Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and safety of an intravenous monoclonal anti-HBs in chronic hepatitis B patients.

BACKGROUND/AIMS In this study the safety and efficacy of a monoclonal anti-HBs, Tuvirumab (Mab), were investigated. Tuvirumab is a human monoclonal antibody recognizing the stable 'a'-determinant of the HBsAg. METHODS We included ten chronic hepatitis B patients: four received monotherapy, and six combination therapy with interferon alpha 2b. RESULTS Because the development of insoluble [HBsAg-HBsAb] complexes led to adverse events, the Mab dose had to be reduced in seven patients. In nine patients treatment was stopped prematurely because of lack of efficacy, i.e. neutralization of HBsAg in serum. However, temporary HBsAg levels were reduced by at least 50% in all patients; in three patients receiving combination therapy, background levels of HBsAg in serum were reached. A loss of serum HBV-DNA was seen in three patients in the combination group, followed by HBeAg seroconversion in two patients. CONCLUSIONS We conclude that Mab was not effective in achieving primary efficacy as assessed by neutralization of circulating HBsAg. Whether a combination of Mab with an antiviral agent that reduces the HBsAg load--and therefore minimizes the risk of adverse events--may result in clinical efficacy should be investigated.
A multi-year perspective on methane cycling in a shallow peat fen in central New York State, USA

Minerotrophic sedge fens are common in sub-arctic regions and are a significant source of atmospheric methane (CH4), yet they have received less attention than other peatlands, such as boreal ombrotrophic bogs, which are smaller sources of CH4. At the process level, CH4 fluxes in sub-arctic systems are limited primarily by cold temperatures, and thus are sensitive to potential climate change. This study examined CH4 dynamics in a temperate sedge-fen to determine controls on the spatial and temporal variability in CH4 fluxes and, therefore, how the biogeochemistry of CH4 in sedge-fen peatlands may respond to predicted changes in climate. We used flux chambers and laboratory peat incubations over a six to seven-year period (1994–2000) to study fluxes, pools, and potential production of CH4 in a peat-forming wetland in central New York State, USA. Results showed that precipitation (i.e., dry years and depth to water table) exerted an important control on annual and seasonal patterns of CH4 fluxes. Mean summer flux rates ranged from 2258 nmol m−2 s−1 in the wettest year to −934 nmol m−2 s−1 (net consumption) in the driest year. CH4 concentrations in the surface peat were as low as 0.01 μatm and as high as 10 matm in the summer months depending on precipitation patterns. In contrast, CH4 concentrations were consistently two to three times greater in sub-surface than in surface peat, and pools persisted during dry years and were temporally less variable. Fluxes were only weakly associated with potential CH4 production rates, which showed little seasonal variation. In-vitro measurements of potential CH4 production did not sufficiently explain fluxes, suggesting a need for improved in-situ methods for measuring CH4 production. Site differences associated with different dominant vegetation had a significant effect on CH4 cycling in all years except the driest, suggesting sensitivity to vegetation changes. These results indicate that predicting responses of fen peatlands to environmental requires an improved understanding of the underlying microbial processes and mechanisms that control CH4 cycling.
Comparison of Participants and Non-Participants in a Population Study of Injuries: The Study of Men Born in 1913 and 1923

In a population study of injuries in two samples from the general population of Göteborg, Sweden, of altogether about 1200 50-and 60-year-old men, the non-participation rates were 25% and 19% respectively. The aim of this report was to estimate the size of the bias caused by non-participation. Besides comparing official register data, e.g., marital status, dwelling conditions and mortality between non-participants and participants, it was also possible to measure certain morbidity variables by using the register of an emergency department over a 7-year period. The non-participants had less stable dwelling conditions and were more often unmarried, divorced or widowed than the participants. They also had more accidents per person and more head injuries, were more often transported to the emergency department by ambulance, tended to have more serious injuries and had a higher mortality rate during follow-up. The non-participants were about six times more often inebriated at the attendance and the differences seemed to be associated mainly with the alcohol factor and less with the participation factor. In conclusion, the bias in incidence estimates caused by non-participation appears to be small to moderate in this type of study as long as the non-participation rate can be kept on the same level as in this study or lower.
SafetyNets: Verifiable Execution of Deep Neural Networks on an Untrusted Cloud

Inference using deep neural networks is often outsourced to the cloud since it is a computationally demanding task. However, this raises a fundamental issue of trust. How can a client be sure that the cloud has performed inference correctly? A lazy cloud provider might use a simpler but less accurate model to reduce its own computational load, or worse, maliciously modify the inference results sent to the client. We propose SafetyNets, a framework that enables an untrusted server (the cloud) to provide a client with a short mathematical proof of the correctness of inference tasks that they perform on behalf of the client. Specifically, SafetyNets develops and implements a specialized interactive proof (IP) protocol for verifiable execution of a class of deep neural networks, i.e., those that can be represented as arithmetic circuits. Our empirical results on three- and four-layer deep neural networks demonstrate the run-time costs of SafetyNets for both the client and server are low. SafetyNets detects any incorrect computations of the neural network by the untrusted server with high probability, while achieving state-of-the-art accuracy on the MNIST digit recognition (99.4%) and TIMIT speech recognition tasks (75.22%).
CK2 Forms a Stable Complex with TFIIIB and Activates RNA Polymerase III Transcription in Human Cells

ABSTRACT CK2 is a highly conserved protein kinase with growth-promoting and oncogenic properties. It is known to activate RNA polymerase III (PolIII) transcription in Saccharomyces cerevisiae and is shown here to also exert a potent effect on PolIII in mammalian cells. Peptide and chemical inhibitors of CK2 block PolIII transcription in human cell extracts. Furthermore, PolIII transcription in mammalian fibroblasts is decreased significantly when CK2 activity is compromised by chemical inhibitors, antisense oligonucleotides, or kinase-inactive mutants. Coimmunoprecipitation and cofractionation show that endogenous human CK2 associates stably and specifically with the TATA-binding protein-containing factor TFIIIB, which brings PolIII to the initiation site of all class III genes. Serum stimulates TFIIIB phosphorylation in vivo, an effect that is diminished by inhibitors of CK2. Binding to TFIIIC2 recruits TFIIIB to most PolIII promoters; this interaction is compromised specifically by CK2 inhibitors. The data suggest that CK2 stimulates PolIII transcription by binding and phosphorylating TFIIIB and facilitating its recruitment by TFIIIC2. CK2 also activates PolI transcription in mammals and may therefore provide a mechanism to coregulate the output of PolI and PolIII. CK2 provides a rare example of an endogenous activity that operates on the PolIII system in both mammals and yeasts. Such evolutionary conservation suggests that this control may be of fundamental importance.
Voice Activity Detection in the Wild via Weakly Supervised Sound Event Detection

Traditional supervised voice activity detection (VAD) methods work well in clean and controlled scenarios, with performance severely degrading in real-world applications. One possible bottleneck is that speech in the wild contains unpredictable noise types, hence frame-level label prediction is difficult, which is required for traditional supervised VAD training. In contrast, we propose a general-purpose VAD (GPVAD) framework, which can be easily trained from noisy data in a weakly supervised fashion, requiring only clip-level labels. We proposed two GPVAD models, one full (GPV-F), trained on 527 Audioset sound events, and one binary (GPV-B), only distinguishing speech and noise. We evaluate the two GPV models against a CRNN based standard VAD model (VAD-C) on three different evaluation protocols (clean, synthetic noise, real data). Results show that our proposed GPV-F demonstrates competitive performance in clean and synthetic scenarios compared to traditional VAD-C. Further, in real-world evaluation, GPV-F largely outperforms VAD-C in terms of frame-level evaluation metrics as well as segment-level ones. With a much lower requirement for frame-labeled data, the naive binary clip-level GPV-B model can still achieve comparable performance to VAD-C in real-world scenarios.
Recruitment of Herpes Simplex Virus Type 1 Transcriptional Regulatory Protein ICP4 into Foci Juxtaposed to ND10 in Live, Infected Cells

ABSTRACT At the early stages of herpes simplex virus type 1 (HSV-1) infection, parental viral genomes have a tendency to become juxtaposed to cellular nuclear structures known as PML (promyelocytic leukemia) nuclear bodies or ND10, while the immediate-early (IE) protein ICP0 precisely colocalizes with these structures. Previous indirect-immunofluorescence studies observed that the HSV-1 transcriptional regulator ICP4 has a mainly diffuse nuclear distribution early in infection and is later recruited into viral replication compartments. We have constructed HSV-1 variants expressing ICP4 and ICP0 linked to ECFP and EYFP, respectively, both singly and in combination. Coupled with an efficient method of expressing autofluorescent PML in ND10, we have studied the dynamics of ICP0, ICP4, and ND10 in live, infected cells. The greater sensitivity and lower background signals in live cells revealed that early in infection, ICP4 forms discrete foci, some of which are juxtaposed to ND10, while ICP0 was found to colocalize precisely with PML. As expected from these results, using a double-labeled virus, we observed that foci of ICP0 and ICP4 were also juxtaposed but not colocalized early in infection. Some of the ICP4 foci must have contained parental viral genomes, because they developed into replication compartments. We propose that a proportion of the ND10-associated ICP4 foci represent ICP4 molecules being recruited onto parental viral genomes, a process likely to be a critical step early in lytic infection. These results may be analogous to the localization of IE1 and IE2 during human cytomegalovirus infection, suggesting a principle common to the alpha- and betaherpesviruses.
Upregulation of CD40 Expression on Endothelial Cells Infected with Human Cytomegalovirus

ABSTRACT CD40 has been identified as an important molecule for a number of processes, such as immune responses, inflammation, and the activation of endothelia. We investigated CD40 in endothelial cells (EC) following infection with an endotheliotropic strain of human cytomegalovirus (HCMV). Between 8 and 72 h postinfection, we observed a significant increase in CD40 levels on the surface of infected EC, as measured by fluorescence-activated cell sorting analysis. As a consequence of CD40 upregulation, increased levels of E-selectin were found on infected EC after stimulation with CD154-expressing T cells. Enhanced expression of CD40 was specific for EC, since infection of fibroblasts did not result in the upregulation of CD40. The addition of neutralizing antibodies as well as UV inactivation of virus completely prevented the upregulation of CD40 on EC. Also, laboratory-adapted HCMV strain AD169 was not able to induce CD40 on EC. De novo protein synthesis was necessary for the increased surface expression. At early times (4 to 24 h) postinfection, this change was not accompanied by increased levels of CD40 protein or mRNA. At late times (48 to 96 h) postinfection, increased amounts of CD40 protein and mRNA were detected. Immunohistochemical analysis of infected tissues demonstrated elevated levels of CD40 on HCMV-infected EC in vivo. Thus, infection of EC by HCMV may result in the activation of endothelia and in the augmentation of inflammatory processes.
Central melanin-concentrating hormone influences liver and adipose metabolism via specific hypothalamic nuclei and efferent autonomic/JNK1 pathways.

BACKGROUND & AIMS Specific neuronal circuits modulate autonomic outflow to liver and white adipose tissue. Melanin-concentrating hormone (MCH)-deficient mice are hypophagic, lean, and do not develop hepatosteatosis when fed a high-fat diet. Herein, we sought to investigate the role of MCH, an orexigenic neuropeptide specifically expressed in the lateral hypothalamic area, on hepatic and adipocyte metabolism. METHODS Chronic central administration of MCH and adenoviral vectors increasing MCH signaling were performed in rats and mice. Vagal denervation was performed to assess its effect on liver metabolism. The peripheral effects on lipid metabolism were assessed by real-time polymerase chain reaction and Western blot. RESULTS We showed that the activation of MCH receptors promotes nonalcoholic fatty liver disease through the parasympathetic nervous system, whereas it increases fat deposition in white adipose tissue via the suppression of sympathetic traffic. These metabolic actions are independent of parallel changes in food intake and energy expenditure. In the liver, MCH triggers lipid accumulation and lipid uptake, with c-Jun N-terminal kinase being an essential player, whereas in adipocytes MCH induces metabolic pathways that promote lipid storage and decreases lipid mobilization. Genetic activation of MCH receptors or infusion of MCH specifically in the lateral hypothalamic area modulated hepatic lipid metabolism, whereas the specific activation of this receptor in the arcuate nucleus affected adipocyte metabolism. CONCLUSIONS Our findings show that central MCH directly controls hepatic and adipocyte metabolism through different pathways.
Evidence of reduced DNA repair in amyotrophic lateral sclerosis brain tissue

OXIDATIVE stress is proposed to play a central role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Anti-oxidant enzymes and DNA repair proteins are two major mechanisms by which cells counteract the deleterious effects of reactive oxygen species (ROS). Neurons may be particularly vulnerable to ROS-induced oxidative DNA damage; this is repaired by the base-excision repair (BER) pathway. Frontal cortical levels and activity of the pivotal BER protein apurinic/apyrimidinic endonuclease (APE) were determined in 11 patients with sporadic ALS and six age-matched control subjects. APE levels (p < 0.003) and activity (p < 0.000007) were significantly lower in ALS subjects than in controls. These findings suggest that ALS brain tissue is inefficient in repairing oxidative DNA damage.
DNA technology for the detection of common genetic variants that predispose to thrombophilia

With the identification of common single locus point mutations as risk factors for thrombophilia, many DNA testing methodologies have been described for detecting these variations. Traditionally, functional or immunological testing methods have been used to investigate quantitative anticoagulant deficiencies. However, with the emergence of the genetic variations, factor V Leiden, prothrombin 20210 and, to a lesser extent, the methylene tetrahydrofolate reductase (MTHFR677) and factor V HR2 haplotype, traditional testing methodologies have proved to be less useful and instead DNA technology is more commonly employed in diagnostics. This review considers many of the DNA techniques that have proved to be useful in the detection of common genetic variants that predispose to thrombophilia. Techniques involving gel analysis are used to detect the presence or absence of restriction sites, electrophoretic mobility shifts, as in single strand conformation polymorphism or denaturing gradient gel electrophoresis, and product formation in allele-specific amplification. Such techniques may be sensitive, but are unwielding and often need to be validated objectively. In order to overcome some of the limitations of gel analysis, especially when dealing with larger sample numbers, many alternative detection formats, such as closed tube systems, microplates and microarrays (minisequencing, real-time polymerase chain reaction, and oligonucleotide ligation assays) have been developed. In addition, many of the emerging technologies take advantage of colourimetric or fluorescence detection (including energy transfer) that allows qualitative and quantitative interpretation of results. With the large variety of DNA technologies available, the choice of methodology will depend on several factors including cost and the need for speed, simplicity and robustness.
Throwing Arm Dominance in Collegiate Baseball Pitching

Background: Left-handed individuals make up about 10% of the general population, yet left-handers comprise approximately 30% of the pitching staffs in Major League and Division I college baseball. Despite speculation regarding differences between right- and left-handed pitchers, distinction between right- and left-handed pitching mechanics has not been documented in the literature at any level of play. Hypothesis: Left-hand–dominant pitchers display similar pitching mechanics and upper extremity joint loads when compared to their right-hand–dominant counterparts. Study Design: Controlled laboratory study. Methods: Three-dimensional, high-speed (240-Hz) video data were collected on fastballs from 84 collegiate baseball pitchers. Kinematic parameters related to pitching mechanics and resultant kinetics on the throwing shoulder and elbow were calculated. The 28 left-handed pitchers in the database were matched with 28 right-handed pitchers for age, height, mass, and ball velocity, and paired t tests were used to compare the kinematic and kinetic parameters. Results: Six parameters were found to have statistically significant differences between left- and right-handed pitchers. Passive nonthrowing shoulder external rotation (right, 113° ± 9°; left, 124° ± 8°), elbow flexion at stride-foot contact (right, 79° ± 16°; left, 94° ± 20°), and shoulder abduction during acceleration (right, 72° ± 11°; left, 105° ± 8°) were greater in left-handed pitchers than right-handed pitchers. Shoulder abduction at stride-foot contact (right, 115° ± 13°; left, 73° ± 10°), shoulder horizontal abduction at stride-foot contact (right, 25° ± 12°; left, 15° ± 12°), and peak horizontal adduction angular velocity (right, 707 ± 185 deg/s; left, 551 ± 160 deg/s) were less for the left-handed pitchers. Conclusion: Biomechanical differences between left- and right-handed pitchers have been demonstrated in a collegiate population. Clinical Relevance: The results of the current study indicate that left-handed pitchers may be at increased risk for certain shoulder injuries compared with their right-handed counterparts. Information has been provided for athletes, coaches, and sports medicine providers to further improve preventive and rehabilitative protocols for college pitchers. The results of the study also suggest that different normative data sets may need to be developed for left- and right-handed pitchers, independently of one another.
Exoribonuclease R in Pseudomonas syringae Is Essential for Growth at Low Temperature and Plays a Novel Role in the 3′ End Processing of 16 and 5 S Ribosomal RNA*

The (3′ → 5′) exoribonuclease RNase R interacts with the endoribonuclease RNase E in the degradosome of the cold-adapted bacterium Pseudomonas syringae Lz4W. We now present evidence that the RNase R is essential for growth of the organism at low temperature (4 °C). Mutants of P. syringae with inactivated rnr gene (encoding RNase R) are cold-sensitive and die upon incubation at 4 °C, a phenotype that can be complemented by expressing RNase R in trans. Overexpressing polyribonucleotide phosphorylase in the rnr mutant does not rescue the cold sensitivity. This is different from the situation in Escherichia coli, where rnr mutants show normal growth, but pnp (encoding polyribonucleotide phosphorylase) and rnr double mutants are nonviable. Interestingly, RNase R is not cold-inducible in P. syringae. Remarkably, however, rnr mutants of P. syringae at low temperature (4 °C) accumulate 16 and 5 S ribosomal RNA (rRNA) that contain untrimmed extra ribonucleotide residues at the 3′ ends. This suggests a novel role for RNase R in the rRNA 3′ end processing. Unprocessed 16 S rRNA accumulates in the polysome population, which correlates with the inefficient protein synthesis ability of mutant. An additional role of RNase R in the turnover of transfer-messenger RNA was identified from our observation that the rnr mutant accumulates transfer-messenger RNA fragments in the bacterium at 4 °C. Taken together our results establish that the processive RNase R is crucial for RNA metabolism at low temperature in the cold-adapted Antarctic P. syringae.
Effect of the 2010 Chilean Earthquake on Posttraumatic Stress: Reducing Sensitivity to Unmeasured Bias Through Study Design

In 2010, a magnitude 8.8 earthquake hit Chile, devastating parts of the country. Having just completed its national socioeconomic survey, the Chilean government reinterviewed a subsample of respondents, creating unusual longitudinal data about the same persons before and after a major disaster. The follow-up evaluated posttraumatic stress symptoms (PTSS) using Davidson’s Trauma Scale. We use these data with two goals in mind. Most studies of PTSS after disasters rely on recall to characterize the state of affairs before the disaster. We are able to use prospective data on preexposure conditions, free of recall bias, to study the effects of the earthquake. Second, we illustrate recent developments in statistical methodology for the design and analysis of observational studies. In particular, we use new and recent methods for multivariate matching to control 46 covariates that describe demographic variables, housing quality, wealth, health, and health insurance before the earthquake. We use the statistical theory of design sensitivity to select a study design with findings expected to be insensitive to small or moderate biases from failure to control some unmeasured covariate. PTSS were dramatically but unevenly elevated among residents of strongly shaken areas of Chile when compared with similar persons in largely untouched parts of the country. In 96% of exposed-control pairs exhibiting substantial PTSS, it was the exposed person who experienced stronger symptoms (95% confidence interval = 0.91–1.00).