Pharmacological screening and transcriptomic functional analyses identify a synergistic interaction between dasatinib and olaparib in triple-negative breast cancer

Identification of druggable vulnerabilities is a main objective in triple-negative breast cancer (TNBC), where no curative therapies exist. Gene set enrichment analyses (GSEA) and a pharmacological evaluation using a library of compounds were used to select potential druggable combinations. MTT and studies with semi-solid media were performed to explore the activity of the combinations. TNBC cell lines (MDAMB-231, BT549, HS-578T and HCC3153) and an additional panel of 16 cell lines were used to assess the activity of the two compounds. Flow cytometry experiments and biochemical studies were also performed to explore the mechanism of action. GSEA were performed using several data sets (GSE21422, GSE26910, GSE3744, GSE65194 and GSE42568), and more than 35 compounds against the identified functions were evaluated to discover druggable opportunities. Analyses done with the Chou and Talalay algorithm confirmed the synergy of dasatinib and olaparib. The combination of both agents significantly induced apoptosis in a caspase-dependent manner and revealed a pleotropic effect on cell cycle: Dasatinib arrested cells in G0/G1 and olaparib in G2/M. Dasatinib inhibited pChk1 and induced DNA damage measured by pH2AX, and olaparib increased pH3. Finally, the effect of the combination was also evaluated in a panel of 18 cell lines representative of the most frequent solid tumours, observing a particularly synergism in ovarian cancer. Breast cancer, triple negative, dasatinib, olaparib, screening.     

Mimosa pigra in eastern and southern Africa: Distribution and socio‐ecological impacts

The semiaquatic weed Mimosa pigra has negative impacts on biodiversity, fishing, crop and livestock production, and tourism in most places where it has been introduced, established and proliferated. Many of the ecological impacts are well known, but its impacts on rural livelihoods are less well documented, especially in Africa. We mapped the distribution of M. pigra in eastern and southern Africa, and then compared that with its potential distribution based on an ecoclimatic niche model. Household interviews were conducted to assess the impacts of this weed on local livelihoods. Mimosa pigra was found to be invasive in western Ethiopia, around the shores of Lake Victoria and Lake Tanganyika, and along the Tanzanian coastline, northern Malawi, parts of Mozambique and along the Kafue River and in the Barotse floodplain on the Zambezi River in Zambia. According to respondents living along the Kafue River floodplains in Zambia, it has a negative impact on biodiversity, wildlife, livestock, crop production, fishing and mobility. Dense stands prevented the movement of people and livestock, limiting access to croplands, grazing lands and fishing areas. Fish catches have been reduced and fishing equipment damaged. All respondents agreed that their livelihood options would be considerably enhanced if M. pigra was removed from the landscape. Based on its current and potential impact, we therefore recommend that an integrated management plan be developed and implemented, including the appropriate use of biological control agents to reduce the negative impacts of the weed.     

Causalities of war: The connection between type VI secretion system and microbiota

Microbiota niches have space and/or nutrient restrictions, which has led to the coevolution of cooperation, specialisation, and competition within the population. Different animal and environmental niches contain defined resident microbiota that tend to be stable over time and offer protection against undesired intruders. Yet fluxes can occur, which alter the composition of a bacterial population. In humans, the microbiota are now considered a key contributor to maintenance of health and homeostasis, and its alteration leads to dysbiosis. The bacterial type VI secretion system (T6SS) transports proteins into the environment, directly into host cells or can function as an antibacterial weapon by killing surrounding competitors. Upon contact with neighbouring cells, the T6SS fires, delivering a payload of effector proteins. In the absence of an immunity protein, this results in growth inhibition or death of prey leading to a competitive advantage for the attacker. It is becoming apparent that the T6SS has a role in modulating and shaping the microbiota at multiple levels, which is the focus of this review. Discussed here is the T6SS, its role in competition, key examples of its effect upon the microbiota, and future avenues of research.     

Antimicrobial effect of different herbal plant extracts against different microbial population

This study evaluates the antimicrobial effects of ethanolic extract of five herbal plants; Guava (Psidium guajava), Sage (Salvia officinalis), Rhamnus (Ziziphusspina Christi), Mulberry (Morusalba L.), and Olive (Oleaeuropaea L) leaves against several microbial population representing Gram positive, Gram negative and Mollicutes; S. aureus, E. coli, Pasteurella multocida, B. cereus, Salmonella Enteritidis and M. gallisepticum using standard agar disc diffusion technique and minimal inhibitory concentration (MIC). Different extracts reveal variable results against the microorganism under study. All extracts have no antibacterial potency for Mycoplasma gallisepticum except Psidium guajava. The results of minimal inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) of the extracts against the six bacteria ranged from 625 to 5000 μg/ml. The used herbal extract could inhibit the selected microorganism under study with variable minimal inhibitory concentration (MIC) and minimum bactericidal concentration (MBC).     

Afforestation for climate change mitigation: Potentials,risks and trade‐offs

Afforestation is considered a cost‐effective and readily available climate change mitigation option. In recent studies afforestation is presented as a major solution to limit climate change. However, estimates of afforestation potential vary widely. Moreover, the risks in global mitigation policy and the negative trade‐offs with food security are often not considered. Here we present a new approach to assess the economic potential of afforestation with the IMAGE 3.0 integrated assessment model framework. In addition, we discuss the role of afforestation in mitigation pathways and the effects of afforestation on the food system under increasingly ambitious climate targets. We show that afforestation has a mitigation potential of 4.9 GtCO₂/year at 200 US$/tCO₂ in 2050 leading to large‐scale application in an SSP2 scenario aiming for 2°C (410 GtCO₂ cumulative up to 2100). Afforestation reduces the overall costs of mitigation policy. However, it may lead to lower mitigation ambition and lock‐in situations in other sectors. Moreover, it bears risks to implementation and permanence as the negative emissions are increasingly located in regions with high investment risks and weak governance, for example in Sub‐Saharan Africa. Afforestation also requires large amounts of land (up to 1,100 Mha) leading to large reductions in agricultural land. The increased competition for land could lead to higher food prices and an increased population at risk of hunger. Our results confirm that afforestation has substantial potential for mitigation. At the same time, we highlight that major risks and trade‐offs are involved. Pathways aiming to limit climate change to 2°C or even 1.5°C need to minimize these risks and trade‐offs in order to achieve mitigation sustainably.     

Morphological divergence in giant fossil dormice

Insular gigantism—evolutionary increases in body size from small-bodied mainland ancestors—is a conceptually significant, but poorly studied, evolutionary phenomenon. Gigantism is widespread on Mediterranean islands, particularly among fossil and extant dormice. These include an extant giant population of Eliomys quercinus on Formentera, the giant Balearic genus †Hypnomys and the exceptionally large †Leithia melitensis of Pleistocene Sicily. We quantified patterns of cranial and mandibular shape and their relationships to head size (allometry) among mainland and insular dormouse populations, asking to what extent the morphology of island giants is explained by allometry. We find that gigantism in dormice is not simply an extrapolation of the allometric trajectory of their mainland relatives. Instead, a large portion of their distinctive cranial and mandibular morphology resulted from the population- or species-specific evolutionary shape changes. Our findings suggest that body size increases in insular giant dormice were accompanied by the evolutionary divergence of feeding adaptations. This complements other evidence of ecological divergence in these taxa, which span predominantly faunivorous to herbivorous diets. Our findings suggest that insular gigantism involves context-dependent phenotypic modifications, underscoring the highly distinctive nature of island faunas.     

Energy–water and seasonal variations in climate underlie the spatial distribution patterns of gymnosperm species richness in China

Studying the pattern of species richness is crucial in understanding the diversity and distribution of organisms in the earth. Climate and human influences are the major driving factors that directly influence the large‐scale distributions of plant species, including gymnosperms. Understanding how gymnosperms respond to climate, topography, and human‐induced changes is useful in predicting the impacts of global change. Here, we attempt to evaluate how climatic and human‐induced processes could affect the spatial richness patterns of gymnosperms in China. Initially, we divided a map of the country into grid cells of 50 × 50 km² spatial resolution and plotted the geographical coordinate distribution occurrence of 236 native gymnosperm taxa. The gymnosperm taxa were separated into three response variables: (a) all species, (b) endemic species, and (c) nonendemic species, based on their distribution. The species richness patterns of these response variables to four predictor sets were also evaluated: (a) energy–water, (b) climatic seasonality, (c) habitat heterogeneity, and (d) human influences. We performed generalized linear models (GLMs) and variation partitioning analyses to determine the effect of predictors on spatial richness patterns. The results showed that the distribution pattern of species richness was highest in the southwestern mountainous area and Taiwan in China. We found a significant relationship between the predictor variable set and species richness pattern. Further, our findings provide evidence that climatic seasonality is the most important factor in explaining distinct fractions of variations in the species richness patterns of all studied response variables. Moreover, it was found that energy–water was the best predictor set to determine the richness pattern of all species and endemic species, while habitat heterogeneity has a better influence on nonendemic species. Therefore, we conclude that with the current climate fluctuations as a result of climate change and increasing human activities, gymnosperms might face a high risk of extinction.     

Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis

Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.