The study aimed to confirm the presence of historic oyster banks of Qatar and code the biotopes present. The research also collated historical records and scientific publications to create a timeline ...of fishery activity. The oyster banks where once an extremely productive economic resource however, intense overfishing, extreme environmental conditions and anthropogenic impacts caused a fishery collapse. The timeline highlighted the vulnerability of ecosystem engineering bivalves if overexploited. The current status of the oyster banks meant only one site could be described as oyster dominant. This was unexpected as the sites were located in areas which once supported a highly productive oyster fishery. The research revealed the devastating effect that anthropogenic impacts can have on a relatively robust marine habitat like an oyster bed and it is hoped these findings will act as a driver to investigate and map other vulnerable habitats within the region before they too become compromised.
•The first biotope classification of oyster banks of Qatar•Oyster densities seriously diminished•Oyster fishery collapse in 1950’s•Overfishing, extreme environmental conditions, anthropogenic impacts resulted in dramatic habitat change.
SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in ...the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein–ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro4.5decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
Abstract
Distimake vitifolius comb. nov. (Convolvulaceae), currently treated as Camonea vitifolia, is a common and widespread species in South-East Asia. A recent study on the re-delimitation of the ...genus Merremia classified its species into six genera. The results of molecular phylogenetic analyses and the presence of hexazonocolpate pollen informed the transfer of Merremia vitifolia to Camonea. We present new molecular, morphological and palynological data and reinterpret previous results, demonstrating that the species should be classified in Distimake instead, reflecting the phylogenetic relationships of the species. Thus, the occurrence of hexazonocolpate pollen in both Distimake and Camonea is found to be the result of the convergent evolution of this apertural pattern in ‘Merremieae’, with implications for pollen evolution studies in the family. We formally transfer Camonea vitifolia to Distimake and present this reclassification as an example of the relevance of reciprocal reinterpretation of different sources of evidence in systematic studies.
Chagas disease (CD) is still an important public health issue in Latin America. This study aims to analyse the association between socio-epidemiological factors and comorbidities with clinical ...manifestations of CD.
We performed a cross-sectional study of 985 adult patients (65±11 y; 59.5% women) with CD. Data collection was based on questionnaires and medical records review. CD clinical forms (indeterminate, digestive, cardiac and cardiodigestive) and the stages of the cardiac form were classified according to the II Brazilian Consensus on CD. Statistical analyses were based on univariate and multivariate logistic regression.
Older age and Brazilian birth state (Minas Gerais and Bahia) were associated with a greater likelihood of the cardiac form of CD. A greater likelihood of the digestive form was seen in men and those of older age. Patients with arterial hypertension and diabetes were less likely to have the digestive form. Men had a greater likelihood of having a more severe cardiac presentation. Those from Minas Gerais and Bahia states had a greater likelihood of having stage B1 or B2.
The results reinforce the aging of the CD population living in urban areas in Brazil, the high prevalence of comorbidities and that epidemiology, sex and the presence of comorbidities may be related to the clinical form of CD.
MELK kinase has been implicated in playing an important role in tumorigenesis. Our previous studies suggested that MELK is involved in the regulation of cell cycle and its genetic depletion leads to ...growth inhibition in a subset of high MELK-expressing basal-like breast cancer cell lines. Herein we describe the discovery and optimization of novel MELK inhibitors 8a and 8b that recapitulate the cellular effects observed by short hairpin ribonucleic acid (shRNA)-mediated MELK knockdown in cellular models. We also discovered a novel fluorine-induced hydrophobic collapse that locked the ligand in its bioactive conformation and led to a 20-fold gain in potency. These novel pharmacological inhibitors achieved high exposure in vivo and were well tolerated, which may allow further in vivo evaluation.
Twelve countries were compared with respect to occupational class differences in ischemic heart disease mortality in order to identify factors that are associated with smaller or larger mortality ...differences.
Data on mortality by occupational class among men aged 30 to 64 years were obtained from national longitudinal or cross-sectional studies for the 1980s. A common occupational class scheme was applied to most countries. Potential effects of the main data problems were evaluated quantitatively.
A north-south contrast existed within Europe. In England and Wales, Ireland, and Nordic countries, manual classes had higher mortality rates than nonmanual classes. In France, Switzerland, and Mediterranean countries, manual classes had mortality rates as low as, or lower than, those among nonmanual classes. Compared with Northern Europe, mortality differences in the United States were smaller (among men aged 30-44 years) or about as large (among men aged 45-64 years).
The results underline the highly variable nature of socioeconomic inequalities in ischemic heart disease mortality. These inequalities appear to be highly sensitive to social gradients in behavioral risk factors. These risk factor gradients are determined by cultural as well as socioeconomic developments.
While adding the structural features that are more favored by on-target activity is the more common strategy in selectivity optimization, the opposite strategy of subtracting the structural features ...that contribute more to off-target activity can also be very effective. Reported here is our successful effort of improving the kinase selectivity of type II maternal embryonic leucine zipper kinase inhibitors by applying these two complementary approaches together, which clearly demonstrates the powerful synergy between them.
High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1R132H. Synthesis of the four ...separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1wt. Initial structure–activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood–brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model.
The use of cannabidiol in some neurological conditions was allowed by Conselho Regional de Medicina de São Paulo and by Agência Nacional de Vigilância Sanitária (ANVISA). Specialists on behalf of ...Academia Brasileira de Neurologia prepared a critical statement about use of cannabidiol and other cannabis derivatives in neurological diseases.
In Billhardt et al. (Semigroup Forum 79:101–118,
2009
) the authors introduced the notion of an associate inverse subsemigroup of a regular semigroup, extending the concept of an associate subgroup ...of a regular semigroup, first presented in Blyth et al. (Glasg. Math. J. 36:163–171,
1994
). The semigroups of these two classes admit axiomatic characterisations in terms of unary operations and can, therefore, be considered as unary semigroups. In this paper we introduce the notion of
unary semigroup with associate inverse subsemigroup
with associate subgroup
and show that the classes of such unary semigroups form varieties.
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