Miracle-dz/UniFAR-FTUs huggingface dataset:
Roles of Capsid-Interacting Host Factors in Multimodal Inhibition of HIV-1 by PF74

ABSTRACT The viral capsid of HIV-1 interacts with a number of host factors to orchestrate uncoating and regulate downstream events, such as reverse transcription, nuclear entry, and integration site targeting. PF-3450074 (PF74), an HIV-1 capsid-targeting low-molecular-weight antiviral compound, directly binds to the capsid (CA) protein at a site also utilized by host cell proteins CPSF6 and NUP153. Here, we found that the dose-response curve of PF74 is triphasic, consisting of a plateau and two inhibitory phases of different slope values, consistent with a bimodal mechanism of drug action. High PF74 concentrations yielded a steep curve with the highest slope value among different classes of known antiretrovirals, suggesting a dose-dependent, cooperative mechanism of action. CA interactions with both CPSF6 and cyclophilin A (CypA) were essential for the unique dose-response curve. A shift of the steep curve at lower drug concentrations upon blocking the CA-CypA interaction suggests a protective role for CypA against high concentrations of PF74. These findings, highlighting the unique characteristics of PF74, provide a model in which its multimodal mechanism of action of both noncooperative and cooperative inhibition by PF74 is regulated by interactions of cellular proteins with incoming viral capsids. IMPORTANCE PF74, a novel capsid-targeting antiviral against HIV-1, shares its binding site in the viral capsid protein (CA) with the host factors CPSF6 and NUP153. This work reveals that the dose-response curve of PF74 consists of two distinct inhibitory phases that are differentially regulated by CA-interacting host proteins. PF74's potency depended on these CA-binding factors at low doses. In contrast, the antiviral activity of high PF74 concentrations was attenuated by cyclophilin A. These observations provide novel insights into both the mechanism of action of PF74 and the roles of host factors during the early steps of HIV-1 infection.
Azure Accelerated Networking: SmartNICs in the Public Cloud

Modern cloud architectures rely on each server running its own networking stack to implement policies such as tunneling for virtual networks, security, and load balancing. However, these networking stacks are becoming increasingly complex as features are added and as network speeds increase. Running these stacks on CPU cores takes away processing power from VMs, increasing the cost of running cloud services, and adding latency and variability to network performance. We present Azure Accelerated Networking (AccelNet), our solution for offloading host networking to hardware, using custom Azure SmartNICs based on FPGAs. We define the goals of AccelNet, including programmability comparable to software, and performance and efficiency comparable to hardware. We show that FPGAs are the best current platform for offloading our networking stack as ASICs do not provide sufficient programmability, and embedded CPU cores do not provide scalable performance, especially on single network flows. Azure SmartNICs implementing AccelNet have been deployed on all new Azure servers since late 2015 in a fleet of >1M hosts. The AccelNet service has been available for Azure customers since 2016, providing consistent <15µs VM-VM TCP latencies and 32Gbps throughput, which we believe represents the fastest network available to customers in the public cloud. We present the design of AccelNet, including our hardware/software codesign model, performance results on key workloads, and experiences and lessons learned from developing and deploying AccelNet on FPGA-based Azure SmartNICs.
UvA-DARE ( Digital Academic Repository ) Simultaneous NIR / sub-mm observation of flare emission from Sagittarius A *

Context. We report on a successful, simultaneous observation and modeling of the sub-millimeter to near-infrared flare emission of the Sgr A* counterpart associated with the super-massive (4 × 106 M ) black hole at the Galactic center. Aims. We study and model the physical processes giving rise to the variable emission of Sgr A*. Methods. Our non-relativistic modeling is based on simultaneous observations that have been carried out on 03 June, 2008. We used the NACO adaptive optics (AO) instrument at the European Southern Observatory’s Very Large Telescope and the LABOCA bolometer at the Atacama Pathfinder Experiment (APEX). We emphasize the importance of a multi-wavelength simultaneous fitting as a tool for imposing adequate constraints on the flare modeling. Results. The observations reveal strong flare activity in the 0.87 mm (345 GHz) sub-mm domain and in the 3.8 μ/2.2 μm NIR. Inspection and modeling of the light curves show that the sub-mm follows the NIR emission with a delay of 1.5 ± 0.5 h. We explain the flare emission delay by an adiabatic expansion of the source components. The derived physical quantities that describe the flare emission give a source component expansion speed of vexp ∼ 0.005c, source sizes around one Schwarzschild radius with flux densities of a few Janskys, and spectral indices of α = 0.8 to 1.8, corresponding to particle spectral indices ∼2.6 to 4.6. At the start of the flare the spectra of these components peak at frequencies of a few THz. Conclusions. These parameters suggest that the adiabatically expanding source components either have a bulk motion greater than vexp or the expanding material contributes to a corona or disk, confined to the immediate surroundings of Sgr A*.
Larval trematodes in the Upper Midwest and the Pacific Northwest which are known to induce skeletal malformations in anurans

Recent laboratory studies have shown that exposing developing tadpoles of Hyla regilla and Bufo boreas to cercariae of the trematode Ribeiroia elicits malformations similar to those observed in field-caught anuran metamorphs. In the summer of 1999, Ribeiroia metacercariae were found for the first time in anurans from Minnesota and Wisconsin. Massive infections of Ribeiroia metacercariae in Rana septentrionalis from the CWB site in Minnesota were positively correlated with development of satellite limbs and mandibular deformities. Ribeiroia was infrequently reported elsewhere in Minnesota and Wisconsin in both deformed and normal Rana pipiens. In order to determine the species of Ribeiroia that occur in Minnesota, California, Oregon, Washington and Montana, surrogate definitive hosts (rock dove, chick, duckling and laboratory rat) were successfully infected with Ribeiroia metacercariae obtained from frogs collected in those states. All adult worms obtained from surrogate feedings conform to the description of R. ondatrae. Furthermore, analysis of numerous voucher specimens obtained from throughout the Americas indicates that R. thomasi, R. insignis and R. marini should be synonymized with R. ondatrae.
Impact of Inorganic Pollutants Perchlorate and Hexavalent Chromium on Efficacy of Bacillus sphaericus and Bacillus thuringiensis subsp. israelensis Against Culex quinquefasciatus (Diptera: Culicidae)

Abstract The effects of two widespread environmental pollutants, perchlorate and hexavalent chromium, were assessed on the efficacy of Bacillus thuringiensis subsp. israelensis (Bti) and Bacillus sphaericus (Bsph) against fourth instars of Culex quinquefasciatus Say (Diptera: Culicidae) in 24-h laboratory bioassays. Although 250 mg/liter perchlorate, a level somewhat higher than would be considered ecologically relevant, did not affect the control provided by either larvicide, presence of 1.04 mg/liter hexavalent chromium, an ecologically relevant concentration, increased the efficacy of both Bti and Bsph by 21 and 80%, respectively. In the presence of hexavalent chromium, improved suppression could be expected from Bacillus applications at the current label rates. However, because hexavalent chromium has been shown to affect many taxa, we propose that the potential exists for increased susceptibility of nontarget organisms to Bacillus products in polluted habitats.
PL-VIO: Tightly-Coupled Monocular Visual–Inertial Odometry Using Point and Line Features

To address the problem of estimating camera trajectory and to build a structural three-dimensional (3D) map based on inertial measurements and visual observations, this paper proposes point–line visual–inertial odometry (PL-VIO), a tightly-coupled monocular visual–inertial odometry system exploiting both point and line features. Compared with point features, lines provide significantly more geometrical structure information on the environment. To obtain both computation simplicity and representational compactness of a 3D spatial line, Plücker coordinates and orthonormal representation for the line are employed. To tightly and efficiently fuse the information from inertial measurement units (IMUs) and visual sensors, we optimize the states by minimizing a cost function which combines the pre-integrated IMU error term together with the point and line re-projection error terms in a sliding window optimization framework. The experiments evaluated on public datasets demonstrate that the PL-VIO method that combines point and line features outperforms several state-of-the-art VIO systems which use point features only.
Genomic Analysis of the Evolution of Fluoroquinolone Resistance in Mycobacterium tuberculosis Prior to Tuberculosis Diagnosis

ABSTRACT Fluoroquinolones (FQs) are effective second-line drugs for treating antibiotic-resistant tuberculosis (TB) and are being considered for use as first-line agents. Because FQs are used to treat a range of infections, in a setting of undiagnosed TB, there is potential to select for drug-resistant Mycobacterium tuberculosis mutants during FQ-based treatment of other infections, including pneumonia. Here we present a detailed characterization of ofloxacin-resistant M. tuberculosis samples isolated directly from patients in Taiwan, which demonstrates that selection for FQ resistance can occur within patients who have not received FQs for the treatment of TB. Several of these samples showed no mutations in gyrA or gyrB based on PCR-based molecular assays, but genome-wide next-generation sequencing (NGS) revealed minority populations of gyrA and/or gyrB mutants. In other samples with PCR-detectable gyrA mutations, NGS revealed subpopulations containing alternative resistance-associated genotypes. Isolation of individual clones from these apparently heterogeneous samples confirmed the presence of the minority drug-resistant variants suggested by the NGS data. Further NGS of these purified clones established evolutionary links between FQ-sensitive and -resistant clones derived from the same patient, suggesting de novo emergence of FQ-resistant TB. Importantly, most of these samples were isolated from patients without a history of FQ treatment for TB. Thus, selective pressure applied by FQ monotherapy in the setting of undiagnosed TB infection appears to be able to drive the full or partial emergence of FQ-resistant M. tuberculosis, which has the potential to confound diagnostic tests for antibiotic susceptibility and limit the effectiveness of FQs in TB treatment.
Virulence gene profiling of porcine Pasteurella multocida isolates of Assam

Aim: The present study was conducted to detect and identify the virulence genes in Pasteurella multocida isolates of porcine origin from Assam. Materials and Methods: A total of 21 porcine P. multocida isolates were subjected to capsular typing and detection of virulence-associated genes (pfhA, tbpA, hgbB, toxA, oma87, ompH, and nanB) using various polymerase chain reaction (PCR) methods reported elsewhere. Further, pathogenicity of the porcine isolates of P. multocida was studied in mice. For each strain of P. multocida selected for pathogenicity trial, the group of mice was injected intraperitoneally (i/p) with 0.1 ml of the inoculum prepared from respective field isolates, containing 109 organisms per ml. Results: Capsular typing of the isolates by multiplex PCR showed two capsular types, type A (66.66%) and type D (33.33%). All the isolates were positive for outer membrane protein genes, oma87 and ompH genes. Iron acquisition genes, tbpA and hgbB, were detected in 14.28% and 19.04% of the isolates. The dermonecrotoxin encoding gene, toxA, was present in 23.80% of the isolates. Filamentous hemagglutinin encoding gene, pfhA, was detected in 28.57%. The virulence gene distribution pattern of the isolates indicates the important role of the genes in disease pathogenesis. Conclusion: From the present study, it can be concluded that toxA gene is an important marker gene for defining the pathogenic potential of P. multocida strains in swine.
Clinical Ophthalmology Dovepress Measurement of Serum and Vitreous Concentrations of Anti-type Ii Collagen Antibody in Diabetic Retinopathy

Background: Autoimmune mechanisms have been postulated as a cause of diabetic retinopathy (DR), as several autoantibodies have reportedly been detected in the serum of DR patients. In this present study, we measured serum and vitreous levels of anti-type II collagen (anti-II-C) antibodies in DR patients and investigated their association with the mechanism of development of DR. Patients and methods: Blood samples were obtained from patients with proliferative DR and from patients with diabetic macular edema who underwent vitrectomy at Osaka Medical College, Takatsuki City, Osaka, Japan. Diabetic patients without DR were also included. The control group consisted of age-and sex-matched patients with noninflammatory eye diseases who underwent eye surgery for retinal detachment or for cataracts. The levels of anti-II-C immunoglobulin (Ig)G antibody in the vitreous and serum were measured using a human/ monkey anti-II-C IgG assay kit. Results: The serum levels of anti-II-C IgG antibody were significantly higher in the DR patients than in the patients with noninflammatory eye disease (56.8±33.8 units/mL versus 30.5±13.7 units/mL, respectively; P,0.05, Fisher's exact test). These levels were also significantly higher in the diabetic patients without DR than in the patients with noninflammatory eye disease (76.3±49.7 units/mL versus 30.5±13.7 units/mL, respectively; P,0.01, Fisher's exact test). However, anti-II-C IgG antibody levels were unable to be detected in all of the obtained vitreous fluid samples. Conclusion: The development and progression of DR may be related to a mechanism involving intraocular type II collagen, which normally has immunological tolerance as a sequestered antigen. In DR, the disruption of the blood–retinal barrier leads to contact between the intraocular type II collagen and immunocompetent cells, and to subsequent activation of the autoimmune mechanism.
Efficacy of green tea-based mouthwashes on dental plaque and gingival inflammation: A systematic review and meta-analysis

Objectives: The purpose of this study was to conduct a systematic review and if appropriate a meta-analysis of the efficacy of daily rinsing with green tea-based mouthwashes in terms of plaque index (PI) and/or gingival index (GI) as compared to other mouthwashes in plaque-induced gingivitis patients. Materials and Methods: MEDLINE, Cochrane Central Register of Controlled Trials, IndMed, Google Scholar, and major journals were searched for studies up to December 2016. A comprehensive search strategy was designed, and the eligible articles were independently screened for eligibility by two reviewers. Randomized controlled trials in which individuals were intervened with oral mouthwashes of interest were included. Where appropriate, a meta-analysis was performed and standardized mean differences (SMDs) for GI and PI were calculated. Results: A total of 9 articles out of the 311 titles met the eligibility criteria. A meta-analysis was performed for five studies that compared green tea-based mouthwashes with chlorhexidine (CHX). The SMD for PI was −0.14 (95% CI: −1.70, 1.43; P = 0.86 and I2 = 94%), while that for GI was 0.43 ((95% CI: -0.63, 1.49; P = 0.43, I2 = 89%). Both these estimates suffered from significant heterogeneity. For both PI and GI, two studies were in favor of green tea while three studies were in favor of CHX. Conclusions: Green tea-based mouthwashes can be considered an alternative to CHX mouthwashes in sustaining oral hygiene, especially because of the added advantages provided by such herbal preparations.
A hypothalamic circuit that controls body temperature

Significance Thermal homeostasis is essential for survival in mammals. Although it is known that temperature-sensitive neurons in the hypothalamus can control body temperature, the precise neural types and dynamics of neurons responding to changes in environmental temperature are not well defined. In this study, we identified subsets of temperature-activated neurons in two hypothalamic nuclei, the preoptic area (POA) and the dorsomedial hypothalamus (DMH), and showed that modulating their activity can lead to alterations in core temperature. The data further suggest that heat-activated GABAergic neurons in the POA reduce the activity of cold-activated neurons in the DMH, which function to increase thermogenesis and physical activity. These data identify a neural circuit that controls core temperature and thermogenesis. The homeostatic control of body temperature is essential for survival in mammals and is known to be regulated in part by temperature-sensitive neurons in the hypothalamus. However, the specific neural pathways and corresponding neural populations have not been fully elucidated. To identify these pathways, we used cFos staining to identify neurons that are activated by a thermal challenge and found induced expression in subsets of neurons within the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial hypothalamus (DMD). Activation of GABAergic neurons in the vLPO using optogenetics reduced body temperature, along with a decrease in physical activity. Optogenetic inhibition of these neurons resulted in fever-level hyperthermia. These GABAergic neurons project from the vLPO to the DMD and optogenetic stimulation of the nerve terminals in the DMD also reduced body temperature and activity. Electrophysiological recording revealed that the vLPO GABAergic neurons suppressed neural activity in DMD neurons, and fiber photometry of calcium transients revealed that DMD neurons were activated by cold. Accordingly, activation of DMD neurons using designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics increased body temperature with a strong increase in energy expenditure and activity. Finally, optogenetic inhibition of DMD neurons triggered hypothermia, similar to stimulation of the GABAergic neurons in the vLPO. Thus, vLPO GABAergic neurons suppressed the thermogenic effect of DMD neurons. In aggregate, our data identify vLPO→DMD neural pathways that reduce core temperature in response to a thermal challenge, and we show that outputs from the DMD can induce activity-induced thermogenesis.
When Voters and Parties Agree: Valence Issues and Party Competition

There has been much talk of valence, consensus or competence politics but little theoretical explanation or empirical investigation of how this has arisen. In this article I argue that British political competition has become competence-based because the major parties and the electorate have converged on the dominant left–right dimension of British voting behaviour. As a result, commonly cited core vote explanations for party polarisation have only limited application. The electorate has converged on left–right issues, narrowing the policy space and the available positional strategies of political parties. A different pattern is found for the issue of Europe, and this is interpreted in light of possible causal mechanisms. The article offers a formal model for a rise in valence politics as parties and voters converge, and the implications are discussed for theories of party competition. I argue in favour of competence and salience-based theories of party strategy in place of a reliance on traditional spatial models.
Glial alterations in human prion diseases

Background: Neuroinflammation has recently been proposed to be a major component of neurodegenerative diseases. The aim of this study was to determine how the interaction between microglia and astroglia, which are the primary immune cell populations in the brain, and pathological prion protein (PrPsc) could influence the development and propagation of this neurodegenerative disease. Because a relevant role for glial response in prion disease has been clearly demonstrated in our previous studies using the natural animal model, a similar approach has been taken here using the natural human model. Methods: A morphological approach has been developed to analyze cerebellar samples from patients with Creutzfeldt-Jakob disease (CJD) in comparison with healthy control cases. Histopathological lesions were assessed, and PrPsc, glial fibrillary acidic protein (GFAP) and reactive microglia were immunolabelled by specific antibodies. Furthermore, co-location studies using confocal microscopy were performed to determine the possible relationships between both types of glial cells in all samples. Results: The results presented in this study support the involvement of both types of glial cells in CJD. Evidence of increased astrocyte and microglia reactivity can be observed in all CJD cases, and a close relationship between the types of glia is demonstrated by co-location studies. Conclusion: Proteinopathies such as Alzheimer, Parkinson, and Huntington diseases, where aberrant proteins spread throughout the brain during disease progression, may share a molecular basis and mechanisms of propagation. Therefore, studies elucidating the interaction between gliosis and prion propagation may be relevant to these other neurodegenerative diseases and may provide new targets for therapeutic intervention.
Errors in performance testing: a comparison of ethanol and temazepam

Both ethanol and benzodiazepines impair psychomotor function. Previous work has suggested that ethanol may have a greater effect on errors while benzodiazepines may cause greater slowing, but this has not been tested in a direct comparison. We assessed the effects of ethanol, at blood concentrations of approximately 80–100 mg/100 ml, compared to two doses of temazepam (20 mg and 30 mg) on psychomotor speed and accuracy and on long-term memory. Sixteen healthy volunteers (eight male, aged 20–25 years) took part in a four-period, placebo-controlled cross-over study. Performance was evaluated using analysis of covariance (critical significance level, p= 0.05) comparing the areas under the response-time curves. Performance on a psychomotor maze showed an almost complete dissociation, with ethanol leading to a substantial and significant increase in errors with little effect on speed, while temazepam slowed performance with no significant change in accuracy. Other tasks showed a similar pattern, but the dissociation was less complete. Handwriting size was substantially increased by ethanol, but not by temazepam. Information processing capacity and long-term memory formation were reduced by a similar amount both for ethanol and 30 mg temazepam. The faster, more error-prone, behaviour on ethanol than with a similarly impairing dose of temazepam has clear implications for the relative potential of the two drugs to contribute to accidents. The results are also important in understanding the differential effects of drugs with different mechanisms of action on human performance.
Small amplitude homogenization applied to models of non-periodic fibrous materials

In this paper, we compare a biomechanics empirical model of the heart fibrous structure to two models obtained by a non-periodic homogenization process. To this end, the two homogenized models are simplified using the small amplitude homogenization procedure of Tartar, both in conduction and in elasticity. A new small amplitude homogenization expansion formula for a mixture of anisotropic elastic materials is also derived and allows us to obtain a third simplified model.