bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial correlation structures for detections of individuals in spatial capture–recapture models
Authors: Stevenson Ben C. , Fewster Rachel M. , Sharma Koustubh 
Published: June 2021

AbstractSpatial capture–recapture (SCR) models are commonly used to estimate animal density from surveys on which detectors passively detect animals without physical capture, for example, using camera traps, hair snares, or microphones. An individual is more likely to be recorded by detectors close to its activity center, the centroid of its movement throughout the survey. Existing models to account for this spatial heterogeneity in detection probabilities rely on an assumption of independence between detection records at different detectors conditional on the animals' activity centers, which are treated as latent variables. In this paper, we show that this conditional independence assumption may be violated due to the way animals move around the survey region and encounter detectors, such that additional spatial correlation is almost inevitable. We highlight the links between the well‐studied issue of unmodeled temporal heterogeneity in nonspatial capture–recapture and this variety of unmodeled spatial heterogeneity in SCR, showing that the latter causes predictable bias in the same way as the former. We address this by introducing a latent detection field into the model, and illustrate the resulting approach with a simulation study and an application to a camera‐trap survey of snow leopards Panthera uncia. Our method is a unifying model for several existing SCR approaches, with special cases including standard SCR, models that account for nonspatial individual heterogeneity, and models with overdispersed detection counts.
The transition from salt diapir to weld and thrust: Examples from the Northern Flinders Ranges in South Australia
Authors: Vidal‐Royo Oskar , Rowan Mark G. , Ferrer Oriol , Fischer Mark P. , Fiduk J. Carl , Canova David P. , Hearon Thomas E. , Giles Katherine A. 
Published: June 2021

AbstractThe interactions between salt diapirs, thrust welds and thrusts in contractional belts are poorly understood due to, first, the inability of seismic data to distinguish between thrusts and welds or resolve associated sub‐resolution deformation, and second, the paucity of good field examples. The Warraweena area in the Northern Flinders Ranges of South Australia contains examples of Neoproterozoic to Early Cambrian squeezed diapirs linked by steep reverse faults formed during the Delamerian Orogeny. Benefiting from good field exposures, we use geological mapping, cross‐section construction and conceptual structural models to assess the three‐dimensional geometry and evolution of the structures, the lateral transition from diapirs to linking faults and the variability of associated meso‐ and small‐scale deformation. Three discrete diapirs consist of narrow outcrops of Callanna Group megabreccia (Willouran in age) up to 5‐km long. Their diapiric origin is confirmed by local development of caprock, steepening of flanking strata in composite halokinetic sequences and reworked diapir and roof debris in adjacent strata. The surrounding rocks display only background levels of small‐scale deformation. In contrast, the linking faults show no evidence of precursor diapirism, have fault‐related anticlines up to 100s of m in wavelength in their hanging walls, and an associated increase in small‐scale deformation (i.e. millimetre to metre scale folds, fractures and shear fabrics). The transitions from diapirs to faults occur within less than 200 m as short thrust welds at the diapir terminations. The exposed structures are analogous to those found on the subsurface of other salt basins such as the Gulf of Mexico and the South Atlantic conjugate margins. The results of this work can aid geoscientists evaluating three‐way traps against squeezed diapirs, welds or faults, and can help them to predict the style and abundance of both halokinetic and small‐scale structures that are below seismic resolution.
The gut microbiota associated with high‐Gleason prostate cancer
Authors: Matsushita Makoto , Fujita Kazutoshi , Motooka Daisuke , Hatano Koji , Fukae Shota , Kawamura Norihiko , Tomiyama Eisuke , Hayashi Yujiro , Banno Eri , Takao Tetsuya , Takada Shingo , Yachida Shinichi , Uemura Hirotsugu , Nakamura Shota , Nonomura Norio 
Published: June 2021

AbstractWe have found that intestinal bacteria and their metabolites, short‐chain fatty acids (SCFAs), promote cancer growth in prostate cancer (PCa) mouse models. To clarify the association between gut microbiota and PCa in humans, we analyzed the gut microbiota profiles of men with suspected PCa. One hundred and fifty‐two Japanese men undergoing prostate biopsies (96 with cancer and 56 without cancer) were included in the study and randomly divided into two cohorts: a discovery cohort (114 samples) and a test cohort (38 samples). The gut microbiota was compared between two groups, a high‐risk group (men with Grade group 2 or higher PCa) and a negative + low‐risk group (men with negative biopsy or Grade group 1 PCa), using 16S rRNA gene sequencing. The relative abundances of Rikenellaceae, Alistipes, and Lachnospira, all SCFA‐producing bacteria, were significantly increased in high‐risk group. In receiver operating characteristic curve analysis, the index calculated from the abundance of 18 bacterial genera which were selected by least absolute shrinkage and selection operator regression detected high‐risk PCa in the discovery cohort with higher accuracy than the prostate specific antigen test (area under the curve [AUC] = 0.85 vs 0.74). Validation of the index in the test cohort showed similar results (AUC = 0.81 vs 0.67). The specific bacterial taxa were associated with high‐risk PCa. The gut microbiota profile could be a novel useful marker for the detection of high‐risk PCa and could contribute to the carcinogenesis of PCa.
Phytochemical library screening reveals betulinic acid as a novel Skp2‐SCF E3 ligase inhibitor in non–small cell lung cancer
Authors: He Dan‐Hua , Chen Yu‐Fei , Zhou Yi‐Le , Zhang Shi‐Bing , Hong Ming , Yu Xianjun , Wei Su‐Fen , Fan Xiang‐Zhen , Li Si‐Yi , Wang Qi , Lu Yongzhi , Liu Yong‐Qiang 
Published: June 2021

AbstractSkp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome‐dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant‐derived Skp2 inhibitor, betulinic acid (BA), via high‐throughput structure‐based virtual screening of a phytochemical library. BA significantly inhibited the proliferation and migration of non–small cell lung cancer (NSCLC) through targeting Skp2‐SCF E3 ligase both in vitro and in vivo. Mechanistically, BA binding to Skp2, especially forming H‐bonds with residue Lys145, decreases its stability by disrupting Skp1‐Skp2 interactions, thereby inhibiting the Skp2‐SCF E3 ligase and promoting the accumulation of its substrates; that is, E‐cadherin and p27. In both subcutaneous and orthotopic xenografts, BA significantly inhibited the proliferation and metastasis of NSCLC through targeting Skp2‐SCF E3 ligase and upregulating p27 and E‐cadherin protein levels. Taken together, BA can be considered a valuable therapeutic candidate to inhibit metastasis of NSCLC.
Synthesis andin vitroanticancer activities of seleniumN‐heterocyclic carbene compounds
Authors: Huang Sheng , Sheng Xinyu , Bian Mianli , Yang Zhibin , Lu Yunlong , Liu Wukun 
Published: June 2021

AbstractFourteen novel seleniumN‐heterocyclic carbene (Se‐NHC) compounds derived from 4,5‐diarylimidazole were designed, synthesized, and evaluated as antiproliferative agents. Most of them were more effective toward A2780 ovarian cancer cells than HepG2 hepatocellular carcinoma cells. Among them, the most active compound2bwas about fourfold more active than the positive control ebselen against A2780 cells. In addition, this compound displayed twofold higher cytotoxicity to A2780 cells than to IOSE80 normal ovarian epithelial cells. Further studies revealed that2bcould induce reactive oxygen species production, damage mitochondrial membrane potential, block the cells in the G0/G1 phase, and finally promote A2780 cell apoptosis.
Sarcoidosis of the ear, nose and throat: A review of the literature
Authors: Cereceda‐Monteoliva Nicholas , Rouhani Maral J. , Maughan Elizabeth F , Rotman Anthony , Orban Nara , Al Yaghchi Chadwan , Sandhu Guri 
Published: June 2021

ObjectivesSarcoidosis is a multisystemic inflammatory disease with extrathoracic manifestations, most commonly affecting the young and middle‐aged, female and Black populations. Diagnosis usually requires evidence of non‐caseating granulomata and, when treated, prognosis is usually favourable. We aim to establish the incidence, clinical features and optimal treatment of ENT manifestations of this disease.DesignWe performed a PubMed literature review to determine the evidence base supporting this.ResultsENT manifestations are present in 5%‐15% of patients with sarcoidosis, often as a presenting feature, and require vigilance for swift recognition and coordinated additional treatment specific to the organ. Laryngeal sarcoidosis presents with difficulty in breathing, dysphonia and cough, and may be treated by speech and language therapy (SLT) or intralesional injection, dilatation or tissue reduction. Nasal disease presents with crusting, rhinitis, nasal obstruction and anosmia, usually without sinus involvement. It is treated by topical nasal or intralesional treatments but may also require endoscopic sinus surgery, laser treatment or even nasal reconstruction. Otological disease is uncommon but includes audiovestibular symptoms, both sensorineural and conductive hearing loss, and skin lesions.ConclusionsThe consequences of ENT manifestations of sarcoidosis can be uncomfortable, disabling and even life‐threatening. Effective management strategies require good diagnostic skills and use of specific therapies combined with established treatments such as corticosteroids. Comparisons of treatment outcomes are needed to establish best practice in this area.
Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome
Authors: Eudy‐Byrne Rena , Zane Nicole , Adeniyi‐Jones Susan C. , Gastonguay Marc R. , Ruiz‐Garcia Ana , Kaushal Gagan , Kraft Walter K. 
Published: June 2021

AbstractResults from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up‐titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning, and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when up‐titration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 µg/kg/day, 33% titration, and 15% wean rate. Five subjects required adjuvant therapy. Half‐maximal effective concentration (EC50) values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model‐based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.
Hydrogen sulfide donor protects against mechanical ventilation‐induced atrophy and contractile dysfunction in the rat diaphragm
Authors: Ichinoseki‐Sekine Noriko , Smuder Ashley J. , Morton Aaron B. , Hinkley James M. , Mor Huertas Andres , Powers Scott K. 
Published: June 2021

AbstractMechanical ventilation (MV) is a clinical tool providing adequate alveolar ventilation in patients that require respiratory support. Although a life‐saving intervention for critically ill patients, prolonged MV results in the rapid development of inspiratory muscle weakness due to both diaphragmatic atrophy and contractile dysfunction; collectively known as “ventilator‐induced diaphragm dysfunction” (VIDD). VIDD is a severe clinical problem because diaphragmatic weakness is a risk factor for difficulties in weaning patients from MV. Currently, no standard treatment to prevent VIDD exists. Nonetheless, growing evidence reveals that hydrogen sulfide (H2S) possesses cytoprotective properties capable of protecting skeletal muscles against several hallmarks of VIDD, including oxidative damage, accelerated proteolysis, and mitochondrial damage. Therefore, we used an established animal model of MV to test the hypothesis that treatment with sodium sulfide (H2S donor) will defend against VIDD. Our results confirm that sodium sulfide was sufficient to protect the diaphragm against both MV‐induced fiber atrophy and contractile dysfunction. H2S prevents MV‐induced damage to diaphragmatic mitochondria as evidenced by protection against mitochondrial uncoupling. Moreover, treatment with sodium sulfide prevented the MV‐induced activation of the proteases, calpain, and caspase‐3 in the diaphragm. Taken together, these results support the hypothesis that treatment with a H2S donor protects the diaphragm against VIDD. These outcomes provide the first evidence that H2S has therapeutic potential to protect against MV‐induced diaphragm weakness and to reduce difficulties in weaning patients from the ventilator.Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Mechanical ventilation (MV) results in diaphragm atrophy and contractile dysfunction, known as ventilator‐induced diaphragm dysfunction (VIDD). VIDD is important because diaphragm weakness is a risk factor for problems in weaning patients from MV. Currently, no accepted treatment exists to protect against VIDD. Growing evidence reveals that hydrogen sulfide (H2S) donors protect skeletal muscle against ischemia‐reperfusion‐induced injury. Nonetheless, it is unknown if treatment with a H2S donor can protect against VIDD.WHAT QUESTION DID THIS STUDY ADDRESS?Can treatment with an H2S donor protect against VIDD?WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?This study provides the first evidence that treatment with a H2S donor protects against VIDD.HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?These new findings provide the basis for further exploration of H2S donors as a therapy to prevent VIDD and reduce the risk of problems in weaning patients from MV.
Pharmacogenomic‐based personalized medicine: Multistakeholder perspectives on implementational drivers and barriers in the Canadian healthcare system
Authors: Subasri Mathushan , Barrett David , Sibalija Jovana , Bitacola Lisa , Kim Richard B. 
Published: June 2021

AbstractPharmacogenomics (PGx)‐based personalized medicine (PM) is increasingly utilized to guide treatment decisions for many drug‐disease combinations. Notably, London Health Sciences Centre (LHSC) has pioneered a PGx program that has become a staple for London‐based specialists. Although implementational studies have been conducted in other jurisdictions, the Canadian healthcare system is understudied. Herein, the multistakeholder perspectives on implementational drivers and barriers are elucidated. Using a mixed‐method qualitative model, key stakeholders, and patients from LHSC’s PGx‐based PM clinic were interviewed and surveyed, respectively. Interview transcripts were thematically analyzed in a stepwise process of customer profiling, value mapping, and business model canvasing. Value for LHSC located specialist users of PGx was driven by the quick turnaround time, independence of the PGx clinic, and the quality of information. Engagement of external specialists was only limited by access and awareness, whereas other healthcare nonusers were limited by education and applicability. The major determinant of successful adoption at novel sites were institutional champions. Patients valued and approved of the service, expressed a general willingness to pay, but often traveled far to receive genotyping. This paper discusses the critical pillars of education, awareness, advocacy, and efficiency required to address implementation barriers to healthcare service innovation in Canada. Further adoption of PGx practices into Canadian hospitals is an important factor for advancing system‐level changes in care delivery, patient experiences, and outcomes. The findings in this paper can help inform efforts to advance clinical PGx practices, but also the potential adoption and implementation of other innovative healthcare service solutions.
Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship
Authors: Karkucinska‐Wieckowska Agnieszka , Simoes Ines C. M. , Kalinowski Piotr , Lebiedzinska‐Arciszewska Magdalena , Zieniewicz Krzysztof , Milkiewicz Piotr , Górska‐Ponikowska Magdalena , Pinton Paolo , Malik Afshan N. , Krawczyk Marcin , Oliveira Paulo J. , Wieckowski Mariusz R. 
Published: June 2021

AbstractAccording to the ‘multiple‐hit’ hypothesis, several factors can act simultaneously in nonalcoholic fatty liver disease (NAFLD) progression. Increased nitro‐oxidative (nitroso‐oxidative) stress may be considered one of the main contributors involved in the development and risk of NAFLD progression to nonalcoholic steatohepatitis (NASH) characterized by inflammation and fibrosis. Moreover, it has been repeatedly postulated that mitochondrial abnormalities are closely related to the development and progression of liver steatosis and NAFLD pathogenesis. However, it is difficult to determine with certainty whether mitochondrial dysfunction or oxidative stress are primary events or a simple consequence of NAFLD development. On the one hand, increasing lipid accumulation in hepatocytes could cause a wide range of effects from mild to severe mitochondrial damage with a negative impact on cell fate. This can start the cascade of events, including an increase of cellular reactive nitrogen species (RNS) and reactive oxygen species (ROS) production that promotes disease progression from simple steatosis to more severe NAFLD stages. On the other hand, progressing mitochondrial bioenergetic catastrophe and oxidative stress manifestation could be considered accompanying events in the vast spectrum of abnormalities observed during the transition from NAFL to NASH and cirrhosis. This review updates our current understanding of NAFLD pathogenesis and clarifies whether mitochondrial dysfunction and ROS/RNS are culprits or bystanders of NAFLD progression.
Predictive factors for a severe course of COVID‐19 infection in myasthenia gravis patients with an overall impact on myasthenic outcome status and survival
Authors: Jakubíková Michala , Týblová Michaela , Tesař Adam , Horáková Magda , Vlažná Daniela , Ryšánková Irena , Nováková Iveta , Dolečková Kristýna , Dušek Pavel , Piťha Jiří , Voháňka Stanislav , Bednařík Josef 
Published: June 2021

AbstractBackground and purposeMyasthenia gravis (MG) patients could be a vulnerable group in the pandemic era of coronavirus 2019 (COVID‐19) mainly due to respiratory muscle weakness, older age and long‐term immunosuppressive treatment. We aimed to define factors predicting the severity of COVID‐19 in MG patients and risk of MG exacerbation during COVID‐19.MethodsWe evaluated clinical features and outcomes after COVID‐19 in 93 MG patients.ResultsThirty‐five patients (38%) had severe pneumonia and we recorded 10 deaths (11%) due to COVID‐19. Higher forced vital capacity (FVC) values tested before COVID‐19 were shown to be protective against severe infection (95% CI 0.934–0.98) as well as good control of MG measured by the quantified myasthenia gravis score (95% CI 1.047–1.232). Long‐term chronic corticosteroid treatment worsened the course of COVID‐19 in MG patients (95% CI 1.784–111.43) and this impact was positively associated with dosage (p = 0.005). Treatment using azathioprine (95% CI 0.448–2.935), mycophenolate mofetil (95% CI 0.91–12.515) and ciclosporin (95% CI 0.029–2.212) did not influence the course of COVID‐19. MG patients treated with rituximab had a high risk of death caused by COVID‐19 (95% CI 3.216–383.971). Exacerbation of MG during infection was relatively rare (15%) and was not caused by remdesivir, convalescent plasma or favipiravir (95% CI 0.885–10.87).ConclusionsAs the most important predictors of severe COVID‐19 in MG patients we identified unsatisfied condition of MG with lower FVC, previous long‐term corticosteroid treatment especially in higher doses, older age, the presence of cancer, and recent rituximab treatment.
ETS‐dependent enhancers for endothelial‐specific expression of serum/glucocorticoid‐regulated kinase 1 during mouse embryo development
Authors: Harada Yukihiro , Tanaka Toru , Arai Yuji , Isomoto Yoshie , Nakano Atsushi , Nakao Shu , Urasaki Akihiro , Watanabe Yusuke , Kawamura Teruhisa , Nakagawa Osamu 
Published: June 2021

AbstractSerum/glucocorticoid‐regulated kinase 1 (SGK1) is predominantly expressed in endothelial cells of mouse embryos, and Sgk1 null mice show embryonic lethality due to impaired vascular formation. However, how the SGK1 expression is controlled in developing vasculature remains unknown. In this study, we first identified a proximal endothelial enhancer through lacZ reporter mouse analyses. The mouse Sgk1 proximal enhancer was narrowed down to the 5’ region of the major transcription initiation site, while a human corresponding region possessed relatively weak activity. We then searched for distal enhancer candidates using in silico analyses of publicly available databases for DNase accessibility, RNA polymerase association and chromatin modification. A region approximately 500 kb distant from the human SGK1 gene was conserved in the mouse, and the mouse and human genomic fragments drove transcription restricted to embryonic endothelial cells. Minimal fragments of both proximal and distal enhancers had consensus binding elements for the ETS transcription factors, which were essential for the responsiveness to ERG, FLI1 and ETS1 proteins in luciferase assays and the endothelial lacZ reporter expression in mouse embryos. These results suggest that endothelial SGK1 expression in embryonic vasculature is maintained through at least two ETS‐regulated enhancers located in the proximal and distal regions.