Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence

Metformin, an oral hypoglycemic agent, has been used for decades to treat type 2 diabetes mellitus. Recent studies indicate that mice treated with metformin live longer and have fewer manifestations of age-related chronic disease. However, the molecular mechanisms underlying this phenotype are unknown. Here, we show that metformin treatment increases the levels of the microRNA-processing protein DICER1 in mice and in humans with diabetes mellitus. Our results indicate that metformin upregulates DICER1 through a post-transcriptional mechanism involving the RNA-binding protein AUF1. Treatment with metformin altered the subcellular localization of AUF1, disrupting its interaction with DICER1 mRNA and rendering DICER1 mRNA stable, allowing DICER1 to accumulate. Consistent with the role of DICER1 in the biogenesis of microRNAs, we found differential patterns of microRNA expression in mice treated with metformin or caloric restriction, two proven life-extending interventions. Interestingly, several microRNAs previously associated with senescence and aging, including miR-20a, miR-34a, miR-130a, miR-106b, miR-125, and let-7c, were found elevated. In agreement with these findings, treatment with metformin decreased cellular senescence in several senescence models in a DICER1- dependent manner. Metformin lowered p16 and p21 protein levels and the abundance of inflammatory cytokines and oncogenes that are hallmarks of the senescence-associated secretory phenotype (SASP). These data lead us to hypothesize that changes in DICER1 levels may be important for organismal aging and to propose that interventions that upregulate DICER1 expression (e.g., metformin) may offer new pharmacotherapeutic approaches for age-related disease

Response of radial growth to warming and CO2 enrichment in southern Northeast China: a case of Pinus tabulaeformis

The southern part of northeast China has experienced a marked warming and drying climate. We provide dendrochronological evidence for atmospheric CO2 fertilization and the impacts of warming on Chinese pine (Pinus tabulaeformis) growth. The results of this study show that increased temperature has a negative effect on pine growth during a major part of the growing season and a weakly positive effects on growth during the remaining portion of the year. The monthly temperatures explain ca. 20 % of the total variance in the annual radial growth of Chinese pine from 1901 to 2009. An increase of approximately 3–5 °C is the maximum that Chinese pine can tolerate in this region with an annual rainfall of 500–700 mm. Our results suggest a that there is a proportional response to warming only up to a maximum of 1 °C warming, and indicate the complexities of succession in forest ecosystems in terms of adaptation and evolution in local pine populations under a rapid warming condition. In addition, increasing atmospheric CO2 concentrations have a positive effect on tree growth. This effect can be detected with conventional dendrochronological methods

Extension of summer (June–August) temperature records for northern Inner Mongolia (1715–2008), China using tree rings

This paper presents a spatially and temporally improved reconstruction of mean summer (June–August) temperature derived from tree-ring width data of Dahurian larch (Larix gmelinii Rupr.) from the northern Great Xing'an Mountains, Northeast China. Three new chronologies were added to the original 2011 reconstruction, and the reconstruction extended back to AD 1715. The reconstruction was generated using a simple linear regression method, verified by independent meteorological data, and accounts for 47.0% of the actual temperature variance during the common period (1957–2008). The reconstruction captures decadal and century-scale regional temperature variability, such as cold decades (1940s, 1930s, 1790s, 1950s and 1850s), warm decades (2000s, 1870s, 1750s, 1980s and 1840s), a cold half-century (ca. 1750–1799), and a warm half-century (ca. 1900–1949). It also reveals slightly higher frequency of cold years (20.4%) than warm years (18.0%), and a recent warming trend. Compared to the original 2011 reconstruction, this reconstruction has lower inter-annual temperature variability, high explained variance and high representativeness of regional climate. The reconstruction also correlates with the East Asian Monsoon and the Pacific Ocean signals, and indicates the feasibility of using tree rings from high latitude Northeast China to reconstruct summer temperature in permafrost forest environments

MMPs/TIMPs imbalances in the peripheral blood and cerebrospinal fluid are associated with the pathogenesis of HIV-1-associated neurocognitive disorders: A pilot study

HIV-1-associated neurocognitive disorders (HAND) continue to be a major concern in the infected population, despite the widespread use of combined antiretroviral therapy (cART). Growing evidence suggests that an imbalance between matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs) contributes to the pathogenesis of HAND. In our present study, we examined protein levels and enzymatic activities of MMPs and TIMPs in both plasma and cerebrospinal fluid (CSF) samples from HIV-1 patients with or without HAND and HIV-1-negative controls. Imbalances between MMPs and TIMPs with distinct patterns were revealed in both the peripheral blood and CSF of HIV-1 patients, especially those with HAND. In the peripheral blood, the protein levels of MMP-2, MMP-9, TIMP-1, TIMP-2, and the enzymatic activities of MMP-2 and MMP-9 were increased in HIV-1 patients with or without HAND when compared with HIV-1-negative controls. The enzymatic activity of MMP-2, but not MMP-9, was further increased in plasma samples of HAND patients than that of HIV-1 patients without HAND. Notably, the ratio of MMP-2/TIMP-2 in plasma was significantly increased in HAND patients, not in patients without HAND. In the CSF, MMP-2 activity was increased, but the ratio of MMP-2/TIMP-2 was not altered. De novo induction and activation of MMP-9 in the CSF of HAND patients was particularly prominent. The imbalances between MMPs and TIMPs in the blood and CSF were related to the altered profiles of inflammatory cytokines/chemokines and monocyte activation in these individuals. In addition, plasma from HIV-1 patients directly induced integrity disruption of an in vitro blood-brain barrier (BBB) model, leading to increased BBB permeability and robust transmigration of monocytes/macrophages. These results indicate that imbalances between MMPs and TIMPs are involved in BBB disruption and are implicated in the pathogenesis of neurological disorders such as HAND in HIV-1 patients

INTEGRATE: Gene fusion discovery using whole genome and transcriptome data

While next-generation sequencing (NGS) has become the primary technology for discovering gene fusions, we are still faced with the challenge of ensuring that causative mutations are not missed while minimizing false positives. Currently, there are many computational tools that predict structural variations (SV) and gene fusions using whole genome (WGS) and transcriptome sequencing (RNA-seq) data separately. However, as both WGS and RNA-seq have their limitations when used independently, we hypothesize that the orthogonal validation from integrating both data could generate a sensitive and specific approach for detecting high-confidence gene fusion predictions. Fortunately, decreasing NGS costs have resulted in a growing quantity of patients with both data available. Therefore, we developed a gene fusion discovery tool, INTEGRATE, that leverages both RNA-seq and WGS data to reconstruct gene fusion junctions and genomic breakpoints by split-read mapping. To evaluate INTEGRATE, we compared it with eight additional gene fusion discovery tools using the well-characterized breast cell line HCC1395 and peripheral blood lymphocytes derived from the same patient (HCC1395BL). The predictions subsequently underwent a targeted validation leading to the discovery of 131 novel fusions in addition to the seven previously reported fusions. Overall, INTEGRATE only missed six out of the 138 validated fusions and had the highest accuracy of the nine tools evaluated. Additionally, we applied INTEGRATE to 62 breast cancer patients from The Cancer Genome Atlas (TCGA) and found multiple recurrent gene fusions including a subset involving estrogen receptor. Taken together, INTEGRATE is a highly sensitive and accurate tool that is freely available for academic use

Widespread recent ecosystem state shifts in high-latitude peatlands of northeastern Canada and implications for carbon sequestration

Northern peatlands are a major component of the global carbon (C) cycle. Widespread climate-driven ecohydrological changes in these ecosystems can have major consequences on their C sequestration function. Here, we synthesize plant macrofossil data from 33 surficial peat cores from different ecoclimatic regions, with high-resolution chronologies. The main objectives were to document recent ecosystem state shifts and explore their impact on C sequestration in high-latitude undisturbed peatlands of northeastern Canada. Our synthesis shows widespread recent ecosystem shifts in peatlands, such as transitions from oligotrophic fens to bogs and Sphagnum expansion, coinciding with climate warming which has also influenced C accumulation during the last similar to 100 years. The rapid shifts towards drier bog communities and an expansion of Sphagnum sect. Acutifolia after 1980 CE were most pronounced in the northern subarctic sites and are concurrent with summer warming in northeastern Canada. These results provide further evidence of a northward migration of Sphagnum-dominated peatlands in North America in response to climate change. The results also highlight differences in the timing of ecosystem shifts among peatlands and regions, reflecting internal peatland dynamics and varying responses of vegetation communities. Our study suggests that the recent rapid climate-driven shifts from oligotrophic fen to drier bog communities have promoted plant productivity and thus peat C accumulation. We highlight the importance of considering recent ecohydrological trajectories when modelling the potential contribution of peatlands to climate change. Our study suggests that, contrary to expectations, peat C sequestration could be promoted in high-latitude non-permafrost peatlands where wet sedge fens may transition to drier Sphagnum bog communities due to warmer and longer growing seasons.Peer reviewe

Sensory processing deficits and related cortical pathological changes in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily affecting cognitive functions. However, sensory deficits in AD start to draw attention due to their high prevalence and early onsets which suggest that they could potentially serve as diagnostic biomarkers and even contribute to the disease progression. This literature review examines the sensory deficits and cortical pathological changes observed in visual, auditory, olfactory, and somatosensory systems in AD patients, as well as in various AD animal models. Sensory deficits may emerge at the early stages of AD, or even precede the cognitive decline, which is accompanied by cortical pathological changes including amyloid-beta deposition, tauopathy, gliosis, and alterations in neuronal excitability, synaptic inputs, and functional plasticity. Notably, these changes are more pronounced in sensory association areas and superficial cortical layers, which may explain the relative preservation of basic sensory functions but early display of deficits of higher sensory functions. We propose that sensory impairment and the progression of AD may establish a cyclical relationship that mutually perpetuates each condition. This review highlights the significance of sensory deficits with or without cortical pathological changes in AD and emphasizes the need for further research to develop reliable early detection and intervention through sensory systems

Tree-ring based precipitation variability since AD 1828 in northwestern Liaoning, China

A 183-year record of total precipitation from September to current July was reconstructed using tree rings from Chinese pine (Pinus tabulaeformis) to explore regional moisture variations in northwestern Liaoning province. The reconstruction accounts for 35.4% of the total variance of the instrumental precipitation from 1957 to 2010. The reconstruction shows eleven persistent dry periods (e.g. 1856–1866, 1886–1891, 1898–1905), and eleven persistent wet periods (e.g. 1835–1855, 1867–1878, 1892–1897). Spectral analysis of the reconstruction shows several significant spectral peaks in the ca. 2–4-year periodicity band, suggesting inter-annual variability of El Niño-Southern Oscillation (ENSO). The precipitation reconstruction shows correlations related to the East Asian Monsoon and possible teleconnection of regional moisture variations to Pacific Ocean signals, such as El Niño and La Niña

Triazole Inhibitors of Cryptosporidium parvum Inosine 5?-Monophosphate Dehydrogenase

Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. This protozoan parasite cannot salvage guanine or guanosine and therefore relies on inosine 5?-monophosphate dehydrogenase (IMPDH) for biosynthesis of guanine nucleotides and hence for survival. Because C. parvum IMPDH is highly divergent from the host counterpart, selective inhibitors could potentially be used to treat cryptosporidiosis with minimal effects on its mammalian host. A series of 1,2,3-triazole containing ether CpIMPDH inhibitors are described. A structure?activity relationship study revealed that a small alkyl group on the ?-position of the ether was required, with the (R)-enantiomer significantly more active than the (S)-enantiomer. Electron-withdrawing groups in the 3- and/or 4-positions of the pendent phenyl ring were best, and conversion of the quinoline containing inhibitors to quinoline-N-oxides retained inhibitory activity both in the presence and absence of bovine serum albumin. The 1,2,3-triazole CpIMPDH inhibitors provide new tools for elucidating the role of IMPDH in C. parvum and may serve as potential therapeutics for treating cryptosporidiosis