HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N6-methyladenosine.

Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N6-methyladenosine (m6A). Furthermore, exposure to ganetespib leads to elevated modification levels at m6A motif sites in the 5'-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5'-UTR promotes the translation of the reporter gene mRNA. This m6A-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism

Exploring the impacts of water resources on economic development in Beijing-Tianjin-Hebei Region

Beijing-Tianjin-Hebei region is one of the most developed areas in China with a most rapid rate of economic growth. It is also a well-known region suffering great water scarcity. The water resources per capita is 118.60m³, 99.46 m³, 240.57 m³ respectively in Beijing, Tianjin and Hebei in 2013, all below 500 m³ that is defined as absolute scarcity by the United Nations. Water resources scarcity restricts the economic growth of the region at large and may account to the economic gaps between the three cities/ provinces. Economic growth in return aggravates its water shortage. The coordinated development of Beijing-Tianjin-Hebei region has been emphasized in recent years by the central government and means of solving regional problems and promoting its coordinated development need to be put forward. This study investigates the impacts of water resources factors on the regional economic growth to explore the direct influential factors of water resources, using panel data collected from 2004 to 2013. The main results show that: (1) the share of water for agricultural use and annual domestic water use per capita are statistically significant to the regional GDP per capita, with coefficients of 0.86 and 0.32 and (2) thus the impact of water resources on regional economic development is attributable to regional water use structure and domestic water use efficiency. Integrated regional governance of water resources, especially regional policies towards efficient water use and enhanced economic structure optimizing would be effective options for governments to propel the sustainable development of the region

LncRNA TUG1 facilitates the development of endometrial cancer via interaction with FXR1

Purpose: To investigate the potential influence of long non-coding RNA (lncRNA) TUG1 on the development of endometrial cancer (EC).Methods: A total of 24 paired EC species and paracancerous species were collected, and the differential expressions of TUG1 in them were determined. The regulatory effects of TUG1 on proliferative and migratory potential in Ishikawa and HEC-1A cells were assessed using cell counting kit-8 (CCK-8) and Transwell assay, respectively. Potential protein binding TUG1 was predicted by bioinformatics analysis and subsequently verified using RIP (RNA-Binding Protein Immunoprecipitation) assay. Rescue experiments were conducted to uncover the mechanism of TUG1 in regulating the development of EC.Results: TUG1 was highly expressed in EC species and cell lines. Higher levels of TUG1 was observed in EC patients with metastases than those without metastatic cancer (p < 0.05). Overexpression of TUG1 markedly facilitated proliferative and migratory potential in EC cells. Taurine-upregulated gene 1 (TUG1) directly bound Fragile X-related protein 1 (FXR1) and positively regulated its level (p < 0.05). Through interaction with FXR1, TUG1 stimulated the malignant development of EC.Conclusion: LncRNA TUG1 is upregulated in EC species, which facilitates proliferative and migratory potentials in EC cells by interacting with FXR1

Integrated Regulatory and Metabolic Networks of the Marine Diatom Phaeodactylum tricornutum Predict the Response to Rising CO2 Levels.

Diatoms are eukaryotic microalgae that are responsible for up to 40% of the ocean's primary productivity. How diatoms respond to environmental perturbations such as elevated carbon concentrations in the atmosphere is currently poorly understood. We developed a transcriptional regulatory network based on various transcriptome sequencing expression libraries for different environmental responses to gain insight into the marine diatom's metabolic and regulatory interactions and provide a comprehensive framework of responses to increasing atmospheric carbon levels. This transcriptional regulatory network was integrated with a recently published genome-scale metabolic model of Phaeodactylum tricornutum to explore the connectivity of the regulatory network and shared metabolites. The integrated regulatory and metabolic model revealed highly connected modules within carbon and nitrogen metabolism. P. tricornutum's response to rising carbon levels was analyzed by using the recent genome-scale metabolic model with cross comparison to experimental manipulations of carbon dioxide. IMPORTANCE Using a systems biology approach, we studied the response of the marine diatom Phaeodactylum tricornutum to changing atmospheric carbon concentrations on an ocean-wide scale. By integrating an available genome-scale metabolic model and a newly developed transcriptional regulatory network inferred from transcriptome sequencing expression data, we demonstrate that carbon metabolism and nitrogen metabolism are strongly connected and the genes involved are coregulated in this model diatom. These tight regulatory constraints could play a major role during the adaptation of P. tricornutum to increasing carbon levels. The transcriptional regulatory network developed can be further used to study the effects of different environmental perturbations on P. tricornutum's metabolism

Aldehyde‐forming fatty acyl‐ C o A reductase from cyanobacteria: expression, purification and characterization of the recombinant enzyme

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101857/1/febs12443.pd

Decision-making after continuous wins or losses in a randomized guessing task: implications for how the prior selection results affect subsequent decision-making

BACKGROUND: Human decision-making is often affected by prior selections and their outcomes, even in situations where decisions are independent and outcomes are unpredictable. METHODS: In this study, we created a task that simulated real-life non-strategic gambling to examine the effect of prior outcomes on subsequent decisions in a group of male college students. RESULTS: Behavioral performance showed that participants needed more time to react after continuous losses (LOSS) than continuous wins (WIN) and discontinuous outcomes (CONTROL). In addition, participants were more likely to repeat their selections in both WIN and LOSS conditions. Functional MRI data revealed that decisions in WINs were associated with increased activation in the mesolimbic pathway, but decreased activation in the inferior frontal gyrus relative to LOSS. Increased prefrontal cortical activation was observed during LOSS relative to WIN and CONTROL conditions. CONCLUSION: Taken together, the behavioral and neuroimaging findings suggest that participants tended to repeat previous selections during LOSS trials, a pattern resembling the gambler’s fallacy. However, during WIN trials, participants tended to follow their previous lucky decisions, like the ‘hot hand’ fallacy

A Programmable Escherichia coli Consortium via Tunable Symbiosis

Synthetic microbial consortia that can mimic natural systems have the potential to become a powerful biotechnology for various applications. One highly desirable feature of these consortia is that they can be precisely regulated. In this work we designed a programmable, symbiotic circuit that enables continuous tuning of the growth rate and composition of a synthetic consortium. We implemented our general design through the cross-feeding of tryptophan and tyrosine by two E. coli auxotrophs. By regulating the expression of genes related to the export or production of these amino acids, we were able to tune the metabolite exchanges and achieve a wide range of growth rates and strain ratios. In addition, by inverting the relationship of growth/ratio vs. inducer concentrations, we were able to “program” the co-culture for pre-specified attributes with the proper addition of inducing chemicals. This programmable proof-of-concept circuit or its variants can be applied to more complex systems where precise tuning of the consortium would facilitate the optimization of specific objectives, such as increasing the overall efficiency of microbial production of biofuels or pharmaceuticals

Temperature regulation as a tool for enabling and programming synthetic microbial communities

As target applications grow more elaborate, researchers are developing new approaches to program increasingly complex functionality into synthetic biology platforms. One emerging approach is engineering cooperative, multi-species synthetic microbial communities, which offer significant potential advantages compared to single species systems for numerous applications such as biosynthesis of target compounds through complex pathways enabled by division of labor. However, population dynamics, inter-species interactions, and differing ecological niches of resident microorganisms also introduce complexities that must be addressed to achieve effective and robust synthetic microbial communities. One fundamental challenge is regulation of community composition. At the most basic level, maintaining coexistence of resident community members is required to enable the desired community level functionality. Additionally, community composition often needs to be tuned to optimize overall functionality. For example, when a complex pathway is divided into multiple components hosted by different community members, fluxes through different enzymatic reactions can be coordinated through modulation of each sub-population size to maximize overall efficiency. This type of microbial community manipulation has not been fully utilized in synthetic biology applications, likely due in part to limited available tools. Here we develop temperature regulation as a general tool to enable coexistence and control community composition in synthetic microbial communities. We demonstrate that rationally selected constant temperature regimes can be used to enable coexistence of species from distinct thermal niches. Furthermore, cycling temperature regimes can be used to regulate relative species abundance in microbial communities. We employ mathematical modeling to design cycling temperature regimes for desired community compositions and related features. As microbial communities are increasingly used in a variety of applications, we envision that tools for modulating community composition will continue to expand and we see temperature regulation as a powerful new approach in this area

Arsenite binds to the RING finger domains of RNF20-RNF40 histone E3 ubiquitin ligase and inhibits DNA double-strand break repair.

Arsenic is a widespread environmental contaminant. However, the exact molecular mechanisms underlying the carcinogenic effects of arsenic remain incompletely understood. Core histones can be ubiquitinated by RING finger E3 ubiquitin ligases, among which the RNF20-RNF40 heterodimer catalyzes the ubiquitination of histone H2B at lysine 120. This ubiquitination event is important for the formation of open and biochemically accessible chromatin fiber that is conducive for DNA repair. Herein, we found that arsenite could bind directly to the RING finger domains of RNF20 and RNF40 in vitro and in cells, and treatment with arsenite resulted in substantially impaired H2B ubiquitination in multiple cell lines. Exposure to arsenite also diminished the recruitment of BRCA1 and RAD51 to laser-induced DNA double-strand break (DSB) sites, compromised DNA DSB repair in human cells, and rendered cells sensitive toward a radiomimetic agent, neocarzinostatin. Together, the results from the present study revealed, for the first time, that arsenite may exert its carcinogenic effect by targeting cysteine residues in the RING finger domains of histone E3 ubiquitin ligase, thereby altering histone epigenetic mark and compromising DNA DSB repair. Our results also suggest arsenite as a general inhibitor for RING finger E3 ubiquitin ligases