bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hydroxylated Tropolones Inhibit Hepatitis B Virus Replication by Blocking Viral Ribonuclease H Activity
Authors: Lu Gaofeng , Lomonosova Elena , Cheng Xiaohong , Moran Eileen A. , Meyers Marvin J. , Le Grice Stuart F. J. , Thomas Craig J. , Jiang Jian-kang , Meck Christine , Hirsch Danielle R. , D'Erasmo Michael P. , Suyabatmaz Duygu M. , Murelli Ryan P. , Tavis John E. 
Published: December 2014

ABSTRACT

Hepatitis B virus (HBV) remains a major human pathogen despite the development of both antiviral drugs and a vaccine, in part because the current therapies do not suppress HBV replication far enough to eradicate the virus. Here, we screened 51 troponoid compounds for their ability to suppress HBV RNaseH activity and HBV replication based on the activities of α-hydroxytropolones against HIV RNaseH, with the goal of determining whether the tropolone pharmacophore may be a promising scaffold for anti-HBV drug development. Thirteen compounds inhibited HBV RNaseH, with the best 50% inhibitory concentration (IC
50
) being 2.3 μM. Similar inhibition patterns were observed against HBV genotype D and C RNaseHs, implying limited genotype specificity. Six of 10 compounds tested against HBV replication in culture suppressed replication via blocking of viral RNaseH activity, with the best 50% effective concentration (EC
50
) being 0.34 μM. Eighteen compounds inhibited recombinant human RNaseH1, and moderate cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC
50
] = 25 to 79 μM). Therapeutic indexes ranged from 3.8 to 94. Efficient inhibition required an intact α-hydroxytropolone moiety plus one or more short appendages on the tropolone ring, but a wide variety of constituents were permissible. These data indicate that troponoids and specifically α-hydroxytropolones are promising lead candidates for development as anti-HBV drugs, providing that toxicity can be minimized. Potential anti-RNaseH drugs are envisioned to be employed in combination with the existing nucleos(t)ide analogs to suppress HBV replication far enough to block genomic maintenance, with the goal of eradicating infection.
The Role of Host Phylogeny Varies in Shaping Microbial Diversity in the Hindguts of Lower Termites
Authors: Tai Vera , James Erick R. , Nalepa Christine A. , Scheffrahn Rudolf H. , Perlman Steve J. , Keeling Patrick J. 
Published: December 2014

ABSTRACT

The hindguts of lower termites and
Cryptocercus
cockroaches are home to a distinct community of archaea, bacteria, and protists (primarily parabasalids and some oxymonads). Within a host species, the composition of these hindgut communities appears relatively stable, but the evolutionary and ecological factors structuring community composition and stability are poorly understood, as are differential impacts of these factors on protists, bacteria, and archaea. We analyzed the microbial composition of parabasalids and bacteria in the hindguts of
Cryptocercus punctulatus
and 23 species spanning 4 families of lower termites by pyrosequencing variable regions of the small-subunit rRNA gene. Especially for the parabasalids, these data revealed undiscovered taxa and provided a phylogenetic basis for a more accurate understanding of diversity, diversification, and community composition. The composition of the parabasalid communities was found to be strongly structured by the phylogeny of their hosts, indicating the importance of historical effects, although exceptions were also identified. Particularly, spirotrichonymphids and trichonymphids likely were transferred between host lineages. In contrast, host phylogeny was not sufficient to explain the majority of bacterial community composition, but the compositions of the
Bacteroidetes
,
Elusimicrobia
,
Tenericutes
,
Spirochaetes
, and
Synergistes
were structured by host phylogeny perhaps due to their symbiotic associations with protists. All together, historical effects probably resulting from vertical inheritance have had a prominent role in structuring the hindgut communities, especially of the parabasalids, but dispersal and environmental acquisition have played a larger role in community composition than previously expected.
Development of a Matrix Tool for the Prediction of Vibrio Species in Oysters Harvested from North Carolina
Authors: Froelich B. A. , Ayrapetyan M. , Fowler P. , Oliver J. D. , Noble R. T. 
Published: December 2014

ABSTRACT

The United States has federal regulations in place to reduce the risk of seafood-related infection caused by the estuarine bacteria
Vibrio vulnificus
and
Vibrio parahaemolyticus
. However, data to support the development of regulations have been generated in a very few specific regions of the nation. More regionally specific data are needed to further understand the dynamics of human infection relating to shellfish-harvesting conditions in other areas. In this study, oysters and water were collected from four oyster harvest sites in North Carolina over an 11-month period. Samples were analyzed for the abundances of total
Vibrio
spp.,
V. vulnificus
, and
V. parahaemolyticus
; environmental parameters, including salinity, water temperature, wind velocity, and precipitation, were also measured simultaneously. By utilizing these data, preliminary predictive management tools for estimating the abundance of
V. vulnificus
bacteria in shellfish were developed. This work highlights the need for further research to elucidate the full suite of factors that drive
V. parahaemolyticus
abundance.
Klebsiella pneumoniae Translocates across the Intestinal Epithelium via Rho GTPase- and Phosphatidylinositol 3-Kinase/Akt-Dependent Cell Invasion
Authors: Hsu Chun-Ru , Pan Yi-Jiun , Liu Ju-Yun , Chen Chun-Tang , Lin Tzu-Lung , Wang Jin-Town 
Published: December 2014

ABSTRACT

Klebsiella pneumoniae
is an important pathogen that causes hospital-acquired septicemia and is associated with the recent emergence of community-acquired pyogenic liver abscess (PLA). Clinical typing suggests that
K. pneumoniae
infections originate from the gastrointestinal reservoir. However, the underlying mechanism remains unknown. Here, we have sought to determine how
K. pneumoniae
penetrates the intestinal barrier. We identified that bacteremia and PLA clinical isolates adhered to and invaded intestinal epithelial cells. Internalization of
K. pneumoniae
in three different human colonic cell lines was visualized by confocal microscopy and three-dimensional (3D) imaging. Using a Transwell system, we demonstrated that these
K. pneumoniae
isolates translocated across a polarized Caco-2 monolayer. No disruptions of transepithelial electrical resistance and altered distribution of tight junction protein ZO-1 or occludin were observed. Therefore,
K. pneumoniae
appeared to penetrate the intestinal epithelium via a transcellular pathway. Using specific inhibitors, we characterized the host signaling pathways involved. Inhibition by cytochalasin D and nocodazole suggested that actin and microtubule cytoskeleton were both important for
K. pneumoniae
invasion. A Rho inhibitor, ML141, LY294002, and an Akt1/2 inhibitor diminished
K. pneumoniae
invasion in a dose-dependent manner, indicating that Rho family GTPases and phosphatidylinositol 3-kinase (PI3K)/Akt signaling were required. By a mouse model of gastrointestinal colonization,
in vivo
invasion of
K. pneumoniae
into colonic epithelial cells was demonstrated. Our results present evidence to describe a possible mechanism of gastrointestinal translocation for
K. pneumoniae
. Cell invasion by manipulating host machinery provides a pathway for gut-colonized
K. pneumoniae
cells to penetrate the intestinal barrier and access extraintestinal locations to cause disease.
B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent
Authors: Hoyt Teri R. , Dobrinen Erin , Kochetkova Irina , Meissner Nicole 
Published: December 2014

ABSTRACT

HIV infection results in a complex immunodeficiency due to loss of CD4
+
T cells, impaired type I interferon (IFN) responses, and B cell dysfunctions causing susceptibility to opportunistic infections such as
Pneumocystis murina
pneumonia and unexplained comorbidities, including bone marrow dysfunctions. Type I IFNs and B cells critically contribute to immunity to
Pneumocystis
lung infection. We recently also identified B cells as supporters of on-demand hematopoiesis following
Pneumocystis
infection that would otherwise be hampered due to systemic immune effects initiated in the context of a defective type I IFN system. While studying the role of type I IFNs in immunity to
Pneumocystis
infection, we discovered that mice lacking both lymphocytes and type I IFN receptor (IFrag
−/−
) developed progressive bone marrow failure following infection, while lymphocyte-competent type I IFN receptor-deficient mice (IFNAR
−/−
) showed transient bone marrow depression and extramedullary hematopoiesis. Lymphocyte reconstitution of lymphocyte-deficient IFrag
−/−
mice pointed to B cells as a key player in bone marrow protection. Here we define how B cells protect on-demand hematopoiesis following
Pneumocysti
s lung infection in our model. We demonstrate that adoptive transfer of B cells into IFrag
−/−
mice protects early hematopoietic progenitor activity during systemic responses to
Pneumocystis
infection, thus promoting replenishment of depleted bone marrow cells. This activity is independent of CD4
+
T cell help and B cell receptor specificity and does not require B cell migration to bone marrow. Furthermore, we show that B cells protect on-demand hematopoiesis in part by induction of interleukin-10 (IL-10)- and IL-27-mediated mechanisms. Thus, our data demonstrate an important immune modulatory role of B cells during
Pneumocystis
lung infection that complement the modulatory role of type I IFNs to prevent systemic complications.
One-Carbon Metabolic Pathway Rewiring in Escherichia coli Reveals an Evolutionary Advantage of 10-Formyltetrahydrofolate Synthetase (Fhs) in Survival under Hypoxia
Authors: Sah Shivjee , Aluri Srinivas , Rex Kervin , Varshney Umesh 
Published: December 2014

ABSTRACTIn cells,N10-formyltetrahydrofolate (N10-fTHF) is required for formylation of eubacterial/organellar initiator tRNA and purine nucleotide biosynthesis. Biosynthesis ofN10-fTHF is catalyzed by 5,10-methylene-tetrahydrofolate dehydrogenase/cyclohydrolase (FolD) and/or 10-formyltetrahydrofolate synthetase (Fhs). All eubacteria possess FolD, but some possess both FolD and Fhs. However, the reasons for possessing Fhs in addition to FolD have remained unclear. We usedEscherichia coli, which naturally lacksfhs, as our model. We show that inE. coli, the essential function offolDcould be replaced byClostridium perfringensfhswhen it was provided on a medium-copy-number plasmid or integrated as a single-copy gene in the chromosome. Thefhs-supportedfolDdeletion (ΔfolD) strains grow well in a complex medium. However, these strains require purines and glycine as supplements for growth in M9 minimal medium. Thein vivolevels ofN10-fTHF in the ΔfolDstrain (supported by plasmid-bornefhs) were limiting despite the high capacity of the available Fhs to synthesizeN10-fTHFin vitro. Auxotrophy for purines could be alleviated by supplementing formate to the medium, and that for glycine was alleviated by engineering THF import into the cells. The ΔfolDstrain (harboringfhson the chromosome) showed a high NADP+-to-NADPH ratio and hypersensitivity to trimethoprim. The presence offhsinE. coliwas disadvantageous for its aerobic growth. However, under hypoxia,E. colistrains harboringfhsoutcompeted those lacking it. The computational analysis revealed a predominant natural occurrence offhsin anaerobic and facultative anaerobic bacteria.
Examining the reliability and validity of a modified version of the International Physical Activity Questionnaire, long form (IPAQ-LF) in Nigeria: a cross-sectional study
Authors: Oyeyemi Adewale L , Bello Umar M , Philemon Saratu T , Aliyu Habeeb N , Majidadi Rebecca W , Oyeyemi Adetoyeje Y 
Published: December 2014

ObjectivesTo investigate the reliability and an aspect of validity of a modified version of the long International Physical Activity Questionnaire (Hausa IPAQ-LF) in Nigeria.DesignCross-sectional study, examining the reliability and construct validity of the Hausa IPAQ-LF compared with anthropometric and biological variables.SettingMetropolitan Maiduguri, the capital city of Borno State in Nigeria.Participants180 Nigerian adults (50% women) with a mean age of 35.6 (SD=10.3) years, recruited from neighbourhoods with diverse socioeconomic status and walkability.Outcome measuresDomains (domestic physical activity (PA), occupational PA, leisure-time PA, active transportation and sitting time) and intensities of PA (vigorous, moderate and walking) were measured with the Hausa IPAQ-LF on two different occasions, 8 days apart. Outcomes for construct validity were measured body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressure (DBP).ResultsThe Hausa IPAQ-LF demonstrated good test–retest reliability (intraclass correlation coefficient, ICC>75) for total PA (ICC=0.79, 95% CI 0.65 to 0.82), occupational PA (ICC=0.77, 95% CI 0.68 to 0.82), active transportation (ICC=0.82, 95% CI 0.75 to 0.87) and vigorous intensity activities (ICC=0.82, 95% CI 0.76 to 0.87). Reliability was substantially higher for total PA (ICC=0.80), occupational PA (ICC=0.78), leisure-time PA (ICC=0.75) and active transportation (ICC=0.80) in men than in women, but domestic PA (ICC=0.38) and sitting time (ICC=0.71) demonstrated more substantial reliability coefficients in women than in men. For the construct validity, domestic PA was significantly related mainly with SBP (r=−0.27) and DBP (r=−0.17), and leisure-time PA and total PA were significantly related only with SBP (r=−0.16) and BMI (r=−0.29), respectively. Similarly, moderate-intensity PA was mainly related with SBP (r=−0.16, p<0.05) and DBP (r=−0.21, p<0.01), but vigorous-intensity PA was only related with BMI (r=−0.11, p<0.05).ConclusionsThe modified Hausa IPAQ-LF demonstrated sufficient evidence of test–retest reliability and may be valid for assessing context specific PA behaviours of adults in Nigeria.
An evaluation of factors associated with completion and benefit from pulmonary rehabilitation in COPD
Authors: Boutou Afroditi K , Tanner Rebecca J , Lord Victoria M , Hogg Lauren , Nolan Jane , Jefford Helen , Corner Evelyn J , Falzon Christine , Lee Cassandra , Garrod Rachel , Polkey Michael I , Hopkinson Nicholas S 
Published: December 2014

BackgroundPulmonary Rehabilitation (PR) is an important treatment for patients with chronic obstructive pulmonary disease (COPD) but it is not established whether any baseline parameter can predict response or compliance.AimTo identify whether baseline measures can predict who will complete the programme and who will achieve a clinically significant benefit from a Minimum Clinical Important Difference (MCID) in terms of exercise capacity and health-related quality of life (HRQoL).MethodsData were collected prospectively from patients with COPD at their baseline assessment for an outpatient PR programme in one of eight centres across London. ‘Completion’ was defined as attending at least 75% of the designated PR visits and return for the follow-up evaluation. The MCID for outcome measures was based on published data.Results787 outpatients with COPD (68.1±10.5 years old; 49.6% males) were included. Patients who completed PR (n=449, 57.1%) were significantly older with less severe airflow obstruction, lower anxiety and depression scores, less dyspnoea and better HRQoL. Only baseline CAT score (OR=0.925; 95% CI 0.879 to 0.974; p=0.003) was retained in multivariate analysis. Patients with the lowest baseline walking distance were most likely to achieve the MCID for exercise capacity. No baseline variable could independently predict achievement of an MCID in HRQoL.ConclusionsPatients with better HRQoL are more likely to complete PR while worse baseline exercise performance makes the achievement of a positive MCID in exercise capacity more likely. However, no baseline parameter could predict who would benefit the most in terms of HRQoL.
X10 and APGAS at Petascale
Authors: Tardieu Olivier , Herta Benjamin , Cunningham David , Grove David , Kambadur Prabhanjan , Saraswat Vijay , Shinnar Avraham , Takeuchi Mikio , Vaziri Mandana 
Published: December 2014

X10 is a high-performance, high-productivity programming language aimed at large-scale distributed and shared-memory parallel applications. It is based on the Asynchronous Partitioned Global Address Space (APGAS) programming model, supporting the same fine-grained concurrency mechanisms within and across shared-memory nodes.
We demonstrate that X10 delivers solid performance at petascale by running (weak scaling) eight application kernels on an IBM Power 775 supercomputer utilizing up to 55,680 Power7 cores (for 1.7 Pflop/s of theoretical peak performance). We detail our advances in distributed termination detection, distributed load balancing, and use of high-performance interconnects that enable X10 to scale out to tens of thousands of cores.
For the four HPC Class 2 Challenge benchmarks, X10 achieves 41% to 87% of the system's potential at scale (as measured by IBM's HPCC Class 1 optimized runs). We also implement K-Means, Smith-Waterman, Betweenness Centrality, and Unbalanced Tree Search (UTS) for geometric trees. Our UTS implementation is the first to scale to petaflop systems.
Towards fair and efficient SMP virtual machine scheduling
Authors: Rao Jia , Zhou Xiaobo 
Published: December 2014

As multicore processors become prevalent in modern computer systems, there is a growing need for increasing hardware utilization and exploiting the parallelism of such platforms. With virtualization technology, hardware utilization is improved by encapsulating independent workloads into virtual machines (VMs) and consolidating them onto the same machine. SMP virtual machines have been widely adopted to exploit parallelism. For virtualized systems, such as a public cloud, fairness between tenants and the efficiency of running their applications are keys to success. However, we find that existing virtualization platforms fail to enforce fairness between VMs with different number of virtual CPUs (vCPU) that run on multiple CPUs. We attribute the unfairness to the use of per-CPU schedulers and the load imbalance on these CPUs that incur inaccurate CPU allocations. Unfortunately, existing approaches to reduce unfairness, e.g., dynamic load balancing and CPU capping, introduce significant inefficiencies to parallel workloads.
In this paper, we present Flex, a vCPU scheduling scheme that enforces fairness at VM-level and improves the efficiency of hosted parallel applications. Flex centers on two key designs: (1) dynamically adjusting vCPU weights (FlexW) on multiple CPUs to achieve VM-level fairness and (2) flexibly scheduling vCPUs (FlexS) to minimize wasted busy-waiting time. We have implemented Flex in Xen and performed comprehensive evaluations with various parallel workloads. Results show that Flex is able to achieve CPU allocations with on average no more than 5% error compared to the ideal fair allocation. Further, Flex outperforms Xen's credit scheduler and two representative co-scheduling approaches by as much as 10X for parallel applications using busy-waiting or blocking synchronization methods.
Resilient X10
Authors: Cunningham David , Grove David , Herta Benjamin , Iyengar Arun , Kawachiya Kiyokuni , Murata Hiroki , Saraswat Vijay , Takeuchi Mikio , Tardieu Olivier 
Published: December 2014

Scale-out programs run on multiple processes in a cluster. In scale-out systems, processes can fail. Computations using traditional libraries such as MPI fail when any component process fails. The advent of Map Reduce, Resilient Data Sets and MillWheel has shown dramatic improvements in productivity are possible when a high-level programming framework handles scale-out and resilience automatically.
We are concerned with the development of general-purpose languages that support resilient programming. In this paper we show how the X10 language and implementation can be extended to support resilience. In Resilient X10, places may fail asynchronously, causing loss of the data and tasks at the failed place. Failure is exposed through exceptions. We identify a {\em Happens Before Invariance Principle} and require the runtime to automatically repair the global control structure of the program to maintain this principle. We show this reduces much of the burden of resilient programming. The programmer is only responsible for continuing execution with fewer computational resources and the loss of part of the heap, and can do so while taking advantage of domain knowledge.
We build a complete implementation of the language, capable of executing benchmark applications on hundreds of nodes. We describe the algorithms required to make the language runtime resilient. We then give three applications, each with a different approach to fault tolerance (replay, decimation, and domain-level checkpointing). These can be executed at scale and survive node failure. We show that for these programs the overhead of resilience is a small fraction of overall runtime by comparing to equivalent non-resilient X10 programs. On one program we show end-to-end performance of Resilient X10 is ~100x faster than Hadoop.
A decomposition for in-place matrix transposition
Authors: Catanzaro Bryan , Keller Alexander , Garland Michael 
Published: December 2014

We describe a decomposition for in-place matrix transposition, with applications to Array of Structures memory accesses on SIMD processors. Traditional approaches to in-place matrix transposition involve cycle following, which is difficult to parallelize, and on matrices of dimension m by n require O(mn log mn) work when limited to less than O(mn) auxiliary space. Our decomposition allows the rows and columns to be operated on independently during in-place transposition, reducing work complexity to O(mn), given O(max(m, n)) auxiliary space. This decomposition leads to an efficient and naturally parallel algorithm: we have measured median throughput of 19.5 GB/s on an NVIDIA Tesla K20c processor. An implementation specialized for the skinny matrices that arise when converting Arrays of Structures to Structures of Arrays yields median throughput of 34.3 GB/s, and a maximum throughput of 51 GB/s.
Because of the simple structure of this algorithm, it is particularly suited for implementation using SIMD instructions to transpose the small arrays that arise when SIMD processors load from or store to Arrays of Structures. Using this algorithm to cooperatively perform accesses to Arrays of Structures, we measure 180 GB/s throughput on the K20c, which is up to 45 times faster than compiler-generated Array of Structures accesses.
In this paper, we explain the algorithm, prove its correctness and complexity, and explain how it can be instantiated efficiently for solving various transpose problems on both CPUs and GPUs.