Miracle-dz/UniFAR-FTUs huggingface dataset:
Hashed and hierarchical timing wheels: data structures for the efficient implementation of a timer facility

Conventional algorithms to implement an Operating System timer module take &Ogr;(n) time to start or maintain a timer, where n is the number of outstanding timers: this is expensive for large n. This paper begins by exploring the relationship between timer algorithms, time flow mechanisms used in discrete event simulations, and sorting techniques. Next a timer algorithm for small timer intervals is presented that is similar to the timing wheel technique used in logic simulators. By using a circular buffer or timing wheel, it takes &Ogr;(1) time to start, stop, and maintain timers within the range of the wheel. Two extensions for larger values of the interval are described. In the first, the timer interval is hashed into a slot on the timing wheel. In the second, a hierarchy of timing wheels with different granularities is used to span a greater range of intervals. The performance of these two schemes and various implementation trade-offs are discussed.
Surgical outcomes using a medial-to-lateral endonasal endoscopic approach to pituitary adenomas invading the cavernous sinus.

OBJECT This study details the extent of resection and complications associated with endonasal endoscopic surgery for pituitary tumors invading the cavernous sinus (CS) using a moderately aggressive approach to maximize extent of resection through the medial CS wall while minimizing the risk of cranial neuropathy and blood loss. Tumor in the medial CS was aggressively pursued while tumor in the lateral CS was debulked in preparation for radiosurgery. METHODS A prospective surgical database of consecutive endonasal pituitary surgeries with verified CS invasion on intraoperative visual inspection was reviewed. The extent of resection as a whole and within the CS was assessed by an independent neuroradiologist using pre- and postoperative Knosp-Steiner (KS) categorization and volumetrics of the respective MR images. The extent of resection and clinical outcomes were compared for medial (KS 1-2) and lateral (KS 3-4) lesions. RESULTS Thirty-six consecutive patients with pituitary adenomas involving the CS who had surgery via an endonasal endoscopic approach were identified. The extent of resection was 84.6% for KS 1-2 and 66.6% for KS 3-4 (p = 0.04). The rate of gross-total resection was 53.8% for KS 1-2 and 8.7% for KS 3-4 (p = 0.0006). Six patients (16.7%) had preoperative cranial neuropathies, and all 6 had subjective improvement after surgery. Surgical complications included 2 transient postoperative cranial neuropathies (5.6%), 1 postoperative CSF leak (2.8%), 1 reoperation for mucocele (2.8%), and 1 infection (2.8%). CONCLUSIONS The endoscopic endonasal "medial-to-lateral" approach permits safe debulking of tumors in the medial and lateral CS. Although rates of gross-total resection are moderate, particularly in the lateral CS, the risk of permanent cranial neuropathy is extremely low and there is a high chance of improvement of preexisting deficits. This approach can also facilitate targeting for postoperative radiosurgery.
Overexpression of UBR5 promotes tumor growth in gallbladder cancer via PTEN/PI3K/Akt signal pathway

As a key regulator of the ubiquitin‐proteasome system, ubiquitin protein ligase E3 component N‐recognin 5 (UBR5) plays an important role in various cancers. In this study, our results showed for the first time that UBR5 was overexpressed in gallbladder cancer (GBC) tumor tissues. UBR5 overexpression was significantly associated with tumor size, histological and tumor differentiation. UBR5 overexpression was also associated with poor prognosis in patients with GBC. The knockdown of UBR5 remarkably inhibited the cell proliferation and colony formation of GBC‐Shandong (SD) cells in vitro and in vivo. UBR5 potentially increases the level of protein kinase B phosphorylation via the degradation of phosphatase and tensin homolog, which contributes to tumor growth in GBC. UBR5 may be an important biomarker for predicting the prognosis of patients with GBC.
Genome-wide analysis of flanking sequences reveals that Tnt1 insertion is positively correlated with gene methylation in Medicago truncatula.

From a single transgenic line harboring five Tnt1 transposon insertions, we generated a near-saturated insertion population in Medicago truncatula. Using thermal asymmetric interlaced-polymerase chain reaction followed by sequencing, we recovered 388 888 flanking sequence tags (FSTs) from 21 741 insertion lines in this population. FST recovery from 14 Tnt1 lines using the whole-genome sequencing (WGS) and/or Tnt1-capture sequencing approaches suggests an average of 80 insertions per line, which is more than the previous estimation of 25 insertions. Analysis of the distribution pattern and preference of Tnt1 insertions showed that Tnt1 is overall randomly distributed throughout the M. truncatula genome. At the chromosomal level, Tnt1 insertions occurred on both arms of all chromosomes, with insertion frequency negatively correlated with the GC content. Based on 174 546 filtered FSTs that show exact insertion locations in the M. truncatula genome version 4.0 (Mt4.0), 0.44 Tnt1 insertions occurred per kb, and 19 583 genes contained Tnt1 with an average of 3.43 insertions per gene. Pathway and gene ontology analyses revealed that Tnt1-inserted genes are significantly enriched in processes associated with 'stress', 'transport', 'signaling' and 'stimulus response'. Surprisingly, gene groups with higher methylation frequency were more frequently targeted for insertion. Analysis of 19 583 Tnt1-inserted genes revealed that 59% (1265) of 2144 transcription factors, 63% (765) of 1216 receptor kinases and 56% (343) of 616 nucleotide-binding site-leucine-rich repeat genes harbored at least one Tnt1 insertion, compared with the overall 38% of Tnt1-inserted genes out of 50 894 annotated genes in the genome.
Endothelial toll‐like receptor 4 maintains lung integrity via epigenetic suppression of p16INK4a

We previously reported that the canonical innate immune receptor toll‐like receptor 4 (TLR4) is critical in maintaining lung integrity. However, the molecular mechanisms via which TLR4 mediates its effect remained unclear. In the present study, we identified distinct contributions of lung endothelial cells (Ec) and epithelial cells TLR4 to pulmonary homeostasis using genetic‐specific, lung‐ and cell‐targeted in vivo methods. Emphysema was significantly prevented via the reconstituting of human TLR4 expression in the lung Ec of TLR4−/− mice. Lung Ec‐silencing of TLR4 in wild‐type mice induced emphysema, highlighting the specific and distinct role of Ec‐expressed TLR4 in maintaining lung integrity. We also identified a previously unrecognized role of TLR4 in preventing expression of p16INK4a, a senescence‐associated gene. Lung Ec‐p16INK4a‐silencing prevented TLR4−/− induced emphysema, revealing a new functional role for p16INK4ain lungs. TLR4 suppressed endogenous p16INK4a expression via HDAC2‐mediated deacetylation of histone H4. These findings suggest a novel role for TLR4 in maintaining of lung homeostasis via epigenetic regulation of senescence‐related gene expression.
Cumulative evidence for association between genetic polymorphisms and esophageal cancer susceptibility: A review with evidence from meta‐analysis and genome‐wide association studies

An increasing number of publications had reported the association between single‐nucleotide polymorphisms (SNPs) and esophageal cancer (EC) risk in the past decades. Results from these publications were controversial. We used PubMed, Medline, and Web of Science to identify meta‐analysis articles published before 30 July 2018, that summarize a comprehensive investigation for cumulative evidence of genetic polymorphisms of EC and its subtype risk. Two methods, Venice criteria and false‐positive report probability (FPRP) tests, were used to assess cumulative evidence of significant associations. At last, 107 meta‐analyses were considered to be in conformity with the inclusion criteria, yielding 51 variants associated with EC or esophageal squamous cell carcinoma (ESCC). Thirty‐eight variants were considered to be nominally significant associated with risk of EC or ESCC, whereas the rest showed non‐association. In additional, five variants on five genes were rated as strong cumulative epidemiological evidence for a nominally significant association with EC and ESCC risk, including CYP1A1 rs1048943, EGF rs444903, HOTAIR rs920778, MMP2 rs243865, and PLCE1 rs2274223, 10 variants were rated as moderate, and 18 variants were rated as weak. Additionally, 17 SNPs were verified noteworthy in six genomewide association studies (GWAS) using FPRP methods. Collectively, this review offered a comprehensively referenced information with cumulative evidence of associations between genetic polymorphisms and EC and ESCC risk.
Associations of Sensor-Derived Physical Behavior with Metabolic Health: A Compositional Analysis in the Record Multisensor Study

Previous studies about the effects of physical activity and sedentary behaviors on health rarely recorded the exact body postures and movements, although they might be of metabolic relevance. Moreover, few studies treated the time budget of behaviors as compositions and little was done to characterize the distribution of durations of behavior sequences in relation with health. Data from the RECORD (Residential Environment and CORonary heart Disease) study of two combined VitaMove accelerometers worn at the trunk and upper leg for a week by 154 male and female adults (age = 50.6 ± 9.6 years, BMI = 25.8 ± 3.9 kg/m2) were analyzed. Using both iso-temporal substitution and compositional analysis, we examined associations between five physical behaviors (lying, sitting, standing, low physical activity, moderate-to-vigorous activity) and seven health outcomes (fasting serum glucose, low- and high-density lipoprotein, and triglycerides levels, body mass index, and waist circumference). After adjustment for confounding variables, total standing time was positively associated with better lipid profile, and lying during the day with adiposity. No significant association was observed between breaking up moderate-to-vigorous physical activity and health. This study highlights the importance of refined categories of postures in research on physical activity and health, as well as the necessity for new tools to characterize the distribution of behavior sequence durations, considering both bouts and micro-sequences.
Antitumor Efficacy of Anti-GD2 IgG1 Is Enhanced by Fc Glyco-Engineering

Most effective antibody immunotherapy relies on ADCC. A potent ADCC-enhanced antibody is described that, in comparison with Abs with altered affinities for Fc receptors, significantly improved the growth control of tumors expressing cancer-antigen GD2. The affinity of therapeutic antibodies for Fcγ receptors (FcγRs) strongly influences their antitumor potency. To generate antibodies with optimal binding and immunologic efficacy, we compared the affinities of different versions of an IgG1 Fc region that had an altered peptide backbone, altered glycans, or both. To produce IgG1 with glycans that lacked α1,6-fucose, we used CHO cells that were deficient in the enzyme UDP-N-acetylglucosamine: α-3-d-mannoside-β-1,2-N-acetylglucosaminyltransferase I (GnT1), encoded by the MGAT1 gene. Mature N-linked glycans require this enzyme, and without it, CHO cells synthesize antibodies carrying only Man5-GlcNAc2, which were more effective in antibody-dependent cell-mediated cytotoxicity (ADCC). Our engineered IgG1, hu3F8-IgG1, is specific for GD2, a neuroendocrine tumor ganglioside. Its peptide mutant is IgG1-DEL (S239D/I332E/A330L), both produced in wild-type CHO cells. When produced in GnT1-deficient CHO cells, we refer to them as IgG1n and IgG1n-DEL, respectively. Affinities for human FcγRs were measured using Biacore T-100 (on CD16 and CD32 polymorphic alleles), their immunologic properties compared for ADCC and complement-mediated cytotoxicity (CMC) in vitro, and pharmacokinetics and antitumor effects were compared in vivo in humanized mice. IgG1n and IgG1n-DEL contained only mannose and acetylglucosamine and had preferential affinity for activating CD16s, over inhibitory CD32B, receptors. In vivo, the antitumor effects of IgG1, IgG1-DEL, and IgG1n-DEL were similar but modest, whereas IgG1n was significantly more effective (P < 0.05). Thus, IgG1n antibodies produced in GnT1-deficient CHO cells may have potential as improved anticancer therapeutics. Cancer Immunol Res; 4(7); 631–8. ©2016 AACR.
Effect of dietary boron on learning and behavior in rats administered with boric acid.

This study was designed to investigate the effect of dietary boron on spatial learning, anxiety, some vitamins and oxidative parameters in rats. Thirty-two Wistar albino male rats were used in the study. The rats were equally divided into four groups with 8 rats each: I control group: standard pellet diet only, II. group: 250 ppm boric acid, III. group: 500 ppm boric acid and IV. group: 1000 ppm boric acid added into standard pellet diet. Over a five-week period, elevated plus-maze test was used for anxiety assessment and Morris water maze test was used for evaluating spatial learning. Additionally, blood samples were obtained at the end of the experiment and were used to determine the serum levels of some vitamins and oxidative parameters. Dietary boron significantly increased weight gain (p<0.001) and food consumption in the 250 ppm and 500 ppm groups (p<0.05). Although boron supplementation had no significant effect on learning and anxiety-related behavior, it had beneficiary effects on memory retention in the 1000 ppm group (p<0.05). Biochemical analyses showed a significant decrease in the MDA levels (p<0.05) and an increase in vitamin D3 levels (p<0.01) in the 500 ppm group, a significant increase in GSH-Px activity in the 250 ppm and 500 ppm groups (p<0.05), and a decrease in vitamin E levels in all the experimental groups (p<0.05). In conclusion, our study demonstrated that dietary boron can be beneficial for health when administered at appropriate doses.
Examining Clinical Meaningfulness in Randomized Controlled Trials: Revisiting the Well Elderly II

OBJECTIVE. Randomized controlled trial (RCT) interventions often rely on p values, where statistical significance is assumed to provide evidence of an intervention effect. This study provides a secondary data analysis of the Well Elderly II RCT using multiple approaches that examine clinical meaningfulness. METHOD. We reanalyzed the Well Elderly II RCT using effect size, standard deviation, standard error of measurement, minimal difference, a fragility index, an assessment of poor scores at baseline, and an analysis with a small subgroup of participants removed. RESULTS. Although some participants improved on several scales, most stayed the same, and a small subset declined. Omitting a small subgroup of participants led to nonsignificant p values. CONCLUSION. There is evidence that disparities in baseline scores and regression to the mean may have created the appearance of an intervention effect. Our methods of considering clinical meaningfulness suggest improved approaches to analyzing RCT data.
Coculturing Bacteria Leads to Reduced Phenotypic Heterogeneities

Laboratory studies have shown the impact of phenotypic heterogeneity on the survival and functionality of isogenic populations. Because phenotypic heterogeneity plays an important role in pathogenicity and virulence, antibiotic resistance, biotechnological applications, and ecosystem properties, it is crucial to understand its influencing factors. An unanswered question is whether bacteria in mixed communities influence the phenotypic heterogeneity of their community partners. We found that coculturing bacteria leads to a reduction in their individual phenotypic heterogeneities, which led us to the hypothesis that the individual phenotypic diversity of a taxon is dependent on the community composition. ABSTRACT Isogenic bacterial populations are known to exhibit phenotypic heterogeneity at the single-cell level. Because of difficulties in assessing the phenotypic heterogeneity of a single taxon in a mixed community, the importance of this deeper level of organization remains relatively unknown for natural communities. In this study, we have used membrane-based microcosms that allow the probing of the phenotypic heterogeneity of a single taxon while interacting with a synthetic or natural community. Individual taxa were studied under axenic conditions, as members of a coculture with physical separation, and as a mixed culture. Phenotypic heterogeneity was assessed through both flow cytometry and Raman spectroscopy. Using this setup, we investigated the effect of microbial interactions on the individual phenotypic heterogeneities of two interacting drinking water isolates. Through flow cytometry we have demonstrated that interactions between these bacteria lead to a reduction of their individual phenotypic diversities and that this adjustment is conditional on the bacterial taxon. Single-cell Raman spectroscopy confirmed a taxon-dependent phenotypic shift due to the interaction. In conclusion, our data suggest that bacterial interactions may be a general driver of phenotypic heterogeneity in mixed microbial populations. IMPORTANCE Laboratory studies have shown the impact of phenotypic heterogeneity on the survival and functionality of isogenic populations. Because phenotypic heterogeneity plays an important role in pathogenicity and virulence, antibiotic resistance, biotechnological applications, and ecosystem properties, it is crucial to understand its influencing factors. An unanswered question is whether bacteria in mixed communities influence the phenotypic heterogeneity of their community partners. We found that coculturing bacteria leads to a reduction in their individual phenotypic heterogeneities, which led us to the hypothesis that the individual phenotypic diversity of a taxon is dependent on the community composition.
Rapid Divergence of Predator Functional Traits Affects Prey Composition in Aquatic Communities

Identifying traits that underlie variation in individual performance of consumers (i.e., trait utility) can help reveal the ecological causes of population divergence and the subsequent consequences for species interactions and community structure. Here, we document a case of rapid divergence (over the past 100 generations, or ∼150 years) in foraging traits and feeding efficiency between a lake and stream population pair of threespine stickleback. Building on predictions from functional trait models of fish feeding, we analyzed foraging experiments with a Bayesian path analysis and elucidated the traits explaining variation in foraging performance and the species composition of ingested prey. Despite extensive previous research on the divergence of foraging traits among populations and ecotypes of stickleback, our results provide novel experimental evidence of trait utility for jaw protrusion, gill raker length, and gill raker spacing when foraging on a natural zooplankton assemblage. Furthermore, we discuss how these traits might contribute to the differential effects of lake and stream stickleback on their prey communities, observed in both laboratory and mesocosm conditions. More generally, our results illustrate how the rapid divergence of functional foraging traits of consumers can impact the biomass, species composition, and trophic structure of prey communities.
Volta Phase Plate Cryo-EM Structure of the Human Heterodimeric Amino Acid Transporter 4F2hc-LAT2

Heteromeric amino acid transporters (HATs) are protein complexes that catalyze the transport of amino acids across plasma membranes. HATs are composed of two subunits, a heavy and a light subunit, which belong to the solute carrier (SLC) families SLC3 and SLC7. The two subunits are linked by a conserved disulfide bridge. Several human diseases are associated with loss of function or overexpression of specific HATs making them drug targets. The human HAT 4F2hc-LAT2 (SLC3A2-SLC7A8) is specific for the transport of large neutral L-amino acids and specific amino acid-related compounds. Human 4F2hc-LAT2 can be functionally overexpressed in the methylotrophic yeast Pichia pastoris and pure recombinant protein purified. Here we present the first cryo-electron microscopy (cryo-EM) 3D-map of a HAT, i.e., of the human 4F2hc-LAT2 complex. The structure could be determined at ~13 Å resolution using direct electron detector and Volta phase plate technologies. The 3D-map displays two prominent densities of different sizes. The available X-ray structure of the 4F2hc ectodomain fitted nicely into the smaller density revealing the relative position of 4F2hc with respect to LAT2 and the membrane plane.
Idiopathic Acute Mitral Regurgitation Due to Chordal Rupture in Infants: Surgical Management and Results

Objective: Emergency surgical treatment is required for idiopathic acute mitral regurgitation due to chordae rupture in infants. Nevertheless, mitral valve repair for such a patient population still remains challenging. We report our experience with mitral valve repair for idiopathic acute mitral regurgitation due to chordae rupture in infants. Methods: From 2005 to 2017, six infants (four boys) were diagnosed with acute mitral regurgitation due to chordae rupture and underwent mitral valve repair. The median age, mean body weight, and median follow-up period were 5.5 months (range: 4-9 months), 6.8 kg (range: 5.5-8.0 kg), and 6.4 years (range: 6 months to 10 years), respectively. Results: In all cases, surgical intervention was performed within 24 hours of admission. Artificial chordae reconstruction and paracommissural edge-to-edge repair were utilized in three and four cases, respectively, while Kay’s annuloplasty was performed in all cases. Mean cardiopulmonary bypass time and aortic cross-clamp time were 117 minutes (range: 70-143 minutes) and 73 minutes (range: 35-108 minutes), respectively. No early or late deaths and reoperations had occurred during the follow-up period. Moreover, postoperative mitral regurgitation was significantly reduced, while no chronologic progression of mitral regurgitation was observed. Conclusions: The combination of various techniques, such as artificial chordae reconstruction, paracomissural edge-to-edge repair, and Kay’s annuloplasty, can be a promising surgical option for idiopathic acute mitral regurgitation due to chordae rupture in infants.
Insight into the B3Transcription Factor Superfamily and Expression Profiling of B3 Genes in Axillary Buds after Topping in Tobacco (Nicotiana tabacum L.)

Members of the plant-specific B3 transcription factor superfamily play important roles in various growth and developmental processes in plants. Even though there are many valuable studies on B3 genes in other species, little is known about the B3 superfamily in tobacco. We identified 114 B3 proteins from tobacco using comparative genome analysis. These proteins were classified into four subfamilies based on their phylogenetic relationships, and include the ARF, RAV, LAV, and REM subfamilies. The chromosomal locations, gene structures, conserved protein motifs, and sub-cellular localizations of the tobacco B3 proteins were analyzed. The patterns of exon-intron numbers and arrangement and the protein structures of the tobacco B3 proteins were in general agreement with their phylogenetic relationships. The expression patterns of 114 B3 genes revealed that many B3 genes show tissue-specific expression. The expression levels of B3 genes in axillary buds after topping showed that the REM genes are mainly up-regulated in response to topping, while the ARF genes are down-regulated after topping.