Widespread mRNA decay, an unappreciated feature of apoptosis, enhances cell death and depends on mitochondrial outer membrane permeabilization (MOMP), TUTases, and DIS3L2. Which RNAs are decayed and ...the decay-initiating event are unknown. Here, we show extensive decay of mRNAs and poly(A) noncoding (nc)RNAs at the 3′ end, triggered by the mitochondrial intermembrane space 3′-to-5′ exoribonuclease PNPT1, released during MOMP. PNPT1 knockdown inhibits apoptotic RNA decay and reduces apoptosis, while ectopic expression of PNPT1, but not an RNase-deficient mutant, increases RNA decay and cell death. The 3′ end of PNPT1 substrates thread through a narrow channel. Many non-poly(A) ncRNAs contain 3′-secondary structures or bind proteins that may block PNPT1 activity. Indeed, mutations that disrupt the 3′-stem-loop of a decay-resistant ncRNA render the transcript susceptible, while adding a 3′-stem-loop to an mRNA prevents its decay. Thus, PNPT1 release from mitochondria during MOMP initiates apoptotic decay of RNAs lacking 3′-structures.
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•Global decay of polyadenylated RNAs depends on MOMP and begins at the 3′ end•3′ to 5′ exoribonuclease PNPT1 is released from mitochondria during MOMP•PNPT1 initiates apoptotic RNA decay and promotes apoptosis•3′ structures or protein binding of noncoding RNAs prevent their degradation by PNPT1
Widespread RNA decay during apoptosis is initiated by the mitochondrial exoribonuclease PNPT1.
Rising demand for food, fiber, and biofuels drives expanding irrigation withdrawals from surface water and groundwater. Irrigation efficiency and water savings have become watchwords in response to ...climate-induced hydrological variability, increasing freshwater demand for other uses including ecosystem water needs, and low economic productivity of irrigation compared to most other uses. We identify three classes of unintended consequences, presented here as paradoxes. Ever-tighter cycling of water has been shown to increase resource use, an example of the efficiency paradox. In the absence of effective policy to constrain irrigated-area expansion using "saved water", efficiency can aggravate scarcity, deteriorate resource quality, and impair river basin resilience through loss of flexibility and redundancy. Water scarcity and salinity effects in the lower reaches of basins (symptomatic of the scale paradox) may partly be offset over the short-term through groundwater pumping or increasing surface water storage capacity. However, declining ecological flows and increasing salinity have important implications for riparian and estuarine ecosystems and for non-irrigation human uses of water including urban supply and energy generation, examples of the sectoral paradox. This paper briefly considers three regional contexts with broadly similar climatic and water-resource conditions - central Chile, southwestern US, and south-central Spain - where irrigation efficiency directly influences basin resilience. The comparison leads to more generic insights on water policy in relation to irrigation efficiency and emerging or overdue needs for environmental protection.
MicroRNAs (miRNAs) are endogenous small non-coding RNAs that have a pivotal role in the post-transcriptional regulation of gene expression and their misregulation is common in different types of ...cancer. Although it has been shown that miR-7 plays an oncogenic role in different cellular contexts, the molecular mechanisms by which miR-7 promotes cell transformation are not well understood. Here we show that the transcription factor KLF4 is a direct target of miR-7 and present experimental evidence indicating that the regulation of KLF4 by miR-7 has functional implications in epithelial cell transformation. Stable overexpression of miR-7 into lung and skin epithelial cells enhanced cell proliferation, cell migration and tumor formation. Alteration of these cellular functions by miR-7 resulted from misregulation of KLF4 target genes involved in cell cycle control. miR-7-induced tumors showed decreased p21 and increased Cyclin D levels. Taken together, these findings indicate that miR-7 acts as an oncomiR in epithelial cells in part by directly regulating KLF4 expression. Thus, we conclude that miR-7 acts as an oncomiR in the epithelial cellular context, where through the negative regulation of KLF4-dependent signaling pathways, miR-7 promotes cellular transformation and tumor growth.
Despite significant reductions in malaria transmission across Africa since 2000, progress is stalling. This has been attributed to the development of insecticide resistance and behavioural ...adaptations in malaria vectors. Whilst insecticide resistance has been widely investigated, there is poorer understanding of the emergence, dynamics and impact of mosquito behavioural adaptations. We conducted a longitudinal investigation of malaria vector host choice over 3 years and resting behaviour over 4 years following a mass long-lasting insecticidal nets (LLINs) distribution in Tanzania. By pairing observations of mosquito ecology with environmental monitoring, we quantified longitudinal shifts in host-choice and resting behaviour that are consistent with adaptation to evade LLINs. The density of An. funestus s.l., declined significantly through time. In tandem, An. arabiensis and An. funestus s.l. exhibited an increased rate of outdoor relative to indoor resting; with An. arabiensis reducing the proportion of blood meals taken from humans in favour of cattle. By accounting for environmental variation, this study detected clear evidence of intra-specific shifts in mosquito behaviour that could be obscured in shorter-term or temporally-coarse surveys. This highlights the importance of mosquito behavioural adaptations to vector control, and the value of longer-term behavioural studies.
Droughts can have serious negative impacts on the water quality needed for irrigated agriculture. The Metropolitan region of Chile is a relevant producer of high-value crops and is prone to droughts. ...Standardized Drought Indices were used to characterize meteorological and hydrological droughts for the period from 1985 to 2015. To understand the relationship between droughts and water quality, we evaluated the correlations between daily discharge and surface water quality observations. The threshold level method was used to compare physicochemical parameters during hydrological drought periods with the Chilean water quality thresholds for agricultural uses. A significant (p < 0.05) negative relationship between discharge and electrical conductivity and major ions was found in most of the basin. Hydrological stations located in irrigation districts exceeded the official thresholds for these parameters during hydrological drought periods seriously threatening irrigated agriculture of the region.
Summary
In addition to its roles in controlling infection and tissue repair, inflammation plays a critical role in diverse and distinct chronic diseases, such as cancer, metabolic syndrome, and ...neurodegenerative disorders, underscoring the harmful effect of an uncontrolled inflammatory response. Regardless of the nature of the stimulus, initiation of the inflammatory response is mediated by assembly of a multimolecular protein complex called the inflammasome, which is responsible for the production of inflammatory cytokines, such as interleukin‐1β (IL‐1β) and IL‐18. The different stimuli and mechanisms that control inflammasome activation are fairly well understood, but the mechanisms underlying the control of undesired inflammasome activation and its inactivation remain largely unknown. Here, we review recent advances in our understanding of the molecular mechanisms that negatively regulate inflammasome activation to prevent unwanted activation in the resting state, as well as those involved in terminating the inflammatory response after a specific insult to maintain homeostasis.
Glioblastoma (GB) is the most aggressive and common type of cancer within the central nervous system (CNS). Despite the vast knowledge of its physiopathology and histology, its etiology at the ...molecular level has not been completely understood. Thus, attaining a cure has not been possible yet and it remains one of the deadliest types of cancer. Usually, GB is diagnosed when some symptoms have already been presented by the patient. This diagnosis is commonly based on a physical exam and imaging studies, such as computed tomography (CT) and magnetic resonance imaging (MRI), together with or followed by a surgical biopsy. As these diagnostic procedures are very invasive and often result only in the confirmation of GB presence, it is necessary to develop less invasive diagnostic and prognostic tools that lead to earlier treatment to increase GB patients' quality of life. Therefore, blood-based biomarkers (BBBs) represent excellent candidates in this context. microRNAs (miRNAs) are small, non-coding RNAs that have been demonstrated to be very stable in almost all body fluids, including saliva, serum, plasma, urine, cerebrospinal fluid (CFS), semen, and breast milk. In addition, serum-circulating and exosome-contained miRNAs have been successfully used to better classify subtypes of cancer at the molecular level and make better choices regarding the best treatment for specific cases. Moreover, as miRNAs regulate multiple target genes and can also act as tumor suppressors and oncogenes, they are involved in the appearance, progression, and even chemoresistance of most tumors. Thus, in this review, we discuss how dysregulated miRNAs in GB can be used as early diagnosis and prognosis biomarkers as well as molecular markers to subclassify GB cases and provide more personalized treatments, which may have a better response against GB. In addition, we discuss the therapeutic potential of miRNAs, the current challenges to their clinical application, and future directions in the field.
Background
Inflammation in adipose tissue, resulting from imbalanced caloric intake and energy expenditure, contributes to the metabolic dysregulation observed in obesity. The production of ...inflammatory cytokines, such as IL‐1β and IL‐18, plays a key role in this process. While IL‐1β promotes insulin resistance and diabetes, IL‐18 regulates energy expenditure and food intake. Previous studies have suggested that caspase‐1, activated by the Nlrp3 inflammasome in response to lipid excess, mediates IL‐1β production, whereas activated by the Nlrp1b inflammasome in response to energy excess, mediates IL‐18 production. However, this has not been formally tested.
Methods
Wild‐type and caspase‐1‐deficient Balb/c mice, carrying the Nlrp1b1 allele, were fed with regular chow or a high‐fat diet for twelve weeks. Food intake and mass gain were recorded weekly. At the end of the twelve weeks, glucose tolerance and insulin resistance were evaluated. Mature IL‐18 protein levels and the inflammatory process in the adipose tissue were determined. Fasting lipid and cytokine levels were quantified in the sera of the different experimental groups.
Results
We found that IL‐18 production in adipose tissue is independent of caspase‐1 activity, regardless of the metabolic state, while Nlrp3‐mediated IL‐1β production remains caspase‐1 dependent. Additionally, caspase‐1 null Balb/c mice did not develop metabolic abnormalities in response to energy excess from the high‐fat diet.
Conclusion
Our findings suggest that IL‐18 production in the adipose tissue is independent of Nlrp3 inflammasome and caspase‐1 activation, regardless of caloric food intake. In contrast, Nlrp3‐mediated IL‐1β production is caspase‐1 dependent. These results provide new insights into the mechanisms underlying cytokine production in the adipose tissue during both homeostatic conditions and metabolic stress, highlighting the distinct roles of caspase‐1 and the Nlrp inflammasomes in regulating inflammatory responses.
Our findings challenge previous notions about cytokine production in the adipose tissue, revealing independent pathways for IL‐1β and IL‐18. Nlrp1b inflammasome mediates caspase‐1‐independent IL‐18 production, while IL‐1β maturation by the Nlrp3 inflammasome remains caspase‐1 dependent.
microRNAs: key triggers of neuronal cell fate Meza-Sosa, Karla F; Pedraza-Alva, Gustavo; Pérez-Martínez, Leonor
Frontiers in cellular neuroscience,
06/2014, Letnik:
8
Journal Article
Recenzirano
Odprti dostop
Development of the central nervous system (CNS) requires a precisely coordinated series of events. During embryonic development, different intra- and extracellular signals stimulate neural stem cells ...to become neural progenitors, which eventually irreversibly exit from the cell cycle to begin the first stage of neurogenesis. However, before this event occurs, the self-renewal and proliferative capacities of neural stem cells and neural progenitors must be tightly regulated. Accordingly, the participation of various evolutionary conserved microRNAs is key in distinct central nervous system (CNS) developmental processes of many organisms including human, mouse, chicken, frog, and zebrafish. microRNAs specifically recognize and regulate the expression of target mRNAs by sequence complementarity within the mRNAs 3' untranslated region and importantly, a single microRNA can have several target mRNAs to regulate a process; likewise, a unique mRNA can be targeted by more than one microRNA. Thus, by regulating different target genes, microRNAs let-7, microRNA-124, and microRNA-9 have been shown to promote the differentiation of neural stem cells and neural progenitors into specific neural cell types while microRNA-134, microRNA-25 and microRNA-137 have been characterized as microRNAs that induce the proliferation of neural stem cells and neural progenitors. Here we review the mechanisms of action of these two sets of microRNAs and their functional implications during the transition from neural stem cells and neural progenitors to fully differentiated neurons. The genetic and epigenetic mechanisms that regulate the expression of these microRNAs as well as the role of the recently described natural RNA circles which act as natural microRNA sponges regulating post-transcriptional microRNA expression and function during the early stages of neurogenesis is also discussed.
•We evaluate differences in CMIP3 and CMIP5 climate projections.•We evaluate climate-attributed changes in the Mataquito river basin Chile, South America.•The location of snow line will shift to ...higher elevations.•Reduction in the number of days with precipitation falling as snow.•Extreme precipitation and streamflow events expected to become more frequent in 21st century.
Due to global warming the climate of central Chile is expected to experience dramatic changes in the 21st century including declining precipitation, earlier streamflow peaks, and a greater proportion of precipitation falling as rain. We used 12-member ensembles of General Circulation Models (GCMs) from the Coupled Model Intercomparison Project Phase 3 (CMIP3) and Phase 5 (CMIP5) to evaluate climate-attributed changes in the hydrology of the Mataquito river basin in central Chile, South America. Simulations using the Variable Infiltration Capacity (VIC) hydrology model indicate that a drier and warmer future will shift the location of snow line to higher elevations and reduce the number of days with precipitation falling as snow. Extreme precipitation and streamflow events are expected to become more frequent. Conversely, low flow conditions will intensify during the warm months. The changes in the mean of hydrologic states and fluxes by the end of the 21st century are statistically robust, whereas changes in the variance are not found to be statistically significant. Results of the ensembles for CMIP3 and CMIP5 are generally indistinguishable regarding projected impacts on hydrology.
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