The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor

BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.     

Dyspessa peri (Lepidoptera: Cossidae), a new species of Cossidae from Afghanistan

Dyspessa peri sp. n. (Lepidoptera: Cossidae) is described from Sarobi in Central Afghanistan. The new species is closely related to D. tristis A. Bang-Haas, 1912, and is distinguished by peculiarities of the wing pattern and structure of the male genitalia.

http://www.zoobank.org/urn:lsid:zoobank.org:pub:D58AAAC5-90F2-4D06-9DB2-C4D3CDE36265     

Characterization of estrous cycles and pregnancy in Somali wild asses (Equus africanus somaliensis) through fecal hormone analyses

Although reproduction in the domestic horse has been well described, less is known about reproduction in wild equids. This study describes endocrine patterns associated with estrous cycles and pregnancy for Somali wild asses (Equus africanus somaliensis), an endangered African equid. Fecal samples were collected three times per week for more than 2 years from five female Somali wild asses at the Saint Louis Zoo; progestagen and estrogen metabolites were quantified using commercially available immunoassays. Progestagen analysis indicated that cycle lengths were 27.2 ± 1.2 days and females cycled throughout the year. Progestagen levels during early pregnancy were low and not sustained above baseline until approximately 40 weeks prior to partition. Concentrations increased markedly around 16 weeks prior to delivery and peaked 2–3 weeks before birth. Fecal estrogen levels also increased significantly starting 40–45 weeks before parturition and reached their maximal value approximately 20 weeks prior to birth. Neither foal heat nor lactational suppression of estrus was observed, and females cycled within 45 days after delivery. These data are the first to describe the reproductive physiology of Somali wild asses. As the species faces increasing threats in the wild, this information may support conservation efforts by assisting with ex situ breeding programs.     

Coping with shift work-related circadian disruption: A mixed-methods case study on napping and caffeine use in Australian nurses and midwives

ABSTRACT

Introduction: Two of the most ubiquitous fatigue countermeasures used by shift-working nurses are napping and caffeine. This mixed-methods case study investigated the ways nurses and midwives utilised napping and caffeine countermeasures to cope with shift work, and associated sleep, physical health and psychological health outcomes.

Materials and Methods: N = 130 Australian shift-working nurses and midwives (mean age = 44 years, range = 21–67, 115F, 15M) completed the Standard Shiftwork Index. A sub-set of 22 nurses and midwives completed an in-depth interview.

Results: Nearly 70% of participants reported napping. Those who napped during night shifts had significantly less total sleep time before (F_2,75 = 5.5, p < 0.01) and between days off (F_2,82 = 3.9, p < 0.05). By the end of the night shift, average hours of time awake were significantly less for prophylactic and on-shift nappers compared to non-nappers (F_2,85 = 97.2, p < 0.001). Since starting shift work, the percentage of high caffeine consumers (>400 mg/day) increased from 15% to 33% of the sample and an average of 4 (SD = 2) caffeinated beverages per day was reported. Increased caffeine consumption was associated with greater sleep disturbance (r = 0.26, p < 0.05), psychological distress (r = 0.37, p < 0.001), abdomen pain (r = 0.27, p < 0.05) and weight gain since starting shift work (r = 0.25, p < 0.05). Interviews confirmed these relationships and revealed that caffeine consumption on night shift was common, whereas napping on night shift was dependent on a number of factors including ability to sleep during the day.

Conclusion: This study identified reasons shift workers chose to engage in or abstain from napping and consuming caffeine, and how these strategies related to poor sleep and health outcomes. Further research is required to help develop recommendations for shift workers regarding napping and caffeine consumption as fatigue countermeasures, whilst taking into account the associated hazards of each strategy.     

Efficient and low-cost alternative of lipase concentration aiming at the application in the treatment of waste cooking oils

Bioprocess and Biosystems Engineering - In this study, we evaluated the concentration of lipases from Aspergillus niger using efficient and low-cost methods aiming at application in the treatment...     

Drivers of vegetative dormancy across herbaceous perennial plant species

Vegetative dormancy, that is the temporary absence of aboveground growth for ≥ 1 year, is paradoxical, because plants cannot photosynthesise or flower during dormant periods. We test ecological and evolutionary hypotheses for its widespread persistence. We show that dormancy has evolved numerous times. Most species displaying dormancy exhibit life‐history costs of sprouting, and of dormancy. Short‐lived and mycoheterotrophic species have higher proportions of dormant plants than long‐lived species and species with other nutritional modes. Foliage loss is associated with higher future dormancy levels, suggesting that carbon limitation promotes dormancy. Maximum dormancy duration is shorter under higher precipitation and at higher latitudes, the latter suggesting an important role for competition or herbivory. Study length affects estimates of some demographic parameters. Our results identify life historical and environmental drivers of dormancy. We also highlight the evolutionary importance of the little understood costs of sprouting and growth, latitudinal stress gradients and mixed nutritional modes.     

The survey on cellular and tissue-engineered therapies in Europe and neighboring Eurasian countries in 2014 and 2015

Background aims

With the support of five established scientific organizations, this report, the seventh of its kind, describes activity in Europe for the years 2014 and 2015 in the area of cellular and tissue-engineered therapies, excluding hematopoietic stem cell (HSC) treatments for the reconstitution of hematopoiesis.

A guide to the contained use of plant virus infectious clones

Plant virus infectious clones are important tools with wide‐ranging applications in different areas of biology and medicine. Their uses in plant pathology include the study of plant–virus interactions, and screening of germplasm as part of prebreeding programmes for virus resistance. They can also be modified to induce transient plant gene silencing (Virus Induced Gene Silencing – VIGS) and as expression vectors for plant or exogenous proteins, with applications in both plant pathology and more generally for the study of plant gene function. Plant viruses are also increasingly being investigated as expression vectors for in planta production of pharmaceutical products, known as molecular farming. However, plant virus infectious clones may pose a risk to the environment due to their ability to reconstitute fully functional, transmissible viruses. These risks arise from both their inherent pathogenicity and the effect of any introduced genetic modifications. Effective containment measures are therefore required. There has been no single comprehensive review of the biosafety considerations for the contained use of genetically modified plant viruses, despite their increasing importance across many biological fields. This review therefore explores the biosafety considerations for working with genetically modified plant viruses in contained environments, with focus on plant growth facilities. It includes regulatory frameworks, risk assessment, assignment of biosafety levels, facility features and working practices. The review is based on international guidance together with information provided by plant virus researchers.     

A Drosophila Model of Intellectual Disability Caused by Mutations in the Histone Demethylase KDM5

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Primary Cilium-Mediated Retinal Pigment Epithelium Maturation Is Disrupted in Ciliopathy Patient Cells

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