bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional response to the host cell environment of a multidrug-resistant Mycobacterium tuberculosis clonal outbreak Beijing strain reveals its pathogenic features
Authors: Aiewsakun Pakorn , Prombutara Pinidphon , Siregar Tegar Adriansyah Putra , Laopanupong Thanida , Kanjanasirirat Phongthon , Khumpanied Tanawadee , Borwornpinyo Suparerk , Tong-Ngam Pirut , Tubsuwan Alisa , Srilohasin Prapaporn , Chaiprasert Angkana , Ruangchai Wuthiwat , Palittapongarnpim Prasit , Prammananan Therdsak , VanderVen Brian C. , Ponpuak Marisa 
Published: February 2021

AbstractTuberculosis is a global public health problem with emergence of multidrug-resistant infections. Previous epidemiological studies of tuberculosis in Thailand have identified a clonal outbreak multidrug-resistant strain of Mycobacterium tuberculosis in the Kanchanaburi province, designated “MKR superspreader”, and this particular strain later was found to also spread to other regions. In this study, we elucidated its biology through RNA-Seq analyses and identified a set of genes involved in cholesterol degradation to be up-regulated in the MKR during the macrophage cell infection, but not in the H37Rv reference strain. We also found that the bacterium up-regulated genes associated with the ESX-1 secretion system during its intracellular growth phase, while the H37Rv did not. All results were confirmed by qRT-PCR. Moreover, we showed that compounds previously shown to inhibit the mycobacterial ESX-1 secretion system and cholesterol utilisation, and FDA-approved drugs known to interfere with the host cholesterol transportation were able to decrease the intracellular survival of the MKR when compared to the untreated control, while not that of the H37Rv. Altogether, our findings suggested that such pathways are important for the MKR’s intracellular growth, and potentially could be targets for the discovery of new drugs against this emerging multidrug-resistant strain of M. tuberculosis.
Simultaneous quantification method for 5-FU, uracil, and tegafur using UPLC-MS/MS and clinical application in monitoring UFT/LV combination therapy after hepatectomy
Authors: Shiraiwa Ken , Suzuki Yosuke , Uchida Hiroki , Iwashita Yukio , Tanaka Ryota , Iwao Motoshi , Tada Kazuhiro , Hirashita Teijiro , Masuda Takashi , Endo Yuichi , Inomata Masafumi , Itoh Hiroki 
Published: February 2021

AbstractCombination therapy of tegafur/uracil (UFT) and leucovorin (LV) is widely used to treat colorectal cancers. Although this therapy has a significant therapeutic effect, severe adverse effects occur frequently. Therapeutic drug monitoring (TDM) may help to prevent adverse effects. A useful assay that can quantitate plasma levels of 5-FU, uracil, and tegafur simultaneously for TDM has been desired, but such a method is not currently available. In this study, we aimed to develop a sensitive method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). After preparing plasma samples by protein precipitation and liquid extraction, 5-FU, uracil, and tegafur were analyzed by UPLC-MS/MS in negative electrospray ionization mode. Validation was performed according to US Food and Drugs Administration guidance. The calibration curves were linear over concentration ranges of 2–500 ng/mL for 5-FU, 20–5000 ng/mL for uracil, and 200–50,000 ng/mL for tegafur. The corresponding average recovery rates were 79.9, 80.9, and 87.8%. The method provides accuracy within 11.6% and precision below 13.3% for all three analytes. Matrix effects of 5-FU, uracil, and tegafur were higher than 43.5, 84.9, and 100.2%, respectively. This assay was successfully applied to assess the time courses of plasma 5-FU, uracil, and tegafur concentrations in two patients with colorectal liver metastasis who received UFT/LV therapy after hepatectomy. In conclusion, we succeeded to develop a sensitive and robust UPLC-MS/MS method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma. This method is potentially useful for TDM in patients receiving UFT/LV combination therapy.
Dynamics of binding ability prediction between spike protein and human ACE2 reveals the adaptive strategy of SARS-CoV-2 in humans
Authors: Xue Xia , Shi Jianxiang , Xu Hongen , Qin Yaping , Yang Zengguang , Feng Shuaisheng , Liu Danhua , Jian Liguo , Hua Linlin , Wang Yaohe , Zhang Qi , Huang Xueyong , Zhang Xiaoju , Li Xinxin , Chen Chunguang , Guo Jiancheng , Tang Wenxue , Liu Jianbo 
Published: February 2021

AbstractSARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus causing the COVID-19 pandemic in 2020. High adaptive plasticity on the spike protein of SASR-CoV-2 enables it to transmit across different host species. In the present study, we collected 2092 high-quality genome sequences of SARS-CoV-2 from 160 regions in over 50 countries and reconstructed their phylogeny. We also analyzed the polymorphic interaction between spike protein and human ACE2 (hACE2). Phylogenetic analysis of SARS-CoV-2 suggests that SARS-CoV-2 is probably originated from a recombination event on the spike protein between a bat coronavirus and a pangolin coronavirus that endows it humans infectivity. Compared with other regions in the S gene of SARS-CoV-2, the direct-binding sites of the receptor-binding domain (RBD) is more conserved. We focused on 3,860 amino acid mutations in spike protein RBD (T333-C525) of SARS-CoV-2 and simulated their differential stability and binding affinity to hACE2 (S19-D615). The results indicate no preference for SARS-CoV-2 infectivity on people of different ethnic groups. The variants in the spike protein of SARS-CoV-2 may also be a good indicator demonstrating the transmission route of SARS-CoV-2 from its natural reservoir to human hosts.
Mastoid effusion on temporal bone MRI in patients with Bell’s palsy and Ramsay Hunt syndrome
Authors: Choi Jin Woo , Lee Jiyeon. , Lee Dong-Han , Shin Jung Eun , Kim Chang-Hee 
Published: February 2021

AbstractThis study aimed to investigate the incidence of mastoid effusion on temporal bone magnetic resonance imaging (MRI) in patients with Bell’s palsy (BP) and Ramsay Hunt syndrome (RHS), and evaluate the usefulness of mastoid effusion in early differential diagnosis between BP and RHS. The incidence of mastoid effusion on 3.0 T—temporal bone MRI, which was conducted within 10 days after the onset of acute facial nerve palsy, was compared between 131 patients with BP and 33 patients with RHS. Findings of mastoid cavity on temporal bone MRI were classified into three groups as normal mastoid, mastoid effusion, and sclerotic change, and the incidence of ipsilesional mastoid effusion was significantly higher in RHS than BP (P < 0.001). Tympanic membrane was normal in 7 of 14 RHS patients with mastoid effusion, and injected without middle ear effusion in 7 patients. This study highlights significantly higher incidence of ipsilesional mastoid effusion in RHS than BP, and suggests that the presence of mastoid effusion may provide additional information for differential diagnosis between RHS and BP.
Predicting COVID-19 mortality with electronic medical records
Authors: Estiri Hossein , Strasser Zachary H. , Klann Jeffy G. , Naseri Pourandokht , Wagholikar Kavishwar B. , Murphy Shawn N. 
Published: February 2021

AbstractThis study aims to predict death after COVID-19 using only the past medical information routinely collected in electronic health records (EHRs) and to understand the differences in risk factors across age groups. Combining computational methods and clinical expertise, we curated clusters that represent 46 clinical conditions as potential risk factors for death after a COVID-19 infection. We trained age-stratified generalized linear models (GLMs) with component-wise gradient boosting to predict the probability of death based on what we know from the patients before they contracted the virus. Despite only relying on previously documented demographics and comorbidities, our models demonstrated similar performance to other prognostic models that require an assortment of symptoms, laboratory values, and images at the time of diagnosis or during the course of the illness. In general, we found age as the most important predictor of mortality in COVID-19 patients. A history of pneumonia, which is rarely asked in typical epidemiology studies, was one of the most important risk factors for predicting COVID-19 mortality. A history of diabetes with complications and cancer (breast and prostate) were notable risk factors for patients between the ages of 45 and 65 years. In patients aged 65–85 years, diseases that affect the pulmonary system, including interstitial lung disease, chronic obstructive pulmonary disease, lung cancer, and a smoking history, were important for predicting mortality. The ability to compute precise individual-level risk scores exclusively based on the EHR is crucial for effectively allocating and distributing resources, such as prioritizing vaccination among the general population.
Gametes deficient for Pot1 telomere binding proteins alter levels of telomeric foci for multiple generations
Authors: Lister-Shimauchi Evan H. , Dinh Michael , Maddox Paul , Ahmed Shawn 
Published: February 2021

AbstractDeficiency for telomerase results in transgenerational shortening of telomeres. However, telomeres have no known role in transgenerational epigenetic inheritance. C. elegans Protection Of Telomeres 1 (Pot1) proteins form foci at the telomeres of germ cells that disappear at fertilization and gradually accumulate during development. We find that gametes from mutants deficient for Pot1 proteins alter levels of telomeric foci for multiple generations. Gametes from pot-2 mutants give rise to progeny with abundant POT-1::mCherry and mNeonGreen::POT-2 foci throughout development, which persists for six generations. In contrast, gametes from pot-1 mutants or pot-1; pot-2 double mutants induce diminished Pot1 foci for several generations. Deficiency for MET-2, SET-25, or SET-32 methyltransferases, which promote heterochromatin formation, results in gametes that induce diminished Pot1 foci for several generations. We propose that C. elegans POT-1 may interact with H3K9 methyltransferases during pot-2 mutant gametogenesis to induce a persistent form of transgenerational epigenetic inheritance that causes constitutively high levels of heterochromatic Pot1 foci.
Full-length in meso structure and mechanism of rat kynurenine 3-monooxygenase inhibition
Authors: Mimasu Shinya , Yamagishi Hiroaki , Kubo Satoshi , Kiyohara Mie , Matsuda Toshihiro , Yahata Toshiko , Thomson Heather A. , Hupp Christopher D. , Liu Julie , Okuda Takao , Kakefuda Kenichi 
Published: February 2021

AbstractThe structural mechanisms of single-pass transmembrane enzymes remain elusive. Kynurenine 3-monooxygenase (KMO) is a mitochondrial protein involved in the eukaryotic tryptophan catabolic pathway and is linked to various diseases. Here, we report the mammalian full-length structure of KMO in its membrane-embedded form, complexed with compound 3 (identified internally) and compound 4 (identified via DNA-encoded chemical library screening) at 3.0 Å resolution. Despite predictions suggesting that KMO has two transmembrane domains, we show that KMO is actually a single-pass transmembrane protein, with the other transmembrane domain lying laterally along the membrane, where it forms part of the ligand-binding pocket. Further exploration of compound 3 led to identification of the brain-penetrant compound, 5. We show that KMO is dimeric, and that mutations at the dimeric interface abolish its activity. These results will provide insight for the drug discovery of additional blood-brain-barrier molecules, and help illuminate the complex biology behind single-pass transmembrane enzymes.
A multiplex CRISPR interference tool for virulence gene interrogation in Legionella pneumophila
Authors: Ellis Nicole A. , Kim Byoungkwan , Tung Jessica , Machner Matthias P. 
Published: February 2021

AbstractCatalytically inactive dCas9 imposes transcriptional gene repression by sterically precluding RNA polymerase activity at a given gene to which it was directed by CRISPR (cr)RNAs. This gene silencing technology, known as CRISPR interference (CRISPRi), has been employed in various bacterial species to interrogate genes, mostly individually or in pairs. Here, we developed a multiplex CRISPRi platform in the pathogen Legionella pneumophila capable of silencing up to ten genes simultaneously. Constraints on precursor-crRNA expression were overcome by combining a strong promoter with a boxA element upstream of a CRISPR array. Using crRNAs directed against virulence protein-encoding genes, we demonstrated that CRISPRi is fully functional not only during growth in axenic media, but also during macrophage infection, and that gene depletion by CRISPRi recapitulated the growth defect of deletion strains. By altering the position of crRNA-encoding spacers within the CRISPR array, our platform achieved the gradual depletion of targets that was mirrored by the severity in phenotypes. Multiplex CRISPRi thus holds great promise for probing large sets of genes in bulk in order to decipher virulence strategies of L. pneumophila and other bacterial pathogens.
Unconventional magnonic surface and interface states in layered ferromagnets
Authors: Zakeri Khalil , Qin Huajun , Ernst Arthur 
Published: February 2021

AbstractElectronic surface, interface and edge states are well-known concepts in low-dimensional solids and have already been utilised for practical applications. It is expected that magnons–the bosonic quasiparticles representing the magnetic excitations– shall also exhibit such exotic states. However, how these states are formed in layered magnetic structures is hitherto unknown. Here we bring the topic of magnonic surface and interface states in layered ferromagnets into discussion. We provide experimental examples of synthetic layered structures, supporting our discussions and show that these states can be tailored in artificially fabricated structures. We demonstrate that the magnonic surface or interface states may show peculiar features, including "standing” or "ultrafast” states. We argue that these states can drastically change their electronic and magnonic transport properties. In this way one can design layered ferromagnets which act as magnon conductor, semiconductor and insulator of specific states.
Dynamics of resilience–equity interactions in resource-based communities
Authors: Molla Nusrat , DeIonno John , Herman Jonathan 
Published: February 2021

AbstractDespite the growing focus on understanding how to build resilience, the interaction between resilience and equity, particularly in the context of power asymmetries like those in communities reliant on resource-based industries, or resource-based communities, is not well understood. Here we present a stylized dynamical systems model of asymmetric resource access and control in resource-based communities that links industrial resource degradation, community well-being, and migration in response to economic and resource conditions. The model reveals a mechanism of collapse due to these dynamics in which over-extraction and resource degradation trigger irreversible population decline. Regulating resource extraction can increase resilience (in the sense of persistence) while also shifting the sustainable equilibrium and the implications for equity. Resilience does not guarantee equity at equilibrium, and this misalignment is more pronounced in the transient interactions between short term equity and long term resilience. The misalignment between resilience and equity demonstrates how equity considerations change the policy design process in important ways.
Future changes in the frequency of temperature extremes may be underestimated in tropical and subtropical regions
Authors: Freychet N. , Hegerl G. , Mitchell D. , Collins M. 
Published: February 2021

AbstractIn a warming world, temperature extremes are expected to show a distinguishable change over much of the globe even at 1.5 °C warming, and in many regions this change has already been detected in observations. Although many studies predict an increase in heat extreme events, the magnitude of the change varies greatly among different models even for the same mean warming. This uncertainty has been linked to differences in land–atmosphere feedback across models. Here we show that a significant constraint for future projections can be based on the ability of climate models to accurately simulate the present day variability of daily surface maximum temperature. An emergent constraint on Coupled Model Intercomparison Project Phase 5 (CMIP5) and 6 (CMIP6) models, applied to ERA5 reanalysis, indicates that the best estimate in hot extreme changes by the end of the century could be worse than previously estimated, mostly for tropical and subtropical regions as well as South and East Asia.
Transformation of abundant magnesium silicate minerals for enhanced CO2 sequestration
Authors: Scott Allan , Oze Christopher , Shah Vineet , Yang Nan , Shanks Barney , Cheeseman Chris , Marshall Aaron , Watson Matthew 
Published: February 2021

AbstractGlobal climate change related to anthropogenic CO2 emissions is one of the most significant challenges for the future of human life on Earth. There are many potential options for reducing or even eliminating atmospheric CO2 emissions including underground sequestration, carbon mineralization and ocean storage. One of the most promising materials for carbon mineralization is Mg(OH)2 which is highly reactive and capable of forming stable carbonates. Here we show a novel low-carbon method of producing Mg(OH)2, from globally abundant olivine-rich silicate rocks. A combination of acid digestion and electrolysis of olivine were used to produce Mg(OH)2 in a fully recoverable system. The use of Mg(OH)2 from olivine provides a viable pathway for significant industrial scale reductions in global anthropogenic greenhouse gas emissions.
First and second order optimality conditions for the control of Fokker-Planck equations
Authors: Soledad Aronna M. , Tröltzsch Fredi 
Published: February 2021

In this article we study an optimal control problem subject to the Fokker-Planck equation∂tρ−ν∆ρ− div(ρB[u]) = 0The control variableuis time-dependent and possibly multidimensional, and the functionBdepends on the space variable and the control. The cost functional is of tracking type and includes a quadratic regularization term on the control. For this problem, we prove existence of optimal controls and first order necessary conditions. Main emphasis is placed on second order necessary and sufficient conditions.
Klinische Aspekte des subchondralen Knochens bei der Arthrose
Authors: Holzer Lukas 
Published: February 2021

ZusammenfassungWissenschaftliche Erkenntnisse der letzten Jahrzehnte lassen vermuten, dass Veränderungen im Bereich des subchondralen Knochens in der Genese und Progression der Arthrose mitverantwortlich sind. Vordergründig scheinen hierfür mechanische Faktoren wie Achsfehlstellung und Instabilität verantwortlich. Die Veränderungen im subchondralen Knochen sind biphasisch. Primär kommt es durch ein erhöhtes Remodeling zu einer Reduktion des Knochenvolumens im Bereich des subchondralen Knochen, sekundär zu einer Dichtezunahme und Abnahme der Gewebsmineralisation. Die veränderten strukturellen Gegebenheiten des Knochens begünstigen die Progression der Knorpeldegeneration. Medikamente, die das Bone Remodeling beeinflussen, werden daher auch als potenzielle Behandlungsoptionen für die Arthrose betrachtet.
Third generation radioimmunoassay (RIA) for TSH receptor autoantibodies (TRAb) – one step less, similar results?
Authors: Roggenbuck Johannes J. , Zarske Grit , Schierack Peter , Wunderlich Gerd , Conrad Karsten , Kotzerke Joerg , Roggenbuck Dirk , Zöphel Klaus 
Published: February 2021

Abstract
Aim TSH-receptor (TSHR)-autoantibody (TRAb) is the serological hallmark of Graves’ disease (GD). Recently, 3rd-generation radioimmunoassays (RIA) employing monoclonal TRAb such as M22 or T7 instead of TSH for the inhibition of human TRAb binding with solid-phase TSHR (coated tubes) have been introduced into laboratory routine.
Methods As current assays typically employ a consecutive incubation of patient serum and labelled monoclonal TRAb, automation of TRAb RIA is a challenge. Thus, the assay procedure using human TSHR-coated tubes and the mouse monoclonal TRAb T7 was modified by combining both steps. The novel one-step method was compared with its corresponding consecutive 3rd-generation RIA by investigating 304 individuals encompassing 102 patients with active GD (GDa), 43 patients with GD after successful therapy (GDt), 31 with Hashimoto’s disease (HD), 28 with non-autoimmune thyroid diseases (NAITD) and 100 healthy subjects (HS).
Results With the new method, the incubation time was shortened by approximately one hour. Both 3rd-generation RIAs did not reveal a significantly different assay performance by comparing areas under the curve (AUC) with receiver operating characteristics curve analysis (AUC one-step: 0.94, AUC two-step: 0.96, p > 0.05, respectively). The two-step TRAb RIA demonstrated sensitivity and specificity values of 87.5 % and 96.2 %, respectively, whereas the one-step revealed 84.6 % and 96.2 %, respectively.
Conclusion One-step 3rd-generation RIA may be used for the reliable detection of TRAb. The shorter and easier assay design may improve its use and enable automation in routine nuclear medicine laboratories.
Neuronale Korrelate unangenehmer somatosensorischer Stimulation bei Patienten mit Borderline-Persönlichkeitsstörung und Depression
Authors: Malejko Kathrin , Abler Birgit , Graf Heiko 
Published: February 2021

ZUSAMMENFASSUNGDas Empfinden von unangenehmen Reizen, wie auch die Schmerzempfindung im engeren Sinne, wird nicht nur durch rein somatosensorische und nozizeptive Informationen, sondern ebenso durch affektive und kognitive Prozesse moduliert. Klinische Beobachtungen sowie wissenschaftliche Untersuchungen belegen eine veränderte Wahrnehmung der Schmerzempfindung bei psychischen Erkrankungen wie beispielsweise der emotional-instabilen Persönlichkeitsstörung vom Borderline-Typ (BPS) oder bei depressiven Störungen (MD). Die Untersuchung der verschiedenen Modalitäten der Schmerzverarbeitung, welche zu einem großen Teil mit der Verarbeitung unangenehmer Reize überlappt, ist mittels verschiedener Stimulationsparadigmen möglich. Für die Darstellung der zugrunde liegenden neurofunktionellen Mechanismen eignet sich die funktionelle Magnetresonanztomografie (fMRT). Unter experimentellen Bedingungen kann der somatosensorisch-diskriminative Aspekt der Verarbeitung und Wahrnehmung von Schmerz und unangenehmen Reizen mit einem elektrischen Stimulationsparadigma operationalisiert werden. Die neuronalen Korrelate unangenehmer somatosensorischer Stimulation bei Patienten mit BPS und MD werden anhand eigener fMRT-Untersuchungen dargestellt und die veränderte Schmerzverarbeitung der beiden klinischen Gruppen erörtert.