Role of YAP/TAZ in cell plasticity

The employment of somatic stem cells (SCs) as therapeutic elements is an important goal in the field of regenerative medicine. However, this is hampered by the fact that tissue stem cells are rare, difficult to purify and maintain in culture. Direct conversion of terminally differentiated cells back into their corresponding stem cells could provide a great effort in this sense. Here we show that ectopic YAP/TAZ expression in primary luminal differentiated cells of the mammary gland epithelium stably converts them into cells that display molecular and functional traits of mammary gland stem cells such as self-renewal, self-organization into structure that resemble the mammary gland in vitro and mammary gland reconstitution ability

SUSTAINABLE CROP MANAGEMENT MODEL IN SYRIAN STRATEGIC CROPS THE EXPERIENCE OF THE COOPERATION PROJECT RATIONALIZATION OF RAS EL AIN IRRIGATION SYSTEMS

N° ISBN - 978-2-7380-1284-5International audienceThis paper reports the main results of an integrated initiative of international technical cooperation in agriculture financed by the Italian Ministry of Foreign Affairs and jointly implemented by the CIHEAM MAI Bari and the Syrian Ministries of Irrigation and of Agriculture and Agrarian Reform. The project entitled: “Rationalization of Ras El Ain Irrigation Systems” started in January 2005 and ended in March 2008. The project was aimed at addressing the problem of water resources scarcity in the project area of Ras El Ain, around the springs of Al Khabour, located in the Hassakeh province (North Mesopotamia) of the Syrian Arab Republic. During the project implementation, a real field experience was carried out involving national and international researchers, local officers and technicians, and local farmers as direct beneficiaries. An appropriate sustainable model concerning the crop management practice was elaborated to save both water resources and production inputs for cotton and wheat. In this paper the main results of this innovative cooperation approach in a multiethnic context are presented

mapping the suitability for ice core drilling of glaciers in the european alps and the asian high mountains

ABSTRACTIce cores from mid-latitude mountain glaciers provide detailed information on past climate conditions and regional environmental changes, which is essential for placing current climate change into a longer term perspective. In this context, it is important to define guidelines and create dedicated maps to identify suitable areas for future ice-core drillings. In this study, the suitability for ice-core drilling (SICD) of a mountain glacier is defined as the possibility of extracting an ice core with preserved stratigraphy suitable for reconstructing past climate. Morphometric and climatic variables related to SICD are selected through literature review and characterization of previously drilled sites. A quantitative Weight of Evidence method is proposed to combine selected variables (i.e. slope, local relief, temperature and direct solar radiation) to map the potential drilling sites in mid-latitude mountain glaciers. The method was first developed in the European Alps and then applied to the Asian High Mountains. Model performances and limitations are discussed and first indications of new potential drilling sites in the Asian High Mountains are provided. Results presented here can facilitate the selection of future drilling sites especially on unexplored Asian mountain glaciers towards the understanding of climate and environmental changes

Effects of Ultramicronized Palmitoylethanolamide (um-PEA) in COVID-19 Early Stages: A Case-Control Study

Ultramicronized palmitoylethanolamide (um-PEA), a compound with antioxidant, anti-inflammatory and neuroprotective properties, appears to be a potential adjuvant treatment for early stages of Coronavirus disease 2019 (COVID-19). In our study, we enrolled 90 patients with confirmed diagnosis of COVID-19 that were randomized into two groups, homogeneous for age, gender and BMI. The first group received oral supplementation based on um-PEA at a dose of 1800 mg/day for a total of 28 days; the second group was the control group (R.S. 73.20). At baseline (T0) and after 28 days of um-PEA treatment (T1), we monitored: routine laboratory parameters, inflammatory and oxidative stress (OS) biomarkers, lymphocytes subpopulation and COVID-19 serological response. At T1, the um-PEA-treated group presented a significant reduction in inflammation compared to the control group (CRP p = 0.007; IL-6 p = 0.0001; neutrophils to lymphocytes ratio p = 0.044). At T1, the controls showed a significant increase in OS compared to the treated group (FORT p = 0.05). At T1, the um-PEA group exhibited a significant decrease in D-dimer levels (p = 0.0001) and higher levels of IgG against SARS-CoV-2 (p = 0.0001) compared to the controls. Our data demonstrated, in a randomized clinical trial, the beneficial effects of um-PEA in both asymptomatic and mild-symptomatic patients related to reductions in inflammatory state, OS and coagulative cascade alterations

Early immune modulation by single-agent trastuzumab as a marker of trastuzumab benefit

BACKGROUND: Optimising the selection of HER2-targeted regimens by identifying subsets of HER2-positive breast cancer (BC) patients who need more or less therapy remains challenging. We analysed BC samples before and after treatment with 1 cycle of trastuzumab according to the response to trastuzumab. METHODS: Gene expression profiles of pre- and post-treatment tumour samples from 17 HER2-positive BC patients were analysed on the Illumina platform. Tumour-associated immune pathways and blood counts were analysed with regard to the response to trastuzumab. HER2-positive murine models with differential responses to trastuzumab were used to reproduce and better characterise these data. RESULTS: Patients who responded to single-agent trastuzumab had basal tumour biopsies that were enriched in immune pathways, particularly the MHC-II metagene. One cycle of trastuzumab modulated the expression levels of MHC-II genes, which increased in patients who had a complete response on treatment with trastuzumab and chemotherapy. Trastuzumab increased the MHC-II-positive cell population, primarily macrophages, only in the tumour microenvironment of responsive mice. In patients who benefited from complete trastuzumab therapy and in mice that harboured responsive tumours circulating neutrophil levels declined, but this cell subset rose in nonresponsive tumours. CONCLUSIONS: Short treatment with trastuzumab induces local and systemic immunomodulation that is associated with clinical outcomes

Induction of Expandable Tissue-Specific Stem/Progenitor Cells through Transient Expression of YAP/TAZ

The ability to induce autologous tissue-specific stem cells in culture could have a variety of applications in regenerative medicine and disease modeling. Here we show that transient expression of exogenous YAP or its closely related paralogue TAZ in primary differentiated mouse cells can induce conversion to a tissue-specific stem/progenitor cell state. Differentiated mammary gland, neuronal, and pancreatic exocrine cells, identified using a combination of cell sorting and lineage tracing approaches, efficiently convert to proliferating cells with properties of stem/progenitor cells of their respective tissues after YAP induction. YAP-induced mammary stem/progenitor cells show molecular and functional properties similar to endogenous MaSCs, including organoid formation and mammary gland reconstitution after transplantation. Because YAP/TAZ function is also important for self-renewal of endogenous stem cells in culture, our findings have implications for understanding the molecular determinants of the somatic stem cell state

GSK3 Inhibits Macropinocytosis and Lysosomal Activity through the Wnt Destruction Complex Machinery

Summary: Canonical Wnt signaling is emerging as a major regulator of endocytosis. Here, we report that Wnt-induced macropinocytosis is regulated through glycogen synthase kinase 3 (GSK3) and the β-catenin destruction complex. We find that mutation of Axin1, a tumor suppressor and component of the destruction complex, results in the activation of macropinocytosis. Surprisingly, inhibition of GSK3 by lithium chloride (LiCl), CHIR99021, or dominant-negative GSK3 triggers macropinocytosis. GSK3 inhibition causes a rapid increase in acidic endolysosomes that is independent of new protein synthesis. GSK3 inhibition or Axin1 mutation increases lysosomal activity, which can be followed with tracers of active cathepsin D, β-glucosidase, and ovalbumin degradation. Microinjection of LiCl into the blastula cavity of Xenopus embryos causes a striking increase in dextran macropinocytosis. The effects of GSK3 inhibition on protein degradation in endolysosomes are blocked by the macropinocytosis inhibitors EIPA or IPA-3, suggesting that increases in membrane trafficking drive lysosomal activity

Case report: bullous pemphigoid development underlies dystrophic epidermolysis bullosa disease worsening

Autoimmune response to cutaneous basement membrane components superimposed on a genetic skin fragility disease, hereditary epidermolysis bullosa (EB), has been described, but its effects on disease course remain unclear. We report a 69-year-old individual with congenital skin fragility and acral trauma-induced blistering that had suddenly worsened with the onset of severe itch and diffuse spontaneous inflammatory blisters. Next-generation sequencing identified compound heterozygous null and missense COL7A1 mutations, allowing the diagnosis of recessive dystrophic EB. However, the patient’s clinical history prompted us to investigate whether he might have developed a pathological autoimmune response against basement membrane components. Tissue-bound and circulating IgG antibodies to the major bullous pemphigoid (BP) antigen, BP180, were detected in the patient’s skin and serum, respectively, consistent with a diagnosis of BP. Corticosteroid therapy was initiated resulting in remission of BP manifestations. EB patients presenting rapid disease worsening should be investigated for the development of a concomitant autoimmune blistering disease