Miracle-dz/UniFAR-FTUs huggingface dataset:
(Alkylamino) piperidine bis(heteroaryl)piperizine analogs are potent, broad-spectrum nonnucleoside reverse transcriptase inhibitors of drug-resistant isolates of human immunodeficiency virus type 1 (HIV-1) and select for drug-resistant variants of HIV-1IIIB with reduced replication phenotypes

The (alkylamino)piperidine bis(heteroaryl)piperizines (AAP-BHAPs) are a new class of human immunodeficiency virus type 1 (HIV-1)-specific inhibitors which were identified by targeted screening of recombinant reverse transcriptase (RT) enzymes carrying key nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-conferring mutations and NNRTI-resistant variants of HIV-1. Phenotypic profiling of the two most potent AAP-BHAPs, U-95133 and U-104489, against in vitro-selected drug-resistant HIV-1 variants carrying the NNRTI resistance-conferring mutation (Tyr->Cys) at position 181 of the HIV-1 RT revealed submicromolar 90% inhibitory concentration estimates for these compounds. Moreover, U-104489 demonstrated potent activity against BHA-P-resistant HIV-1MF harboring the Pro-236->Leu RT substitution and significantly suppressed the replication of clinical isolates of HIV-1 resistant to both delavirdine (BHAP U-90152T) and zidovudine. Biochemical and phenotypic characterization of AAP-BHAPresistant HIV-1IIIB variants revealed that high-level resistance to the AAP-BHAPs was mediated by a Gly-190->Glu substitution in RT, which had a deleterious effect on the integrity and enzymatic activity of virion-associated RT heterodimers, as well as the replication capacity of these resistant viruses.
Relationship of inbreeding with sperm quality and reproductive success in Mexican gray wolves

The ultimate goal of the Mexican gray wolf Canis lupus baileyi captive management program is reintroduction of healthy individuals into wild habitats. To this end, zoo population managers work to provide not only for the physical well‐being but also for the genetic health of these animals. However, the very limited genetic founder base, exacerbated by breeding within three distinct lineages, resulted in very high coefficients of inbreeding. Because support for measurable levels of inbreeding depression in the captive wolf population, as defined by reductions in common fitness measures such as juvenile survival or reproductive success, has been weak, we investigated the potential effects on male reproductive capacity. We analyzed semen samples from wolves from all three lineages and compared them with samples from subsequent lineage crosses and from generic gray wolves. We not only found a significant effect of inbreeding on sperm quality but we related both inbreeding and sperm quality to reproductive success. Samples from male offspring of lineage crosses, with inbreeding coefficients of zero were similar in quality to those from generic gray wolves. However, samples from a limited number of offspring from back‐crosses were of extremely poor quality. Although it is reassuring that sperm quality was so much improved in male offspring of lineage crosses, the concomitant reduction in inbreeding coefficient does not eliminate the potentially deleterious alleles. Our results demonstrate that sperm quality is an important indicator of fertility and reproductive success in Mexican wolves. In addition, our data lend further support to the presence of inbreeding depression in this taxon.
Cadmium‐induced melatonin synthesis in rice requires light, hydrogen peroxide, and nitric oxide: Key regulatory roles for tryptophan decarboxylase and caffeic acid O‐methyltransferase

In plants, melatonin production is induced by stimuli such as cold and drought, and cadmium (Cd) is the best elicitor of melatonin production in rice. However, the mechanism by which Cd induces melatonin synthesis in plants remains unknown. We challenged rice seedlings with Cd under different light conditions and found that continuous light produced the highest levels of melatonin, while continuous dark failed to induce melatonin production. Transcriptional and translational induction of tryptophan decarboxylase contributed to the light induction of melatonin during Cd treatment, whereas the protein level of light‐induced caffeic acid O‐methyltransferase (COMT) was decreased by Cd treatment. In analogy, COMT enzyme activity was inhibited in vitro by Cd in a dose‐dependent manner. Notably, the Cd‐induced melatonin synthesis was significantly impaired by treatment with either an H2O2 production inhibitor (DPI) or an NO scavenger (cPTIO). The combination of both inhibitors almost completely abolished Cd‐induced melatonin synthesis, suggesting an absolute requirement for H2O2 and NO. However, neither serotonin nor N‐acetylserotonin (NAS) was induced by H2O2 alone. In contrast, NO significantly induced serotonin production but not NAS or melatonin production. This indicated that serotonin did not enter chloroplasts, where serotonin N‐acetyltransferase (SNAT) is constitutively expressed. This suggests that chloroplastidic SNAT expression prevents increased melatonin production after exposure to stress, ultimately leading to the maintenance of a steady‐state melatonin level inside cells.
Sleep-Related Breathing Disorders and Rehabilitation Outcome of Stroke Patients: A Prospective Study

Cherkassky T, Oksenberg A, Froom P, Ring H: Sleep-related breathing disorders and rehabilitation outcome of stroke patients: A prospective study. Am J Phys Med Rehabil 2003;82:452–455. Objective Sleep-related breathing disorder (SRBD) is more prevalent in stroke patients than in age- and sex-matched controls, but the relationship between SRBD, functional levels at admission, and subsequent recovery is unclear. We evaluated patients after a first stroke to determine the prevalence of SRBD and the influence of SRBD on the recovery of discharge functional status after a rehabilitation program. Design In a prospective study, 30 stroke patients were studied by continuous overnight pulse oximetry during sleep for the presence of desaturation events (fall of arterial saturation of >4% from the baseline). The Respiratory Disturbance Index was defined as number of desaturations per hour of sleep. Functional assessment was done at admission using the FIM™ instrument. The patients were asked about total hours of sleep and the presence or absence of habitual snoring before and after the stroke. The outcome measure at discharge was the FIM score. Results On linear regression, after including the FIM score at admission, in the model, the Respiratory Disturbance Index score was negatively correlated with the FIM gain (coefficient, −0.635 ± 0.27;P = 0.025), and together, the variables explained 20.9% of the total variance (adjusted r2). All patients with an admission FIM score of ≥70 (only mild functional impairment) had a good outcome (FIM score of >100 at discharge). However, only two of six of those with FIM scores of <70 with SRBD (defined as a Respiratory Disturbance Index score of >10) had significant improvement (≥30 points), whereas this occurred in seven of nine of those without SRBD (prevalence ratio, 0.43; 95% confidence interval, 0.13–1.40;P = 0.085) Conclusions Even after adjusting for the admission functional status, the presence of hypoxic events during sleep predicts a poorer recovery, especially in stroke patients with poor function at admission.
Metabolic Influences on Circadian Rhythmicity in Siberian and Syrian Hamsters Exposed to Long Photoperiods

Calorie restriction and other situations of reduced glucose availability in rodents alter the entraining effects of light on the circadian pacemaker located in the suprachiasmatic nuclei. Siberian and Syrian hamsters are photoperiodic species that are sexually active when exposed to long summer‐like photoperiods, while both species show opposite changes in body mass when transferred from long to short or short to long days. Because metabolic cues may fine tune the photoperiodic responses via the suprachiasmatic nuclei, we tested whether timed calorie restriction can alter the photic synchronization of the light‐entrainable pacemaker in these two hamster species exposed to long photoperiods. Siberian and Syrian hamsters were exposed to 16 h:8 h light:dark cycles and received daily hypocaloric (75% of daily food intake) or normocaloric diet (100% of daily food intake) 4 h after light onset. Four weeks later, hamsters were transferred to constant darkness and fed ad libitum. The onset of the nocturnal pattern of locomotor activity was phase advanced by 1.5 h in calorie‐restricted Siberian hamsters, but not in Syrian hamsters. The lack of phase change in calorie‐restricted Syrian hamsters was also observed in individuals exposed to 14 h:10 h dim light:dark cycles and fed with lower hypocaloric food (i.e. 60% of daily food intake) 2 h after light onset. Moreover, in hamsters housed in constant darkness and fed ad lib. , light‐induced phase shifts of the locomotor activity in Siberian hamsters, but not in Syrian hamsters were significantly reduced when glucose utilization was blocked by pretreatment with 500 mg/kg i.p. 2‐deoxy‐ d‐glucose. Taken together, these results show that the photic synchronization of the light‐entrainable pacemaker can be modulated by metabolic cues in Siberian hamsters, but not in Syrian hamsters maintained on long days.
Identifying the psychosocial correlates of condom use by female sex workers in Hong Kong

This study examined factors affecting condom use by Hong Kong female sex workers when they have sex with their clients and steady partners. Our respondents consisted of 109 active female sex workers, mainly streetwalkers or sex workers who worked in villas. During a 30-minute interview, respondents were interviewed individually and were asked questions regarding their condom use practice. These questions were designed to measure various factors affecting their condom use practice, including attitudes toward condom use, normative pressure, perceived behavioural control, perceived AIDS risks, past condom use behaviour, and future condom use intentions with respect to the two types of partners. Multiple regression analyses reveal that perceived behavioural control is the most important factor associated with these respondents’ future condom use across the two types of partners. Perceived AIDS risk is the additional predictor for condom use with clients, while normative pressure is the additional predictor for condom use with steady partners. Past condom use behaviour also provided significant additional prediction for both types of partners, implying the habitual nature of condom use among our respondents. These results have significant implications for designing intervention programmes targeting at increasing condom use by female sex workers in Hong Kong.
Expression of concern reaffirmed.

On December 8, 2005, we published an expression of concern1 regarding an article by Bombardier et al. on the Vioxx Gastrointestinal Outcomes Research (VIGOR) study that was published in the Journal on November 23, 2000.2 Our expression of concern was prompted by evidence that the VIGOR article did not accurately represent the safety data available to the authors when the article was being reviewed for publication. More than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR .
Biologic Effects of Platelet-Derived Growth Factor Receptor α Blockade in Uterine Cancer

Purpose: Platelet-derived growth factor receptor α (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer. Experimental Design: Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer. Results: PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and mitogen-activated protein kinase (MAPK). Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in the PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis. Conclusions: These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer. Clin Cancer Res; 20(10); 2740–50. ©2014 AACR.
Amiodarone pneumonitis. Bronchoalveolar lavage findings in 15 patients and review of the literature.

UNLABELLED Amiodarone (Am) pneumonitis is currently a common and potentially severe adverse reaction, the accurate diagnosis of which remains difficult to establish. OBJECTIVES To determine the contribution of bronchoalveolar lavage (BAL) in the diagnostic workup of patients suspected of having Am pneumonitis. METHODS Diagnosis of Am pneumonitis was established on the basis of (1) development of recent symptoms and pulmonary opacities while receiving the drug, (2) exclusion of other possible causes, and (3) improvement following cessation of Am and/or steroid therapy. (4) Confirmatory changes were obtained by histopathologic examination in eight cases. BAL was performed in each patient at the time of initial evaluation. RESULTS Am pneumonitis was diagnosed in 15 consecutive patients between 1985 and 1991. The disease was associated with significant morbidity and mortality. Six patients died; four died of Am pneumonitis. A neutrophilic BAL was found in nine patients (average PMN = 26.6 percent). A mixed pattern (lymphocytic + neutrophilic) was seen in four patients (average: Ly = 19.9 percent; PMN = 11.9 percent). Two patients had a normal BAL. No patient had a lymphocytic pattern. A low CD4+/CD8+ ratio was seen in two patients. A literature survey indicated 70 cases of Am pneumonitis with detailed information on BAL. The BAL pattern was mixed in 23 (33 percent), neutrophilic in 18 (26 percent), lymphocytic in 15 (21 percent), and normal in 14 (20 percent). No correlation was found between BAL pattern and prognosis. Also, BAL pattern was related neither to daily or total dose of Am nor to duration of treatment with Am. CONCLUSION The cellular profile of BAL in Am pneumonitis is highly variable, and no cellular pattern of BAL seems to be predictive of a detrimental outcome or of irreversible fibrosis. Aside from excluding other illnesses, and due to its extreme variability, the contribution of BAL differential in the initial workup of patients suspected of having Am pneumonitis is limited.
Pooled analysis on the necessity of random 4-quadrant cervical biopsies and endocervical curettage in women with positive screening but negative colposcopy

Abstract Controversy remains over whether random cervical biopsies and endocervical curettage (ECC) should be used in women with positive screening but negative colposcopy. Our paper aims to determine the indications for random biopsies and ECC among these screened positive women. Three thousand two hundred thirteen women with any positive screening test result but negative colposcopy, who received random 4-quadrant biopsies, were pooled from 17 population-based cervical cancer screening studies done in China from 1999 to 2008. The detection rates of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN grade 3 or worse (CIN3+) stratified by cytology and high-risk human papillomavirus (HR-HPV) status were assessed, as well as the false negative rates for CIN2+ and CIN3+ by random biopsies without ECC. Compared with women with negative cytology and positive HR-HPV, those with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (ASC-US/LSIL) and negative HR-HPV had the equivalent lower risks of CIN2+ and CIN3+, but ascending risks were observed in the groups of ASC-US/LSIL and positive HR-HPV, and atypical glandular cells/atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion or worse (AGC/ASC-H/HSIL+). If random biopsies were only taken without ECC, 9.3% of CIN2+ and 18.5% of CIN3+ would have been missed. For women with any positive screening but negative colposcopy, in areas with good cytological infrastructure, it was necessary to perform random biopsies plus ECC on those with cytological ASC-US/LSIL and positive HR-HPV, AGC, ASC-H, or HSIL+. In contrast, those with other results should be followed up.
Role of the Transmembrane Domains of prM and E Proteins in the Formation of Yellow Fever Virus Envelope

ABSTRACT Flavivirus envelope proteins have been shown to play a major role in virus assembly. These proteins are anchored into cellular and viral membranes by their C-terminal domain. These domains are composed of two hydrophobic stretches separated by a short hydrophilic segment containing at least one charged residue. We investigated the role of the transmembrane domains of prM and E in the envelope formation of the flavivirus yellow fever virus (YFV). Alanine scanning insertion mutagenesis has been used to examine the role of the transmembrane domains of prM and E in YFV subviral particle formation. Most of the insertions had a dramatic effect on the release of YFV subviral particles. Some of these mutations were introduced into the viral genome. The ability of these mutant viruses to produce infectious particles was severely reduced. The alanine insertions did not affect prM-E heterodimerization. In addition, replacement of the charged residues present in the middle of the transmembrane domains had no effect on subviral particle release. Taken together, these data indicate that the transmembrane domains of prM and E play a crucial role in the biogenesis of YFV envelope. In addition, these data indicate some differences between the transmembrane domains of the hepaciviruses and the flaviviruses.
Numerical studies of quasi‐static tectonic loading and dynamic rupture of bi‐material interfaces

Dynamic simulations of homogeneous and bi‐material fault rupture are modeled using different loading approaches. We demonstrate that a numerical method of quasi‐static loading is capable of immediately loading bi‐material interfaces to rupture without the iteration over multiple time steps. We show that our method is a computationally inexpensive approach to tectonic loading and is capable of loading a fault to failure. We observe earthquake rupture speed, slip distances and slip rates for homogeneous and bi‐material faults for various applied stresses, friction properties and material contrasts across the bi‐material interface. We comment on causes for unilateral rupture growth. The results are consistent with experimental results and highlight the importance of material heterogeneity in determining the rupture characteristics of earthquake faults. Copyright © 2009 John Wiley & Sons, Ltd.
Soldering tests with biodegradable printed circuit boards

The paper presents soldering tests on biodegradable printed circuit boards (PCB) focusing on different alternative base materials. The aim of the work was to investigate and optimize different low-temperature soldering profiles on cellulose-acetate (CA) and polylactide (PLA) biopolymer-based PCBs with the application of special lead-free solder alloy suited for the temperatures. The investigations were focused on the minimization of the heating effect on the heat-sensitive biopolymers, where on the other hand, sufficient thermal energy is required to melt the solder alloys. The soldering profiles were created with a custom vapour phase soldering (VPS) approach where the heat transfer is controlled with an adaptive height-setting, temperature tracking sample holder. The profiles were evaluated according to their heating factor values. The soldered joints were evaluated with X-Ray microscopy and Shear Tests. The deformation of the PCB tracks was also investigated. The preliminary results reveal the priority of CA for further experiments.
Complexity-Aware Frame-Level Bit Allocation and Rate Control for H.264 Scalable Video Coding

This study aimed to investigate efficient bit-allocation and rate-control methods for H.264 scalable video encoders. We first presented a new bit-allocation algorithm at the frame level for H.264 temporal scalability. Additional to the target bit-rate and buffer occupancy, the temporal hierarchical level and visual complexity were considered for determining the bit budget of a frame. This bit-allocation scheme was followed by a quantization parameter (QP) estimation procedure to achieve the desired bit-rate. We improved the conventional QP assignment by identifying and correcting inappropriate QP values due to incorrect visual complexity prediction. Furthermore, the proposed bit-allocation and rate-control algorithm for temporal scalability was seamlessly integrated with spatial/quality scalabilities to offer flexible bit-rate/quality combinations. Rate-control performance of an investigated method was extensively evaluated in the accuracy of produced bit rates, rate-distortion behavior, and stability of the decoder’s buffer occupancy. Experimental results showed that the proposed algorithm achieved accurate bit-rates, prevented buffer overflow and underflow, and simultaneously produced more favorable and stable visual quality as compared to the state-of-the-art approaches in the literature.
Pharmacokinetic Evaluation of Ethionamide Suppositories

The absorption and elimination of ethionamide (ETA) after oral tablets and rectal suppositories were determined in 12 healthy, adult male volunteers. A randomized, double‐blind, double‐dummy, crossover design was used. Treatments compared 250‐mg ETA tablets and a placebo suppository to a 500‐mg ETA suppository and two placebo tablets, given 7 days apart. Blood samples were collected at predetermined intervals for 12 hours after the dose. Serum concentrations of ETA were determined using high‐performance liquid chromatography. The area under the serum concentration‐time curve was used to compare the relative bioavailability of ETA from the two preparations. Relative bioavailability after rectal administration was 57.3% of that after oral administration. The maximum serum concentration after rectal administration was 33% of that after oral administration. Higher doses of ETA and serum concentration monitoring are recommended whenever the suppositories are used.