Miracle-dz/UniFAR-FTUs huggingface dataset:
Atezolizumab, Bevacizumab, and Chemotherapy for Newly Diagnosed Stage III or IV Ovarian Cancer: Placebo-Controlled Randomized Phase III Trial (IMagyn050/GOG 3015/ENGOT-OV39)

PURPOSE To evaluate the addition of the humanized monoclonal antiprogrammed death ligand-1 (PD-L1) antibody, atezolizumab, to platinum-based chemotherapy and bevacizumab in newly diagnosed stage III or IV ovarian cancer (OC). METHODS This multicenter placebo-controlled double-blind randomized phase III trial (ClinicalTrials.gov identifier: NCT03038100) enrolled patients with newly diagnosed untreated International Federation of Gynecology and Obstetrics (FIGO) stage III or IV OC who either had undergone primary cytoreductive surgery with macroscopic residual disease or were planned to receive neoadjuvant chemotherapy and interval surgery. Patients were stratified by FIGO stage, Eastern Cooperative Oncology Group performance status, tumor immune cell PD-L1 staining, and treatment strategy and randomly assigned 1:1 to receive 3-weekly cycles of atezolizumab 1,200 mg or placebo (day 1, cycles 1-22), with paclitaxel plus carboplatin (day 1, cycles 1-6) plus bevacizumab 15 mg/kg (day 1, cycles 2-22), omitting perioperative bevacizumab in neoadjuvant patients. The co-primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat and PD-L1–positive populations. RESULTS Between March 8, 2017, and March 26, 2019, 1,301 patients were enrolled. The median progression-free survival was 19.5 versus 18.4 months with atezolizumab versus placebo, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.07; stratified log-rank P = .28), in the intention-to-treat population and 20.8 versus 18.5 months, respectively (hazard ratio, 0.80; 95% CI, 0.65 to 0.99; P = .038), in the PD-L1–positive population. The interim (immature) overall survival results showed no significant benefit from atezolizumab. The most common grade 3 or 4 adverse events were neutropenia (21% with atezolizumab v 21% with placebo), hypertension (18% v 20%, respectively), and anemia (12% v 12%). CONCLUSION Current evidence does not support the use of immune checkpoint inhibitors in newly diagnosed OC. Insight from this trial should inform further evaluation of immunotherapy in OC.
Detection of truncated isoforms of human neuroserpin lacking the reactive center loop: Implications in noninhibitory role

Neuroserpin is a serine protease inhibitor expressed mainly in the brain and at low levels in other tissues like the kidney, testis, heart, and spinal cord. It is involved in the inhibition of tissue plasminogen activator (tPA), plasmin, and to a lesser extent, urokinase‐type plasminogen (uPA). Neuroserpin has also been shown to plays noninhibitory roles in the regulation of N‐cadherin‐mediated cell adhesion. It is involved in neuroprotection from seizure and stroke through tPA‐mediated inhibition and also through its other protease targets. Mutations in critical domains of neuroserpin lead to its polymerization and neuronal death. In this study, a novel truncated isoform of human neuroserpin was identified in the brain and liver, which was confirmed by reverse transcriptase‐PCR and DNA sequencing using exon‐specific primers. Structural characterization of novel isoform using MD simulations studies indicated that it lacks the reactive center loop (RCL) but largely maintains its secondary structure fold. The novel truncated variant was cloned, expressed, and purified. A comparative intrinsic fluorescence and 4,4′‐bis‐1‐anilino naphthalene 8‐sulfonate studies revealed a decrease in fluorescence emission intensity and a more exposed hydrophobic surface as compared to the reported isoform. However, the novel isoform has lost its ability for tPA inhibition and complex formation. The absence of RCL indicates a noninhibitory role for the truncated isoform, prompting a detailed search and identification of two smaller isoforms in the human brain. With indications of the noninhibitory role of neuroserpin, identifying novel isoforms that appear to be without the tPA recognition domain is significant.
Comparative genomic analysis of sifakas (Propithecus) reveals selection for folivory and high heterozygosity despite endangered status

Critically endangered sifaka lemurs exhibit high genetic diversity and genomic evidence for dietary adaptation. Sifakas (genus Propithecus) are critically endangered, large-bodied diurnal lemurs that eat leaf-based diets and show corresponding anatomical and microbial adaptations to folivory. We report on the genome assembly of Coquerel’s sifaka (P. coquereli) and the resequenced genomes of Verreaux’s (P. verreauxi), the golden-crowned (P. tattersalli), and the diademed (P. diadema) sifakas. We find high heterozygosity in all sifakas compared with other primates and endangered mammals. Demographic reconstructions nevertheless suggest declines in effective population size beginning before human arrival on Madagascar. Comparative genomic analyses indicate pervasive accelerated evolution in the ancestral sifaka lineage affecting genes in several complementary pathways relevant to folivory, including nutrient absorption and xenobiotic and fatty acid metabolism. Sifakas show convergent evolution at the level of the pathway, gene family, gene, and amino acid substitution with other folivores. Although sifakas have relatively generalized diets, the physiological challenges of habitual folivory likely led to strong selection.
The structural plasticity of nucleic acid duplexes revealed by WAXS and MD

The structural diversity of nucleic acid duplexes reflects the critical roles of sequence, ions, and waters. Double-stranded DNA (dsDNA) and RNA (dsRNA) helices display an unusual structural diversity. Some structural variations are linked to sequence and may serve as signaling units for protein-binding partners. Therefore, elucidating the mechanisms and factors that modulate these variations is of fundamental importance. While the structural diversity of dsDNA has been extensively studied, similar studies have not been performed for dsRNA. Because of the increasing awareness of RNA’s diverse biological roles, such studies are timely and increasingly important. We integrate solution x-ray scattering at wide angles (WAXS) with all-atom molecular dynamics simulations to explore the conformational ensemble of duplex topologies for different sequences and salt conditions. These tightly coordinated studies identify robust correlations between features in the WAXS profiles and duplex geometry and enable atomic-level insights into the structural diversity of DNA and RNA duplexes. Notably, dsRNA displays a marked sensitivity to the valence and identity of its associated cations.
Characterization of sleep habits of children with Sotos syndrome

Sotos syndrome (SS) is a genetic disorder characterized by accelerated growth in childhood, developmental deficits, and characteristic craniofacial features. While clinicians and parents have reported unusual sleep habits, only one study by Rutter and Cole in 1991 mentioned sleep complaints (Rutter and Cole, Developmental Medicine and Child Neurology, 1991, 33, 898–902). This study aimed to characterize the sleep habits of individuals with SS. We performed a cross‐sectional study of individuals with a definite, probable, or possible diagnosis of Sotos syndrome. Participants were asked to complete the Children's Sleep Habits Questionnaire (CHSQ). We compared our data to historical data available from the literature. Subjects with SS showed more sleep disturbance than typically developing individuals (TD), although their sleep onset was less likely to be delayed and their sleep duration was longer. Participants with SS also showed different sleep patterns compared to children with other forms of intellectual and developmental disabilities (IDD). Individuals with SS exhibited early bed and rise times, frequently used transitional objects, displayed repetitive motion at sleep onset, and did not show a decrease in sleep duration with age. The majority of participants fell asleep at the same time each night, in their own bed, and within 20 min, and rarely showed signs of sleepwalking or night terrors. These results improve our understanding of sleep habits of individuals with SS and may be used to guide treatment and provide normalization for children with SS.
Three-dimensional microscale hanging drop arrays with geometric control for drug screening and live tissue imaging

Tiny silicon microchip–based high-throughput hanging drop arrays allow drug screening and geometric control. Existing three-dimensional (3D) culture techniques are limited by trade-offs between throughput, capacity for high-resolution imaging in living state, and geometric control. Here, we introduce a modular microscale hanging drop culture where simple design elements allow high replicates for drug screening, direct on-chip real-time or high-resolution confocal microscopy, and geometric control in 3D. Thousands of spheroids can be formed on our microchip in a single step and without any selective pressure from specific matrices. Microchip cultures from human LN229 glioblastoma and patient-derived mouse xenograft cells retained genomic alterations of originating tumors based on mate pair sequencing. We measured response to drugs over time with real-time microscopy on-chip. Last, by engineering droplets to form predetermined geometric shapes, we were able to manipulate the geometry of cultured cell masses. These outcomes can enable broad applications in advancing personalized medicine for cancer and drug discovery, tissue engineering, and stem cell research.
Correlation of Regulatory T Cell Numbers with Disease Tolerance upon Virus Infection

The goal of a successful immune response is to clear the pathogen while sparing host tissues from damage associated with pathogen replication and active immunity. Regulatory T cells (Treg) have been implicated in maintaining this balance as they contribute both to the organization of immune responses as well as restriction of inflammation and immune activation to limit immunopathology. To determine if Treg abundance prior to pathogen encounter can be used to predict the success of an antiviral immune response, we used genetically diverse mice from the collaborative cross infected with West Nile virus (WNV). We identified collaborative cross lines with extreme Treg abundance at steady state, either high or low, and used mice with these extreme phenotypes to demonstrate that baseline Treg quantity predicted the magnitude of the CD8 T cell response to WNV infection, although higher numbers of baseline Tregs were associated with reduced CD8 T cell functionality in terms of TNF and granzyme B expression. Finally, we found that abundance of CD44+ Tregs in the spleen at steady state was correlated with an increased early viral load within the spleen without an association with clinical disease. Thus, we propose that Tregs participate in disease tolerance in the context of WNV infection by tuning an appropriately focused and balanced immune response to control the virus while at the same time minimizing immunopathology and clinical disease. We hypothesize that Tregs limit the antiviral CD8 T cell function to curb immunopathology at the expense of early viral control as an overall host survival strategy.
Addressing the maldistribution of health resources in Sichuan Province, China: A county-level analysis

Introduction The equity of health resource allocation geographically is a contested topic. Sichuan Province, located in Southwest China, has varied topography, providing us with natural materials to explore the determinants of health resource distribution. Materials and methods Spatial panel econometric models were constructed to explore the relationship between health resources and factors such as health care service demand and socioeconomic and demographic perspectives using data from Sichuan Province for eight consecutive years (2010–2017). Results Health care service demands were found to be a major driving force behind the distribution of health resources, showing that an increase in health care service demands draws health resources to specific counties and surrounding areas. From a socioeconomic perspective, gross domestic product per capita and the average wage show a positive association with health resources. In addition, the total population and proportion of the urban population have diverse effects in regard to health-related human resources but have the same effects on material and financial health resources. Conclusions Our results provide the Chinese government with evidence needed to formulate and promulgate effective policies, especially those aiming to tackle inequity among different regions.
Disrupting Irreversible Bacterial Adhesion and Biofilm Formation with an Engineered Enzyme

In this study, the ability of an engineered enzyme to reduce bacterial adhesion and biofilm formation of several foodborne pathogens was demonstrated, representing a promising option for enhancing or replacing chlorine and other chemical sanitizers in food processing applications. Specifically, significant reductions of biofilms of the pathogens Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes are observed, as are reductions in initial adhesion. ABSTRACT Biofilm formation is often attributed to postharvest bacterial persistence on fresh produce and food handling surfaces. In this study, a predicted glycosyl hydrolase enzyme was expressed, purified, and validated for the removal of microbial biofilms from biotic and abiotic surfaces under conditions used for chemical cleaning agents. Crystal violet biofilm staining assays revealed that 0.1 mg/ml of enzyme inhibited up to 41% of biofilm formation by Escherichia coli O157:H7, E. coli 25922, Salmonella enterica serovar Typhimurium, and Listeria monocytogenes. Furthermore, the enzyme was effective at removing mature biofilms, providing a 35% improvement over rinsing with a saline solution alone. Additionally, a parallel-plate flow cell was used to directly observe and quantify the impact of enzyme rinses on E. coli O157:H7 cells adhering to spinach leaf surfaces. The presence of 1 mg/liter enzyme resulted in nearly 6-times-higher detachment rate coefficients than a deionized (DI) water rinse, while the total cells removed from the surface increased from 10% to 25% over the 30-min rinse time, reversing the initial phases of biofilm formation. Enzyme treatment of all 4 cell types resulted in significantly reduced cell surface hydrophobicity and collapse of negatively stained E. coli 25922 cells imaged by electron microscopy, suggesting potential polysaccharide surface modification of enzyme-treated bacteria. Collectively, these results point to the broad substrate specificity and robustness of the enzyme for different types of biofilm stages, solution conditions, and pathogen biofilm types and may be useful as a method for the removal or inhibition of bacterial biofilm formation. IMPORTANCE In this study, the ability of an engineered enzyme to reduce bacterial adhesion and biofilm formation of several foodborne pathogens was demonstrated, representing a promising option for enhancing or replacing chlorine and other chemical sanitizers in food processing applications. Specifically, significant reductions of biofilms of the pathogens Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes are observed, as are reductions in initial adhesion. Enzymes have the added benefits of being green, sustainable alternatives to chemical sanitizers, as well as having a minimal impact on food properties, in contrast to many alternative antimicrobial options such as bleach that aim to minimize food safety risks.
Weaker bonding can give larger thermal conductance at highly mismatched interfaces

Thermal conductance at interface with weak van der Waals bonding can become larger than that with strong covalent bonding. Thermal boundary conductance is typically positively correlated with interfacial adhesion at the interface. Here, we demonstrate a counterintuitive experimental result in which a weak van der Waals interface can give a higher thermal boundary conductance than a strong covalently bonded interface. This occurs in a system with highly mismatched vibrational frequencies (copper/diamond) modified by a self-assembled monolayer. Using finely controlled fabrication and detailed characterization, complemented by molecular simulation, the effects of bridging the vibrational spectrum mismatch and bonding at the interface are systematically varied and understood from a molecular dynamics viewpoint. The results reveal that the bridging and binding effects have a trade-off relationship and, consequently, that the bridging can overwhelm the binding effect at a highly mismatched interface. This study provides a comprehensive understanding of phonon transport at interfaces, unifying physical and chemical understandings, and allowing interfacial tailoring of the thermal transport in various material systems.
Oxy-Combustion of Hydrogen-Enriched Methane: Experimental Measurements and Analysis

Oxy-combustion characteristics of methane and hydrogen-enriched methane have been investigated experimentally in a nonpremixed swirl-stabilized combustor. Experiments were conducted at different firing rates ranging from 2.5 to 4.5 MW/m3-bar and 0% to 20% hydrogen content in methane/hydrogen fuel mixtures. When the combustor is operated under gas turbine conditions (≥3.5 MW/m3-bar), the flame transitions exhibit trimodal regime (i.e., attached flame → lifted flame → no flame) below which the flame transitions exhibit bimodal regime (i.e., attached flame → no flame). Weak flames at the nozzle exit were generally observed to precede the attached flame → lifted flame transition. The weak flame is due to the entrainment of more CO2-containing oxidizer (O2/CO2) to the fuel stream that reduces the flame burning rate. The attached flame → lifted flame transition occurs at a critical oxidizer velocity. The critical oxidizer velocity strongly depends on the fuel composition. Moreover, lifted flame oscillates about.
Development of a tip enhanced near-field laser ablation system for sub-micrometric analysis of solid samples

We have studied the influence of the laser wavelength (266 nm and 532 nm) on the tip-enhanced near-field laser ablation of conducting gold and semiconducting silicon samples. The near-field laser ablation effect was obtained by coupling a nanosecond Nd:YAG laser to an atomic force microscope. Experiments were carried out at atmospheric pressure with one and multiple laser pulses. The near-field ablation showed distinct differences in the dimensions of the craters according to the laser wavelength and the nature of the sample. On gold samples, with the same number of laser pulses, larger craters were obtained at 532 nm while the crater depths remained almost constant for both wavelengths. On silicon samples and under the same experimental conditions, craters were only obtained at 266 nm, while at 532 nm no defined structure was observed below 200 laser pulses. These experimental results were in accordance with the numerical simulations of the localized heating given by a home-made 3D code. Both the experimental and theoretical approaches showed that the sample absorption coefficient set by the laser wavelength was one of
Theanine and cancer: A systematic review of the literature

A growing literature indicates several health benefits of theanine, a major nonprotein derivative amino acid special to tea, and a nonedible mushroom. This study aimed to systematically review the scientific evidence regarding the anticarcinogen and anticancer effects of natural theanine. A systematic search for the relevant articles published until January 2021 on MEDLINE, Scopus, and Web of Knowledge was conducted. Out of 377 initial records, 14 in vitro, ex vivo, and in vivo studies met our inclusion criteria. Most of the included in vitro and ex vivo studies reported beneficial effects of theanine on the proliferation, apoptosis, metastasis, migration, and invasion in various cancer cell lines. The in vivo studies also supported the potential impacts of theanine on cancer incidence or progression. Theanine exerted its anticancer function by inhibiting EGFR, VEGFR, Met, and Akt/mTOR, JAK2/STAT3, and ERK/NFκB pathways, as well as activating the intrinsic apoptosis pathway and caspase‐independent programmed cell death. In conclusion, the results indicated moderate apoptotic, antimetastatic, antimigration, and anti‐invasion effects, along with the mild antiproliferative influence of theanine on cancer. Further studies are necessary to ascertain the effectiveness of theanine on the prevention and suppression of cancer and shed light upon the attributable mechanisms in the in vivo condition.
Safety and feasibility of transradial use of 8F balloon guide catheter Flowgate2 for endovascular thrombectomy in acute ischemic stroke

Background While Balloon Guide Catheters (BGC) have been shown to increase the rate of reperfusion during mechanical thrombectomy (MT), its implementation with transfemoral approach is at times limited due to unfavorable vascular anatomy. Objective to determine safety, feasibility and performance of the transradial use of 8 F BGC Flowgate 2 during mechanical thrombectomy procedures in patients with unfavorable vascular anatomies (type 3 or bovine arch) Material/Methods: We performed a retrospective cohort study of consecutive transradial mechanical thrombectomies performed with BGC Flowgate 2 between January and December 2019. Patient demographics, procedural and radiographic metrics, and clinical data were analyzed. Results 20 (8.7%) out of 230 overall thrombectomy procedures underwent transradial approach using an 8 F BGC Flowgate. 2 Successful approach was achieved in 17/20 cases, and in 3 cases radial was switched to femoral, after failure. TICI 2 C/3 was achieved in 18 cases (90%), followed by TICI 2 b and 2a in 1 (5%) case respectively. The average number of passes was 1.8. The average radial puncture-to-first pass time was 22 min. Radial vasospasm was observed in 3/20 cases. The Flowgate 2 was found kinked in 4/20 cases (20%), all of them during right internal carotid procedures. There were no postprocedural complications at puncture site, as hematoma, pseudoaneurysm or local ischemic events Conclusion The use of 8 F Balloon Guide Catheter during MT via transradial approach might represent an alternative in selected cases with unfavorable vascular anatomies. Its use in right ICA catheterizations was associated with a high rate of catheter kinking.
Avoiding organelle mutational meltdown across eukaryotes with or without a germline bottleneck

Mitochondrial DNA (mtDNA) and plastid DNA (ptDNA) encode vital bioenergetic apparatus, and mutations in these organelle DNA (oDNA) molecules can be devastating. In the germline of several animals, a genetic “bottleneck” increases cell-to-cell variance in mtDNA heteroplasmy, allowing purifying selection to act to maintain low proportions of mutant mtDNA. However, most eukaryotes do not sequester a germline early in development, and even the animal bottleneck remains poorly understood. How then do eukaryotic organelles avoid Muller’s ratchet—the gradual buildup of deleterious oDNA mutations? Here, we construct a comprehensive and predictive genetic model, quantitatively describing how different mechanisms segregate and decrease oDNA damage across eukaryotes. We apply this comprehensive theory to characterise the animal bottleneck with recent single-cell observations in diverse mouse models. Further, we show that gene conversion is a particularly powerful mechanism to increase beneficial cell-to-cell variance without depleting oDNA copy number, explaining the benefit of observed oDNA recombination in diverse organisms which do not sequester animal-like germlines (for example, sponges, corals, fungi, and plants). Genomic, transcriptomic, and structural datasets across eukaryotes support this mechanism for generating beneficial variance without a germline bottleneck. This framework explains puzzling oDNA differences across taxa, suggesting how Muller’s ratchet is avoided in different eukaryotes.