Sequencing identifies a distinct signature of circulating microRNAs in early radiographic knee osteoarthritis

OBJECTIVE: MicroRNAs act locally and systemically to impact osteoarthritis (OA) pathophysiology, but comprehensive profiling of the circulating miRNome in early vs late stages of OA has yet to be conducted. Sequencing has emerged as the preferred method for microRNA profiling since it offers high sensitivity and specificity. Our objective is to sequence the miRNome in plasma from 91 patients with early [Kellgren-Lawrence (KL) grade 0 or 1 (n = 41)] or late [KL grade 3 or 4 (n = 50)] symptomatic radiographic knee OA to identify unique microRNA signatures in each disease state. DESIGN: MicroRNA libraries were prepared using the QIAseq miRNA Library Kit and sequenced on the Illumina NextSeq 550.Counts were produced for microRNAs captured in miRBase and for novel microRNAs. Statistical, bioinformatics, and computational biology approaches were used to refine and interpret the final list of microRNAs. RESULTS: From 215 differentially expressed microRNAs (FDR \u3c 0.01), 97 microRNAs showed an increase or decrease in expression in ≥85% of samples in the early OA group as compared to the median expression in the late OA group. Increasing this threshold to ≥95%, seven microRNAs were identified: hsa-miR-335-3p, hsa-miR-199a-5p, hsa-miR-671-3p, hsa-miR-1260b, hsa-miR-191-3p, hsa-miR-335-5p, and hsa-miR-543. Four novel microRNAs were present in ≥50% of early OA samples and had 27 predicted gene targets in common with the prioritized set of predicted gene targets from the 97 microRNAs, suggesting common underlying mechanisms. CONCLUSION: Applying sequencing to well-characterized patient cohorts produced unbiased profiling of the circulating miRNome and identified a unique panel of 11 microRNAs in early radiographic knee OA

Local Difference Measures between Complex Networks for Dynamical System Model Evaluation

Acknowledgments We thank Reik V. Donner for inspiring suggestions that initialized the work presented herein. Jan H. Feldhoff is credited for providing us with the STARS simulation data and for his contributions to fruitful discussions. Comments by the anonymous reviewers are gratefully acknowledged as they led to substantial improvements of the manuscript.Peer reviewedPublisher PD

Effects of external nutrient sources and extreme weather events on the nutrient budget of a Southern European coastal lagoon

The seasonal and annual nitrogen (N), phosphorus (P), and carbon (C) budgets of the mesotidal Ria Formosa lagoon, southern Portugal, were estimated to reveal the main inputs and outputs, the seasonal patterns, and how they may influence the ecological functioning of the system. The effects of extreme weather events such as long-lasting strong winds causing upwelling and strong rainfall were assessed. External nutrient inputs were quantified; ocean exchange was assessed in 24-h sampling campaigns, and final calculations were made using a hydrodynamic model of the lagoon. Rain and stream inputs were the main freshwater sources to the lagoon. However, wastewater treatment plant and groundwater discharges dominated nutrient input, together accounting for 98, 96, and 88 % of total C, N, and P input, respectively. Organic matter and nutrients were continuously exported to the ocean. This pattern was reversed following extreme events, such as strong winds in early summer that caused upwelling and after a period of heavy rainfall in late autumn. A principal component analysis (PCA) revealed that ammonium and organic N and C exchange were positively associated with temperature as opposed to pH and nitrate. These variables reflected mostly the benthic lagoon metabolism, whereas particulate P exchange was correlated to Chl a, indicating that this was more related to phytoplankton dynamics. The increase of stochastic events, as expected in climate change scenarios, may have strong effects on the ecological functioning of coastal lagoons, altering the C and nutrient budgets.Portuguese Science and Technology Foundation (FCT) [POCI/MAR/58427/2004, PPCDT/MAR/58427/2004]; Portuguese Science and Technology Foundation (FCT

NtGNL1 Plays an Essential Role in Pollen Tube Tip Growth and Orientation Likely via Regulation of Post-Golgi Trafficking

Background: Tobacco GNOM LIKE 1 (NtGNL1), a new member of the Big/GBF family, is characterized by a sec 7 domain. Thus, we proposed that NtGNL1 may function in regulating pollen tube growth for vesicle trafficking. Methodology/Principal Findings: To test this hypothesis, we used an RNAi technique to down-regulate NtGNL1 expression and found that pollen tube growth and orientation were clearly inhibited. Cytological observations revealed that both timing and behavior of endocytosis was disrupted, and endosome trafficking to prevacuolar compartments (PVC) or multivesicular bodies (MVB) was altered in pollen tube tips. Moreover, NtGNL1 seemed to partially overlap with Golgi bodies, but clearly colocalized with putative late endosome compartments. We also observed that in such pollen tubes, the Golgi apparatus disassembled and fused with the endoplasmic reticulum, indicating abnormal post-Golgi trafficking. During this process, actin organization was also remodeled. Conclusions/Significance: Thus, we revealed that NtGNL1 is essential for pollen tube growth and orientation and it likel

A Genome Wide Association Scan of Bovine Tuberculosis Susceptibility in Holstein-Friesian Dairy Cattle

peer-reviewedBackground: Bovine tuberculosis is a significant veterinary and financial problem in many parts of the world. Although many factors influence infection and progression of the disease, there is a host genetic component and dissection of this may enlighten on the wider biology of host response to tuberculosis. However, a binary phenotype of presence/absence of infection presents a noisy signal for genomewide association study. Methodology/Principal Findings: We calculated a composite phenotype of genetic merit for TB susceptibility based on disease incidence in daughters of elite sires used for artificial insemination in the Irish dairy herd. This robust measure was compared with 44,426 SNP genotypes in the most informative 307 subjects in a genome wide association analysis. Three SNPs in a 65 kb genomic region on BTA 22 were associated (i.e. p,1025, peaking at position 59588069, p = 4.0261026) with tuberculosis susceptibility. Conclusions/Significance: A genomic region on BTA 22 was suggestively associated with tuberculosis susceptibility; it contains the taurine transporter gene SLC6A6, or TauT, which is known to function in the immune system but has not previously been investigated for its role in tuberculosis infection

Profiling Insulin Like Factor 3 (INSL3) Signaling in Human Osteoblasts

Abstract BACKGROUND: Young men with mutations in the gene for the INSL3 receptor (Relaxin family peptide 2, RXFP2) are at risk of reduced bone mass and osteoporosis. Consistent with the human phenotype, bone analyses of Rxfp2(-/-) mice showed decreased bone volume, alterations of the trabecular bone, reduced mineralizing surface, bone formation, and osteoclast surface. The aim of this study was to elucidate the INSL3/RXFP2 signaling pathways and targets in human osteoblasts. METHODOLOGY/PRINCIPAL FINDINGS: Alkaline phosphatase (ALP) production, protein phosphorylation, intracellular calcium, gene expression, and mineralization studies have been performed. INSL3 induced a significant increase in ALP production, and Western blot and ELISA analyses of multiple intracellular signaling pathway molecules and their phosphorylation status revealed that the MAPK was the major pathway influenced by INSL3, whereas it does not modify intracellular calcium concentration. Quantitative Real Time PCR and Western blotting showed that INSL3 regulates the expression of different osteoblast markers. Alizarin red-S staining confirmed that INSL3-stimulated osteoblasts are fully differentiated and able to mineralize the extracellular matrix. CONCLUSIONS/SIGNIFICANCE: Together with previous findings, this study demonstrates that the INSL3/RXFP2 system is involved in bone metabolism by acting on the MAPK cascade and stimulating transcription of important genes of osteoblast maturation/differentiation and osteoclastogenesis

Physical and chemical impacts of a major storm on a temperate lake: a taste of things to come?

Extreme weather can have a substantial influence on lakes and is expected to become more frequent with climate change. We explored the influence of one particular extreme event, Storm Ophelia, on the physical and chemical environment of England's largest lake, Windermere. We found that the substantial influence of Ophelia on meteorological conditions at Windermere, in particular wind speed, resulted in a 25-fold increase (relative to the study-period average) in the wind energy flux at the lake-air interface. Following Ophelia, there was a short-lived mixing event in which the Schmidt stability decreased by over 100 Jm-2 and the thermocline deepened by over 10 m during a 12-hour period. As a result of changes to the strength of stratification, Ophelia also changed the internal seiche regime of Windermere with the dominant seiche period increasing from ~17 h pre-storm to ~21 h post-storm. Following Ophelia, there was an upwelling of cold and low-oxygenated waters at the southern-end of the lake. This had a substantial influence on the main outflow of Windermere, the River Leven, where dissolved oxygen concentrations decreased by ~48 %, from 9.3 mg L-1 to 4.8 mg L-1, while at the mid-lake monitoring station in Windermere, it decreased by only ~3%. This study illustrates that the response of a lake to extreme weather can cause important effects downstream, the influence of which may not be evident at the lake surface. To understand the impact of future extreme events fully, the whole lake and downstream-river system need to be studied together

Climate change and the emergence of vector-borne diseases in Europe: Case study of dengue fever

Background: Dengue fever is the most prevalent mosquito-borne viral disease worldwide. Dengue transmission is critically dependent on climatic factors and there is much concern as to whether climate change would spread the disease to areas currently unaffected. The occurrence of autochthonous infections in Croatia and France in 2010 has raised concerns about a potential re-emergence of dengue in Europe. The objective of this study is to estimate dengue risk in Europe under climate change scenarios. Methods. We used a Generalized Additive Model (GAM) to estimate dengue fever risk as a function of climatic variables (maximum temperature, minimum temperature, precipitation, humidity) and socioeconomic factors (population density, urbanisation, GDP per capita and population size), under contemporary conditions (1985-2007) in Mexico. We then used our model estimates to project dengue incidence under baseline conditions (1961-1990) and three climate change scenarios: short-term 2011-2040, medium-term 2041-2070 and long-term 2071-2100 across Europe. The model was used to calculate average number of yearly dengue cases at a spatial resolution of 10 × 10 km grid covering all land surface of the currently 27 EU member states. To our knowledge, this is the first attempt to model dengue fever risk in Europe in terms of disease occurrence rather than mosquito presence. Results: The results were presented using Geographical Information System (GIS) and allowed identification of areas at high risk. Dengue fever hot spots were clustered around the coastal areas of the Mediterranean and Adriatic seas and the Po Valley in northern Italy. Conclusions: This risk assessment study is likely to be a valuable tool assisting effective and targeted adaptation responses to reduce the likely increased burden of dengue fever in a warmer world

The life of the cortical column: opening the domain of functional architecture of the cortex

The concept of the cortical column refers to vertical cell bands with similar response properties, which were initially observed by Vernon Mountcastle’s mapping of single cell recordings in the cat somatic cortex. It has subsequently guided over 50 years of neuroscientific research, in which fundamental questions about the modularity of the cortex and basic principles of sensory information processing were empirically investigated. Nevertheless, the status of the column remains controversial today, as skeptical commentators proclaim that the vertical cell bands are a functionally insignificant by-product of ontogenetic development. This paper inquires how the column came to be viewed as an elementary unit of the cortex from Mountcastle’s discovery in 1955 until David Hubel and Torsten Wiesel’s reception of the Nobel Prize in 1981. I first argue that Mountcastle’s vertical electrode recordings served as criteria for applying the column concept to electrophysiological data. In contrast to previous authors, I claim that this move from electrophysiological data to the phenomenon of columnar responses was concept-laden, but not theory-laden. In the second part of the paper, I argue that Mountcastle’s criteria provided Hubel Wiesel with a conceptual outlook, i.e. it allowed them to anticipate columnar patterns in the cat and macaque visual cortex. I argue that in the late 1970s, this outlook only briefly took a form that one could call a ‘theory’ of the cerebral cortex, before new experimental techniques started to diversify column research. I end by showing how this account of early column research fits into a larger project that follows the conceptual development of the column into the present