Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular Dynamics Simulations Reveal Proton Transfer Pathways in Cytochrome C-Dependent Nitric Oxide Reductase

Nitric oxide reductases (NORs) are membrane proteins that catalyze the reduction of nitric oxide (NO) to nitrous oxide (N2O), which is a critical step of the nitrate respiration process in denitrifying bacteria. Using the recently determined first crystal structure of the cytochrome c-dependent NOR (cNOR) [Hino T, Matsumoto Y, Nagano S, Sugimoto H, Fukumori Y, et al. (2010) Structural basis of biological N2O generation by bacterial nitric oxide reductase. Science 330: 1666–70. ], we performed extensive all-atom molecular dynamics (MD) simulations of cNOR within an explicit membrane/solvent environment to fully characterize water distribution and dynamics as well as hydrogen-bonded networks inside the protein, yielding the atomic details of functionally important proton channels. Simulations reveal two possible proton transfer pathways leading from the periplasm to the active site, while no pathways from the cytoplasmic side were found, consistently with the experimental observations that cNOR is not a proton pump. One of the pathways, which was newly identified in the MD simulation, is blocked in the crystal structure and requires small structural rearrangements to allow for water channel formation. That pathway is equivalent to the functional periplasmic cavity postulated in cbb 3 oxidase, which illustrates that the two enzymes share some elements of the proton transfer mechanisms and confirms a close evolutionary relation between NORs and C-type oxidases. Several mechanisms of the critical proton transfer steps near the catalytic center are proposed.
Fault-Tolerant Streaming Computation with BlockMon

As the amount of data being exchanged over the network increases, algorithms originally implemented for running on a single machine have been re-designed to work in a distributed manner, with a processing platform that splits tasks among machines and cores. Brand new frameworks have emerged for the analysis of unbound streams of data, aiming at processing data and retrieving information nearly real-time by using clusters of machines. Node failure and recovery are crucial issues related to distributed systems, especially when using commodity hardware and when continuously processing data coming real- time into the system. In this paper we present the performance of the distributed stream-processing platform Blockmon, with the novel fault-tolerant mechanism that we implement on top, and compare it against Spark, the state-of-the art in terms of fault-tolerant stream-processing platform. Our experimental results suggest that Blockmon performs around two times faster than Spark, with a twenty times reduced memory footprint, showing the feasibility of using Blockmon on popular energy- efficient architectures such as the ARM ones.
Human bone marrow osteoprogenitors express estrogen receptor‐alpha and bone morphogenetic proteins 2 and 4 mRNA during osteoblastic differentiation

Understanding the mechanisms that control the proliferation and commitment of human stem cells into cells of the osteogenic lineage for the preservation of skeletal structure is of basic importance in bone physiology. This study examines some aspects of the differentiation in vitro of human bone marrow fibroblastic cells cultured in the absence (basal media) or presence of 1nM dexamethasone and 50 μg/ml ascorbate for 6, 10, 14, and 21 days. Northern blot analysis and in situ hybridisation with digoxygenin‐labelled riboprobes for Type I collagen, osteocalcin, bone morphogenetic proteins 2 (BMP‐2), and 4 (BMP‐4) and the estrogen receptor alpha (ERα), together with immunocytochemical analysis of ERα expression and histochemical staining of alkaline phosphatase was performed. In basal media, alkaline phosphatase activity and collagen expressions were detected at day 6, ERα from day 10 and osteocalcin from day 10. In the presence of dexamethasone and ascorbate, cell proliferation and alkaline phosphatase were markedly stimulated over 10 to 14 days with a dramatic increase in the temporal expression of Type I collagen, ERα, and osteocalcin mRNAs in these cultures. Northern blot analysis showed cells cultured in basal media, expressed the highest levels of the mRNA for each marker protein at day 14, whereas in the presence of ascorbate and dexamethasone, the highest levels for alkaline phosphatase, ERα, osteocalcin, BMP‐2, and BMP‐4 were observed at day 21. ERα, BMP‐2, and BMP‐4 expression were found to correlate temporally with induction of the osteoblast phenotype as determined by alkaline phosphatase, collagen, and osteocalcin expression. These results give additional information on the development of the osteoblast phenotype from early fibroblastic stem cells and on the biological factors involved in this process. These studies suggest a role for estrogen and BMP‐2 and ‐4 in the differentiation of osteoprogenitor cells. J. Cell. Biochem. 75:382–392, 1999. © 1999 Wiley‐Liss, Inc.
Modulation of Hyperthermophilic DNA Polymerase Activity by Archaeal Chromatin Proteins*

Sulfolobus synthesizes a large quantity of highly conserved 7-kDa DNA-binding proteins suspected to be involved in chromosomal organization. The effect of the 7-kDa proteins on the polymerization and 3′-5′ exonuclease activities of a family B DNA polymerase (polB1) from the hyperthermophilic archaeon Sulfolobus solfataricus was investigated. polB1 degraded both single-stranded DNA and double-stranded DNA at similar rates in vitro at temperatures of physiological relevance. The 7-kDa proteins were capable of significantly inhibiting the excision and enhancing the extension of matched template primers by the polymerase. However, the proteins did not protect single-stranded DNA from cleavage by polB1. In addition, the 7-kDa proteins did not affect the proofreading ability of polB1 and were not inhibitory to the excision of mismatched primers by the polymerase. The dNTP concentrations required for the effective inhibition of the 3′-5′ exonuclease activity of polB1 were lowered from ∼1 mm in the absence of the 7-kDa proteins to ∼50 μm in the presence of the proteins at 65 °C. Our data suggest that the 7-kDa chromatin proteins serve to modulate the extension and excision activities of the hyperthermophilic DNA polymerase, reducing the cost of proofreading by the enzyme at high temperature.
Explososcan: A Parallel Processing Technique For High Speed Ultrasound Imaging With Linear Phased Arrays

The data acquisition rate in medical ultrasonic imaging devices is limited by the acoustic propagation velocity in the tissues. Typically in such machines the image lines are produced sequentially one line per transmitted pulse. A parallel processing scheme has been implemented which enables the data acquisition rate to increase by a factor of four through the simultaneous acquisition of four B-mode image lines from each individual broadened transmit pulse. The higher data rate can be used to increase the image frame rate, to produce independent images that can be averaged in the image frame to reduce noise, or to produce a conventional image at standard video frame rates while reducing patient exposure. Alternatively, the field of view can be increased over that of a normal scan without sacrificing frame rate. These advantages are achieved with little reduction in the measured resolution. The design and performance of this device are described. A sample in vivo image is included.
[Exocrine pancreas function - does it change with age? (author's transl)].

We compared the excretory pancreatic function of a healthy young population (n = 18, mean age 31.8 years) with that of a healthy older people (n = 18, mean age 58.7 years) using a modified secretin-pancreozymin test which comprised short infusion of secretin, injection of pancreozymin, and repetition of this procedure immediately after the end of the collection period following the first stimulation. Secretion rate and bicarbonate following secretin, lipase, amylase and secretin rate following pancreozymin were significantly lower in the old than in the young after first and second stimulation. Trypsin was lower in the old than in the young following repeat stimulation. Trypsin was the only substance which was produced in smaller quantities after the second stimulation than after the first, i.e. pancreatic fatigue was demonstrable in the older age group.
Comparison of classical diagnostic criteria and Chinese revised diagnostic criteria for fever of unknown origin in Chinese patients

Background Fever of unknown origin (FUO) has always been a challenging problem for physicians since it was first reported half a century ago. This study aimed to investigate the clinical features of FUO and to compare the clinical significance of the classical diagnostic criteria and the Chinese revised diagnostic criteria of FUO. Methods We retrospectively collected a series of 140 patients admitted to our hospital between September 2011 and June 2013 because of prolonged febrile illnesses (lasting at least 2 weeks, temperature ≥38.5°C) without diagnosis and categorized them into two groups according to the Chinese revised diagnostic criteria (group A) and classical diagnostic criteria (group B) for FUO. The A group included patients presenting with fever persisting between 2 and 3 weeks with the diagnosis remaining uncertain after three outpatient visits or at least 3 days of hospital investigation. The B group included patients presenting with fever persisting for more than 3 weeks with no established diagnosis after 1 week of hospital investigation. The general conditions, etiologies, definite diagnosis times, and diagnostic methods of the two groups were compared. Results There were no significant differences in the general conditions, etiologies, definite diagnosis times, and diagnostic methods between the Chinese revised diagnostic criteria and classical diagnostic criteria. Conclusion Both the examined FUO diagnostic criteria are suitable for clinical practice in this region.
hTERT Inhibition Triggers Epstein–Barr Virus Lytic Cycle and Apoptosis in Immortalized and Transformed B Cells: A Basis for New Therapies

Purpose: Induction of viral lytic cycle, which induces death of host cells, may constitute a useful adjunct to current therapeutic regimens for Epstein–Barr virus (EBV)-driven malignancies. Human telomerase reverse transcriptase (hTERT), essential for the oncogenic process, may modulate the switch from latent to lytic infection. The possible therapeutic role of hTERT inhibition combined with antiviral drugs was investigated. Experimental Design: EBV-negative BL41 and convertant EBV-positive BL41/B95.8 Burkitt's lymphoma cell lines and lymphoblastoid cell lines (LCL) were infected with retroviral vector encoding short hairpin RNA (shRNA) anti-hTERT and cultured with or without the prodrug ganciclovir. The effects on EBV lytic replication, cell proliferation, and apoptosis were characterized. Results: hTERT silencing by shRNA induced the expression of BZLF1, EA-D, and gp350 EBV lytic proteins and triggered a complete lytic cycle. This effect was associated with downregulation of BATF, a negative regulator of BZLF1 transcription. hTERT silencing also resulted in antiproliferative and proapoptotic effects. In particular, hTERT inhibition induced an accumulation of cells in the S-phase, an effect likely due to the dephosphorylation of 4E-BP1, an AKT1-dependent substrate, which results in a decreased availability of proteins needed for cell-cycle progression. Besides inducing cell death through activation of complete EBV lytic replication, hTERT inhibition triggered AKT1/FOXO3/NOXA–dependent apoptosis in EBV-positive and -negative Burkitt's lymphoma cells. Finally, ganciclovir enhanced the apoptotic effect induced by hTERT inhibition in EBV-positive Burkitt's lymphomas and LCLs. Conclusions: These results suggest that combination of antiviral drugs with strategies able to inhibit hTERT expression may result in therapeutically relevant effects in patients with EBV-related malignancies. Clin Cancer Res; 19(8); 2036–47. ©2013 AACR.
Clonality and Micro-Diversity of a Nationwide Spreading Genotype of Mycobacterium tuberculosis in Japan

Mycobacterium tuberculosis transmission routes can be estimated from genotypic analysis of clinical isolates from patients. In Japan, still a middle-incidence country of TB, a unique genotype strain designated as ‘M-strain’ has been isolated nationwide recently. To ascertain the history of the wide spread of the strain, 10 clinical isolates from different areas were subjected to genome-wide analysis based on deep sequencers. Results show that all isolates possessed common mutations to those of referential strains. The greatest number of accumulated single nucleotide variants (SNVs) from the oldest coalescence was 13 nucleotides, indicating high clonality of these isolates. When an SNV common to the isolates was used as a surrogate marker of the clone, authentic clonal isolates with variation in a reliable subset of variable number of tandem repeat (VNTR) genotyping method can be selected successfully from clinical isolates populations of M. tuberculosis. When the authentic clones can also be assigned to sub-clonal groups by SNVs derived from the genomic comparison, they are classifiable into three sub-clonal groups with a bias of geographical origins. Feedback from genomic analysis of clinical isolates of M. tuberculosis to genotypic markers will be an efficient strategy for the big data in various settings for public health actions against TB.
Multiple V1/V2 env Variants Are Frequently Present during Primary Infection with Human Immunodeficiency Virus Type 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) exists as a complex population of multiple genotypic variants in persons with chronic infection. However, acute HIV-1 infection via sexual transmission is a low-probability event in which there is thought to be low genetic complexity in the initial inoculum. In order to assess the viral complexity present during primary HIV-1 infection, the V1/V2 and V3 variable regions of the env gene were examined by using a heteroduplex tracking assay (HTA) capable of resolving these genotypic variants. Blood plasma samples from 26 primary HIV-1-infected subjects were analyzed for their level of diversity. Half of the subjects had more than one V1/V2 viral variant during primary infection, indicating the frequent transmission of multiple variants. This observation is inconsistent with the idea of infrequent transmission based on a small transmitting inoculum of cell-free virus. In chronically infected subjects, the complexity of the viral populations was even greater in both the V1/V2 and the V3 regions than in acutely infected subjects, indicating that in spite of the presence of multiple variants in acute infection, the virus does pass through a genetic bottleneck during transmission. We also examined how well the infecting virus penetrated different anatomical compartments by using the HTA. Viral variants detected in blood plasma were compared to those detected in seminal plasma and/or cerebral spinal fluid of six individuals. The virus in each of these compartments was to a large extent identical to virus in blood plasma, a finding consistent with rapid penetration of the infecting variant(s). The low-probability transmission of multiple variants could be the result of transient periods of hyperinfectiousness or hypersusceptibility. Alternatively, the inefficient transfer of a multiply infected cell could account for both the low probability of transmission and the transfer of multiple variants.
The foetal sheep: Morphogenesis of the nervous system and histochemical aspects of myelination

The development of the central nervous system of the sheep foetus with particular reference to myelin forming cells and myelination has been studied by morphological and histochemical methods. The development of the spinal cord resembles that described for other species and broadly similar patterns of development have been found for the other major regions. Differentiation of definitive cell types is marked by the appearance of cytochrome oxidase activity in their cytoplasm. In gray matter strong cytochrome oxidase activity persists into post‐natal life whereas in white matter activity declines following commencement of myelination.
Family Perception of Rapists and Pedophiles

Previous research indicates that sex offenders were more likely to have been reared in dysfunctional families and to have identified less with their parents than were individuals in most comparison groups. It is unclear whether such failure to identify may be related to the perceived parenting styles and attitudes of the sex offenders' parents. 16 rapists, 18 pedophiles, 9 general offenders, and 11 college students completed the Children's Report of Parental Behavior Inventory to assess perceived parental communication patterns and attitudes. It was predicted that rapists and pedophiles would perceive their parents as (1) having been more rejecting, (2) as having exerted more control while encouraging less autonomy, and (3) as having provided harsher discipline than would individuals in comparison groups. Results supported the first two predictions.
Observations of isolated enterocytes and of their subcellular components using transmission and scanning electron microscopy

Isolated epithelial cells and their subcellular organelles were examined both by transmission and by scanning electron microscopy. It was shown that scanning electron microscopy is particularly useful for displaying the three-dimensional structure of the brush border. Furthermore, it has been possible to observe the basal aspect of separated epithelium for the first time. Studies on the scanning electron microscopic appearance of isolated nuclei, mitochondria, and lysosomes did not reveal any evidence of surface structure.
Product Differentiation and the Use of Information Technology: New Evidence from the Trucking Industry

Since the mid-1980s many authors have investigated the influence of information technology (IT) on productivity. Until recently there has been no clear evidence that productivity increases as a result of IT spending. This productivity paradox is partly due to the difficulty in correctly identifying outputs, particularly in the service sector such as the trucking industry. Products are often differentiated by quality attributes of the service provided, rather than merely the physical content of the good delivered by motor carriers. A carrier's primary marketing objective, e.g. on-time-performance vs. lowest rate carrier, are precisely what differentiates a trucking firm's service. This paper uses cross-sectional data to show that the use of increasingly sophisticated IT by trucking firms varies depending upon marketing objectives. Our empirical results imply that in order to measure the impact of IT on productivity it is crucial to account for how the firm differentiates its product. We conclude that the productivity paradox can be alleviated if measures of output incorporate firms' marketing objectives.
Response Time Upper Bounds for Fixed Priority Real-Time Systems

This paper derives closed form upper bounds on the response times of tasks in fixed priority real-time systems. These bounds are valid for tasks with arbitrary deadlines, release jitter, and blocking. Response time upper bounds are given for tasks that are scheduled pre-emptively, cooperatively with intervals where pre-emption is deferred, and non-preemptively. The set of upper bounds for n tasks can be computed in O(n) time, providing a linear-time sufficient schedulability test, applicable to complex commercial real-time systems.
Magnesium for the treatment of nocturnal leg cramps: a crossover randomized trial.

BACKGROUND Nocturnal leg cramps are a common health problem in the ambulatory setting. Our objective was to evaluate the efficacy of magnesium in the treatment of nocturnal leg cramps. METHODS Our study was a crossover randomized double-blind placebo-controlled trial. We included patients from a large university-based ambulatory clinic in Buenos Aires, Argentina, with at least 6 cramps during the previous month. A total of 93 subjects took part in a 4-week washout period with placebo. Those who were still eligible (n = 45) were randomized to receive either (1) an oral dose of 900 mg magnesium citrate twice daily for 1 month, followed by a matching placebo for 1 month, or (2) the placebo first, followed by magnesium. Both groups had a 4-week washout period with placebo between each treatment month. Forty-two patients completed the 4-month study. The main outcome was the number of nocturnal leg cramps, and the secondary outcomes were duration, severity, and sleep disorders caused by those cramps. RESULTS There were no significant differences between magnesium and placebo in any of the evaluated outcomes. The mean number of cramps was 11.1 (standard deviation [SD] +/- 7.3) for placebo versus 11.8 (SD +/- 7.6) for magnesium (P = .59). We observed a significant period-effect bias: All patients improved over time regardless of the treatment sequence they received. CONCLUSIONS Magnesium was not effective for the treatment of nocturnal leg cramps. The period-effect bias probably occurred because of a combination of the natural history of this condition, a regression to the mean, and a true placebo effect.
XPO1 target occupancy measurements confirm the selinexor recommended phase 2 dose

XPO1 (exportin 1) is the main nuclear export protein with over 200 different protein cargos. XPO1 is overexpressed in tumor cells and high levels are correlated with poor prognosis. Selective Inhibitor of Nuclear Export (SINE) compounds block nuclear export by inhibiting XPO1. The first SINE compound, selinexor, shows promising anti-cancer activity across hematological and solid tumors in Phase 2 and 3 clinical trials. The 2nd generation SINE compound KPT-8602 is being evaluated as an anti-cancer agent in a Phase 1 clinical trial. To predict patient response to treatment and confirm the selinexor recommended phase 2 dose (RP2D), an assay based on fluorescence cross correlation spectroscopy that measures XPO1 occupancy in cancer cells was developed. Studies comparing cytotoxicity and XPO1 occupancy in cell lines treated with selinexor or KPT-8602 indicated that XPO1 occupancy by both compounds could reach saturation regardless of drug sensitivity. However, higher levels of XPO1 protein correlated with lower sensitivity to SINE compound cytotoxicity. In vivo mouse studies showed XPO1 occupancy could be measured in tumors and was dose-dependent, with >90% target saturation at 10 mg/kg (∼50 mg flat dose in humans). Drug-target occupancy was measured in a dose-response time course and full occupancy occurred by 6 hours at all doses. The duration of occupancy was dose-dependent, where 10-15 mg/kg in mice (∼ 50-75 mg human flat dose) was necessary to maintain XPO1 occupancy up to 48 hours post-dose. These findings confirm the selinexor RP2D of 60 mg for achieving target occupancy and inhibition up to 48 hours.