Fission yeast 26S proteasome mutants are multi-drug resistant due to stabilization of the pap1 transcription factor

Here we report the result of a genetic screen for mutants resistant to the microtubule poison methyl benzimidazol-2-yl carbamate (MBC) that were also temperature sensitive for growth. In total the isolated mutants were distributed in ten complementation groups. Cloning experiments revealed that most of the mutants were in essential genes encoding various 26S proteasome subunits. We found that the proteasome mutants are multi-drug resistant due to stabilization of the stress-activated transcription factor Pap1. We show that the ubiquitylation and ultimately the degradation of Pap1 depend on the Rhp6/Ubc2 E2 ubiquitin conjugating enzyme and the Ubr1 E3 ubiquitin-protein ligase. Accordingly, mutants lacking Rhp6 or Ubr1 display drug-resistant phenotypes

From START to FINISH : the influence of osmotic stress on the cell cycle

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Building Partnerships to Address Social and Technological Challenges to Enhance Farm Profitability and Improve Water Quality Through Better Grassland Management

With 2.1 million acres of pastureland and 1.25 million acres of hay land in Virginia, the rural Virginia landscape is predominately grassland. These lands form the base of the $3.96 billion-dollar livestock and dairy industry in Virginia. Managing these livestock in a profitable manner for farmers and beneficial to the environment is important. A cultural tradition with roots in colonial times has been to run animals in large fields year-round throughout Virginia. Livestock often graze from spring until fall (about 220 days), and farmers feed hay the remainder of the year. Spikes in the cost of fuel, fertilizer, and equipment are making traditional grazing/haying systems less profitable. The Virginia Cooperative Extension Farm Enterprise budgets show that that the cost of hay accounts for over 50$75 per cow by extending their grazing season. The same phenomenon applies to other types of grazing livestock. If ten percent of the livestock producers in the state adopted better grazing management to extend their grazing season by 60 days, profitability is expected for Virginia grazing livestock producers by over $5 million per year. Practices such as rotational grazing and stream exclusion are directly tied to National and State goals to improve water quality in the Chesapeake Bay. Virginia’s Phase III WIP (Chesapeake Bay Watershed Improvement Plan) seeks the exclusion of livestock from all perennial streams and achieving good rotational grazing practices on 347,000 acres of pasture. A number of agencies and private sector groups have been providing cost share and technical guidance to incentivize livestock stream exclusion and the installation of pasture management infrastructure. Installation is only part of the challenge. Farmers also need to be taught how to how to manage the system in a profitable manner and have been slow to adopt good pasture management practices. Preliminary data show that 87% of Virginia’s cow-calf producers manage their grasslands using traditional methods. Only six percent have extended their grazing season beyond 265 days

Translating global recommendations on HIV and infant feeding to the local context: the development of culturally sensitive counselling tools in the Kilimanjaro Region, Tanzania

BACKGROUND: This paper describes the process used to develop an integrated set of culturally sensitive, evidence-based counselling tools (job aids) by using qualitative participatory research. The aim of the intervention was to contribute to improving infant feeding counselling services for HIV positive women in the Kilimanjaro Region of Tanzania. METHODS: Formative research using a combination of qualitative methods preceded the development of the intervention and mapped existing practices, perceptions and attitudes towards HIV and infant feeding (HIV/IF) among mothers, counsellors and community members. Intervention Mapping (IM) protocol guided the development of the overall intervention strategy. Theories of behaviour change, a review of the international HIV/IF guidelines and formative research findings contributed to the definition of performance and learning objectives. Key communication messages and colourful graphic illustrations related to infant feeding in the context of HIV were then developed and/or adapted from existing generic materials. Draft materials were field tested with intended audiences and subjected to stakeholder technical review. RESULTS: An integrated set of infant feeding counselling tools, referred to as 'job aids', was developed and included brochures on feeding methods that were found to be socially and culturally acceptable, a Question and Answer Guide for counsellors, a counselling card on the risk of transmission of HIV, and an infant feeding toolbox for demonstration. Each brochure describes the steps to ensure safer infant feeding using simple language and images based on local ideas and resources. The brochures are meant to serve as both a reference material during infant feeding counselling in the ongoing prevention of mother to child transmission (pMTCT) of HIV programme and as take home material for the mother. CONCLUSION: The study underscores the importance of formative research and a systematic theory based approach to developing an intervention aimed at improving counselling and changing customary feeding practices. The identification of perceived barriers and facilitators for change contributed to developing the key counselling messages and graphics, reflecting the socio-economic reality, cultural beliefs and norms of mothers and their significant others

The prognostic significance of Cdc6 and Cdt1 in breast cancer

DNA replication is a critical step in cell proliferation. Overexpression of MCM2-7 genes correlated with poor prognosis in breast cancer patients. However, the roles of Cdc6 and Cdt1, which work with MCMs to regulate DNA replication, in breast cancers are largely unknown. In the present study, we have shown that the expression levels of Cdc6 and Cdt1 were both significantly correlated with an increasing number of MCM2-7 genes overexpression. Both Cdc6 and Cdt1, when expressed in a high level, alone or in combination, were significantly associated with poorer survival in the breast cancer patient cohort (n = 1441). In line with this finding, the expression of Cdc6 and Cdt1 was upregulated in breast cancer cells compared to normal breast epithelial cells. Expression of Cdc6 and Cdt1 was significantly higher in ER negative breast cancer, and was suppressed when ER signalling was inhibited either by tamoxifen in vitro or letrozole in human subjects. Importantly, breast cancer patients who responded to letrozole expressed significantly lower Cdc6 than those patients who did not respond. Our results suggest that Cdc6 is a potential prognostic marker and therapeutic target in breast cancer patients

Estimating species relative abundances from museum records

Funding: C.F., U.B. and D.J.R. acknowledge COST Action ‘European Soil-Biology Data Warehouse for Soil Protection’ (EUdaphobase), CA18237, supported by COST (European Cooperation in Science and Technology). AEM thanks the Leverhulme Trust (RPG-2019-401). D.B.B. was supported by an NSF Postdoc Research Fellowship in Biology (NSF 000733206), S.M.R. was supported by an NSERC Discovery Grant Author Contributions, A.V.S. was supported by NSF 1755336, C.S.M was supported by NSF 1398620 and N.J.G was supported by NSF 2019470.1. Dated, geo-referenced museum specimens are a rich data source for reconstructing species' distribution and abundance patterns. However, museum records are potentially biased towards over-representation of rare species, and it is unclear whether museum records can be used to estimate relative abundance in the field. 2. We assembled 17 coupled field and museum datasets to quantitatively compare relative abundance estimates with the Dirichlet distribution. Collectively, these datasets comprise 73,039 museum records and 1,405,316 field observations of 2,240 species. 3. Although museum records of rare species overestimated relative abundance by 1-fold to over 100-fold (median study = 9.0), the relative abundance of species estimated from museum occurrence records was strongly correlated with relative abundance estimated from standardized field surveys (r2 range of 0.10-0.91, median study = 0.43). 4. These analyses provide a justification for estimating species relative abundance with carefully curated museum occurrence records, which may allow for the detection of temporal or spatial shifts in the rank ordering of common and rare species.Publisher PDFPeer reviewe

A Cyclin-Dependent Kinase that Promotes Cytokinesis through Modulating Phosphorylation of the Carboxy Terminal Domain of the RNA Pol II Rpb1p Sub-Unit

In Schizosaccharomyces pombe, the nuclear-localized kinase, Lsk1p, promotes cytokinesis by positively regulating the Septation Initiation Network (SIN). Although a member of the cyclin-dependent kinase (CDK) family, neither a cyclin partner nor a physiological target has been identified. In this report we identify a cyclin, Lsc1p, that physically interacts and co-localizes with Lsk1p. Furthermore, lsk1Δ, lsc1Δ, as well as kinase-dead lsk1-K306R mutants, display highly similar cytokinesis defects. Lsk1p is related to CDKs that phosphorylate the carboxy-terminal domain (CTD) of the largest sub-unit of RNA polymerase II (Rpb1p). Interestingly, we find that Lsk1p and Lsc1p are required for phosphorylation of Ser-2 residues found in the heptad repeats of the CTD. To determine if Rpb1p could be a physiological target, we replaced the native rpb1 gene with a synthetic gene encoding a Rpb1p protein in which Ser-2 was substituted with the non-phosphorylatable amino-acid alanine in all heptads. Cells carrying this allele were similar to lsk1Δ mutants: They were viable, displayed genetic interactions with the SIN, and were unable to complete cytokinesis upon perturbation of the cell division machinery. We conclude that Ser-2 phosphorylation of the CTD heptads plays a novel physiological role in the regulation of cytokinesis