Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes

Skeletal muscle insulin resistance (IR) is considered a critical component of type II diabetes, yet to date IR has evaded characterization at the global gene expression level in humans. MicroRNAs (miRNAs) are considered fine-scale rheostats of protein-coding gene product abundance. The relative importance and mode of action of miRNAs in human complex diseases remains to be fully elucidated. We produce a global map of coding and non-coding RNAs in human muscle IR with the aim of identifying novel disease biomarkers. We profiled >47,000 mRNA sequences and >500 human miRNAs using gene-chips and 118 subjects (n = 71 patients versus n = 47 controls). A tissue-specific gene-ranking system was developed to stratify thousands of miRNA target-genes, removing false positives, yielding a weighted inhibitor score, which integrated the net impact of both up- and down-regulated miRNAs. Both informatic and protein detection validation was used to verify the predictions of in vivo changes. The muscle mRNA transcriptome is invariant with respect to insulin or glucose homeostasis. In contrast, a third of miRNAs detected in muscle were altered in disease (n = 62), many changing prior to the onset of clinical diabetes. The novel ranking metric identified six canonical pathways with proven links to metabolic disease while the control data demonstrated no enrichment. The Benjamini-Hochberg adjusted Gene Ontology profile of the highest ranked targets was metabolic (P < 7.4 × 10-8), post-translational modification (P < 9.7 × 10-5) and developmental (P < 1.3 × 10-6) processes. Protein profiling of six development-related genes validated the predictions. Brain-derived neurotrophic factor protein was detectable only in muscle satellite cells and was increased in diabetes patients compared with controls, consistent with the observation that global miRNA changes were opposite from those found during myogenic differentiation. We provide evidence that IR in humans may be related to coordinated changes in multiple microRNAs, which act to target relevant signaling pathways. It would appear that miRNAs can produce marked changes in target protein abundance in vivo by working in a combinatorial manner. Thus, miRNA detection represents a new molecular biomarker strategy for insulin resistance, where micrograms of patient material is needed to monitor efficacy during drug or life-style interventions

First detection of NH3 (1,0 - 0,0) from a low mass cloud core: On the low ammonia abundance of the rho Oph A core

Odin has successfully observed the molecular core rho Oph A in the 572.5 GHz rotational ground state line of ammonia, NH3 (J,K = 1,0 - 0,0). The interpretation of this result makes use of complementary molecular line data obtained from the ground (C17O and CH3OH) as part of the Odin preparatory work. Comparison of these observations with theoretical model calculations of line excitation and transfer yields a quite ordinary abundance of methanol, X(CH3OH) = 3e-9. Unless NH3 is not entirely segregated from C17O and CH3OH, ammonia is found to be significantly underabundant with respect to typical dense core values, viz. X(NH3) = 8e-10.Comment: 4 pages, 2 figures, 2 tables, to appear in Astron. Astrophys. Letter

Cell-Free Synthesis of the Mitochondrial ADP/ATP Carrier Protein of Neurospora crassa

ADP/ATP carrier protein was synthesized in heterologous cell-free systems programmed with Neurospora poly(A)-containing RNA and homologous cell-free systems from Neurospora. The apparent molecular weight of the product obtained in vitro was the same as that of the authentic mitochondrial protein. The primary translation product obtained in reticulocyte lysates starts with formylmethionine when formylated initiator methionyl-tRNA (fMet-tRNAfMet) was present. The product synthesized in vitro was released from the ribosomes into the postribosomal supernatant. The evidence presented indicates that the ADP/ATP carrier is synthesized as a polypeptide with the same molecular weight as the mature monomeric protein and does not carry an additional sequence

Thermoelectric properties of lead chalcogenide core-shell nanostructures

We present the full thermoelectric characterization of nanostructured bulk PbTe and PbTe-PbSe samples fabricated from colloidal core-shell nanoparticles followed by spark plasma sintering. An unusually large thermopower is found in both materials, and the possibility of energy filtering as opposed to grain boundary scattering as an explanation is discussed. A decreased Debye temperature and an increased molar specific heat are in accordance with recent predictions for nanostructured materials. On the basis of these results we propose suitable core-shell material combinations for future thermoelectric materials of large electric conductivities in combination with an increased thermopower by energy filtering.Comment: 12 pages, 8 figure

Biosynthesis of Mitochondrial Porin and Insertion into the Outer Mitochondrial Membrane of Neuruspora crassa

Mitochondrial porin, the major protein of the outer mitochondrial membrane is synthesized by free cytoplasmic polysomes. The apparent molecular weight of the porin synthesized in homologous or heterologous cell-free systems is the same as that of the mature porin. Transfer in vitro of mitochondrial porin from the cytosolic fraction into the outer membrane of mitochondria could be demonstrated. Before membrane insertion, mitochondrial porin is highly sensitive to added proteinase; afterwards it is strongly protected. Binding of the precursor form to mitochondria occurs at 4°C and appears to precede insertion into the membrane. Unlike transfer of many precursor proteins into or across the inner mitochondrial membrane, assembly of the porin is not dependent on an electrical potential across the inner membrane

Submillimeter Emission from Water in the W3 Region

We have mapped the submillimeter emission from the 1(10)-1(01) transition of ortho-water in the W3 star-forming region. A 5'x5' map of the W3 IRS4 and W3 IRS5 region reveals strong water lines at half the positions in the map. The relative strength of the Odin lines compared to previous observations by SWAS suggests that we are seeing water emission from an extended region. Across much of the map the lines are double-peaked, with an absorption feature at -39 km/s; however, some positions in the map show a single strong line at -43 km/s. We interpret the double-peaked lines as arising from optically thick, self-absorbed water emission near the W3 IRS5, while the narrower blue-shifted lines originate in emission near W3 IRS4. In this model, the unusual appearance of the spectral lines across the map results from a coincidental agreement in velocity between the emission near W3 IRS4 and the blue peak of the more complex lines near W3 IRS5. The strength of the water lines near W3 IRS4 suggests we may be seeing water emission enhanced in a photon-dominated region.Comment: Accepted to A&A Letters as part of the special Odin issue; 4 page

Integrated multidimensional sustainability assessment of energy system transformation pathways

Sustainable development embraces a broad spectrum of social, economic and ecological aspects. Thus, a sustainable transformation process of energy systems is inevitably multidimensional and needs to go beyond climate impact and cost considerations. An approach for an integrated and interdisciplinary sustainability assessment of energy system transformation pathways is presented here. It first integrates energy system modeling with a multidimensional impact assessment that focuses on life cycle-based environmental and macroeconomic impacts. Then, stakeholders’ preferences with respect to defined sustainability indicators are inquired, which are finally integrated into a comparative scenario evaluation through a multi-criteria decision analysis (MCDA), all in one consistent assessment framework. As an illustrative example, this holistic approach is applied to the sustainability assessment of ten different transformation strategies for Germany. Applying multi-criteria decision analysis reveals that both ambitious (80%) and highly ambitious (95%) carbon reduction scenarios can achieve top sustainability ranks, depending on the underlying energy transformation pathways and respective scores in other sustainability dimensions. Furthermore, this research highlights an increasingly dominant contribution of energy systems’ upstream chains on total environmental impacts, reveals rather small differences in macroeconomic effects between different scenarios and identifies the transition among societal segments and climate impact minimization as the most important stakeholder preferences

Conservation decisions under pressure: lessons from an exercise in rapid response to wildlife disease

Novel outbreaks of emerging pathogens require rapid responses to enable successful mitigation. We simulated a 1‐day emergency meeting where experts were engaged to recommend mitigation strategies for a new outbreak of the amphibian fungal pathogen Batrachochytrium salamandrivorans. Despite the inevitable uncertainty, experts suggested and discussed several possible strategies. However, their recommendations were undermined by imperfect initial definitions of the objectives and scope of management. This problem is likely to arise in most real‐world emergency situations. The exercise thus highlighted the importance of clearly defining the context, objectives, and spatial–temporal scale of mitigation decisions. Managers are commonly under pressure to act immediately. However, an iterative process in which experts and managers cooperate to clarify objectives and uncertainties, while collecting more information and devising mitigation strategies, may be slightly more time consuming but ultimately lead to better outcomes

The Role and Limitations of 18-Fluoro-2-deoxy-d-glucose Positron Emission Tomography (FDG-PET) Scan and Computerized Tomography (CT) in Restaging Patients with Hepatic Colorectal Metastases Following Neoadjuvant Chemotherapy: Comparison with Operative and Pathological Findings

BACKGROUND: Recent data confirmed the importance of 18-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in the selection of patients with colorectal hepatic metastases for surgery. Neoadjuvant chemotherapy before hepatic resection in selected cases may improve outcome. The influence of chemotherapy on the sensitivity of FDG-PET and CT in detecting liver metastases is not known. METHODS: Patients were assigned to either neoadjuvant treatment or immediate hepatic resection according to resectability, risk of recurrence, extrahepatic disease, and patient preference. Two-thirds of them underwent FDG-PET/CT before chemotherapy; all underwent preoperative contrast-enhanced CT and FDG-PET/CT. Those without extensive extrahepatic disease underwent open exploration and resection of all the metastases according to original imaging findings. Operative and pathological findings were compared to imaging results. RESULTS: Twenty-seven patients (33 lesions) underwent immediate hepatic resection (group 1), and 48 patients (122 lesions) received preoperative neoadjuvant chemotherapy (group 2). Sensitivity of FDG-PET and CT in detecting colorectal (CR) metastases was significantly higher in group 1 than in group 2 (FDG-PET: 93.3 vs 49%, P < 0.0001; CT: 87.5 vs 65.3, P = 0.038). CT had a higher sensitivity than FDG-PET in detecting CR metastases following neoadjuvant therapy (65.3 vs 49%, P < 0.0001). Sensitivity of FDG-PET, but not of CT, was lower in group 2 patients whose chemotherapy included bevacizumab compared to patients who did not receive bevacizumab (39 vs 59%, P = 0.068). CONCLUSIONS: FDG-PET/CT sensitivity is lowered by neoadjuvant chemotherapy. CT is more sensitive than FDG-PET in detecting CR metastases following neoadjuvant therapy. Surgical decision-making requires information from multiple imaging modalities and pretreatment findings. Baseline FDG-PET and CT before neoadjuvant therapy are mandatory

Intensive follo w-up after liver resection for colorectal liver metastases: results of combined serial tumour marker estimations and computed tomography of the chest and abdomen – a prospective study

The aim of the study was to prospectively evaluate an intensive follow-up programme using serial tumour marker estimations and contrast-enhanced computed tomography (CT) of the chest and abdomen in patients undergoing potentially curative resection of colorectal liver metastases. Seventy-six consecutive patients having undergone potentially curative resections of colorectal liver metastases in a single unit were followed up with a protocol of 3 monthly carcinoembryonic antigen and carbohydrate antigen 19-9 estimations and contrast-enhanced spiral CT of the chest, abdomen and pelvis for the first 2 years following surgery and 6 monthly thereafter. The median period of follow-up was 24 months (range 18–60). Recurrent tumour was classed as early if within 6 months of liver resection. Thirty-seven of the 76 patients (49%) developed recurrence on follow-up. Nineteen recurrences were in the liver alone (51%), 16 liver and extrahepatic (43%) and two extrahepatic alone (6%). Of the 19 patients with isolated liver recurrence, eight developed within 6 months of liver resection none of which were resectable. Of the 11 recurrences after 6 months, five (45%) were resectable. Of the 37 recurrences, CT indicated recurrence despite normal tumour markers in 19 patients. Tumour markers suggested recurrence before imaging in 12 and concurrently with imaging in 6. In the 12 patients who presented with elevated tumour markers before imaging, there was a median lag period of 3 months (range 1–21) in recurrence being detected on further serial imaging. Seventeen patients who developed recurrence had normal tumour markers before initial resection of their liver metastases. Of these 17, 10 (58%) had an elevation of tumour markers associated with recurrence. Over a median follow-up of 2 years following liver resection, the use of CT or tumour markers alone would have failed to demonstrate early recurrence in 12 and 18 patients respectively. A combination of tumour markers and CT detected significantly more (P<0.05) recurrence than either modality alone. Tumour markers and CT should be used in combination in the follow-up of patients with resected colorectal liver metatases, including patients whose markers are normal at the time of initial liver resection