Targeting the dysregulated BRAF-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRAF and MEK, ...resistance develops often involving nongenomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in patients with triple-negative breast cancer (TNBC) induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTK) comparing tumor samples before and after one week of treatment. In preclinical models, MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation, and p300 that drives transcriptional adaptation. Inhibition of the P-TEFb-associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts, and syngeneic mouse TNBC models. Pharmacologic targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.
Widespread transcriptional adaptation to pharmacologic MEK inhibition was observed in TNBC patient tumors. In preclinical models, MEK inhibition induces dramatic genome-wide modulation of chromatin, in the form of
enhancer formation and enhancer remodeling. Pharmacologic targeting of P-TEFb complex members at enhancers is an effective strategy to durably inhibit such adaptation.
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•APSIM was evaluated using an Asian dataset covering 12 countries, numerous soils, crops, and practices.•Assessment was from both crop and soil simulation perspectives, including sequence ...effects.•The model performed well in simulating the diversity of cropping systems to which it was applied.•Input parameter estimation challenges, some indicating possible model deficiencies, were noted.•Desirable future APSIM improvements were identified.
Resource shortages, driven by climatic, institutional and social changes in many regions of Asia, combined with growing imperatives to increase food production whilst ensuring environmental sustainability, are driving research into modified agricultural practices. Well-tested cropping systems models that capture interactions between soil water and nutrient dynamics, crop growth, climate and farmer management can assist in the evaluation of such new agricultural practices. One such cropping systems model is the Agricultural Production Systems Simulator (APSIM). We evaluated APSIM’s ability to simulate the performance of cropping systems in Asia from several perspectives: crop phenology, production, water use, soil dynamics (water and organic carbon) and crop CO2 response, as well as its ability to simulate cropping sequences without reset of soil variables. The evaluation was conducted over a diverse range of environments (12 countries, numerous soils), crops and management practices throughout the region. APSIM’s performance was statistically assessed against assembled replicated experimental datasets. Once properly parameterised, the model performed well in simulating the diversity of cropping systems to which it was applied with RMSEs generally less than observed experimental standard deviations (indicating robust model performance), and with particular strength in simulation of multi-crop sequences. Input parameter estimation challenges were encountered, and although ‘work-arounds’ were developed and described, in some cases these actually represent model deficiencies which need to be addressed. Desirable future improvements have been identified to better position APSIM as a useful tool for Asian cropping systems research into the future. These include aspects related to harsh environments (high temperatures, diffuse light conditions, salinity, and submergence), conservation agriculture, greenhouse gas emissions, as well as aspects more specific to Southern Asia and low input systems (such as deficiencies in soil micro-nutrients).
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise ...tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical.
Abstract The study was aimed to assess impact of high fat diet (HFD) and synthetic human gut microbiota (GM) combined with HFD and chow diet (CD) in inducing type-2 diabetes (T2D) using mice model. ...To our knowledge, this is the first study using selected human GM transplantation via culture based method coupled dietary modulation in mice for in vivo establishment of inflammation leading to T2D and gut dysbiosis. Twenty bacteria (T2D1-T2D20) from stool samples of confirmed T2D subjects were found to be morphologically different and subjected to purification on different media both aerobically and anerobically, which revealed seven bacteria more common among 20 isolates on the basis of biochemical characterization. On the basis of 16S rRNA gene sequencing, these seven isolates were identified as Bacteroides stercoris (MT152636), Lactobacillus acidophilus (MT152637), Lactobacillus salivarius (MT152638), Ruminococcus bromii (MT152639), Klebsiella aerogenes (MT152640), Bacteroides fragilis (MT152909), Clostridium botulinum (MT152910). The seven isolates were subsequently used as synthetic gut microbiome (GM) for their role in inducing T2D in mice. Inbred strains of albino mice were divided into four groups and were fed with CD, HFD, GM+HFD and GM+CD. Mice receiving HFD and GM+modified diet (CD/HFD) showed highly significant (P<0.05) increase in weight and blood glucose concentration as well as elevated level of inflammatory cytokines (TNF-α, IL-6, and MCP-1) compared to mice receiving CD only. The 16S rRNA gene sequencing of 11 fecal bacteria obtained from three randomly selected animals from each group revealed gut dysbiosis in animals receiving GM. Bacterial strains including Bacteroides gallinarum (MT152630), Ruminococcus bromii (MT152631), Lactobacillus acidophilus (MT152632), Parabacteroides gordonii (MT152633), Prevotella copri (MT152634) and Lactobacillus gasseri (MT152635) were isolated from mice treated with GM+modified diet (HFD/CD) compared to strains Akkermansia muciniphila (MT152625), Bacteriodes sp. (MT152626), Bacteroides faecis (MT152627), Bacteroides vulgatus (MT152628), Lactobacillus plantarum (MT152629) which were isolated from mice receiving CD/HFD. In conclusion, these findings suggest that constitution of GM and diet plays significant role in inflammation leading to onset or/and possibly progression of T2D. .
Resumo O estudo teve como objetivo avaliar o impacto da dieta rica em gordura (HFD) e da microbiota intestinal humana sintética (GM) combinada com HFD e dieta alimentar (CD) na indução de diabetes tipo 2 (T2D) usando modelo de camundongos. Para nosso conhecimento, este é o primeiro estudo usando transplante de GM humano selecionado através do método baseado em cultura acoplada à modulação dietética em camundongos para o estabelecimento in vivo de inflamação que leva a T2D e disbiose intestinal. Vinte bactérias (T2D1-T2D20) de amostras de fezes de indivíduos T2D confirmados verificaram ser morfologicamente diferentes e foram submetidas à purificação em meios diferentes aerobicamente e anaerobicamente, o que revelou sete bactérias mais comuns entre 20 isolados com base na caracterização bioquímica. Com base no sequenciamento do gene 16S rRNA, esses sete isolados foram identificados como Bacteroides stercoris (MT152636), Lactobacillus acidophilus (MT152637), Lactobacillus salivarius (MT152638), Ruminococcus bromii (MT152639), Klebsiella aerogenides (MT152640), Bacteroides fragilis (MT152909), Clostridium botulinum (MT152910). Esses sete isolados foram, posteriormente, usados como microbioma intestinal sintético (GM) por seu papel na indução de T2D em camundongos. Linhagens consanguíneas de camundongos albinos foram divididas em quatro grupos e foram alimentadas com CD, HFD, GM + HFD e GM + CD. Camundongos que receberam a dieta modificada com HFD e GM + (CD / HFD) mostraram um aumento altamente significativo (P < 0,05) no peso e na concentração de glicose no sangue, bem como um nível elevado de citocinas inflamatórias (TNF-α, IL-6 e MCP-1) em comparação com os ratos que receberam apenas CD. O sequenciamento do gene 16S rRNA de 11 bactérias fecais obtidas de três animais selecionados aleatoriamente de cada grupo revelou disbiose intestinal em animais que receberam GM. Cepas bacterianas, incluindo Bacteroides gallinarum (MT152630), Ruminococcus bromii (MT152631), Lactobacillus acidophilus (MT152632), Parabacteroides gordonii (MT152633), Prevotella copri (MT152634) e Lactobacillus Gasseri (MT152635D), foram tratadas com dieta modificada / CD) em comparação com as linhagens Akkermansia muciniphila (MT152625), Bacteriodes sp. (MT152626), Bacteroides faecis (MT152627), Bacteroides vulgatus (MT152628), Lactobacillus plantarum (MT152629), que foram isoladas de camundongos recebendo CD / HFD. Em conclusão, esses resultados sugerem que a constituição de GM e dieta desempenham papel significativo na inflamação levando ao início ou/e possivelmente à progressão de T2D.
Modern forestry is gradually moving towards man-made forests on a large scale. Plantations with advanced forestry system have been introduced with the goal of sustainable forestry development and to ...enhance social, ecological, and economic benefits. Forest plantations with native and exotic species have been established in China and worldwide with shorter rotation cycles than natural forests. In this paper, we discuss the role and perspectives of plantation forests in the Chinese sustainable forest development, the evolution of various plantation programs, the ecological effects of plantations, and the measures to improve plantation forestry. The Chinese government has given substantial importance to nurturing plantation forest resources through various large scale afforestation programs. In 2019, the total area covered by plantations in China reached 79.54 million ha, with a stock volume of 3.39 billion m³ (59.30 m³ per ha); coniferous forests (26.11 million ha, 32.83%) and broad-leaved forests (26.45 million ha, 33.25%) are the dominant types. Plantations have been primarily distributed in the central and southern parts of the country. Plantations with fast-growing and high-yielding tree species facilitated Chinese afforestation activities and improved the administration of forest production, which effectively boosted the forest industry. Plantation forest resources offer many potential productive, economic, and social advantages, though they are also associated with a loss of biodiversity and climate change makes them likely susceptible to disease and insect attack. Appropriate forest management practices during planning, execution, and maintenance of plantations can contribute to the conservation, promotion, and restoration of biodiversity, with the final aim of attaining a balance between having forest plantations and natural forests.
Oncofetal antigens (OFAs) are conserved tumor-associated autoantigens or transplantation antigens present on the surface of all major classes of rodent and human tumors and on midgestational fetal ...cells but not on normal neonatal or adult human and rodent tissues. A syngeneically derived monoclonal antibody, MAb-115, recognizes murine OFAs of 44 and 200 kd in molecular mass.
Our goal was to clone and characterize the complementary DNAs (cDNAs) that encode these murine OFAs.
Rabbit antiserum raised against purified 44-kd OFA glycoprotein was used to screen a mouse embryo cDNA-lambda phage expression library. Recombinant phage clones positive for the expression of OFAs were detected by immunohistochemical staining, then isolated and plaque purified. The presence of an OFA-encoding sequence in the recombinant phage was confirmed by specific reaction of the expressed protein with MAb-115. Recombinant fusion protein was purified from the extracts of corresponding lysogens. Rabbit antiserum against purified recombinant fusion protein was raised, and the capacity of this antiserum to detect the expression of OFA on rodent tumor and fetal cells was determined by flow cytometry. In addition, immunoreactivity of tumor bearer and hyperimmune murine sera to bacterially expressed recombinant OFA protein was evaluated by enzyme-linked immunosorbent assay. The OFA-expressing insert DNA from plaque-purified lambda clones was subcloned into phagemid vectors for sequencing analysis.
Antiserum derived against the isolated recombinant mouse embryo polypeptide mimicked MAb-115 in its specific binding to all OFA-positive rodent tumor and fetal cell lines tested and likewise did not show reactivity to normal adult tissues. This antiserum specifically recognized the native 44- and 200-kd OFAs in extracts of murine lymphocytic lymphoma. Furthermore, sera of tumor-bearing mice or mice immunized with purified OFA or intact, irradiated OFA-positive lymphocytic lymphoma cells also reacted with the recombinant fusion protein. The characterization of the isolated clone included nucleotide sequence information followed by analysis of the deduced primary structure of the protein.
These data suggest that the isolated cDNA clones encode a distinct gene product which is widely expressed on the surface of tumor and fetal cells and represents the first characterized sequence of a true OFA.
The availability of this cDNA, encoding a protein expressed only on tumor and fetal cells, provides a direct means to assess biological characteristics of malignant tissue which can be assayed by biochemical, histochemical, and molecular methods.
Alzheimer’s disease is an incurable neurodegenerative disease primarily affecting the elderly population. Efficient automated techniques are needed for early diagnosis of Alzheimer’s. Many novel ...approaches are proposed by researchers for classification of Alzheimer’s disease. However, to develop more efficient learning techniques, better understanding of the work done on Alzheimer’s is needed. Here, we provide a review on 165 papers from 2005 to 2019, using various feature extraction and machine learning techniques. The machine learning techniques are surveyed under three main categories: support vector machine (SVM), artificial neural network (ANN), and deep learning (DL) and ensemble methods. We present a detailed review on these three approaches for Alzheimer’s with possible future directions.
Ongoing declines in the structure and function of the world’s coral reefs require novel approaches to sustain these ecosystems and the millions of people who depend on them3. A presently unexplored ...approach that draws on theory and practice in human health and rural development is to systematically identify and learn from the ‘outliers’—places where ecosystems are substantially better (‘bright spots’) or worse (‘dark spots’) than expected, given the environmental conditions and socioeconomic drivers they are exposed to. Here we compile data from more than 2,500 reefs worldwide and develop a Bayesian hierarchical model to generate expectations of how standing stocks of reef fish biomass are related to 18 socioeconomic drivers and environmental conditions. We identify 15 bright spots and 35 dark spots among our global survey of coral reefs, defined as sites that have biomass levels more than two standard deviations from expectations. Importantly, bright spots are not simply comprised of remote areas with low fishing pressure; they include localities where human populations and use of ecosystem resources is high, potentially providing insights into how communities have successfully confronted strong drivers of change. Conversely, dark spots are not necessarily the sites with the lowest absolute biomass and even include some remote, uninhabited locations often considered near pristine6. We surveyed local experts about social, institutional, and environmental conditions at these sites to reveal that bright spots are characterized by strong sociocultural institutions such as customary taboos and marine tenure, high levels of local engagement in management, high dependence on marine resources, and beneficial environmental conditions such as deep-water refuges. Alternatively, dark spots are characterized by intensive capture and storage technology and a recent history of environmental shocks. Our results suggest that investments in strengthening fisheries governance, particularly aspects such as participation and property rights, could facilitate innovative conservation actions that help communities defy expectations of global reef degradation.
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