Miracle-dz/UniFAR-FTUs huggingface dataset:
Urelumab alone or in combination with rituximab in patients with relapsed or refractory B‐cell lymphoma

Urelumab, a fully human, non‐ligand binding, CD137 agonist IgG4 monoclonal antibody, enhances T‐cell and natural killer‐cell antitumor activity in preclinical models, and may enhance cytotoxic activity of rituximab. Here we report results in patients with relapsed or refractory diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma (FL), and other B‐cell lymphomas, in phase 1 studies evaluating urelumab alone (NCT01471210) or combined with rituximab (NCT01775631). Sixty patients received urelumab (0.3 mg/kg IV Q3W, 8 mg IV Q3W, or 8 mg IV Q6W); 46 received urelumab (0.1 mg/kg, 0.3 mg/kg, or 8 mg IV Q3W) plus rituximab 375 mg/m2 IV QW. The maximum tolerated dose (MTD) of urelumab was determined to be 0.1 mg/kg or 8 mg Q3W after a single event of potential drug‐induced liver injury occurred with urelumab 0.3 mg/kg. Treatment‐related AEs were reported in 52% (urelumab: grade 3/4, 15%) and 72% (urelumab + rituximab: grade 3/4, 28%); three led to discontinuation (grade 3 increased AST, grade 4 acute hepatitis [urelumab]; one death from sepsis syndrome [urelumab plus rituximab]). Objective response rates/disease control rates were 6%/19% (DLBCL, n = 31), 12%/35% (FL, n = 17), and 17%/42% (other B‐cell lymphomas, n = 12) with urelumab and 10%/24% (DLBCL, n = 29) and 35%/71% (FL, n = 17) with urelumab plus rituximab. Durable remissions in heavily pretreated patients were achieved; however, many were observed at doses exceeding the MTD. These data show that urelumab alone or in combination with rituximab demonstrated manageable safety in B‐cell lymphoma, but the combination did not enhance clinical activity relative to rituximab alone or other current standard of care.
The Modified Response Evaluation Criteria in Solid Tumors (RECIST) Yield a More Accurate Prognoses Than the RECIST 1.1 in Hepatocellular Carcinoma Treated with Transarterial Radioembolization

Background/Aims The Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and modified RECIST (mRECIST) criteria have been used to assess treatment responses for hepatocellular carcinoma (HCC) patients. We investigated which criteria provides better survival predictions in HCC patients treated with transarterial radioembolization (TARE). Methods In total, 102 patients with unresectable intrahepatic HCC, who were treated with TARE between 2012 and 2017, were reviewed retrospectively. The treatment response after TARE was evaluated at 1, 3, and 6 months by the mRECIST and RECIST 1.1. Responders were defined as patients with complete or partial responses by each criterion. Results The median age of 83 men and 19 women was 64.3 years. The median alpha-fetoprotein and des-gamma-carboxy prothrombin levels were 37.1 ng/mL and 1,780.0 mAU/mL, respectively. The median maximal tumor size was 8.3 cm, and multiple tumors were observed in 36 patients (35.3%). During the follow-up period (median, 20.7 months), 21 patients (20.6%) died, with a mean survival time of 55.5 months. The cumulative survival rate was 96.1% at 6 months and 89.3% at 12 months. Responders, defined by the mRECIST at 1, 3, and 6 months after TARE, showed better survival outcomes than nonresponders (hazard ratio [HR]=5.736, p=0.008 at 1 month; HR=3.145, p=0.022 at 3 months, and HR=2.887, p=0.061 at 6 months). The survival rates of responders and nonresponders defined by the RECIST 1.1 were similar (all p>0.05). Conclusions Response evaluations that use the mRECIST provide more accurate prognoses than those that use the RECIST 1.1 in HCC patients treated with TARE.
Transportation networks inspired by leaf venation algorithms

Biological systems have adapted to environmental constraints and limited resource availability. In the present study, we evaluate the algorithm underlying leaf venation (LV) deployment using graph theory. We compare the traffic balance, travel and cost efficiency of simply-connected LV networks to those of the fan tree and of the spanning tree. We use a Pareto front to show that the total length of leaf venations (LVs) is close to optimal. Then we apply the LV algorithm to design transportation networks in the city of Atlanta. Results show that leaf-inspired models can perform similarly or better than computer-intensive optimization algorithms in terms of network cost and service performance, which could facilitate the design of engineering transportation networks.
Pre-treatment neutrophils count as a prognostic marker to predict chemotherapeutic response and survival outcomes in glioma: a single-center analysis of 288 cases.

BACKGROUND Glioma is the most common and deadliest malignant primary intracranial brain tumor in adults. It remains unclear whether the pre-treatment peripheral blood test parameters might serve as biomarkers for treatment outcome. The purpose of the current study was to investigate the predictive and prognostic value of pre-treatment peripheral blood test parameters in glioma. METHODS In total, 288 glioma patients with complete results of pre-operation peripheral blood test, clinical information and tumor transcriptome data from Chinese Glioma Genome Atlas (CGGA project) were enrolled in our study. Receiver operating characteristic (ROC) curve, Kaplan-Meier analysis and Cox proportional hazards models were performed to evaluate the diagnostic and prognostic value of pre-treatment peripheral blood test parameters in glioma patients. RESULTS The white blood cells (WBC) and neutrophils (NEU) counts and neutrophil to lymphocyte ratio (NLR) were positively correlated with tumor grade. IDH mutation and 1p/19q codeletion occurred frequently in patients with higher NEU counts and NLR. We also found that glioma patients with higher NEU or NLR were more likely to have a significantly decreased overall survival. Meanwhile, NEU count was a prognostic marker for TMZ standard treatment GBM patients or IDH wild-type GBM patients. Further biological and functional analysis revealed that NEU count was positively associated with cell cycle and DNA duplication. CONCLUSION Our study was first to highlight the clinical significance of NEU count in GBM clinical treatment, which should be fully valued for clinical prediction and precise management.
Velocity Loss as a Critical Variable Determining the Adaptations to Strength Training

ABSTRACT Purpose This study aimed to compare the effects of four resistance training (RT) programs with different velocity loss (VL) thresholds: 0% (VL0), 10% (VL10), 20% (VL20), and 40% (VL40) on sprint and jump performance, muscle strength, neuromuscular, muscle hypertrophy, and architectural adaptations. Methods Sixty-four young resistance-trained men were randomly assigned into four groups (VL0, VL10, VL20, and VL40) that differed in the VL allowed in each set. Subjects followed an RT program for 8 wk (two sessions per week) using the full-squat (SQ) exercise, with similar relative intensity (70%–85% 1-repetition maximum), number of sets (3), and interset recovery period (4 min). Before and after the RT program, the following tests were performed: 1) muscle hypertrophy and architecture of the vastus lateralis (VLA), 2) tensiomyography, 3) 20-m running sprint, 4) vertical jump, 5) maximal voluntary isometric contraction in SQ, 6) progressive loading test in SQ, and 7) fatigue test. Results No between-group differences existed for RT-induced gains in sprint, jump, and strength performance despite the differences in the total volume performed by each group. VL20 and VL40 showed significant increases (P < 0.001) in muscle hypertrophy (group–time interaction, P = 0.06). However, only VL40 exhibited a significant slowing (P < 0.001) of the delay time in the VLA muscle (group–time interaction, P = 0.05). Moreover, VL40 showed a significant decrease in the early rate of force development (P = 0.04). Conclusions Higher VL thresholds (i.e., VL20 and VL40) maximized hypertrophic adaptations, although an excessive VL during the set (i.e., VL40) may also induce negative neuromuscular adaptations. Therefore, moderate VL thresholds should be chosen to maximize strength adaptations and to prevent negative neuromuscular adaptations.
Polymerase μ in non-homologous DNA end joining: importance of the order of arrival at a double-strand break in a purified system

Abstract During non-homologous DNA end joining (NHEJ), bringing two broken dsDNA ends into proximity is an essential prerequisite for ligation by XRCC4:Ligase IV (X4L4). This physical juxtaposition of DNA ends is called NHEJ synapsis. In addition to the key NHEJ synapsis proteins, Ku, X4L4, and XLF, it has been suggested that DNA polymerase mu (pol μ) may also align two dsDNA ends into close proximity for synthesis. Here, we directly observe the NHEJ synapsis by pol μ using a single molecule FRET (smFRET) assay where we can measure the duration of the synapsis. The results show that pol μ alone can mediate efficient NHEJ synapsis of 3′ overhangs that have at least 1 nt microhomology. The abundant Ku protein in cells limits the accessibility of pol μ to DNA ends with overhangs. But X4L4 can largely reverse the Ku inhibition, perhaps by pushing the Ku inward to expose the overhang for NHEJ synapsis. Based on these studies, the mechanistic flexibility known to exist at other steps of NHEJ is now also apparent for the NHEJ synapsis step.
The relationship between alexithymia, defense mechanisms, eating disorders, anxiety and depression.

INTRODUCTION Research suggests that alexithymia is a significant element for emotion processing, while defense mechanisms proved to be important factors for adjusting to stressful life events and to cope with potential psychopathologies. AIMS The aims of the present study are to examine the relationships between alexithymia, defense mechanisms, depression, anxiety and eating disorders and to examine the mediation role of defense mechanisms in the relation between alexithymia and anxiety, depression and eating disorders. MATERIAL In a sample of 283 subjects, aged 18-49 (M=2.33, DS=4.81), instruments were administered to measure alexithymia, defense mechanisms, depression, anxiety and eating disorders. RESULTS This study showed that alexithymia was positively related to anxiety, depression, general psychological maladjustment, eating disorder risk, maladaptive style defense mechanisms, image-distorting style defense mechanisms, self-sacrificing style defense mechanisms, whereas it was negatively related to Mature Style Defense Mechanisms. Implications of the findings are discussed.
Comparison of CRISPR and Marker-Based Methods for the Engineering of Phage T7

With the recent rise in interest in using lytic bacteriophages as therapeutic agents, there is an urgent requirement to understand their fundamental biology to enable the engineering of their genomes. Current methods of phage engineering rely on homologous recombination, followed by a system of selection to identify recombinant phages. For bacteriophage T7, the host genes cmk or trx have been used as a selection mechanism along with both type I and II CRISPR systems to select against wild-type phage and enrich for the desired mutant. Here we systematically compare all three systems; we show that the use of marker-based selection is the most efficient method and we use this to generate multiple T7 tail fiber mutants. Furthermore, we found the type II CRISPR-Cas system is easier to use and generally more efficient than a type I system in the engineering of phage T7. These results provide a foundation for the future, more efficient engineering of bacteriophage T7.
Initial Kinetic Characterization of Sterile Alpha and Toll/Interleukin Receptor Motif-Containing Protein 1.

Sterile alpha and toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) plays a pivotal role in triggering the neurodegenerative processes that underlie peripheral neuropathies, traumatic brain injury, and neurodegenerative diseases. Importantly, SARM1 knock down or knock out prevents degeneration, thereby demonstrating that SARM1 is a promising therapeutic target. Recently, SARM1 was shown to promote neurodegeneration via its ability to hydrolyze NAD+, forming nicotinamide and ADP ribose (ADPR). Herein, we describe the initial kinetic characterization of full length SARM1, as well as the truncated constructs corresponding to the SAM1-2TIR and TIR domains, highlighting the distinct challenges that have complicated efforts to characterize this enzyme. Moreover, we show that bacterially expressed full length SARM1 (kcat/KM = 6000 M-1s-1) is at least as active as the TIR domain alone (kcat/KM = 1500 M-1s-1). Finally, we show that the SARM1 hydrolyzes NAD+ via an ordered uni-bi reaction in which nicotinamide is released prior to ADPR.
Toxicity of microwave-synthesized silver-reduced graphene oxide nanocomposites to the microalga Chlorella vulgaris: Comparison with the hydrothermal method synthesized counterparts

Abstract The increased applications of nanomaterials in industry and biomedicine have resulted in a rising concern about their possible toxic impacts on living organisms. It has been claimed that the phytosynthesized nanomaterials have lower toxicity in comparison to their chemically synthesized counterparts. Therefore, it is important to evaluate their toxic effects on the environment. In the present study, we investigated the toxic effects of microwave-synthesized silver-reduced graphene oxide nanocomposites (MS-Ag-rGO) on Chlorella vulgaris. Algal cells were treated by 1, 2, 4 and 6 mg L−1 MS-Ag-rGO for 24 h. The obtained data with three replicates were examined using analysis of variance. Analysis of different growth parameters revealed that MS-Ag-rGO possessed significant dose-dependent toxic effect on C. vulgaris. Scanning electron microscope and fluorescence microscope images of the treated cells established morphological shrinkages and alteration in position of nucleoli. Moreover, reduction in the phenol and flavonoid contents, enhancement of H2O2 content, changes in the antioxidant enzymes activity and decreases in the growth parameters as well as photosynthetic pigments quantities confirmed the toxicity of MS-Ag-rGO to the C. vulgaris cells. Our findings revealed that MS-Ag-rGO possessed higher toxicity on C. vulgaris than Ag-rGO synthesized by hydrothermal technique.
Sulfhydration of AKT triggers Tau-phosphorylation by activating glycogen synthase kinase 3β in Alzheimer’s disease

Significance It is well known that AKT inactivates glycogen synthase kinase 3β (GSK3β) by increasing its phosphorylation. The inactivation of GSK3β leads to aberrant phosphorylation of Tau, which is a hallmark of Alzheimer’s disease. However, we found that if phosphorylated AKT is sulfhydrated, it will be unable to inactivate GSK3β and subsequently increases Tau phosphorylation. The influence of sulfhydrated AKT on GSK3β and Tau phosphorylation was reversed in a transgenic AKT-KI+/+ mouse, where sulfhydration of AKT residue was mutated to alanine. Thus, AKT-sulfhydration represents a unique posttranslational modification of AKT that can be targeted to suppress phosphorylation of GSK3β and subsequently reduce Tau phosphorylation. In Alzheimer’s disease (AD), human Tau is phosphorylated at S199 (hTau-S199-P) by the protein kinase glycogen synthase kinase 3β (GSK3β). HTau-S199-P mislocalizes to dendritic spines, which induces synaptic dysfunction at the early stage of AD. The AKT kinase, once phosphorylated, inhibits GSK3β by phosphorylating it at S9. In AD patients, the abundance of phosphorylated AKT with active GSK3β implies that phosphorylated AKT was unable to inactivate GSK3β. However, the underlying mechanism of the inability of phosphorylated AKT to phosphorylate GSK3β remains unknown. Here, we show that total AKT and phosphorylated AKT was sulfhydrated at C77 due to the induction of intracellular hydrogen sulfide (H2S). The increase in intracellular H2S levels resulted from the induction of the proinflammatory cytokine, IL-1β, which is a pathological hallmark of AD. Sulfhydrated AKT does not interact with GSK3β, and therefore does not phosphorylate GSK3β. Thus, active GSK3β phosphorylates Tau aberrantly. In a transgenic knockin mouse (AKT-KI+/+) that lacked sulfhydrated AKT, the interaction between AKT or phospho-AKT with GSK3β was restored, and GSK3β became phosphorylated. In AKT-KI+/+ mice, expressing the pathogenic human Tau mutant (hTau-P301L), the hTau S199 phosphorylation was ameliorated as GSK3β phosphorylation was regained. This event leads to a decrease in dendritic spine loss by reducing dendritic localization of hTau-S199-P, which improves cognitive dysfunctions. Sulfhydration of AKT was detected in the postmortem brains from AD patients; thus, it represents a posttranslational modification of AKT, which primarily contributes to synaptic dysfunction in AD.
Temperature Effect on the Adsorption and Volumetric Properties of Aqueous Solutions of Kolliphor®ELP

Density, viscosity and surface tension of Kolliphor® ELP, the nonionic surfactant aqueous solutions were measured at temperature T = 293–318 K and at 5K interval. Steady-state fluorescence measurements have been also made using pyrene as a probe. On the basis of the obtained results, a number of thermodynamic, thermo-acoustic and anharmonic parameters of the studied surfactant have been evaluated and interpreted in terms of structural effects and solute–solvent interactions. The results suggest that the molecules of studied surfactant at concentrations higher than the critical micelle concentration act as structure makers of the water structure.
Age-related differences in the gut microbiome of Rhesus macaques.

Aging is a multifactorial process characterized by progressive changes in gut physiology and the intestinal mucosal immune system. These changes, along with alterations in life style, diet, nutrition, inflammation and immune function alter both composition and stability of the gut microbiota. Given the impact of environmental influences on the gut microbiota, animal models are particularly useful in this field. To understand the relationship between the gut microbiota and aging in nonhuman primates, we collected fecal samples from 20 male and 20 female rhesus macaques (Macaca mulatta), across the natural macaque age range, for 16S rRNA gene analyses. Operational taxonomic units (OTUs) were then grouped together to summarize taxon abundance at different hierarchical levels of classification and alpha- and beta-diversity were calculated. There were no age or sex differences in alpha diversity. At the phylum level, relative abundance of Proteobacteria and Firmicutes and Firmicutes to Bacteriodetes ratio were different between age groups though significance disappeared after correction for multiple comparisons. At the class level, relative abundance of Firmicutes_Bacilli decreased and Proteobacteria_Alphaproteobacteria and Proteobacteria_Betaproteobacteria increased with each successively older group. Only differences in Firmicutes_Bacilli remained significant after correction for multiple comparisons. No sex differences were identified in relative abundances after correction for multiple comparisons. Our results are not surprising given the known impact of environmental factors on the gut microbiota.
Phylogenetic analysis reveals an ancient gene duplication as the origin of the MdtABC efflux pump

The efflux pumps from the Resistance-Nodulation-Division family, RND, are main contributors to intrinsic antibiotic resistance in Gram-negative bacteria. Among this family, the MdtABC pump is unusual by having two inner membrane components. The two components, MdtB and MdtC are homologs, therefore it is evident that the two components arose by gene duplication. In this paper, we describe the results obtained from a phylogenetic analysis of the MdtBC pumps in the context of other RNDs. We show that the individual inner membrane components (MdtB and MdtC) are conserved throughout the Proteobacterial species and that their existence is a result of a single gene duplication. We argue that this gene duplication was an ancient event which occurred before the split of Proteobacteria into Alpha-, Beta- and Gamma- classes. Moreover, we find that the MdtABC pumps and the MexMN pump from Pseudomonas aeruginosa share a close common ancestor, suggesting the MexMN pump arose by another gene duplication event of the original Mdt ancestor. Taken together, these results shed light on the evolution of the RND efflux pumps and demonstrate the ancient origin of the Mdt pumps and suggest that the core bacterial efflux pump repertoires have been generally stable throughout the course of evolution.
Experimental Study for the Stripping of PTFE Coatings on Al-Mg Substrates Using Dry Abrasive Materials

Polytetrafluoroethylene (PTFE) coatings are used in many applications and processing industries. With their use, they wear out and lose properties and must be replaced by new ones if the cost of the element so advises. There are different stripping techniques, but almost all of them are very difficult and require strict environmental controls. It is a challenge to approach the process through efficient and more sustainable techniques. In the present work, we have studied the stripping of PTFE coatings by projection with abrasives (1 step) as an alternative to carbonization + sandblasting procedures (2 steps). For this purpose, different types of abrasives have been selected: brown corundum, white corundum, glass microspheres, plastic particles, and a walnut shell. The tests were performed at pressures from 0.4 to 0.6 MPa on PTFE-coated aluminium substrates of EN AW-5182 H111 alloy. Stripping rates, surface roughness, and substrate hardness have been studied. Scanning electron microscopy (SEM) images of sandblasted specimens have also been obtained. All abrasives improved mechanical and surface properties in one-step vs. two-step processes. The abrasives of plastic and glass microspheres are the most appropriate for the one-step process, which increases the hardness and roughness level Ra in the substrate. Corundum abrasives enable the highest stripping rates.
Microfabrication of poly(acrylamide) hydrogels with independently controlled topography and stiffness

The stiffness and topography of a cell’s extracellular matrix (ECM) are physical cues that play a key role in regulating processes that determine cellular fate and function. While substrate stiffness can dictate cell differentiation lineage, migration, and self-organization, topographical features can change the cell’s differentiation profile or migration ability. Although both physical cues are present and intrinsic to the native tissues in vivo, in vitro studies have been hampered by the lack of technological set-ups that would be compatible with cell culture and characterization. In vitro studies therefore either focused on screening stiffness effects in cells cultured on flat substrates or on determining topography effects in cells cultured onto hard materials. Here, we present a reliable, microfabrication method to obtain well defined topographical structures of micrometer size (5–10 μm) on soft polyacrylamide hydrogels with tunable mechanical stiffness (3–145 kPa) that closely mimic the in vivo situation. Topographically microstructured polyacrylamide hydrogels are polymerized by capillary force lithography using flexible materials as molds. The topographical microstructures are resistant to swelling, can be conformally functionalized by ECM proteins and sustain the growth of cell lines (fibroblasts and myoblasts) and primary cells (mouse intestinal epithelial cells). Our method can independently control stiffness and topography, which allows to individually assess the contribution of each physical cue to cell response or to explore potential synergistic effects. We anticipate that our fabrication method will be of great utility in tissue engineering and biophysics, especially for applications where the use of complex in vivo-like environments is of paramount importance.