dynamically changing research landscape1. Scalar field dark matter is a prominent option that is being explored with precision instruments, such as atomic clocks and optical cavities2–8. Here we describe a direct search for scalar field dark matter using a gravitational-wave detector, which operates beyond the quantum shot-noise limit. We set new upper limits on the coupling constants of scalar field dark matter as a function of its mass, by excluding the presence of signals that would be produced through the direct coupling of this dark matter to the beam splitter of the GEO600 interferometer. These constraints improve on bounds from previous direct searches by more than six orders of magnitude and are, in some cases, more stringent than limits obtained in tests of the equivalence principle by up to four orders of magnitude. Our work demonstrates that scalar field dark matter can be investigated or constrained with direct searches using gravitational-wave detectors and highlights the potential of quantum-enhanced interferometry for dark matter detection.
Environmental contaminants and the disproportionate prevalence of type-2 diabetes mellitus among Indigenous Cree women in James Bay Quebec, Canada
Authors: Zuk Aleksandra , Liberda Eric N. , Tsuji Leonard J. S. 
Published: December 2021

AbstractIndigenous populations are disproportionately affected by type 2 diabetes (T2DM) compared to non-Indigenous people. Of importance, the prevalence of T2DM is greater amongst females than males in First Nations communities, in contrast to higher male prevalence reported in non-Indigenous Canadians. Therefore, in this study we extend our previously published work with respect to females, and the potential association between environmental exposures to organochlorine pesticides, such as dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) to explain the greater prevalence of T2DM among Indigenous females compared to males. Using data from the Multi-Community Environment-and-Health Study, Principal Component Analysis (PCA), examined 9-polychlorinated biphenyl congeners, 7-organic pesticides, and 4-metal/metalloids. Modified Poisson regression with robust error variance estimated adjusted prevalence ratios (PR) and corresponding 95% confidence intervals (95% CI), regressing prevalent T2DM on the newly derived principal components (PC), adjusting for a priori covariates, including parity. We further examined the relationship between high detection concentrations of DDT and tertials of categorized DDE exposures on T2DM among Indigenous Cree women. Among 419 female participants, 23% (n = 95) had physician-diagnosed T2DM. PCA analysis show that DDT and Lead (Pb) loaded highly on the second axis (PC-2), although in opposite directions, indicating the different exposure sources. As previously published, T2DM was significantly associated with PC-2 across adjusted models, however, after further adjusting for parity in this analysis, T2DM was no longer significantly associated with increasing PC-2 scores (PR = 0.88, 95% 0.76, 1.03). Furthermore, we found that the highest detectable levels of DDT, and tertiles of DDE were significantly associated with prevalent T2DM in the fully adjusted model (PR = 1.93, 1.17, 3.19), and (PR = 3.58, 1.10, 11.70), respectively. This cross-sectional analysis suggests organochlorines, specifically, detectable high exposure concentrations of DDT and DDE are associated with prevalent type 2 diabetes, signifying a possible important link between parity and environmental organochlorines pesticides among Indigenous Cree women.
Changes in metabolic syndrome and risk of psoriasis: a nationwide population-based study
Authors: Lee Hyun Ji , Han Kyung Do , Park Hae Eun , Han Ju Hee , Bang Chul Hwan , Park Young Min , Lee Ji Hyun 
Published: December 2021

AbstractMetabolic syndrome (MetS) is associated with psoriasis, but it remains unclear whether risk of psoriasis remains in patients whose MetS diagnosis changes. To assess the relationship between risk of psoriasis and changes in MetS components. We obtained data from the National Health Insurance Service of Korea and divided the participants into four groups: individuals without MetS (control); individuals with MetS in 2009, but without MetS in 2012 (pre-MetS); individuals without MetS in 2009, but with newly diagnosed MetS in 2012 (post-MetS); and individuals with MetS during the 2009–2012, period (continuous-MetS). We calculated the risk of psoriasis for each group. Risk of psoriasis was similar in the control and pre-MetS groups but was significantly higher in the post-MetS group (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.04–1.12) and in the continuous-MetS group (HR, 1.11; 95% CI, 1.07–1.15) than in the control group. Among MetS components, waist circumference showed the strongest association with psoriasis, followed by high-density lipoprotein and triglyceride levels. Risk of psoriasis was higher in patients with continuous- or post-MetS than in those with pre-MetS (regardless of prior MetS status).
SARS-CoV-2 infection reduces human nasopharyngeal commensal microbiome with inclusion of pathobionts
Authors: Hoque M. Nazmul , Sarkar Md. Murshed Hasan , Rahman M. Shaminur , Akter Shahina , Banu Tanjina Akhtar , Goswami Barna , Jahan Iffat , Hossain M. Saddam , Shamsuzzaman A. K. Mohammad , Nafisa Tasnim , Molla M. Maruf Ahmed , Yeasmin Mahmuda , Ghosh Asish Kumar , Osman Eshrar , Alam S. K. Saiful , Uzzaman Mohammad Samir , Habib Md Ahashan , Mahmud Abu Sayeed Mohammad , Crandall Keith A. , Islam Tofazzal , Khan Md. Salim 
Published: December 2021

AbstractThe microbiota of the nasopharyngeal tract (NT) play a role in host immunity against respiratory infectious diseases. However, scant information is available on interactions of SARS-CoV-2 with the nasopharyngeal microbiome. This study characterizes the effects of SARS-CoV-2 infection on human nasopharyngeal microbiomes and their relevant metabolic functions. Twenty-two (n = 22) nasopharyngeal swab samples (including COVID-19 patients = 8, recovered humans = 7, and healthy people = 7) were collected, and underwent to RNAseq-based metagenomic investigation. Our RNAseq data mapped to 2281 bacterial species (including 1477, 919 and 676 in healthy, COVID-19 and recovered metagenomes, respectively) indicating a distinct microbiome dysbiosis. The COVID-19 and recovered samples included 67% and 77% opportunistic bacterial species, respectively compared to healthy controls. Notably, 79% commensal bacterial species found in healthy controls were not detected in COVID-19 and recovered people. Similar dysbiosis was also found in viral and archaeal fraction of the nasopharyngeal microbiomes. We also detected several altered metabolic pathways and functional genes in the progression and pathophysiology of COVID-19. The nasopharyngeal microbiome dysbiosis and their genomic features determined by our RNAseq analyses shed light on early interactions of SARS-CoV-2 with the nasopharyngeal resident microbiota that might be helpful for developing microbiome-based diagnostics and therapeutics for this novel pandemic disease.
Research on expansion and classification of imbalanced data based on SMOTE algorithm
Authors: Wang Shujuan , Dai Yuntao , Shen Jihong , Xuan Jingxue 
Published: December 2021

AbstractWith the development of artificial intelligence, big data classification technology provides the advantageous help for the medicine auxiliary diagnosis research. While due to the different conditions in the different sample collection, the medical big data is often imbalanced. The class-imbalance problem has been reported as a serious obstacle to the classification performance of many standard learning algorithms. SMOTE algorithm could be used to generate sample points randomly to improve imbalance rate, but its application is affected by the marginalization generation and blindness of parameter selection. Focusing on this problem, an improved SMOTE algorithm based on Normal distribution is proposed in this paper, so that the new sample points are distributed closer to the center of the minority sample with a higher probability to avoid the marginalization of the expanded data. Experiments show that the classification effect is better when use proposed algorithm to expand the imbalanced dataset of Pima, WDBC, WPBC, Ionosphere and Breast-cancer-wisconsin than the original SMOTE algorithm. In addition, the parameter selection of the proposed algorithm is analyzed and it is found that the classification effect is the best when the distribution characteristics of the original data was maintained best by selecting appropriate parameters in our designed experiments.