bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rational Design of Potent Inhibitors of a Metallohydrolase Using a Fragment‐Based Approach
Authors: Feder Daniel , Mohd‐Pahmi Siti H. , Hussein Waleed M. , Guddat Luke W. , McGeary Ross P. , Schenk Gerhard 
Published: July 2021

AbstractMetallohydrolases form a large group of enzymes that have fundamental importance in a broad range of biological functions. Among them, the purple acid phosphatases (PAPs) have gained attention due to their crucial role in the acquisition and use of phosphate by plants and also as a promising target for novel treatments of bone‐related disorders and cancer. To date, no crystal structure of a mammalian PAP with drug‐like molecules bound near the active site is available. Herein, we used a fragment‐based design approach using structures of a mammalian PAP in complex with the MaybridgeTMfragment CC063346, the amino acid L‐glutamine and the buffer molecule HEPES, as well as various solvent molecules to guide the design of highly potent and efficient mammalian PAP inhibitors. These inhibitors have improved aqueous solubility when compared to the clinically most promising PAP inhibitors available to date. Furthermore, drug‐like fragments bound in newly discovered binding sites mapped out additional scaffolds for further inhibitor discovery, as well as scaffolds for the design of inhibitors with novel modes of action.
Update on ICH E14/S7B Cardiac Safety Regulations: The Expanded Role of Preclinical Assays and the “Double‐Negative” Scenario
Authors: Lester Robert M. 
Published: July 2021

AbstractFor nearly 2 decades, regulators have adopted a harmonized approach to drug development, which has succeeded in bringing new pharmaceuticals to market without significant cardiac liability. Ushered in by technological advancements and better understanding of cellular electrophysiology, the initial paradigm detailed in the 2005 International Conference for Harmonization E14 and S7B documents has undergone evolutionary changes designed to streamline drug development and improve regulatory decision‐making and product labeling. The intent of this review is to summarize the new US Food and Drug Administration (FDA) Question and Answer update from August 2020 and key messaging from a subsequent FDA webinar describing best practices for preclinical and clinical data integration into a QT risk prediction model.
Metformin Stimulates Intestinal Glycolysis and Lactate Release: A single‐Dose Study of Metformin in Patients With Intrahepatic Portosystemic Stent
Authors: Rittig Nikolaj , Aagaard Niels K. , Sundelin Elias , Villadsen Gerda E. , Sandahl Thomas D. , Holst Jens J. , Hartmann Bolette , Brøsen Kim , Grønbæk Henning , Jessen Niels 
Published: July 2021

The pharmacodynamic effects of metformin remain elusive, but several lines of evidence suggest a critical role of direct effects in the gastrointestinal (GI) tract. We investigated if metformin stimulates intestinal glucose metabolism and lactate release in the prehepatic circulation. We included eight patients with transjugular intrahepatic portosytemic stent in an open label study. Portal and arterialized peripheral blood was obtained before and 90 minutes after ingestion of 1,000 mg metformin. Metformin increased lactate concentrations by 23% (95% confidence interval (CI): 6–40) after 90 minutes in the portal vein. The plasma concentration of glucose, insulin, and C‐peptide was higher in the portal vein compared with arterialized blood (P < 0.05, all) and was lowered at both sampling sites following metformin ingestion (P < 0.01, all). Plasma concentration of GLP‐1 was 20% (95% CI: 2–38) higher in the portal vein at baseline and metformin increased the concentration with 11% (1.5 pM, P = 0.05). The median concentration of growth differentiation factor 15 was 10% (95% CI: 1–19) higher in the portal vein compared with arterialized blood. Ninety minutes after metformin administration, the median portal vein concentration increased to around 3,000 ng/mL with a mean portal/arterial ratio of 1.5 (95% CI: 1.2–1.8). Non‐targeted metabolomics showed that metformin acutely affected benzoate‐hippurate metabolism. A single‐dose of metformin directly affects substrate metabolism in the upper GI tract in humans with direct stimulation of nonoxidative glucose metabolism. These data suggest glucose lowering effects of metformin can be intrinsically linked with the GI tract without hepatic uptake of the drug.
Non‐neoplastic inflammatory pseudotumor of the lung after immunotherapy for melanoma: A diagnostic pitfall on fine needle aspiration biopsy of lung
Authors: Nelson Blessie Elizabeth , Hong Angelina , Okereke Ike , Markowitz Avi , Willis Maurice , Muthukumarana Palawinnage V. , Nawgiri Ranjana 
Published: July 2021

AbstractNivolumab is commonly used as monotherapy or in combination therapy for management of locally advanced or metastatic melanoma; however, it is also associated with immunotherapy‐related adverse events concerning for disease progression or tumor flare reaction. This report presents a case of a non‐neoplastic pseudotumor of the lung initially mistaken for malignancy that occurred in a patient receiving adjuvant nivolumab therapy following complete resection of stage IIIB melanoma. The diagnosis was made by lung biopsy and confirmed by a wedge resection, with findings consistent with organizing pneumonia type of pulmonary inflammatory pseudotumor rather than malignancy.
Change in eating‐disorder psychopathology network structure in patients with anorexia nervosa treated with intensive cognitive behavior therapy
Authors: Calugi Simona , Dametti Laura , Chimini Mirko , Dalle Grave Anna , Dalle Grave Riccardo 
Published: July 2021

AbstractObjectiveThis study was designed to compare the change in eating‐disorder feature networks in patients with anorexia nervosa after treatment with intensive enhanced cognitive behavior therapy (CBT‐E).MethodsPatients seeking treatment for anorexia nervosa were consecutively recruited from January 2016 to September 2020. All patients aged ≥16 years who completed a 20‐week intensive CBT‐E program (13 weeks of inpatient followed by 7 weeks of day‐hospital treatment) were included in the study. Body mass index (BMI) was measured, and the Eating Disorder Examination Questionnaire completed for each patient, both at baseline and the end of treatment.ResultsThe sample comprised 214 patients with anorexia nervosa. Treated patients showed significant improvements in BMI and eating‐disorder psychopathology. Network analysis revealed a significant reduction in the network global and connection strengths at the end of treatment. The most central and highly interconnected nodes in the network at baseline were related to the drive for thinness, but at the end of treatment to body image concerns. Some edge connections were significantly stronger at baseline than at the end of treatment, while others were significantly stronger at the end of treatment than at baseline.DiscussionCBT‐E reduces the psychopathology network connectivity over time in patients with anorexia nervosa. The differences in central nodes and edge connections between baseline and end of treatment, not detected by classical inferential analysis, may be informative for understanding the centrality of symptoms in the psychopathology network, and how a specific treatment may act to reduce symptoms and change their connections over time.
Establishing conservation units to promote recovery of two threatened freshwater mussel species (Bivalvia: Unionida: Potamilus)
Authors: Smith Chase H. , Johnson Nathan A. , Robertson Clinton R. , Doyle Robert D. , Randklev Charles R. 
Published: July 2021

AbstractPopulation genomics has significantly increased our ability to make inferences about microevolutionary processes and demographic histories, which have the potential to improve protection and recovery of imperiled species. Freshwater mussels (Bivalvia: Unionida) represent one of the most imperiled groups of organisms globally. Despite systemic decline of mussel abundance and diversity, studies evaluating spatiotemporal changes in distribution, demographic histories, and ecological factors that threaten long‐term persistence of imperiled species remain lacking. In this study, we use genotype‐by‐sequencing (GBS) and mitochondrial sequence data (mtDNA) to define conservation units (CUs) for two highly imperiled freshwater mussel species, Potamilus amphichaenus and Potamilus streckersoni. We then synthesize our molecular findings with details from field collections spanning from 1901 to 2019 to further elucidate distributional trends, contemporary status, and other factors that may be contributing to population declines for our focal species. We collected GBS and mtDNA data for individuals of P. amphichaenus and P. streckersoni from freshwater mussel collections in the Brazos, Neches, Sabine, and Trinity drainages ranging from 2012 to 2019. Molecular analyses resolved disputing number of genetic clusters within P. amphichaenus and P. streckersoni; however, we find defensible support for four CUs, each corresponding to an independent river basin. Evaluations of historical and recent occurrence data illuminated a generally increasing trend of occurrence in each of the four CUs, which were correlated with recent increases in sampling effort. Taken together, these findings suggest that P. amphichaenus and P. streckersoni are likely rare throughout their respective ranges. Because of this, the establishment of CUs will facilitate evidence‐based recovery planning and ensure potential captive propagation and translocation efforts are beneficial. Our synthesis represents a case study for conservation genomic assessments in freshwater mussels and provides a model for future studies aimed at recovery planning for these highly imperiled organisms.
Closely related parasitic plants have similar host requirements and related effects on hosts
Authors: Matthies Diethart 
Published: July 2021

AbstractThe performance of root hemiparasites depends strongly on host species identity, but it remains unknown whether there exist general patterns in the quality of species as hosts for hemiparasites and in their sensitivity to parasitism. In a comparative approach, the model root hemiparasites Rhinanthus minor and R. alectorolophus were grown with 25 host species (grasses, forbs, and legumes) at two nutrient levels. Hosts grown without parasites served as a control. Host species identity strongly influenced parasite biomass and other traits, and both parasites grew better with legumes and grasses than with forbs. The biomass of R. alectorolophus was much higher than that of R. minor with all host plants and R. alectorolophus responded much more strongly to higher nutrient availability than R. minor. The performance of the two species of Rhinanthus with individual hosts was strongly correlated, and it was also correlated with that of R. alectorolophus and the related Odontites vulgaris in previous experiments with many of the same hosts, but only weakly with that of the less closely related Melampyrum arvense. The negative effect of R. minor on host biomass was less strong than that of R. alectorolophus, but stronger relative to its own biomass, suggesting that it is more parasitic. The impact of the two parasites on individual hosts did not depend on nutrient level and was correlated. Several legumes and grasses were tolerant of parasitism. While R. minor slightly reduced mean overall productivity, R. alectorolophus increased it with several species, indicating that the loss of host biomass was more than compensated by that of the parasite. The results show that closely related parasites have similar host requirements and correlated negative effects on individual hosts, but that there are also specific interactions between pairs of parasitic plants and their hosts.
Upland grassland management influences organo‐mineral soil properties and their hydrological function
Authors: Bond Stephanie , Kirkby Mike J. , Holden Joseph 
Published: July 2021

AbstractLand‐use change acts as a potential moderator of flood risk, affecting vegetation and soil properties and thus influencing the storage and flow of water across landscapes. This study, conducted in northwest England, investigated physical soil properties and their hydrological function using overland flow and soil moisture sensors, for five upland grassland habitats each created through management action. Overland flow was common, occurring up to 60% of the time with longer durations in grassland excluded from grazing with higher density vegetation. Soil moisture varied significantly between grassland habitats, but there was no clear soil moisture threshold for overland flow. Surface soil properties to 5‐cm depth varied significantly between grassland types, with saturated hydraulic conductivity (Ks) ranging across several orders of magnitude from 1.3 × 10−3to 1.5 × 102 m day−1. With shallow soils and a medianKsof 2.4 m day−1, saturation‐excess overland flow was determined as the main driver of flood risk. Landscape management was found to be a significant driver of soil physical and hydrological properties in upland grasslands and therefore should be strongly considered as part of flood management.
Bulky and Electron‐Deficient α‐Iminocarboxamidato‐Nickel(II) Complexes: A Study of the Steric and Electronic Effects on Ethylene Activation
Authors: Skarjan Leon , Villegas‐Escobar Nery , Correa Sebastián A. , Daniliuc Constantin G. , Matute Ricardo A. , Rojas René S. 
Published: July 2021

AbstractTwo α‐iminocarboxamidato‐nickel(II) complexes containing ligands with several CF3 groups were synthesized and characterized by NMR spectroscopy, elemental analysis, and density functional theory (DFT) calculations. Surprisingly, the prepared complexes were inactive toward ethylene oligo/polymerization reactions upon activation attempts with common lewis acid co‐catalysts such as B(C6F5)3 and BF3. Quantum chemistry calculations were employed to reveal that adduct formation is thermodynamically favored for small Lewis acids such as BF3 due to the sterically demanding ligand environment of the complex, confirming the experimental findings. DFT results associate the lack of polymerization activity with a highly unfavorable steric environment, undesirable London dispersion interactions between the ligands, and a strong electrostatic stabilization caused by the employed ligands. Our findings should help future researchers to identify necessary electronic and steric requirements for the compounds to generate active Ni(II) catalysts for ethylene oligo/polymerization activated by suitable boron Lewis acids.
Lewis‐Acid‐Catalyzed (3+2)‐Cycloadditions of Donor‐Acceptor Cyclopropanes with Thioketenes
Authors: Mlostoń Grzegorz , Kowalczyk Mateusz , Augustin André U. , Jones Peter G. , Werz Daniel B. 
Published: July 2021

AbstractThe reactivity of donor‐acceptor (D‐A) cyclopropanes towards thioketenes was investigated. In a (3+2)‐cycloaddition using Sc(OTf)3 as a Lewis acidic catalyst, the corresponding exocyclic thioenol ethers (2‐methylidene tetrahydrothiophenes) were formed in moderate to good yields. Unsymmetrical thioketenes provided E/Z mixtures at the double bond, with the Z isomer being preferred.
Comprehensive mechanics‐based virtual model of NHERI@UCSD shake table—Uniaxial configuration and bare table condition
Authors: Ozcelik Ozgur , Conte Joel P. , Luco J. Enrique 
Published: July 2021

AbstractA mechanics‐based virtual model of the NHERI@UCSD large high‐performance outdoor shake table (LHPOST) in its uniaxial configuration and under bare table condition is presented. The virtual model includes: (i) a reprogrammed version (i.e., virtual replica) of the actual controller, (ii) a servovalve model including servovalve spool dynamics and two independent servovalve flow nonlinearities for each of the four servovalves of the system, (iii) an actuator model for each of the two single‐ended actuators, (iv) two accumulators modeling the average supply pressure drop at the entrance of the servovalves, and (v) a one‐degree‐of‐freedom mechanical subsystem model. Based on forced vibration test results for the foundation block, it was found that the soil‐foundation compliance effects do not need to be included in the virtual model of the LHPOST. The virtual model presented is able to predict accurately the actual shake table platen response under narrow and broadband inputs with the controller gains set to the same values as on the actual shake table. Moreover, the fourth stage spool displacements and actuator driving force from actual tests are reproduced accurately by the virtual model. The mechanics‐based virtual model presented in this article can be coupled with FE models of specimens to be tested on the LHPOST and can be used to improve the signal reproduction fidelity of the LHPOST and to develop more advanced model‐based shake table controllers.
Hydrocarbon gas leakage from high‐pressure system in the Yanan Sag, Qiongdongnan Basin, South China Sea
Authors: Su Ao , Chen Honghan , Yang Wei , Feng Yue‐xing , Zhao Jian‐xin , Lei Mingzhu 
Published: July 2021

Despite high pressure being ubiquitous in the Yanan Sag of the Qiongdongnan Basin, South China Sea, its potential effect on gas migration‐accumulation remains unclear. In this study, a series of geochemical indicators combined with the origin of high pressure were used to elucidate the cause of gas accumulation failure in the overpressured YC19‐1 structure. Drill‐stem tests, mud weights, and well‐loggings reveal two vertical overpressure systems. Pore pressure in the deep Lingshui and Yacheng formations almost reaches a lithostatic magnitude, which was interpreted as a result of gas generation and disequilibrium compaction triggered by the Pliocene‐Quaternary rapid subsidence. A thermal anomaly above the high‐pressure system was evidenced by high homogenization temperature (Th) of fluid inclusion, abnormally high vitrinite reflectance, and a rapid transformation from kaolinite to illite. The high thermal field likely resulted from a cross‐stratal fluid migration from the deep high‐pressure system. Both methane‐bearing inclusions in sandstones and abnormal Rock‐Eval data of mudstones above the high‐pressure surface suggest an influx of external hydrocarbons. Based on primary aqueous inclusion Th and salinity, carbon and oxygen isotope compositions, and petrographic observations, widespread silica and carbonate cements near the overpressure surface were interpreted to be derived from extraformational materials carried by deep‐seated basinal fluids. Fluid inclusion Th coupled with burial model suggests that the gas leakage took place at circa 1.6 Ma, coinciding well with the stages of both gas generation and overpressure. These observations suggest an upward leakage of gas‐bearing fluids induced by pressure release, thus leading to the existence of only non‐commercial gas‐bearing aquifers in the overpressured YC19‐1 structure.
Dynamic brain connectome and high risk of mental problem in clinical nurses
Authors: Bai Ling , JI Gong‐Jun , Song Yongxia , Sun Jinmei , Wei Junjie , Xue Fang , Zhu Lu , Li Rui , Han Yanfang , Zhang Liu , Yang Jinying , Qiu Bensheng , Wu Guo‐Rong , Zhang Jing , Hong Jingfang , Wang Kai , Zhu Chunyan 
Published: July 2021

AbstractWith the growing population and rapid change in the social environment, nurses in China are suffering from high rates of stress; however, the neural mechanism underlying this occupation related stress is largely unknown. In this study, mental status was determined for 81 nurses and 61 controls using the Symptom Checklist 90 (SCL‐90) scale. A subgroup (n = 57) was further scanned by resting‐state functional MRI with two sessions. Based on the SCL‐90 scale, “somatic complaints” and “diet/sleeping” exhibited the most prominent difference between nurses and controls. This mental health change in nurses was further supported by the spatial independent component analysis on functional MRI data. First, dynamic functional connectome analysis identified two discrete connectivity configurations (States I and II). Controls had more time in the State I than II, while the nurses had more time in the State II than I. Second, nurses showed a similar static network topology as controls, but altered dynamic properties. Third, the symptom‐imaging correlation analysis suggested the functional alterations in nurses as potential imaging biomarkers indicating a high risk for “diet/sleeping” problems. In summary, this study emphasized the high risk of mental deficits in nurses and explored the underlying neural mechanism using dynamic brain connectome, which provided valuable information for future psychological intervention.
Distributional consequences of including survivor costs in economic evaluations
Authors: Kellerborg Klas , Brouwer Werner , Versteegh Matthijs , Wouterse Bram , van Baal Pieter 
Published: July 2021

AbstractMedical interventions that increase life expectancy of patients result in additional consumption of non‐medical goods and services in ‘added life years’. This paper focuses on the distributional consequences across socio‐economic groups of including these costs in cost effectiveness analysis. In that context, it also highlights the role of remaining quality of life and household economies of scale. Data from a Dutch household spending survey was used to estimate non‐medical consumption and household size by age and educational attainment. Estimates of non‐medical consumption and household size were combined with life tables to estimate what the impact of including non‐medical survivor costs would be on the incremental cost effectiveness ratio (ICER) of preventing a death at a certain age. Results show that including non‐medical survivor costs increases estimated ICERs most strongly when interventions are targeted at the higher educated. Adjusting for household size (lower educated people less often live additional life years in multi‐person households) and quality of life (lower educated people on average spend added life years in poorer health) mitigates this difference. Ignoring costs of non‐medical consumption in economic evaluations implicitly favors interventions targeted at the higher educated and thus potentially amplifies socio‐economic inequalities in health.
Extracapsular extension, pathologic node status, and adjuvant treatment in primary surgery patients with human papillomavirus‐mediated oropharyngeal cancer: National hospital‐based retrospective cohort analysis
Authors: Day Andrew T. , Yang Alex M. , Tanamal Priscilla , Blackwell James‐Michael , Wang Ellen , Sumer Baran D. , Bishop Justin A. , Hughes Randall S. , Khan Saad A. , Sher David J. 
Published: July 2021

AbstractBackgroundThe significance of extracapsular extension (ECE) and adjuvant treatment paradigm in patients with surgically managed human papillomavirus‐positive (HPV+) oropharyngeal cancer (OPC) is debated.MethodsNational, hospital‐based, retrospective cohort study of 2663 patients pN+ HPV+ OPC who underwent primary surgery.ResultsPatients with ECE had a 1.74‐times risk of death (95% confidence interval [CI]: 1.26–2.40, p = 0.001) compared to patients without ECE. Among patients with pN1, ECE‐positive disease, risk of overall mortality was similar across treatment paradigms (surgery alone: ref; adjuvant radiation therapy [RT]: aHR: 0.81; 95% CI: 0.36–1.85; p = 0.62; adjuvant CRT: aHR: 0.66; 95% CI: 0.34–1.32; p = 0.24). Patients with pN2 ECE‐positive disease treated with adjuvant RT alone exhibited similar risk of all‐cause mortality (hazard ratio: 1.04, 95% CI: 0.24–4.47, p = 0.96) compared to adjuvant chemoradiation (CRT). In patients with advanced, ECE‐positive disease (e.g., pT3‐T4pN2), adjuvant CRT did not reduce the risk of overall mortality relative to adjuvant RT.ConclusionAlthough pathologic ECE negatively predicts for survival in patients with HPV+ OPC, our analyses support expansion of postoperative de‐intensification clinical trial eligibility criteria in patients with ECE‐positive disease.