bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Target‐Mediated Drug Disposition Model to Explain Nonlinear Pharmacokinetics of the 11β‐Hydroxysteroid Dehydrogenase Type 1 Inhibitor SPI‐62 in Healthy Adults
Authors: Wu Nan , Katz David A. , An Guohua 
Published: June 2021

AbstractSPI‐62 is a selective and potent small‐molecule inhibitor of 11β‐hydroxysteroid dehydrogenase type 1 (HSD‐1). SPI‐62 has demonstrated substantial and complex nonlinear pharmacokinetics (PK) in humans that is characterized by unusually low plasma exposure at low doses, dose‐dependent volume of distribution, nonlinear PK following the first dose, and dose‐proportional PK at steady state, as well as unusually high accumulation ratios at low doses. The most likely explanation for the observed nonlinearity of SPI‐62 is the saturable binding of SPI‐62 to its pharmacological target HSD‐1, a phenomenon known as target‐mediated drug disposition (TMDD). Because of the nonlinear and complex PK of SPI‐62, the relationship among SPI‐62 dose, exposure, and response is no longer intuitive and consequently dose selection can be challenging. To facilitate dose selection and clinical trial design, in the current study population PK analysis was performed to characterize SPI‐62 dose‐exposure relationship in humans quantitatively. SPI‐62 PK was best characterized by a 2‐compartment TMDD model with 3 transit absorption compartments. The model was successfully established to explain the substantial and unusual nonlinear PK of SPI‐62 in humans, and it provided adequate fitting for both single‐ and multiple‐dose data. Our modeling work has provided a strong foundation for dose selection in future SPI‐62 clinical trials.
The symmetry property of (n,k)‐arrangement graph
Authors: Yin Fu‐Gang , Feng Yan‐Quan , Zhou Jin‐Xin , Guo Yu‐Hong 
Published: June 2021

AbstractThe ‐arrangement graph with , is the graph with vertex set the ordered ‐tuples of distinct elements in and with two ‐tuples adjacent if they differ in exactly one of their coordinates. The ‐arrangement graph was proposed by Day and Tripathi in 1992, and is a widely studied interconnection network topology. The Johnson graph with , is the graph with vertex set the ‐element subsets of , and with two ‐element subsets adjacent if their intersection has elements. In 1989, Brouwer, Cohen and Neumaier determined the automorphism group of , and in 2015, Dobson and Malnič proved that a is Cayley graph if and only if , or with being a prime‐power. In this article we prove that , and as a byproduct, is a normal cover of . Furthermore, is a Cayley graph if and only if , , , , , , , , , , , or , where is a prime‐power. Note that the graph is called the ‐star graph, and its automorphism group can be deduced from a general result given by Feng in 2006. In 1998, Chiang and Chen proved that is a Cayley graph on the alternating group , and in 2011, Zhou determined the automorphism group of .
Projected temperature and precipitation changes using the LARS‐WG statistical downscaling model in the Shire River Basin, Malawi
Authors: Kavwenje Sheila , Zhao Lin , Chen Liang , Chaima Evance 
Published: June 2021

AbstractThis study analyzes local‐scale temperature and precipitation projections in the Shire River Basin (SRB) in Malawi using 10 global circulation models (GCMs) available in the coupled model intercomparison project phase 5 (CMIP5), under two representative concentration pathways (RCP 4.5 and RCP 8.5). For nine stations in the study area, large‐scale maximum temperature (Tmax), minimum temperature (Tmin) and precipitation data from the selected GCMs were downscaled by the sixth version of the Long Ashton Research Station Weather Generator (LARS‐WG6). The mean seasonal and annual change projections for Tmax, Tmin and precipitation during two future periods, that is, the middle future (2041–2070) and late future (2071–2100) periods were analyzed. Modelling results demonstrated that the LARS‐WG model is capable of simulating temperature more accurately than precipitation in the SRB. All 10 GCMs revealed that continually rising temperatures are anticipated in the study area; however, the projected magnitude of change varied across GCMs and between RCPs. Generally, the increase in average Tmax and Tmin was observed to be higher under RCP 8.5 compared with RCP 4.5 due to unmitigated greenhouse gas emissions (GHGs). Future precipitation change results showed more complexity and uncertainty than for temperature; not all GCMs agree on whether there will be positive or negative changes in precipitation and no systematic variations under RCP4.5 and RCP8.5 were observed during the two future time period, illustrating that both GCMs and RCPs are important sources of the relatively large uncertainties in future precipitation projections in the SRB. Thus, this study indicated that uncertainties constrained by both GCMs and RCPs are crucial and need to always be considered when executing climate impact studies and adaptation, particularly at river basin level.
New gridded rainfall dataset over the Korean peninsula: Gap infilling, reconstruction, and validation
Authors: Noh Gyu‐Ho , Ahn Kuk‐Hyun 
Published: June 2021

AbstractThis study describes a new high‐resolution latitude/longitude) gridded daily rainfall dataset (K‐Hidra version 2020) developed from rainfall records of 389 gauge stations irregularly distributed across the Korean peninsula. The observational datasets are often composed of incomplete time series covering different temporal periods with numerous missing values, informing that infilling process is essential. Three supportive but separated evaluation frameworks, which have been paid less attention to, are explicitly addressed to identify the proper infilling model in the study area. After a gridded rainfall dataset is created with infilled dataset, it is validated by comparing the gridded products obtained by observations. Furthermore, K‐Hidra is compared with other gridded rainfall estimates including Climate Prediction Center (CPC), Global Precipitation Climatology Project (GPCP), Asian Precipitation Highly‐Resolved Observational Data Integration Towards Evaluation (APHRODITE), and Tropical Rainfall Measuring Missing (TRMM) Multi‐satellite Precipitation Analysis (TMPA). Our results suggest that the elastic net model algorithm is the most effective in dealing with missing values in the study area. Results also demonstrate that the infilling process is vital to properly produce the reconstructed series although its effects substantially vary based on the size of the available data as well as the spatial and temporal distribution of the observed precipitation. Furthermore, K‐Hidra reveals that the Korean peninsula have experienced significant changes in precipitation‐related characteristics such as annual daily maximum precipitation and total annual dry days, likely leading to frequent hydrologic extremes. Lastly, K‐Hidra is compared with other estimates, CPC has a small bias and high correlations with the new dataset while precipitation variabilities are acceptably represented by all other gridded estimates. From the results demonstrated in this study, when officially released, K‐Hidra is expected to be useful for climate impact and rainfall variability analyses over the Korean peninsula.
Sentinel lymph node biopsy guideline concordance in melanoma: Analysis of the National Cancer Database
Authors: Narang Jatin , Hue Jonathan J. , Bingmer Katherine , Hardacre Jeffrey M. , Winter Jordan M. , Ocuin Lee M. , Ammori John B. , Mangla Ankit , Bordeaux Jeremy , Rothermel Luke D. 
Published: June 2021

AbstractBackground and ObjectivesThis study investigated the impact of treating facility type on guideline‐concordant sentinel lymph node biopsy (SLNB) management in T1a* (defined as a Breslow depth <0.76 mm without ulceration or mitoses) and T2/T3 melanoma.MethodsThis was a retrospective cohort study utilizing the National Cancer Database from 2012 to 2016.ResultsOur cohort included 109,432 patients. For T1a* melanomas, 85% of patients received guideline‐concordant SLNB management at community and academic facilities versus 75% of patients at integrated network facilities (p < .001). Over 83% of patients with T2/T3 melanoma treated at an academic facility received guideline‐concordant SLNB management versus 77% treated at a community facility (p < .001). Adjusting for demographic and clinical factors, integrated (adjusted odds ratio, aOR = 0.54), and comprehensive community (aOR = 0.74) facilities were less likely to provide guideline‐concordant SLNB management in patients with T1a* melanoma compared to academic facilities. Community facilities (aOR = 0.72) were less likely to provide guideline‐concordant SLNB management in patients with T2/T3 melanoma compared to academic facilities.ConclusionAcademic facilities provide the highest rate of guideline‐concordant sentinel lymph node management. Comparatively, community programs may underutilize SLNB in T2/T3 disease, while integrated and comprehensive community facilities may over‐utilize SLNB in T1a* disease.
Flood‐prone area mapping using GIS‐based analytical hierarchy frameworks for Ibadan city, Nigeria
Authors: Ajibade Fidelis Odedishemi , Ajibade Temitope Fausat , Idowu Temitope Ezekiel , Nwogwu Nathaniel Azubuike , Adelodun Bashir , Lasisi Kayode Hassan , Opafola Omobolaji Taofeek , Ajala Oluwaseyi Aderemi , Fadugba Olaolu George , Adewumi James Rotimi 
Published: June 2021

AbstractFlood is one of the highly pronounced ruinous naturally occurring environmental hazards in which human lives and properties are gravely endangered. This study assessed areas prone to flood in Ibadan City, Nigeria. The study applied two multi‐criteria analysis approach—Analytical Hierarchy Process (AHP) and the Fuzzy Analytical Hierarchy Process (FAHP) with the aid of GIS. Ten geomorphological physical characteristics agreed upon by experts as the major factors influencing the susceptibility of an area to floods formed the criteria maps used in this study. The natural breaks and geometrical interval clustering techniques were utilised to group the final flood‐prone area maps into five categories—very low, low, moderate, high, and very high. The result indicated that over 50% of the study area either have low or moderate susceptibility to flooding. The clustering techniques showed some slight differences in the flood classifications where natural breaks consistently grouped more areas into the “very high” category and relatively fewer areas to “very low” category in comparison to the geometrical interval technique. Overall, at least 451 km2 (about 15% of Ibadan) is highly or very highly prone to floods, and these areas are mainly concentrated in the urban and semi‐urban regions of the study area. The findings and maps developed in this study would adequately serve as a planning guide for the policymakers on urban development and flood risk management to achieve sustainable development and management.
Molecular mechanisms of chemo‐ and radiotherapy resistance and the potential implications for cancer treatment
Authors: Liu Ya‐Ping , Zheng Can‐Can , Huang Yun‐Na , He Ming‐Liang , Xu Wen Wen , Li Bin 
Published: June 2021

AbstractCancer is a leading cause of death worldwide. Surgery is the primary treatment approach for cancer, but the survival rate is very low due to the rapid progression of the disease and presence of local and distant metastasis at diagnosis. Adjuvant chemotherapy and radiotherapy are important components of the multidisciplinary approaches for cancer treatment. However, resistance to radiotherapy and chemotherapy may result in treatment failure or even cancer recurrence. Radioresistance in cancer is often caused by the repair response to radiation‐induced DNA damage, cell cycle dysregulation, cancer stem cells (CSCs) resilience, and epithelial‐mesenchymal transition (EMT). Understanding the molecular alterations that lead to radioresistance may provide new diagnostic markers and therapeutic targets to improve radiotherapy efficacy. Patients who develop resistance to chemotherapy drugs cannot benefit from the cytotoxicity induced by the prescribed drug and will likely have a poor outcome with these treatments. Chemotherapy often shows a low response rate due to various drug resistance mechanisms. This review focuses on the molecular mechanisms of radioresistance and chemoresistance in cancer and discusses recent developments in therapeutic strategies targeting chemoradiotherapy resistance to improve treatment outcomes.
Novel compound heterozygous STN1 variants are associated with Coats Plus syndrome
Authors: Acharya Tanvi , Firth Helen V. , Dugar Shilpa , Grammatikopoulos Tassos , Seabra Luis , Walters Angharad , Crow Yanick J. , Parker Alasdair P. J. 
Published: June 2021

AbstractAimCoats plus syndrome (CP) is a rare autosomal recessive disorder, characterised by retinal telangiectasia exudates (Coats disease), leukodystrophy, distinctive intracranial calcification and cysts, as well as extra‐neurological features including abnormal vasculature of the gastrointestinal tract, portal hypertension and osteopenia with a tendency to fractures. CP most frequently occurs due to loss‐of‐function mutations in CTC1. The encoded protein CTC1 constitutes part of the CST (CTC1‐STN1‐TEN1) complex, and three patients have been described with CP due to biallelic mutations in STN1. Together with the identification of homozygosity for a specific loss‐of‐function mutation in POT1 in a sibling pair, these observations highlight a defect in the maintenance of telomere integrity as the cause of CP, although the precise mechanism leading to the micro‐vasculopathy seen at a pathological level remains unclear. Here, we present the investigation of a fourth child who presented to us with retinal exudates, intracranial calcifications and developmental delay, in keeping with a diagnosis of CP, and later went on to develop pancytopenia and gastrointestinal bleeding. Genome sequencing revealed compound heterozygous variants in STN1 as the likely genetic cause of CP in this present case.MethodsWe assessed the phenotype to be CP and undertook targeted sequencing.ResultsWhilst sequencing of CTC1 and POT1 was normal, we identified novel compound heterozygous variants in STN1 (previous gene symbol OBFC1): one loss‐of‐function––c.894dup (p.(Asp299Argfs*58)); and one missense––c.707T>C (p.(Leu236Pro)).ConclusionGiven the clinical phenotype and identified variants we suggest that this is only the fourth patient reported to date with CP due to mutations in STN1.
Pepsin Digest of Gliadin Forms Spontaneously Amyloid‐Like Nanostructures Influencing the Expression of Selected Pro‐Inflammatory, Chemoattractant, and Apoptotic Genes in Caco‐2 Cells: Implications for Gluten‐Related Disorders
Authors: Herrera Maria Georgina , Nicoletti Francesco , Gras Marion , Dörfler Philipp W. , Tonali Nicolo , Hannappel Yvonne , Ennen Inga , Hütten Andreas , Hellweg Thomas , Lammers Karen M. , Dodero Veronica I. 
Published: June 2021

ScopeProteolysis‐resistant gliadin peptides are intensely investigated in biomedical research relates to celiac disease and gluten‐related disorders. Herein, the first integrated supramolecular investigation of pepsin‐digested gliadin peptides (p‐gliadin) is presented in combination with its functional behavior in the Caco‐2 cell line.Methods and ResultsFirst, gliadins are degraded by pepsin at pH 3, and the physicochemical properties of p‐gliadin are compared with gliadin. An integrated approach using interfacial, spectroscopic, and microscopic techniques reveals that the p‐gliadin forms spontaneously soluble large supramolecular structures, mainly oligomers and fibrils, capable of binding amyloid‐sensitive dyes. The self‐assembly of p‐gliadin starts at a concentration of 0.40 µg mL−1. Second, the stimulation of Caco‐2 cells with the p‐gliadin supramolecular system is performed, and the mRNA expression levels of a panel of genes are tested. The experiments show that p‐gliadin composed of supramolecular structures triggers significant mRNA up‐regulation (p < 0.05) of pro‐apoptotic biomarkers (ratio Bcl2/Bak‐1), chemokines (CCL2, CCL3, CCL4, CCL5, CXCL8), and the chemokine receptor CXCR3.ConclusionsThis work demonstrates that p‐gliadin is interfacial active, forming spontaneously amyloid‐type structures that trigger genes in the Caco‐2 cell line involved in recruiting specialized immune cells.
Microwave curing kinetics of carbon‐fiber‐reinforced epoxy composites by wet filament winding process
Authors: Li Mengying , Xiao Jun , Wang Xingbang , Yang Xiao , Chen Xiaodong 
Published: June 2021

AbstractA high‐performance compound epoxy resin system suitable for wet filament winding was designed. The glass transition temperature reached 181.3°C, and the tensile strength, tensile modulus, and elongation of the resin casting body were 90.82 MPa, 3312.72 MPa, and 4.17%, respectively. In order to explore the mechanism of microwave curing, the microwave curing kinetics of the composites was studied. Based on differential scanning calorimetry, the curing degree and curing reaction rate of thermal and microwave curing composites were compared. The results showed that the curing degree and curing reaction rate of microwave curing composites were higher than that of thermal curing in the early and middle stages of curing reaction. The heat transfer mechanism model was proposed. The heat transfer of carbon fiber after absorbing wave is the reason for the above‐mentioned phenomenon. In the later stage of curing reaction, the steric hindrance effect is greater than that of heat transfer mechanism on curing degree and curing rate, so there is little difference between the two curing methods. The kinetic parameters of thermal and microwave curing were calculated by the Malek method, and the activation energies were 70.40 kJ/mol and 61.18 kJ/mol, respectively. The correlation coefficient R2between the curing degree calculated by kinetic equation of microwave curing and measured by experiment was 0.951, indicating that the kinetic equation was in good agreement with the experimental results.
Temperature effect on the single and repeated impact responses of intraply flax/basalt hybrid polypropylene composites
Authors: Ferrante Luca , Sergi Claudia , Tirillò Jacopo , Russo Pietro , Calzolari Andrea , Sarasini Fabrizio 
Published: June 2021

AbstractLow‐velocity impacts can severely jeopardize the structural reliability of polymer composites. In view of this, the present work provides a thorough overview of the impact response of polypropylene (PP) composites reinforced with an ecofriendly intraply flax/basalt hybrid fabric, assessing the effect of different parameters: energy level, temperature, and number of impacts. Indeed, high‐energy single impacts are as dangerous as low‐energy repeated impacts for the structural integrity of laminates. Moreover, considering the poor interfacial adhesion between hydrophobic polyolefin matrices and hydrophilic vegetable fibers, the effect of a maleic anhydride coupling agent was evaluated. A detrimental effect of coupling agent on composites impact response was observed, determining a reduction of the impact life (impacts to failure from 83 to 63 at 10 J and from 30 to 9 at 15 J) because several energy dissipation mechanisms were prevented. Decreasing temperatures (−40°C) caused an embrittlement effect on neat PP composites with an increase between 7.3% and 20.3% of maximum force and a decrease between 7.5% and 10.9% of maximum displacement, whereas increasing temperatures (80°C) led to a softening of compatibilized composites with a decrease between 13.8% and 27.5% of maximum force and an increase between 28.1% and 34.4% of maximum displacement.
Twenty‐year trends in prostate cancer stage and grade migration in a large contemporary german radical prostatectomy cohort
Authors: Würnschimmel Christoph , Kachanov Mykyta , Wenzel Mike , Mandel Philipp , Karakiewicz Pierre I. , Maurer Tobias , Steuber Thomas , Tilki Derya , Graefen Markus , Budäus Lars 
Published: June 2021

AbstractBackgroundA trend towards inverse stage migration in prostate cancer (PCa) was reported. However, previous analyses did not take into account potential differences in sampling strategies (number of biopsy cores), which might have confounded these reports.Material and MethodsWithin our single‐institutional database we identified PCa patients treated with radical prostatectomy (RP) between 2000 and 2020 (n = 21,646). We calculated the estimated annual percentage change (EAPC) for D'Amico risk groups, biopsy Gleason Grade Group (GGG), PSA and cT stage as well as postoperative RP GGG and pT stage relying on log linear regression methodology. Subsequently, we repeated the analyses after adjustment for number of cores obtained at biopsy.ResultsAbsolute rates of D'Amico low risk decreased (−30.1%), while intermediate and high risk increased (+21.2% and +9.0%, respectively). Rates of GGG I decreased (−50.0%), while GGG II–V increased, with the largest increase in GGG II (+22.5%). This trend, albeit less pronounced, was also recorded after adjusted EAPC analyses (p < .05). Specifically, EAPC values for D'Amico low vs intermediate vs high risk were −1.07%, +0.37%, +0.45%, respectively, and EAPC values for GGG ranged between −0.71% (GGG I) and +0.80% (GGG IV). Finally, an increase in ≥cT2 (EAPC: +3.16%) was displayed (all p < .001). These trends were confirmed in EAPC calculations in RP GGG and pT stages (p < .001).ConclusionOur findings confirm the trend towards less frequent treatment of low risk PCa and more frequent treatment of high risk PCa, also after adjustment for number of biopsy cores.
Deep learning approach for guiding three‐dimensional computed tomography reconstruction of lower limbs for robotically‐assisted total knee arthroplasty
Authors: Li Zheng , Zhang Xiaofeng , Ding Lele , Du Kebin , Yan Jun , Chan Matthew T. V. , Wu William K. K. , Li Shugang 
Published: June 2021

AbstractBackgroundRobotic‐assisted total knee arthroplasty (TKA) was performed to promote the accuracy of bone resection and mechanical alignment. Among these TKA system procedures, 3D reconstruction of CT data of lower limbs consumes significant manpower. Artificial intelligence (AI) algorithms applying deep learning has been proved efficient in automated identification and visual processing.MethodsCT data of a total of 200 lower limbs scanning were used for AI‐based 3D model construction and CT data of 20 lower limbs scanning were utilised for verification.ResultsWe showed that the performance of an AI‐guided 3D reconstruction of CT data of lower limbs for robotic‐assisted TKA was similar to that of the operator‐based approach. The time of 3D lower limb model construction using AI was 4.7 min. AI‐based 3D models can be used for surgical planning.ConclusionAI was used for the first time to guide the 3D reconstruction of CT data of lower limbs for facilitating robotic‐assisted TKA. Incorporation of AI in 3D model reconstruction before TKA might reduce the workload of radiologists.