Miracle-dz/UniFAR-FTUs huggingface dataset:
Sialidases on Mammalian Sperm Mediate Deciduous Sialylation during Capacitation

Background: Mammalian sperm lose sialic acids during capacitation through unknown mechanisms. Results: Sialidases Neu1 and Neu3 are present on sperm. Their activity is required for capacitation and zona pellucida binding. Conclusion: Sperm sialidases modulate sperm surface sialic acids en route to fertilization. Significance: Understanding the mechanism of deciduous sialylation in sperm provides novel insights into sperm function and glycan-mediated fertility. Sialic acids (Sias) mediate many biological functions, including molecular recognition during development, immune response, and fertilization. A Sia-rich glycocalyx coats the surface of sperm, allowing them to survive as allogeneic cells in the female reproductive tract despite female immunity. During capacitation, sperm lose a fraction of their Sias. We quantified shed Sia monosaccharides released from capacitated sperm and measured sperm sialidase activity. We report the presence of two sialidases (neuraminidases Neu1 and Neu3) on mammalian sperm. These are themselves shed from sperm during capacitation. Inhibiting sialidase activity interferes with sperm binding to the zona pellucida of the ovum. A survey of human sperm samples for the presence of sialidases NEU1 and NEU3 identified a lack of one or both sialidases in sperm of some male idiopathic infertility cases. The results contribute new insights into the dynamic remodeling of the sperm glycocalyx prior to fertilization.
Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis

Background The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters. Methods and Findings We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D) in solid tumors, termed the tumor ecosystem diversity index (EDI), using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2) breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10−4, hazard ratio = 1.47, 95% CI 1.17–1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26–2.52). Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size. Conclusions To our knowledge, this is the first study to couple unbiased measures of microenvironmental heterogeneity with genomic alterations to predict breast cancer clinical outcome. We propose a clinically relevant role of microenvironmental heterogeneity for advanced breast tumors, and highlight that ecological statistics can be translated into medical advances for identifying a new type of biomarker and, furthermore, for understanding the synergistic interplay of microenvironmental heterogeneity with genomic alterations in cancer cells.
Wide-area traffic: the failure of Poisson modeling

Network arrivals are often modeled as Poisson processes for analytic simplicity, even though a number of traffic studies have shown that packet interarrivals are not exponentially distributed. We evaluate 21 wide-area traces, investigating a number of wide-area TCP arrival processes (session and connection arrivals, FTPDATA connection arrivals within FTP sessions, and TELNET packet arrivals) to determine the error introduced by modeling them using Poisson processes. We find that user-initiated TCP session arrivals, such as remote-login and file-transfer, are well-modeled as Poisson processes with fixed hourly rates, but that other connection arrivals deviate considerably from Poisson; that modeling TELNET packet interarrivals as exponential grievously underestimates the burstiness of TELNET traffic, but using the empirical Tcplib[DJCME92] interarrivals preserves burstiness over many time scales; and that FTPDATA connection arrivals within FTP sessions come bunched into “connection burst”, the largest of which are so large that they completely dominate FTPDATA traffic. Finally, we offer some preliminary results regarding how our findings relate to the possible self-similarity of wide-area traffic.
ON FLUIDIZATION OF BOROSILICATE GLASSES IN INTENSE RADIATION FIELDS

The viscosity is rate-limiting for many processes in glassy materials such as homogenisation and crystallisation. Changes in the viscous flow behaviour in conditions of long-term irradiation are of particular interest for glassy materials used in nuclear installations as well as for nuclear waste immobilising glasses. We analyse the viscous flow behaviour of oxide amorphous materials in conditions of electron-irradiation using the congruent bond lattice model of oxide materials accounting for the flow-mediating role of broken bonds termed configurons. An explicit equation of viscosity was obtained which is in agreement with experimental data for non-irradiated glasses and shows for irradiated glasses, first, a significant decrease of viscosity, and, second, a stepwise reduction of the activation energy of flow. An equation for glass-transition temperature was derived which shows that irradiated glasses have lower glass transition temperatures. Intensive electron irradiation of glasses causes their fluidisation due to non-thermal bond breaking and can occur below the glass transition temperature. Due to surface tension forces fluidisation of glasses at enough high electron flux densities can result in modification of nano-size volumes and particles such as those experimentally observed under TEM electron beams.Copyright © 2009 by ASME
A double-peak phenomenon in the pharmacokinetics of alprazolam after oral administration.

The pharmacokinetics of alprazolam (ALP) after i.v. and p.o. administration in rats were characterized. ALP decayed biexponentially after the i.v. dose (1.25 mg/kg), but the concentration-time profiles after the p.o. doses (7 and 12.5 mg/kg) exhibited a double-peak phenomenon. The presence of two peaks was confirmed by statistical analysis of the serum concentration data of ALP, as well as by observed double peaks in the serum concentration-time profiles of the two active metabolites (alpha-hydroxyalprazolam and 4-hydroxyalprazolam). An absorption model incorporating a delay site is proposed to describe the data, and the absolute oral bioavailability is estimated to be about 30%. The two peaks were approximately 80 to 115 min apart, and there was a delay in the absorption of close to 80% of oral ALP, regardless of dose. We hypothesize that the mechanism underlying the double-peak phenomenon is due to reduction in gastric motility caused by the muscle relaxant effect of ALP. This hypothesis is supported by the observed longer delay in the appearance of the second peak at the higher p.o. dose. Enterohepatic recycling is precluded from being the underlying mechanism, because of the presence of double peaks after the p.o. doses but not after the i.v. dose. This is the first reported case of double peaks for oral ALP, and this phenomenon has not been reported for other benzodiazepines. The double-peak phenomenon caused by the hypothesized mechanism may have important therapeutic and drug interaction implications, especially because benzodiazepines are commonly coadministered with other drugs.
Complete Genome Sequence of Mycoplasma suis and Insights into Its Biology and Adaption to an Erythrocyte Niche

Mycoplasma suis, the causative agent of porcine infectious anemia, has never been cultured in vitro and mechanisms by which it causes disease are poorly understood. Thus, the objective herein was to use whole genome sequencing and analysis of M. suis to define pathogenicity mechanisms and biochemical pathways. M. suis was harvested from the blood of an experimentally infected pig. Following DNA extraction and construction of a paired end library, whole-genome sequencing was performed using GS-FLX (454) and Titanium chemistry. Reads on paired-end constructs were assembled using GS De Novo Assembler and gaps closed by primer walking; assembly was validated by PFGE. Glimmer and Manatee Annotation Engine were used to predict and annotate protein-coding sequences (CDS). The M. suis genome consists of a single, 742,431 bp chromosome with low G+C content of 31.1%. A total of 844 CDS, 3 single copies, unlinked rRNA genes and 32 tRNAs were identified. Gene homologies and GC skew graph show that M. suis has a typical Mollicutes oriC. The predicted metabolic pathway is concise, showing evidence of adaptation to blood environment. M. suis is a glycolytic species, obtaining energy through sugars fermentation and ATP-synthase. The pentose-phosphate pathway, metabolism of cofactors and vitamins, pyruvate dehydrogenase and NAD+ kinase are missing. Thus, ribose, NADH, NADPH and coenzyme A are possibly essential for its growth. M. suis can generate purines from hypoxanthine, which is secreted by RBCs, and cytidine nucleotides from uracil. Toxins orthologs were not identified. We suggest that M. suis may cause disease by scavenging and competing for host' nutrients, leading to decreased life-span of RBCs. In summary, genome analysis shows that M. suis is dependent on host cell metabolism and this characteristic is likely to be linked to its pathogenicity. The prediction of essential nutrients will aid the development of in vitro cultivation systems.
A novel effect of angiotensin on renal sympathetic nerve activity in mice

Objective The goals of this study were to characterize the effects of angiotensin II (Ang II) on renal sympathetic nerve activity (RSNA) and to define mechanisms of its actions in mice. Design The experiments were performed in sodium pentobarbital anesthetized C57BL/6J mice to investigate the effects of intravenous administration of Ang II on RSNA recorded from renal sympathetic post-ganglionic nerve fibers. Results Intravenous (i.v.) administration of Ang II (4 ng/g) increased arterial pressure and evoked a biphasic change in RSNA: inhibition of high-amplitude phasic bursts of RSNA secondary to the initial rise of arterial pressure followed by activation of low-amplitude continuously discharging RSNA that exceeded baseline activity (255 ± 72% baseline, n = 8). The peak change of mean arterial pressure (MAP) was +60 ± 4 mmHg (n = 8). In the same group of animals, norepinephrine (40 ng/g) caused an equivalent increase in MAP (+57 ± 5 mmHg) and essentially abolished RSNA. The Ang II-induced activation of RSNA was dose-dependent (0.5–4 ng/g, n = 7) and was abolished by the Ang II type 1 (AT1) receptor blocker, losartan (10 μg/g, i.v.) (301 ± 61 versus 117 ± 22% baseline , before versus after losartan, n = 5). The ganglionic blocker, hexamethonium (30 μg/g, i.v.), eliminated baseline high-amplitude bursts of RSNA but did not blunt the Ang II-induced RSNA (n = 6). In baroreceptor denervated and vagotomized mice, Ang II failed to inhibit high-amplitude bursts of RSNA but continued to trigger low-amplitude continuous RSNA. Conclusion We conclude that Ang II activates renal sympathetic nerves that discharge in a continuous pattern, distinctly different than the normal baseline high-amplitude bursts of RSNA. The mechanism may involve direct activation of post-ganglionic sympathetic neurons mediated through AT1 receptors.
Computational Complexity and Speedup Factors Analyses for Self-Suspending Tasks

In computing systems, an execution entity (job/process/task) may suspend itself when it has to wait for some activities to continue/finish its execution. For real-time embedded systems, such self-suspending behavior has been shown to cause substantial performance/schedulability degradation in the literature. There are two commonly adopted self-suspending sporadic task models in real-time systems: 1) dynamic self-suspension and 2) segmented self-suspension sporadic task models. A dynamic self-suspending sporadic task is specified with an upper bound on the maximum suspension time for a job (task instance), which allows a job to dynamically suspend itself as long as the suspension upper bound is not violated. By contrast, a segmented self-suspending sporadic task has a predefined execution and suspension pattern in an interleaving manner.Even though some seemingly positive results have been reported for self-suspending task systems, the computational complexity and the theoretical quality (with respect to speedup factors) of fixed-priority preemptive scheduling have not been reported. This paper proves that the schedulability analysis for fixed-priority preemptive scheduling even with only one segmented self-suspending task as the lowest-priority task is coNP-hard in the strong sense. For dynamic self-suspending task systems, we show that the speedup factor for any fixed-priority preemptive scheduling, compared to the optimal schedules, is not bounded by a constant or by the number of tasks, if the suspension time cannot be reduced by speeding up. Such a statement of unbounded speedup factors can also be proved for earliest-deadline-first (EDF), least-laxity-first (LLF), and earliest-deadline-zero-laxity (EDZL) scheduling algorithms. However, if the suspension time can be reduced by speeding up coherently or the suspension time of each task is not comparable with (i.e., sufficiently smaller than) its relative deadline, then we successfully show that rate-monotonic scheduling has a constant speedup factor, with respect to the optimal schedules, for implicit-deadline task systems.
Synthetic Salusins as Cardiac Depressors in Rat

Using bioinformatic analyses of full-length, enriched human cDNA libraries, we recently identified salusins, multifunctional related peptides ubiquitously expressed in major human tissues. Salusins cause transient and profound hypotension when injected intravenously to rats, the hypotensive effect of salusin-&bgr; being especially striking. However, the mechanisms of this hypotensive action remain elusive. To determine whether salusins modulate cardiac function in rats, we studied serial changes of systemic hemodynamics and functions of isolated perfused working and nonworking hearts before and after salusin administration. Intravenous salusin-&bgr; administration to intact anesthetized rats caused a temporary rapid, profound decrease in aortic blood flow concomitantly with hypotension and bradycardia without affecting systemic vascular resistance. Salusin-&bgr;–induced hypotension and bradycardia were completely blocked by pretreatment with atropine, a muscarinic receptor antagonist, but not by propranolol. In isolated perfused working rat hearts, salusin-&bgr; significantly decreased cardiac output, aortic flow, and stroke work. However, it did not affect coronary flow in isolated working and nonworking hearts. Our results indicate that salusins induce potent hypotension via negative inotropic and chronotropic actions. Salusin-&bgr; promotes its actions by facilitating vagal outflows to the heart, whereas the negative inotropism of salusin-&bgr; is also mediated via a direct myotropic effect.
Effects of the Cannabinoid-1 Receptor Antagonist Rimonabant on Psychiatric Symptoms in Overweight People With Schizophrenia: A Randomized, Double-Blind, Pilot Study

Weight gain is a major adverse effect of several second-generation antipsychotic medications. Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population. We conducted a 16-week, double-blind, placebo-controlled study of rimonabant (20 mg/d) in people with schizophrenia or schizoaffective disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, who were clinically stable on second-generation antipsychotics. Participants had a body mass index of 27 kg/m2 or higher with hyperlipidemia or body mass index of 30 kg/m2 or higher, and no current substance abuse/dependence (except nicotine), more than weekly cannabis use, or recent depressive symptoms/suicidality. An exercise and dietary counseling group was offered weekly. Target enrollment was 60; the trial was terminated early because of withdrawal of rimonabant from the European market. Fifteen participants were randomized (7 rimonabant, 8 placebo); 5 completed in each group. Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score versus placebo (mean ± SE difference, −1.9 ± 0.8, P = 0.02), driven by differences in the Brief Psychiatric Rating Scale anxiety/depression (−1.4 ± 0.35, P = 0.0004) and hostility (−0.7 ± 0.3, P = 0.02) factors. Group differences were not significant for the Calgary Depression Scale total score (P = 0.24), Scale for the Assessment of Negative Symptoms total score (P = 0.13), weight, blood pressure, or fasting lipids or glucose. Rimonabant was well tolerated with no significant adverse events. No significant weight loss, metabolic effects, or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia. The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity.
Characterization of the physiological requirements for the bactericidal effects of a monoclonal antibody to OspB of Borrelia burgdorferi by confocal microscopy

A confocal microscopy study was undertaken to characterize the bactericidal effects of the Fab fragments of CB2, an immunoglobulin G1kappa murine monoclonal antibody, to an epitope in the carboxy region of the outer surface protein B (OspB) of Borrelia burgdorferi. Simultaneous direct labeling of both fixed and live spirochetes with fluorochrome-labeled Fab-CB2 and 11G1, and an immunoglobulin Mkappa monoclonal antibody to OspA, showed that OspA and OspB seem to colocalize in dead spirochetes but do not appear to be physically associated when the organisms are alive. A polar bleb composed of a Fab-CB2-OspB complex, followed by incorporation of 11G1-OspA, precedes the formation of a spheroplast. The spheroplasts contain both OspA and OspB and are a terminal stage in the bactericidal process induced by Fab-CB2. Outer membrane destabilization by Fab-CB2, but not cell wall or cytoplasmic membrane alterations, was demonstrated experimentally by the sequential treatment of spirochetes with Fab-CB2 and monoclonal antibodies to flagellin and DnaK. The action of Fab-CB2 is epitope specific, as another monoclonal antibody to an epitope in the amino terminus of OspB was not bactericidal. The bactericidal effect of Fab-CB2 is not dependent on the induction of spirochetal proteases but is dependent on the presence of Ca2+ and Mg2+. Supplementation of Ca2(+)- and Mg2(+)-free medium with these cations restored the bactericidal effects of Fab-CB2. The mechanism by which a Fab fragment of an antibody destroys a bacterium directly may represent a novel form of antibody-organism interaction.
The Influence of Shortening on Clinical Outcome in Healed Displaced Midshaft Clavicular Fractures After Nonoperative Treatment

Background: We aimed to evaluate the effect of clavicular shortening, measured with 3-dimensional computed tomography (3DCT), on functional outcomes and satisfaction in patients with healed displaced midshaft clavicular fractures up to 1 year following injury. Methods: The data used in this study were collected as part of a multicenter, prospective randomized controlled trial of open reduction and plate fixation compared with nonoperative treatment for acute, displaced midshaft clavicular factures. Patients who were randomized to nonoperative treatment and had healed by 1 year were included in the present study. Clavicular shortening relative to the uninjured, contralateral clavicle was measured on 3DCT. Outcome analysis was conducted at 6 weeks, 3 months, 6 months, and 1 year following injury and included the Disabilities of the Arm, Shoulder and Hand (DASH), Constant, and Short Form-12 (SF-12) scores and patient satisfaction. Results: In the original trial, 105 patients were randomized to nonoperative treatment. Thirteen patients were lost to follow-up, leaving 92 patients, and an additional 16 (17%) developed nonunion and were excluded from the present study. Of the remaining 76 patients, 48 who had a 3DCT scan that included the whole length of both clavicles were included in the present study. The shortening of the injured clavicles, relative to the contralateral side, was a mean (and standard deviation) of 11.3 ± 7.6 mm, with a mean proportional shortening of 8%. Proportional shortening did not significantly correlate with the DASH (p ≥ 0.42), Constant (p ≥ 0.32), or SF-12 (p ≥ 0.08) scores at any point during follow-up. There was no significant difference in the mean DASH or Constant scores at any follow-up time point when the cutoff for shortening was defined as 1 cm (p ≥ 0.11) or as 2 cm (p ≥ 0.35). There was no significant difference in clavicular shortening between satisfied and unsatisfied patients (p ≥ 0.49). Conclusions: The present study demonstrated no association between shortening and functional outcome or satisfaction in patients with healed displaced midshaft clavicular fractures up to 1 year following injury. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
NY-ESO-1 Protein Formulated in ISCOMATRIX Adjuvant Is a Potent Anticancer Vaccine Inducing Both Humoral and CD8+ T-Cell-Mediated Immunity and Protection against NY-ESO-1+ Tumors

NY-ESO-1 is a 180 amino-acid human tumor antigen expressed by many different tumor types and belongs to the family of “cancer-testis” antigens. In humans, NY-ESO-1 is one of the most immunogenic tumor antigens and NY-ESO-1 peptides have been shown to induce NY-ESO-1-specific CD8+ CTLs capable of altering the natural course of NY-ESO-1-expressing tumors in cancer patients. Here we describe the preclinical immunogenicity and efficacy of NY-ESO-1 protein formulated with the ISCOMATRIX adjuvant (NY-ESO-1 vaccine). In vitro, the NY-ESO-1 vaccine was readily taken up by human monocyte-derived dendritic cells, and on maturation, these human monocyte-derived dendritic cells efficiently cross-presented HLA-A2-restricted epitopes to NY-ESO-1-specific CD8+ T cells. In addition, epitopes of NY-ESO-1 protein were also presented on MHC class II molecules to NY-ESO-1-specific CD4+ T cells. The NY-ESO-1 vaccine induced strong NY-ESO-1-specific IFN-γ and IgG2a responses in C57BL/6 mice. Furthermore, the NY-ESO-1 vaccine induced NY-ESO-1-specific CD8+ CTLs in HLA-A2 transgenic mice that were capable of lysing human HLA-A2+ NY-ESO-1+ tumor cells. Finally, C57BL/6 mice, immunized with the NY-ESO-1 vaccine, were protected against challenge with a B16 melanoma cell line expressing NY-ESO-1. These data illustrate that the NY-ESO-1 vaccine represents a potent therapeutic anticancer vaccine.