bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel pathomechanism for spontaneous bacterial peritonitis: disruption of cell junctions by cellular and bacterial proteases
Authors: Haderer Marika , Neubert Philip , Rinner Eva , Scholtis Annika , Broncy Lucile , Gschwendtner Heidi , Kandulski Arne , Pavel Vlad , Mehrl Alexander , Brochhausen Christoph , Schlosser Sophie , Gülow Karsten , Kunst Claudia , Müller Martina
Published: March 2021

Objective

Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of liver cirrhosis with a 1-year mortality of 66%. Bacterial translocation (BT) from the intestine to the mesenteric lymph nodes is crucial for the pathogenesis of SBP.

Design

Since BT presupposes a leaky intestinal epithelium, the integrity of mucus and epithelial cell junctions (E-cadherin and occludin) was examined in colonic biopsies from patients with liver cirrhosis and controls. SBP-inducing Escherichia coli (E. coli) and Proteus mirabilis (P. mirabilis) were isolated from ascites of patients with liver cirrhosis and co-cultured with Caco-2 cells to characterise bacteria-to-cell effects.

Results

SBP-derived E. coli and P. mirabilis led to a marked reduction of cell-to-cell junctions in a dose-dependent and time-dependent manner. This effect was enhanced by a direct interaction of live bacteria with epithelial cells. Degradation of occludin is mediated via increased ubiquitination by the proteasome. Remarkably, a novel bacterial protease activity is of pivotal importance for the cleavage of E-cadherin.

Conclusion

Patients with liver cirrhosis show a reduced thickness of colonic mucus, which allows bacteria-to-epithelial cell contact. Intestinal bacteria induce degradation of occludin by exploiting the proteasome of epithelial cells. We identified a novel bacterial protease activity of patient-derived SBP-inducing bacteria, which is responsible for the cleavage of E-cadherin structures. Inhibition of this protease activity leads to stabilisation of cell junctions. Thus, targeting these mechanisms by blocking the ubiquitin-proteasome system and/or the bacterial protease activity might interfere with BT and constitute a novel innovative therapeutic strategy to prevent SBP in patients with liver cirrhosis.
Residency match interview scheduling: quantifying the applicant experience
Authors: Mullen Mark , Barnard Amanda , Gavard Jeffrey A , Miller Chad , Thomure Michael
Published: March 2021

Background

The process of offering and scheduling residency interviews varies widely among programmes. Applicants report distress and have advocated for reform. However, there is a paucity of quantitative data to characterise applicant concerns.

Objective

We quantified the interview scheduling experience for US allopathic medical students in the 2020 main residency match.

Methods

An anonymous, 13 question survey was sent to student representatives from each Association of American Medical Colleges member institution. Recipients were asked to forward the survey to their entire fourth-year class.

Results

Of 4314 applicants to whom the survey was sent, 786 (18.2%) responded. Overall, 20.4% reported missing the opportunity to interview at a programme because they did not have adequate time to respond to an invitation; applicants into surgical specialties were significantly more likely than their non-surgical peers to report this experience (26.4% vs 18.4%, p<0.05). Most (57.4%) respondents scheduled an interview knowing they would likely cancel it in the future. The most commonly cited reason for this behaviour was concern that applicants would not receive invitations from other programmes (85.6%). A majority (56.4%) of respondents did not believe the match interview process functions based on equity and merit.

Conclusions

About one in five respondents missed the opportunity to interview at a programme because they did not respond to an invitation in time. Most respondents scheduled interviews knowing that they were likely to cancel them in the future. Standardisation of the interview invitation timeline would address these concerns.
Geological correlation between northern Cyprus and southern Anatolia
Authors: Yılmaz Yücel
Published: March 2021

The island of Cyprus constitutes a fragment of southern Anatolia separated from the mainland by left-oblique transtension in late Cenozoic time. However, a geological framework of offset features of south-central Anatolia, for comparison of Cyprus with a source region within and west of the southeastern Anatolian suture zone, has not yet been developed. In this paper, I enumerate, describe, and compare a full suite of potentially correlative spatial and temporal elements exposed in both regions. Northern Cyprus and south-central Anatolia have identical tectonostratigraphic units. At the base of both belts, crop out ophiolitic mélange – accretionary complex generated during the northward subduction of the Neo-Tethyan Oceanic lithosphere from the Late Cretaceous until the end of middle Eocene. The nappes of the Taurus carbonate platform were thrust above this internally chaotic unit during late Eocene. They began to move as a coherent nappe pile from that time onward. An asymmetrical flysch basin was formed in front of this southward-moving nappe pile during the early Miocene. The nappes were then thrust over the flysch basin fill and caused its tight folding. Cyprus separated from Anatolia in the Pleistocene–Holocene when transtensional oblique faults with dip-slip components caused the development of the Adana and Iskenderun basins and the separation of Cyprus from Anatolia.
Salty summertime streams—road salt contaminated watersheds and estimates of the proportion of impacted species
Authors: Lawson Lauren , Jackson Donald A.
Published: March 2021

Road salt runoff is a leading cause of secondary freshwater salinization in north temperate climates. Increased chloride concentrations in freshwater can be toxic and lead to changes in organismal behavior, lethality, biotic homogenization, and altered food webs. High chloride concentrations have been reported for winter months in urban centers, as road density is highest in cities. However, summer chloride conditions are not typically studied as road salt is not actively applied outside of winter months, yet summer is when many taxa reproduce and are most sensitive to chloride. In our study, we test the spatial variability of summer chloride conditions across four watersheds in Toronto, Canada. We find 89% of 214 sampled sites exceeded the federal chronic exposure guidelines for chloride, and 13% exceeded the federal acute guidelines. Through a model linking concentration to cumulative proportion of impacted species, we estimate 34% of sites show in excess of one-quarter of all species may be impacted by their site-specific chloride concentrations, with up to two-thirds of species impacted at some sites. Our results suggest that even presumed low seasons for chloride show concentrations sufficient to cause significant negative impacts to aquatic communities.
Transport coefficients in dense active Brownian particle systems: mode-coupling theory and simulation results
Authors: Reichert Julian , Granz Leon F. , Voigtmann Thomas
Published: March 2021

We discuss recent advances in developing a mode-coupling theory of the glass transition (MCT) of two-dimensional systems of active Brownian particles (ABPs). The theory describes the structural relaxation close to the active glass in terms of transient dynamical density correlation functions. We summarize the equations of motion that have been derived for the collective density-fluctuation dynamics and those for the tagged-particle motion. The latter allow to study the dynamics of both passive and active tracers in both passive and active host systems. In the limit of small wave numbers, they give rise to equations of motion describing the mean-squared displacements (MSDs) of these tracers and hence the long-time diffusion coefficients as a transport coefficient quantifying long-range tracer motion. We specifically discuss the case of a single ABP tracer in a glass-forming passive host suspension, a case that has recently been studied in experiments on colloidal Janus particles. We employ event-driven Brownian dynamics (ED-BD) computer simulations to test the ABP-MCT and find good agreement between the two for the MSD, provided that known errors in MCT already for the passive system (i.e., an overestimation of the glassiness of the system) are accounted for by an empirical mapping of packing fractions and host-system self-propulsion forces. The ED-BD simulation results also compare well to experimental data, although a peculiar non-monotonic mapping of self-propulsion velocities is required. The ABP-MCT predicts a specific self-propulsion dependence of the Stokes–Einstein relation between the long-time diffusion coefficient and the host-system viscosity that matches well the results from simulation. An application of ABP-MCT within the integration-through transients framework to calculate the density-renormalized effective swim velocity of the interacting ABP agrees qualitatively with the ED-BD simulation data at densities close to the glass transition and quantitatively for the full density range only after the mapping of packing fractions employed for the passive system.

Graphic abstract
Logarithmic-corrected Einstein–Gauss–Bonnet inflation compatible with GW170817
Authors: Venikoudis S. A. , Fronimos F. P.
Published: March 2021

In this paper, we investigate the inflationary phenomenology of an Einstein–Gauss–Bonnet theory with the extension of a logarithmic modified f(R) gravity, compatible with the GW170817 event. The main idea of our work is to study different results for an almost linear Ricci scalar through logarithmic corrections and examine whether such model is viable. First of all, the theoretical framework under slow-roll evolution of the scalar field is presented and also the formalism of the constant-roll evolution making predictions for the non-Gaussianities of the models is developed, since the constant-roll evolution is known to enhance non-Gaussianities. As shown, the non-Gaussianities are of the order $${\mathcal {O}}\sim (10^{-1})$$

O
∼
(

10

-
1

)

. Furthermore, the slow-roll indices and the observational indices of inflation are calculated for several models of interest. As demonstrated, the phenomenological viability of the models at hand is achieved for a wide range of the free parameters and the logarithmic term has a minor contribution to numerical calculations, as expected.
Effect of Sutellarin on Neurogenesis in Neonatal Hypoxia–Ischemia Rat Model: Potential Mechanisms of Action
Authors: Xiong Liu-Lin , Tan Ya-Xin , Du Ruo-Lan , Peng Yuan , Xue Lu-Lu , Liu Jia , Al-Hawwas Mohammed , Bobrovskaya Larisa , Liu Dong-Hui , Chen Li , Wang Ting-Hua , Zhou Xin-Fu
Published: March 2021

To investigate the therapeutic efficacy of Scutellarin (SCU) on neurite growth and neurological functional recovery in neonatal hypoxic-ischemic (HI) rats. Primary cortical neurons were cultured to detect the effect of SCU on cell viability of neurons under oxygen-glucose deprivation (OGD). Double immunofluorescence staining of Tuj1 and TUNEL then observed the neurite growth and cell apoptosis in vitro,and double immunofluorescence staining of NEUN and TUNEL was performed to examine the neuronal apoptosis and cell apoptosis in brain tissues after HI in vivo. Pharmacological efficacy of SCU was also evaluated in HI rats by neurobehavioral tests, triphenyl tetrazolium chloride staining, Hematoxylin and eosin staining and Nissl staining. Astrocytes and microglia expression in damaged brain tissues were detected by immunostaining of GFAP and Iba1. A quantitative real-time polymerase chain reaction and western blot were applied to investigate the genetic expression changes and the protein levels of autophagy-related proteins in the injured cortex and hippocampus after HI. We found that SCU administration preserved cell viability, promoted neurite outgrowth and suppressed apoptosis of neurons subjected to OGD both in vitroand in vivo. Meanwhile, 20 mg/kg SCU treatment improved neurological functions and decreased the expression of astrocytes and microglia in the cortex and hippocampus of HI rats. Additionally, SCU treatment depressed the elevated levels of autophagy-related proteins and the p75 neurotrophin receptor (p75NTR) in both cortex and hippocampus. This study demonstrated the potential therapeutic efficacy of SCU by enhancing neurogenesis and restoring long-term neurological dysfunctions, which might be associated with p75NTR depletion in HI rats.
Contracturing Granulomatous Myositis with Recurrent Malignant Thymoma and Myasthenia Gravis: A Case Report
Authors: Luk Ching On , Lo Wai Ting Joyce , Kwok Kitty Yan , Leung Moon Ho , Fong Wing Chi , Cheung Yuk Fai
Published: March 2021

Contracturing granulomatous myositis (CGM) is a very rare myopathic syndrome where patients present with slowly progressive muscle pain or weakness affecting mainly proximal muscles together with flexion contractures of the limbs. To date, there have only been several case reports of CGM, which have been reported to occur most commonly in association with sarcoidosis. We report a case of CGM associated with recurrent malignant thymoma and myasthenia gravis (MG).

A gentleman with history of treated malignant thymoma presented with new onset proximal muscle weakness and pain that later evolved into contractures that persisted despite treatment with steroids and intravenous immunoglobulin. A malignancy workup revealed recurrence of his malignant thymoma warranting chemotherapy treatment. His contractures only resolved after addition of chemotherapy treatment. He later developed clinical features of MG 1 year after his initial elevation in Anti-acetylcholine (Anti-AChR) antibody levels.

We postulate CGM to be a paraneoplastic phenomenon of underlying malignant thymoma. Treatment of thymoma together with immunosuppressive therapies led to clinical improvement of our patient’s CGM. The sole elevation of Anti-AChR levels without the accompanying clinical features does not equate to a MG diagnosis, but should raise the clinician’s vigilance for future development of the condition.
Stappen High–Bjørnøya Tectono-Sedimentary Element, Barents Sea
Authors: Tsikalas Filippos , Blaich Olav Antonio , Faleide Jan Inge , Olaussen Snorre
Published: March 2021

The Stappen High–Bjørnøya Tectono-Sedimentary Element (TSE) is located in the western Barents Shelf and is one of the prominent tectonic elements in the area. The Stappen High comprises a shallow platform, and Bjørnøya forms its highest point with exposed outcrops. Modern seismic reflection data of improved quality in the southern part of the TSE and vintage seismic data in the northern portion are utilised. Together with updated geological information at Bjørnøya, the study provides insights into the Paleozoic–early Cenozoic evolution of the Stappen High–Bjørnøya TSE. In this context, we discuss structural inheritance and the rift development, and account for confirmed and potential hydrocarbon systems and plays.
Beyond MPI
Authors: Liu Feilong , Barthels Claude , Blanas Spyros , Kimura Hideaki , Swart Garret
Published: March 2021

Networkswith Remote DirectMemoryAccess (RDMA) support are becoming increasingly common. RDMA, however, offers a limited programming interface to remote memory that consists of read, write and atomic operations. With RDMA alone, completing the most basic operations on remote data structures often requires multiple round-trips over the network. Data-intensive systems strongly desire higher-level communication abstractions that supportmore complex interaction patterns.

A natural candidate to consider is MPI, the de facto standard for developing high-performance applications in the HPC community. This paper critically evaluates the communication primitives of MPI and shows that using MPI in the context of a data processing system comes with its own set of insurmountable challenges. Based on this analysis, we propose a new communication abstraction named RDMO, or Remote DirectMemory Operation, that dispatches a short sequence of reads, writes and atomic operations to remote memory and executes them in a single round-trip.
Dagstuhl Seminar on the Foundations of Composite Event Recognition
Authors: Artikis Alexander , Eiter Thomas , Margara Alessandro , Vansummeren Stijn
Published: March 2021

Composite event recognition (CER) is concerned with continuously matching patterns in streams of 'event' data over (geographically) distributed sources. This paper reports the results of the Dagstuhl Seminar "Foundations of Composite Event Recognition" held in 2020.
Erratum: Heat of Mixing During Fast Charge/Discharge of a Li-Ion Cell: A Study on NMC523 Cathode [
J. Electrochem. Soc., 167, 090560 (2020)]
Authors: Chalise Divya , Lu Wenquan , Srinivasan Venkat , Prasher Ravi
Published: March 2021

In the published paper, the details of the implementation of Newman’s P2D model was incomplete. Additionally, the acknowledgement section failed to note the contributions of a collaborator who provided the P2D simulation code used in the original work.
Graphene Nanoribbon FET Compact Model on the Basis of ANN Configuration Applicable in Different Spice Levels
Authors: Anvarifard Mohammad K. , Ramezani Zeinab , Sadegh Amiri Iraj
Published: March 2021

The artificial neural networks (ANNs) are widely utilized as a powerful approximator for a vast number of complicated nonlinear functions in many fields in different domains. Multi-layer perceptron (MLP) as a unique strategy in this work has been highlighted making an analytical drain current prediction of graphene nanoribbon field-effect transistor (GNRFET) simple and efficient having a linear dependence on the fundamental variables. The MLP structure in this work is configured with three hidden layers and 5-dimensional inputs giving the best result after performing different experiments. Target output as the key parameter is actually the numerically calculated drain current by the Non-Equilibrium Green Function (NEGF) method which is commonly used for the simulation of nanoscale devices. The critical parameters in the cases of gate oxide thickness, gate length, number of carbon atoms across the channel, gate voltage, and drain voltage are selected as the dimensions of the input vector impacting the obtained drain current by the ANN. The comprehensive comparison between the NEGF approach and the proposed ANN-based model revealed an excellent match and correlation between them. As a result, this model can be taken into consideration as a suitable tool in the different spice levels owing to the saving the running time and also increase in the efficiency of nanoscale circuits based on the GNRFET structure.
High fat high sucrose diet-induced dyslipidemia in guinea pigs
Authors: Muller Cynthia R. , Williams Alexander T. , Eaker Allyn M. , Dos Santos Fernando , Palmer Andre F. , Cabrales Pedro
Published: March 2021

In this study, we show a new animal model for diet-induced disease metabolic disorders without obesity in guinea pigs. Moreover, results suggest a strong relation between liver disease and increased cardiovascular risks.
Effects of age and sex on middle cerebral artery blood velocity and flow pulsatility index across the adult lifespan
Authors: Alwatban Mohammed R. , Aaron Stacey E. , Kaufman Carolyn S. , Barnes Jill N. , Brassard Patrice , Ward Jaimie L. , Miller Kathleen B. , Howery Anna J. , Labrecque Lawrence , Billinger Sandra A.
Published: March 2021

We present the largest dataset ( n = 524) pooled from three institutions to study how age and sex affect middle cerebral artery blood velocity (MCAv) and flow pulsatility index (PI) across the adult lifespan. We report the rate of MCAv decline and flow PI rise is significantly greater in females compared with in males. These data suggest that sex-specific trajectories with aging and therapeutic interventions to promote healthy brain aging should consider these findings.
The invention of hypoxia
Authors: Richalet Jean-Paul
Published: March 2021

The word “hypoxia” has recently come to the attention of the general public on two occasions, the Nobel Prize in Medicine or Physiology in 2019 and the recent COVID-19 pandemic. In the academic environment, hypoxia is a current topic of research in biology, physiology, and medicine: in October 2020, there were more than 150,000 occurrences of “hypoxia” in the PubMed database. However, the first occurrence is dated to 1945, while the interest for the effects of oxygen lack on the living organisms started in the mid-19th century, when scientists explored high altitude regions and mainly used the terms “anoxia” or “anoxemia.” I therefore researched online through multiple databases to look for the first appearance of “hypoxia” and related terms “hypoxemia” and “hypoxybiosis” in scientific literature published in English, German, French, Italian, and Spanish. Viault and Jolyet used “Hypohématose” in 1894, but this term has not been used since. Hypoxybiosis first appeared in 1909 in Germany, then hypoxemia in 1923 in Austria, and hypoxia in 1938 in Holland. It was then exported to the United States where it appeared in 1940 in cardiology and anesthesiology. The clinical distinction between anoxia and hypoxia was clearly defined by Carl Wiggers in 1941. Hypoxia (decrease in oxygen), by essence variable in time and in localization in the body, in contrast with anoxia (absence of oxygen), illustrates the concept of homeodynamics that defines a living organism as a complex system in permanent instability, exposed to environmental and internal perturbations.
Tuning Electronic Properties of GaSe/Silicane Van der Waals Heterostructure by External Electric Field and Strain: A First-Principle Study
Authors: Xu Gang , Lei Hao
Published: March 2021

The electronic structure of GaSe/silicane (GaSe/SiH) van der Waals (vdW) heterostructure in response to a vertical electric field and strain was studied via first-principle calculations. The heterostructure had indirect band gap characteristics in the range [−1.0, −0.4] V/Å and direct band gap features in the range [−0.3, 0.2] V/Å. Furthermore, a type-II to type-I band alignment transition appeared at −0.7 and −0.3 V/Å. Additionally, the GaSe/SiH vdW heterostructure had a type-II band alignment under strain, but an indirect to direct band gap semiconductor transition occurred at −3%. These results indicated that the GaSe/SiH vdW heterostructure may have applications in novel nanoelectronic and optoelectronic devices.
A New Quantitative Method for Risk Assessment of Coal Floor Water Inrush Based on PSR Theory and Extension Cloud Model
Authors: Jiang Bingyou , Ren Bo , Su Mingqing , Wang Bao , Li Xin , Yu Guofeng , Wei Tingshuang , Han Yunchun
Published: March 2021

In order to scientifically and reasonably assess the risk of water inrush from the coal seam floor, considering the influence of natural environmental factors such as hydrogeology, mining, and human intervention, the PSR model of ecosystem health evaluation was introduced, and the risk evaluation indicator system of water inrush from the coal seam floor was established. In order to solve the randomness and fuzziness of water inrush event evaluation, the evaluation model is constructed based on extension cloud theory and is applied in the 12123 working face of Pan Er coal mine of Huainan Mining Group. The application results show that the evaluation results are basically consistent with the actual situation, which shows that the model can be used in the actual evaluation work and is scientific.
Hypoglycemic Effect of Vitexin in C57BL/6J Mice and HepG2 Models
Authors: Xu Weidong , Li Jiayao , Qi Weipeng , Peng Ye
Published: March 2021

Apigenin-8-C-glucoside (vitexin), a natural phytochemical contained in hawthorn, has been reported to have versatile beneficial bioactivities, such as antioxidation, anticancer property, and adipogenesis inhibition. The present research aimed to determine the influence of vitexin on insulin resistance elicited by HFD in mice and HepG2 cells. Vitexin markedly alleviated body weight gain and improved glucose and insulin intolerance induced by HFD. Vitexin partially normalized blood glucose, cholesterol, TNF-α, and hepatic lipid content. Moreover, vitexin recovered the reduced glucose uptake induced by glucosamine. The present results indicate that vitexin prevents HFD-induced insulin resistance.
Static Stability Analysis Based on Probabilistic Power Flow Calculation considering P2G Technology
Authors: Yao Jia , Huang Yujia , Hu Jingwei
Published: March 2021

At present, integrated energy systems have received extensive attention, but there is no basic framework for stability analysis of coupled systems. The injection of a large amount of renewable energy also has a great impact on the stability of the system. This paper focuses on how to analyze the static stability of the coupling system with uncertainty, which mainly considers the uncertainty of wind power generation and photovoltaic power generation and also considers the influence of P2G technology on the whole system. Firstly, this paper analyzes the principles of wind power generation and photovoltaic power generation and constructs the probability model of renewable energy power generation power. Then, the three‐point estimation method is used to process the data, and the probability distribution of the unknown quantity is obtained by probabilistic power flow analysis. Finally, the probability distribution of each eigenvalue is obtained by analyzing the sensitivity of the characteristic roots to the voltage. Thus, the static stability of the system is judged. The applicability of proposed methodology is demonstrated by analyzing an integrated IEEE 14‐bus power system and a Belgian 20‐node gas system in this paper.
miR-708 Negatively Regulates TNFα/IL-1β Signaling by Suppressing NF-κB and Arachidonic Acid Pathways
Authors: Monteleone Nicholas J. , Lutz Carol S.
Published: March 2021

Two pathways commonly dysregulated in autoimmune diseases and cancer are tumor necrosis factor alpha (TNFα) and interleukin 1 beta (IL-1β) signaling. Researchers have also shown that both signaling cascades positively regulate arachidonic acid (AA) signaling. More specifically, TNFα/IL-1β promotes expression of the prostaglandin E2- (PGE2-) producing enzymes, cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1). Exacerbated TNFα, IL-1β, and AA signaling have been associated with many diseases. While some TNFα therapies have significantly improved patients’ lives, there is still an urgent need to develop novel therapeutics that more comprehensively treat inflammatory-related diseases. Recently, researchers have begun to use RNA interference (RNAi) to treat various diseases in the clinic. One type of RNAi is microRNA (miRNA), a class of small noncoding RNA found within cells. One miRNA in particular, miR-708, has been shown to target COX-2 and mPGES-1. Previous studies have also suggested that miR-708 may be a negative regulator of TNFα/IL-1β signaling. Therefore, we studied the relationship between miR-708, TNFα/IL-1β, and AA signaling in diseased lung cells. We found that miR-708 negatively regulates TNFα/IL-1β signaling in nondiseased lung cells, which is lost in diseased lung cells. Transient transfection of miR-708 suppressed TNFα/IL-1β-induced changes in COX-2, mPGES-1, and PGE2 levels. Moreover, miR-708 also suppressed TNFα/IL-1β-induced IL-6 independent of AA signaling. Mechanistically, we determined that miR-708 suppressed IL-6 signaling by reducing expression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activator inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ). Collectively, our data suggest miR-708 regulates TNFα/IL-1β signaling by inhibiting multiple points of the signaling cascade.
A Data‐Driven and Knowledge‐Driven Method towards the IRP of Modern Logistics
Authors: Wang Tiexin , Wu Yi , Lamothe Jacques , Benaben Frederick , Wang Ruofan , Liu Wenjing
Published: March 2021

Inventory Routing Problem (IRP) is a typical optimization problem in logistics. To reduce the total cost, which contains the product transportation cost, the inventory holding cost, the customer satisfaction cost, etc., a wide range of impact factors have to be taken into consideration. Since more and more intelligent devices have been adopted in the management of modern logistics, the amount of the collected data (relevant to those impact factors) increases exponentially. However, the quality of the collected data is suffering from a certain number of uncertainties, such as device status and the transmission network environment. Considering the volume and quality of the collected data, the traditional data‐driven distribution optimization methods encounter a bottleneck. In this paper, we propose a hybrid optimization method which combines data‐driven and knowledge‐driven techniques together. In our method, a domain ontology, which has better scalability and generality, is built as an extension of data‐driven optimization algorithms. Knowledge reasoning techniques are also combined to handle data quality issue and uncertainties. To evaluate the performance of our method, we carried out a case study, which is provided by a French company “Pierre Fabre Dermo‐Cosmetics” (PFDC). This case study is a simplified scenario of the practical business process of PFDC.
Estimation of Genetic Parameters of Different Wheat Genotype Traits in Chitwan, Nepal
Authors: Regmi Saroj , Poudel Bikram , Ojha Bishnu Raj , Kharel Raju , Joshi Priyanka , Khanal Shovit , Kandel Bishnu Prasad
Published: March 2021

This research was carried out to estimate the genetic parameters of fifty wheat genotypes received from the Agriculture Botany Division, Nepal Agriculture Research Council (NARC), Khumaltar, Lalitpur, in the winter season of 2014/2015 at Agriculture and Forestry University (AFU), Chitwan, Nepal. The experiment was performed in an alpha lattice design with two replications in five blocks in each replication and ten plots in each block. The analysis of variance showed highly significant differences among the genotypes for all the studied traits except spike length. This implies that, except for spike length, all other traits exhibited genetic variability. The phenotypic coefficient of variation (PCV) was generally higher than the genotypic coefficient of variation (GCV) for all characters. The difference between PCV and GCV was large in spike length followed by grain weight per spike, the number of grains per spike, grain yield, thousand-grain weight, and harvest index indicating that these traits are affected by the environment as well. Moderate to high heritability associated with a high genetic gain was observed for days to flag leaf appearance, panicle length, thousand-grain weight, grain yield, and harvest index indicating the involvement of additive gene action. Grain weight per spike, number of grains per spike, thousand-grain weight, biological yield, and harvest index were significantly correlated with grain yield indicating their important contribution to grain yield. WK 2525, WK 2437, and WK 2506 were three promising genotypes in terms of grain yield.
Application of the Bayesian Model Averaging in Analyzing Freeway Traffic Incident Clearance Time for Emergency Management
Authors: Zou Yajie , Lin Bo , Yang Xiaoxue , Wu Lingtao , Muneeb Abid Malik , Tang Jinjun
Published: March 2021

Identifying the influential factors in incident duration is important for traffic management agency to mitigate the impact of traffic incidents on freeway operation. Previous studies have proposed a variety of approaches to determine the significant factors for traffic incident clearance time. These methods commonly select a single “true” model among a majority of alternative models based on some model selection criteria. However, the conventional methods generally neglect the uncertainty related to the choice of models. This paper proposes a Bayesian Model Averaging (BMA) model to account for model uncertainty by averaging all plausible models using posterior probability as the weight. The BMA model is used to analyze the 2,584 freeway incident records obtained from I-5 corridor in Seattle, WA, USA. The results show that the BMA approach has the capability of interpreting the causal relationship between explanatory variables and clearance time. In addition, the BMA approach can provide better prediction performance than the Cox proportional hazards model and the accelerated failure time models. Overall, the findings in this study can be useful for traffic emergency management agency to apply an alternative methodology for predicting traffic incident clearance time when model uncertainty is considered.
Study on the Effect of Isotropic Initial Stress on the Anchoring Performance of Self‐Expanding Bolts
Authors: Liu Jie , Li Hongya , Li Yunzhou , Yang Yunan , Sun Tao , Song Rui , Sun Rongqi
Published: March 2021

In order to study the anchoring performance of a new type of self‐expanding, high‐strength, precompression anchoring technology with a large amount of expansion agent (ω ≥ 5) cement slurry as anchoring solids under confined surrounding rock conditions, a rock mass anchoring device and methods that simulate in situ stress are developed, and real‐time monitoring of expansion stress and anchor pull‐out tests are carried out. The results show that the internal interface stress has a loss effect over time, and the stress loss value shows a linear increase trend with the dosage, but the loss rate shows a linear decreasing relationship with the dosage. This paper defines the coordinated additional stress and obtains its temporal and spatial evolution law in the rock mass. It is pointed out that there is a lag time difference between the peak of internal interface stress and the peak of coordinated additional stress, explaining its mechanical mechanism from the perspective of stress transfer. The strong restraint of the sealing section of the anchor hole causes the anchor solid to form a “shuttle‐shaped” microexpanded head with thin ends and a middle drum under the expansion stress. During the drawing process, the microexpanded head is “stuck” in the anchor hole and moves upward to form the unique “load platform effect” of the anchoring system. And the mechanical mechanism diagram of this effect is obtained. It is pointed out that this effect can greatly improve the ductility of the anchoring system and the ultimate energy consumption value of damage. A prediction model for the ultimate pull‐out force of self‐expanding bolts is established. It is pointed out that the initial confining stress value has an exponential effect on the ultimate pull‐out force. It shows that the surrounding rock with strong confinement constraints can greatly increase the ultimate pull‐out resistance of the bolt. The self‐expanding strengthening coefficient λ and the surrounding rock stress influence coefficient k are introduced, the bolt interface mechanics formula and energy equation of the self‐expanding anchor system are established, and the feasibility of the formula is verified by the calculation example. It is concluded that the ultimate pull‐out resistance of the anchorage with ω = 30 is increased by 3.38 times compared with the ordinary anchorage under the initial confining stress condition of 0.7 MPa, the prepeak displacement of the bolt is increased by 2.08 times, and the prepeak energy consumption of the anchoring system is increased by 7.34 times. The cost only increased by 0.023% based on the literature example.
UGT1A1 Polymorphism for Irinotecan Dose Escalation in Patients with BRAF-Mutated Metastatic Colorectal Cancer Treated with First-Line Bevacizumab and FOLFIRI
Authors: Hsieh Yi-Chien , Chang Tsung-Kun , Su Wei-Chih , Huang Ching-Wen , Tsai Hsiang-Lin , Chen Yen-Cheng , Li Ching-Chun , Chen Po-Jung , Yin Tzu-Chieh , Ma Cheng-Jen , Wang Jaw-Yuan
Published: March 2021

Background. Patients with metastatic colorectal cancer (mCRC) and BRAF V600E mutation have a poor prognosis, with a median progression-free survival (PFS) of only 5–7 months after initial therapy. The current standard first-line chemotherapy for these patients includes FOLFOX or FOLFIRI plus bevacizumab. In this study, we explored the effects and oncological outcomes of UGT1A1 polymorphism for irinotecan escalation in patients with BRAF-mutated mCRC. Patients and Methods. This retrospective study included 17 patients with BRAF-mutated mCRC between April 2016 and December 2019. UGT1A1 genotyping was performed on all patients prior to initiating bevacizumab plus FOLFIRI chemotherapy. The primary endpoint was PFS, and the secondary endpoints were toxicity, response rate, disease control rate, and overall survival (OS). Results. Fifteen and two patients had UGT1A1 1∗/1∗ and 1∗/28∗, respectively. Eight underwent irinotecan dose escalation with tolerable adverse effects (AEs), and nine maintained an irinotecan dose of 180 mg/m2 or required deescalation to 150 mg/m2 due to intolerable AEs. After a median follow-up period of 15.7 (range, 3–54) months, the median PFS and OS were 9.4 and 15.7 months, respectively. Grade 3/4 AEs were observed in three (6%) patients. The disease control and partial response rates were 64.7% and 11.8%, respectively, indicating that most patients (14, 82.3%) could maintain this as a first-line line therapy with stable disease or proceed to second-line therapy if disease progression occurred, thereby maintaining acceptable performance status. Conclusions. The oncological outcomes of patients with BRAF-mutated mCRC treated using FOLFIRI plus bevacizumab with irinotecan dose escalation as a first-line therapy are acceptable with tolerable AEs; this may be a feasible treatment option in such patients. Pretherapeutic UGT1A1 genotyping-guided dose adjustment can achieve favorable outcomes.
Venography and Selective Ablation for Recurrent Varices after Surgery Using Radiofrequency Ablation Catheter
Authors: Enta Yusuke , Saigan Makoto , Tanaka Akiko , Hata Masaki , Tada Norio
Published: March 2021

Recurrent varices after surgery (REVAS) is a common problem with no established treatment. Ultrasonography is a hard method to identify the source of veins that cause REVAS, especially in obese patients with thick thighs. Here, we report the case of a 64-year-old obese patient who previously underwent endothermal venous ablation for her right great saphenous vein. The patient presented with right leg swelling and venous ulceration due to REVAS. Although the source of REVAS was unclear because the patient had thick thighs on ultrasonography assessment, venography revealed that the source of REVAS was the incompetent perforator vein (IPV). Selective ablation for the IPV with radiofrequency ablation catheter was performed. We could ablate the target veins selectively so as not to ablate within the deep vein. The patient remains asymptomatic for 2 years after the procedure, and there has been no recurrence of her varicose veins. Venography allows better visualization of the source of REVAS than ultrasonography. With selective ablation, it is especially effective procedure in obese patients, in whom it is difficult to identify and access the source of REVAS with ultrasonography.
A Simple‐to‐Use Nomogram for Predicting Survival in Children with Acute Myeloid Leukemia
Authors: Jiang Feng , Yu Xiang , Wu Chuyan , Wang Ming , Wei Ke , Zhou Guoping , Wang Jimei
Published: March 2021

Background. The research analyzed a group of patients to develop a statistical nomogram and a web‐based survival rate predictor for the comprehensive estimate of the overall survival (OS) of children with acute myeloid leukemia. Methods. Between 1999 to 2015, we used the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database to evaluate and randomly divide 440 children diagnosed with AML into the population of training (n = 309) and validation (n = 131). The analysis of Lasso Cox was used to identify separate predictive variables. We have used essential forecasting considerations to construct a nomogram and a web‐based calculator focused on Cox regression analysis. Nomogram validation was tested through discrimination and calibration. Results. Compared to the multivariate training cohort models, a nomogram integrating gender, age of diagnose, WBC at diagnosis, bone marrow leukemic blast percentage, and chromosomal abnormalities [t(8; 21), inv(16)] were designed for the prediction of OS. We also developed a predictive survival nomogram and a web‐based calculator. C‐indexes validated internally and checked externally were 0.747 and 0.716. The calibration curves have shown that the nomogram might accurately forecast 3‐year and 5‐year OS. Conclusions. A nomogram effectively predicts survival in children with AML. This prognostic model can be used in clinical practice.
Robust Control for the Suspension Cable System of the Unmanned Helicopter with Sensor Fault under Complex Environment
Authors: Mei Rong
Published: March 2021

Aiming at the suspension cable system of an unmanned helicopter with sensor fault under complex environment, this paper studies the robust antiswing tolerant control scheme. To suppress the swing of the hanging load when the unmanned helicopter is in the forward flight state, a nonlinear line motion model is firstly established. Considering the sensor fault of the unmanned helicopter, a sensor fault estimator is developed. By using the fault estimator output, the robust antiswing tolerant controller is proposed using the backstepping technique and sliding mode control method. Under the designed robust antiswing tolerant controller, the desired tracking control performance can be obtained and the swing angle of the load is guaranteed small under the sensor fault. Furthermore, the closed‐loop system stability is analyzed by using the Lyapunov technique. Simulation studies are given to show the efficiency of the designed robust antiswing control strategy.
Leucoselect Phytosome Modulates Serum Eicosapentaenoic Acid, Docosahexaenoic Acid, and Prostaglandin E3 in a Phase I Lung Cancer Chemoprevention Study
Authors: Mao Jenny T. , Xue Bingye , Fan Sili , Neis Patricia , Qualls Clifford , Massie Larry , Fiehn Oliver
Published: March 2021

Grape seed procyanidin extract (GSE) has been shown to exert antineoplastic properties in preclinical studies. Recently, we reported findings from a modified phase I, open-label, dose escalation clinical study conducted to evaluate the safety, tolerability, MTD, and potential chemopreventive effects of leucoselect phytosome, a standardized GSE complexed with soy phospholipids to enhance bioavailability, in heavy active and former smokers. Three months of leucoselect phytosome treatment significantly decreased bronchial Ki-67 labeling index (LI), a marker of cell proliferation on the bronchial epithelium. Because GSE is widely used as a supplement to support cardiovascular health, we evaluate the impact of oral leucoselect phytosome on the fasting serum complex lipid metabolomics profiles in our participants. One month of leucoselect phytosome treatment significantly increased eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the omega-3 polyunsaturated fatty acids (n-3 PUFA) with well-established anticancer properties. Leucoselect phytosome also significantly increased unsaturated phosphatidylcholines (PC), likely from soy phospolipids in the phytosome and functioning as transporters for these PUFAs. Furthermore, 3-month leucoselect phytosome treatment significantly increased serum prostaglandin (PG) E3 (PGE3), a metabolite of EPA with anti-inflammatory and antineoplastic properties. Such increases in PGE3 correlated with reductions of bronchial Ki-67 LI (r = −0.9; P = 0.0374). Moreover, posttreatment plasma samples from trial participants significantly inhibited proliferation of human lung cancer cell lines A549 (adenocarcinoma), H520 (squamous cell carcinoma), DMS114 (small cell carcinoma), and 1198 (preneoplastic cell line). Our findings further support the potential utility of leucoselect phytosome in reducing cardiovascular and neoplastic risks in heavy former and active smokers.

Prevention Relevance:

In this correlative study of leucoselect phytosome for lung cancer chemoprevention in heavy active and former smokers, we demonstrate for the first time, favorable modulations of n-3PUFA and downstream PGE3 in fasting serum, further supporting the chemopreventive potential of leucoselect phytosome against lung cancer.
CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor Cells and T Cells
Authors: Kumar Sushil , Zeng Zexian , Bagati Archis , Tay Rong En , Sanz Lionel A. , Hartono Stella R. , Ito Yoshinaga , Abderazzaq Fieda , Hatchi Elodie , Jiang Peng , Cartwright Adam N.R. , Olawoyin Olamide , Mathewson Nathan D. , Pyrdol Jason W. , Li Mamie Z. , Doench John G. , Booker Matthew A. , Tolstorukov Michael Y. , Elledge Stephen J. , Chédin Frédéric , Liu X. Shirley , Wucherpfennig Kai W.
Published: March 2021

A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise antitumor immune function. We discovered that inhibition of CARM1, an epigenetic enzyme and cotranscriptional activator, elicited beneficial antitumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their antitumor function and preserved memory-like populations required for sustained antitumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells, and natural killer cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of CARM1 with a small molecule elicited potent antitumor immunity and sensitized resistant tumors to checkpoint blockade. Targeting of this cotranscriptional regulator thus offers an opportunity to enhance immune function while simultaneously sensitizing resistant tumor cells to immune attack.

Significance:

Resistance to cancer immunotherapy remains a major challenge. Targeting of CARM1 enables immunotherapy of resistant tumors by enhancing T-cell functionality and preserving memory-like T-cell populations within tumors. CARM1 inhibition also sensitizes resistant tumor cells to immune attack by inducing a tumor cell–intrinsic type 1 interferon response.

This article is highlighted in the In This Issue feature, p. 1861
Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo
Authors: Foggetti Giorgia , Li Chuan , Cai Hongchen , Hellyer Jessica A. , Lin Wen-Yang , Ayeni Deborah , Hastings Katherine , Choi Jungmin , Wurtz Anna , Andrejka Laura , Maghini Dylan G. , Rashleigh Nicholas , Levy Stellar , Homer Robert , Gettinger Scott N. , Diehn Maximilian , Wakelee Heather A. , Petrov Dmitri A. , Winslow Monte M. , Politi Katerina
Published: March 2021

In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2—the strongest drivers of growth in a KRAS-driven model—reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment.

Significance:

By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.

This article is highlighted in the In This Issue feature, p. 1601