bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined inhibition/silencing of diacylglycerol kinase α and ζ simultaneously and synergistically enhances interleukin‐2 production in T cells and induces cell death of melanoma cells
Authors: Takao Saki , Akiyama Rino , Sakane Fumio 
Published: January 2021

AbstractThe α‐isozyme of diacylglycerol kinase (DGK) enhances cancer cell proliferation and, conversely, it promotes the nonresponsive immune state known as T‐cell anergy. Moreover, a DGKα‐selective inhibitor, CU‐3, induced cell death in cancer‐derived cells and simultaneously enhanced T‐cell interleukin‐2 production. In addition to DGKα, DGKζ is also known to induce T‐cell anergy. In the present study, we examined whether combined inhibition/silencing of DGKα and DGKζ synergistically enhanced T‐cell activity. Combined treatment with CU‐3 or DGKα‐small interfering RNA (siRNA) and DGKζ‐siRNA more potently enhanced T‐cell receptor‐crosslink‐dependent interleukin‐2 production in Jurkat T cells than treatment with either alone. Intriguingly, in addition to activating T cells, dual inhibition/silencing of DGKα and DGKζ synergistically reduced viability and increased caspase 3/7 activity in AKI melanoma cells. Taken together, these results indicate that combined inhibition/silencing of DGKα and DGKζ simultaneously and synergistically enhances interleukin‐2 production in T cells and induces cell death in melanoma. Therefore, dual inhibition/silencing of these DGK isozymes represents an ideal therapy that potently attenuates cancer cell proliferation and simultaneously enhances immune responses that impact anticancer immunity.
N‐(3‐oxododecanoyl)‐l‐homoserine lactone disrupts intestinal epithelial barrier through triggering apoptosis and collapsing extracellular matrix and tight junction
Authors: Tao Shiyu , Xiong Yi , Han Dandan , Pi Yu , Zhang Hanlu , Wang Junjun 
Published: January 2021

AbstractMicrobes employ autoinducers of quorum sensing (QS) for population communication. Although the autoinducer of Pseudomonas aeruginosa LasI‐LasR system, N‐(3‐oxododecanoyl)‐
l
‐homoserine lactone (3OC12), has been reported with deleterious effects on host cells, its biological effects on integrity of the intestinal epithelium and epithelial barrier are still unclear and need further investigation. In the present study, flow cytometry, transcriptome analysis and western blot technology have been adopted to investigate the potential molecular mechanisms of 3OC12 and its structurally similar analogs damage to intestinal epithelial cells. Our results indicated that 3OC12 and 3OC14 trigger apoptosis rather than necrosis and ferroptosis in intestinal epithelial cells. RNA‐sequencing combined with bioinformatics analysis showed that 3OC12 and 3OC14 reduced the expression of genes from extracellular matrix (ECM)‐receptor interaction pathway. Consistently, protein expressions from ECM and tight junction‐associated pathway were significantly reduced after 3OC12 and 3OC14 challenge. In addition, 3OC12 and 3OC14 led to blocked cell cycle, decreased mitochondrial membrane potential, increased reactive oxygen species level and elevated Ca2+ concentration. Reversely, the antioxidant NAC could effectively mitigate the reduced expression of ECM and tight junction proteins caused by 3OC12 and 3OC14 challenge. Collectively, this study demonstrated that QS autoinducer exposure to intestinal epithelial cells ablates the ECM and tight junctions by triggering oxidative stress and apoptosis, and finally disrupts the intestinal epithelial barrier. These findings provide a rationale for defensing QS‐dependent bacterial infections and potential role of NAC for alleviating the syndrome.
Increased Induction Infliximab Clearance Predicts Early Antidrug Antibody Detection
Authors: Eser Alexander , Reinisch Walter , Schreiber Stefan , Ahmad Tariq , Boulos Suliman , Mould Diane R. 
Published: January 2021

AbstractTreatment of patients with biologics such as infliximab may trigger development of antidrug antibodies, which are associated with faster drug clearance, reduced treatment efficacy, and increased risk of infusion‐related reactions. The aim of this study was to identify predictors of baseline infliximab clearance and early antidrug antibody formation. Pharmacokinetic and pharmacokinetic/pharmacodynamic models for infliximab were developed using 21 178 observations from 859 patients from the PLANETRA (ClinicalTrials.gov identifier: NCT01217086) and PLANETAS (NCT01220518) studies in rheumatoid arthritis and ankylosing spondylitis, respectively, to address the specified aims. Infliximab pharmacokinetics were well described by a 2‐compartment model with linear mean estimated baseline clearance of 0.26 L/day. Alongside increased body weight, serum C‐reactive protein, and antidrug antibody concentrations and decreased serum albumin, elevated serum glucose levels predicted higher clearance. In patients with rheumatoid arthritis, baseline infliximab clearance and body weight were the only identified predictors of early antidrug antibody detection. The odds ratio for antidrug antibody detection for each 0.1 L/day increase in baseline infliximab clearance was 1.78 (95% confidence interval, 1.50–2.12); for each 10‐kg increase in body weight, this was 1.19 (1.06–1.33). Here we describe increased serum glucose levels as a novel independent predictor of baseline infliximab clearance. Estimates of baseline infliximab clearance should be incorporated to guide dosing modifications and/or antidrug antibody prophylaxis in clinical practice.
The optimal cut‐off values for tumor size, number of lesions, and CEA levels in patients with surgically treated colorectal cancer liver metastases: An international, multi‐institutional study
Authors: Kamphues Carsten , Andreatos Nikolaos , Kruppa Jochen , Buettner Stefan , Wang Jaeyun , Sasaki Kazunari , Wagner Doris , Morioka Daisuke , Fitschek Fabian , Løes Inger Marie , Imai Katsunori , Sun Jinger , Poultsides George , Kaczirek Klaus , Lønning Per Eystein , Endo Itaru , Baba Hideo , Kornprat Peter , Aucejo Federico N , Wolfgang Christopher L. , Kreis Martin E. , Weiss Matthew J , Margonis Georgios Antonios 
Published: January 2021

AbstractBackground and ObjectivesDespite the long‐standing consensus on the importance of tumor size, tumor number and carcinoembryonic antigen (CEA) levels as predictors of long‐term outcomes among patients with colorectal liver metastases (CRLM), optimal prognostic cut‐offs for these variables have not been established.MethodsPatients who underwent curative‐intent resection of CRLM and had available data on at least one of the three variables of interest above were selected from a multi‐institutional dataset of patients with known KRAS mutational status. The resulting cohort was randomly split into training and testing datasets and recursive partitioning analysis was employed to determine optimal cut‐offs. The concordance probability estimates (CPEs) for these optimal cut offs were calculated and compared to CPEs for the most widely used cut‐offs in the surgical literature.ResultsA total of 1643 patients who met eligibility criteria were identified. Following recursive partitioning analysis in the training dataset, the following cut‐offs were identified: 2.95 cm for tumor size, 1.5 for tumor number and 6.15 ng/ml for CEA levels. In the entire dataset, the calculated CPEs for the new tumor size (0.52), tumor number (0.56) and CEA (0.53) cut offs exceeded CPEs for other commonly employed cut‐offs.ConclusionThe current study was able to identify optimal cut‐offs for the three most commonly employed prognostic factors in CRLM. While the per variable gains in discriminatory power are modest, these novel cut‐offs may help produce appreciable increases in prognostic performance when combined in the context of future risk scores.
Spine biomechanical testing methodologies: The controversy of consensus vs scientific evidence
Authors: Costi John J. , Ledet Eric H. , O'Connell Grace D. 
Published: January 2021

AbstractBiomechanical testing methodologies for the spine have developed over the past 50 years. During that time, there have been several paradigm shifts with respect to techniques. These techniques evolved by incorporating state‐of‐the‐art engineering principles, in vivo measurements, anatomical structure‐function relationships, and the scientific method. Multiple parametric studies have focused on the effects that the experimental technique has on outcomes. As a result, testing methodologies have evolved, but there are no standard testing protocols, which makes the comparison of findings between experiments difficult and conclusions about in vivo performance challenging. In 2019, the international spine research community was surveyed to determine the consensus on spine biomechanical testing and if the consensus opinion was consistent with the scientific evidence. More than 80 responses to the survey were received. The findings of this survey confirmed that while some methods have been commonly adopted, not all are consistent with the scientific evidence. This review summarizes the scientific literature, the current consensus, and the authors' recommendations on best practices based on the compendium of available evidence.
QcrB in Mycobacterium tuberculosis: The new drug target of antitubercular agents
Authors: Bahuguna Aparna , Rawat Srishti , Rawat Diwan S. 
Published: January 2021

AbstractDrug‐resistance in mycobacterial infections is a major global health problem that leads to high mortality and socioeconomic pressure in developing countries around the world. From finding new targets to discovering novel chemical scaffolds, there is an urgent need for the development of better approaches for the cure of tuberculosis. Recently, energy metabolism in mycobacteria, particularly the oxidative phosphorylation pathway of cellular respiration, has emerged as a novel target pathway in drug discovery. New classes of antibacterials which target oxidative phosphorylation pathway either by interacting with a protein or any step in the pathway of oxidative phosphorylation can combat dormant mycobacterial infections leading to shortening of tuberculosis chemotherapy. Adenosine triphosphate synthase is one such recently discovered target of the newly approved antitubercular drug bedaquiline. Cytochrome bcc is another new target of the antitubercular drug candidate Q203, currently in phase II clinical trial. Research suggests that b subunit of cytochrome bcc, QcrB, is the target of Q203. The review article describes the structure, function, and importance of targeting QcrB throwing light on all chemical classes of QcrB inhibitors discovered to date. An understanding of the structure and function of validated targets and their inhibitors would enable the development of new chemical entities.
Fast online‐customized (FOCUS) parallel transmission pulses: A combination of universal pulses and individual optimization
Authors: Herrler Jürgen , Liebig Patrick , Gumbrecht Rene , Ritter Dieter , Schmitter Sebastian , Maier Andreas , Schmidt Manuel , Uder Michael , Doerfler Arnd , Nagel Armin M. 
Published: January 2021

PurposeTo mitigate spatial flip angle (FA) variations under strict specific absorption rate (SAR) constraints for ultra‐high field MRI using a combination of universal parallel transmit (pTx) pulses and fast subject‐specific optimization.MethodsData sets consisting of B0, maps, and virtual observation point (VOP) data were acquired from 72 subjects (study groups of 48/12 healthy Europeans/Asians and 12 Europeans with pathological or incidental findings) using an 8Tx/32Rx head coil on a 7T whole‐body MR system. Combined optimization values (COV) were defined as combination of spiral‐nonselective (SPINS) trajectory parameters and an energy regularization weight. A set of COV was optimized universally by simulating the individual RF pulse optimizations of 12 training data sets (healthy Europeans). Subsequently, corresponding universal pulses (UPs) were calculated. Using COV and UPs, individually optimized pulses (IOPs) were calculated during the sequence preparation phase (maximum 15 s). Two different UPs and IOPs were evaluated by calculating their normalized root‐mean‐square error (NRMSE) of the FA and SAR in simulations of all data sets. Seven additional subjects were examined using an MPRAGE sequence that uses the designed pTx excitation pulses and a conventional adiabatic inversion.ResultsAll pTx pulses resulted in decreased mean NRMSE compared to a circularly polarized (CP) pulse (CP = ~28%, UPs = ~17%, and IOPs = ~12%). UPs and IOPs improved homogeneity for all subjects. Differences in NRMSE between study groups were much lower than differences between different pulse types.ConclusionUPs can be used to generate fast online‐customized (FOCUS) pulses gaining lower NRMSE and/or lower SAR values.
On topology optimization of design‐dependent pressure‐loaded three‐dimensional structures and compliant mechanisms
Authors: Kumar Prabhat , Langelaar Matthijs 
Published: January 2021

AbstractThis article presents a density‐based topology optimization method for designing three‐dimensional (3D) compliant mechanisms (CMs) and loadbearing structures with design‐dependent pressure loading. Instead of interface‐tracking techniques, the Darcy law in conjunction with a drainage term is employed to obtain pressure field as a function of the design vector. To ensure continuous transition of pressure loads as the design evolves, the flow coefficient of a finite element (FE) is defined using a smooth Heaviside function. The obtained pressure field is converted into consistent nodal loads using a transformation matrix. The presented approach employs the standard FE formulation and also, allows consistent and computationally inexpensive calculation of load sensitivities using the adjoint‐variable method. For CM designs, a multicriteria objective is minimized, whereas minimization of compliance is performed for designing loadbearing structures. Efficacy and robustness of the presented approach is demonstrated by designing various pressure‐actuated 3D CMs and structures.
An adaptive granular representative volume element model with an evolutionary periodic boundary for hierarchical multiscale analysis
Authors: Qu Tongming , Feng Yuntian , Wang Min 
Published: January 2021

AbstractThe hierarchical multiscale analysis normally utilizes a microscopic representative volume element (RVE) model to capture path/history‐dependent macroscopic responses instead of using phenomenological constitutive models. However, for problems involving large deformation, the current RVE model used in geomechanics may lose representative properties due to the progressive distortion of the RVE box, unless a proper reinitialization is applied. This work develops an adaptive RVE model in conjunction with an evolutionary periodic boundary (EPB) algorithm for hierarchical multiscale analysis of granular materials undergoing large deformation based on a recent RVE model proposed for coupling molecular dynamics and the material point method. The proposed adaptive RVE model avoids the reinitialization of the RVE box that even undergoes extremely large shear deformation; meanwhile, it accounts for the deformation history of the RVE model and treats the interaction between boundary particles and other image particles in a more efficient way. Numerical examples with extremely large deformation are used to illustrate the adaptive granular RVE model enhanced by the proposed EPB algorithm. Furthermore, some key features of this new methodology are further discussed for clarification.
Oral health among older adults in nursing homes: A survey in a national quality register, the Senior Alert
Authors: Bellander Lisa , Andersson Pia , Nordvall Dennis , Hägglin Catharina 
Published: January 2021

AbstractAimTo investigate the extent to which the Revised Oral Assessment Guide–Jönköping (ROAG‐J) is used by nursing staff routinely in nursing homes in Sweden and to describe oral health status of the residents.DesignAn observational, retrospective register‐based study.MethodsData from different validated health assessments instruments, including ROAG‐J, for the period 2011–2016 were obtained from the Web‐based national quality register Senior Alert. The basis for the analyses was 190,016 assessments.ResultsAbout half of all residents had underwent at least one annual ROAG‐J assessment (2014–2016). During the period 2011–2016, 42% of the residents (n = 92,827) were registered to have oral health problems. Significantly more oral health problems were found for men and for those with younger age, poorer physical condition, neurophysiological problems, underweight, impaired mobility and many medications. In conclusion, poorer oral health was found for more care‐dependent individuals, which shows a need of preventive actions.
An improved numerical technique for distributed‐order time‐fractional diffusion equations
Authors: Dehestani Haniye , Ordokhani Yadollah , Razzaghi Mohsen 
Published: January 2021

AbstractThis paper considers a novel numerical method based on Lucas‐fractional Lucas functions (L‐FL‐Fs) and collocation method for solving the distributed‐order time‐fractional diffusion equations. In the current investigation, we express the new computational process to gain the integral operational matrix for Lucas polynomials (LPs) and fractional Lucas functions (FLFs). The proposed method creates operational matrices with high accuracy that affect to accuracy and efficiency of the computational scheme directly. The operational matrices, by combining Legendre–Gauss quadrature rule and collocation method, reduce the given distributed‐order time‐fractional diffusion equation to a system of algebraic equations. Also, we investigate the error estimation associated with the presented idea. At last, several examples are given to demonstrate the accuracy and easy implementation of the proposed method.
Quadratic B‐spline collocation method for time dependent singularly perturbed differential‐difference equation arising in the modeling of neuronalactivity
Authors: Shivhare Meenakshi , Podila Pramod Chakravarthy , Ramos Higinio , Vigo‐Aguiar Jesús 
Published: January 2021

AbstractIn this paper, we consider a time‐dependent singularly perturbed differential‐difference equation with small shifts arising in the field of neuroscience. The terms containing the delay and advance parameters are approximated by using the Taylor's series expansion. The continuous problem is semi‐discretized using the Crank–Nicolson finite difference method in the time direction on uniform mesh and quadratic B‐spline collocation method in the space direction on exponentially graded mesh. The method is shown to be second‐order uniformly convergent in space and time direction. Theoretical estimates are carried out which support the obtained numerical experiments.
Mechanical strength retention and service life of Kevlar fiber woven mat reinforced epoxy laminated composites for structural applications
Authors: Sathishkumar T. P. , Muralidharan M. , Ramakrishnan S. , Sanjay M. R. , Siengchin Suchart 
Published: January 2021

AbstractThis work investigates the diffusivity, long‐term tensile performance and prediction of service life of Kevlar fiber woven mat reinforced epoxy laminated composites (KFMRELC). The composites were prepared by hand layup method with compression molding process. The tensile test was conducted on dry and aged composites as per ASTM D 638 standard. These composites were immersed in water at various temperatures of 20°C, 40°C and 60°C and various time periods. The diffusivity was calculated by Fick's law. The activation energy and service life were calculated by Arrhenius principle. In results, the tensile strength was gradually decreased by increasing the immersion time, and the maximum reduction was found at 60°C and 300 days due to loss of bonding between the fiber and matrix. Increasing the aging temperature was decreased bonding between the fiber and matrix which reduced the tensile strength. Therefore, the KFMRELC composite retained long life and exhibited less reduction in tensile stress at 20°C environment. Considering 80% of tensile strength retention, the life of KFMRELC composite was found 50 year less at higher temperature because the rate of diffusivity and degradation were found higher. Hence, the maximum tensile strength retention was showed for 50 years. Based on the life cycle curve, the KFMRELC composite can be selected for suitable applications.
Spinal Cord Injury/Disorder Function, Affiliate Stigma, and Caregiver Burden in Turkey
Authors: Kuzu Duygu , Perrin Paul B. , Pugh Mickeal 
Published: January 2021

AbstractBackgroundThe association among spinal cord injury and disorder (SCI/D) function, caregiver affiliate stigma, and caregiver depression and burden has not been adequately studied. In Turkey, a region with a developing healthcare infrastructure, SCI/D caregivers may have a higher responsibility of care given limited resources and may experience greater psychological distress associated with caregiving than in more developed healthcare systems.ObjectiveTo examine whether SCI/D function, caregiver affiliate stigma, and caregiver burden and depression in Turkey are associated with each other.DesignCross‐sectional survey design.SettingParticipants were recruited from the Turkish Spinal Cord Injury Foundation and from the SCI/D service at Istanbul Physical Rehabilitation Hospital.ParticipantsA total of 82 SCI/D caregivers in Turkey.InterventionsNot applicable.Main Outcome MeasuresBarthel Index, Affiliate Stigma Scale, Zarit Burden Interview, and Patient Health Questionnaire‐9.ResultsIn an initial path model using bootstrapping, SCI/D function did not predict affiliate stigma, and once this path was trimmed, a final path model suggested that SCI/D function and affiliate stigma predicted caregiver burden, which in turn predicted caregiver depression. Burden partially mediated the effects of both SCI/D function and affiliate stigma on caregiver depression. All paths in the final model were statistically significant, and the fit indices suggested good fit.ConclusionsBecause affiliate SCI/D function and stigma exerted a cascade of statistical effects across caregiver burden and depression, interventions should be developed and tested to help caregivers cope with low SCI/D function and combat affiliate stigma, preventing it from exerting harmful effects. Previously developed caregiver interventions should be translated and culturally adapted for a Turkish context, given that the burden and depression outcomes these interventions target are highly relevant for Turkish SCI/D caregivers.