Weighted gene co-expression network analysis of the peripheral blood from Amyotrophic Lateral Sclerosis patients

<p>Abstract</p> <p>Background</p> <p>Amyotrophic Lateral Sclerosis (ALS) is a lethal disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord. Diagnosis is mainly based on clinical symptoms, and there is currently no therapy to stop the disease or slow its progression. Since access to spinal cord tissue is not possible at disease onset, we investigated changes in gene expression profiles in whole blood of ALS patients.</p> <p>Results</p> <p>Our transcriptional study showed dramatic changes in blood of ALS patients; 2,300 probes (9.4%) showed significant differential expression in a discovery dataset consisting of 30 ALS patients and 30 healthy controls. Weighted gene co-expression network analysis (WGCNA) was used to find disease-related networks (modules) and disease related hub genes. Two large co-expression modules were found to be associated with ALS. Our findings were replicated in a second (30 patients and 30 controls) and third dataset (63 patients and 63 controls), thereby demonstrating a highly significant and consistent association of two large co-expression modules with ALS disease status. Ingenuity Pathway Analysis of the ALS related module genes implicates enrichment of functional categories related to genetic disorders, neurodegeneration of the nervous system and inflammatory disease. The ALS related modules contain a number of candidate genes possibly involved in pathogenesis of ALS.</p> <p>Conclusion</p> <p>This first large-scale blood gene expression study in ALS observed distinct patterns between cases and controls which may provide opportunities for biomarker development as well as new insights into the molecular mechanisms of the disease.</p

Plasmatic and urinary glycosaminoglycans characterization in mucopolysaccharidosis II Patient treated with enzyme-replacement therapy with Idursulfase

We report the structural characterization of plasmatic and urinary GAGs in a Patient affected by MPS II (Hunter syndrome) before and during the first ten months of enzyme-replacement therapy (ERT). Plasmatic GAGs before ERT were rich in pathological DS consisting of iduronic acid (IdoA) and composed of ~90% \uf044Di4s and trace amounts of disulfated disaccharides. DS was also characterized as the main (~90%) urinary GAG mainly composed of ~90% \uf044Di4s with minor percentages of monosulfated and disulfated disaccharides, in particular \u394Di2,4dis. After 300 days of ERT, plasmatic DS strongly decreased but ~14% of IdoA-rich \uf044Di4s was still detected. Similarly, urinary galactosaminoglycans were mainly composed of 78% \uf044Di4s, ~11% \uf044Di6s and ~4% \uf044Di0s with the persistence of \u394Di2,4dis (~4%). About 40% of IdoA-formed \uf044Di4s were also calculated thus confirming that pathological DS is still present in excreted urinary GAGs during ERT. By considering the % of IdoA, we observed rather similar kinetics of excretion in fluids from the beginning of the treatment. Immediately after the first enzyme infusion, a large amount of abnormal DS is removed from tissues reaching the blood compartment and eliminated via the urine, and this process lasts for about two weeks. After this, the percentage of IdoA-rich material present in biological fluids remains fairly constant over the following nine months of treatment. To date, these are the first data regarding plasmatic and urinary kinetics directly measured on products released by the activity of the recombinant enzyme Idursulfase, iduronate-2-sulfatase, evaluated using specific and sensitive analytical procedures

Exhausted CD8 T Cells Downregulate the IL-18 Receptor and Become Unresponsive to Inflammatory Cytokines and Bacterial Co-infections

During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon (IFN)-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce IFN-γ and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. The unresponsiveness of exhausted CD8 T cells is associated with downregulation of the IL-18-receptor-α (IL-18Rα). Although IL-18Rα expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18Rαlo exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18Rα downregulation, we tracked the fate of IL-18Rα-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18Rα affects the initial but not later phases of the response. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18Rαhi memory cells upregulated CD25 and produced IFN-γ, the IL-18Rαlo exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial co-infections

Electron quantum metamaterials in van der Waals heterostructures

In recent decades, scientists have developed the means to engineer synthetic periodic arrays with feature sizes below the wavelength of light. When such features are appropriately structured, electromagnetic radiation can be manipulated in unusual ways, resulting in optical metamaterials whose function is directly controlled through nanoscale structure. Nature, too, has adopted such techniques -- for example in the unique coloring of butterfly wings -- to manipulate photons as they propagate through nanoscale periodic assemblies. In this Perspective, we highlight the intriguing potential of designer sub-electron wavelength (as well as wavelength-scale) structuring of electronic matter, which affords a new range of synthetic quantum metamaterials with unconventional responses. Driven by experimental developments in stacking atomically layered heterostructures -- e.g., mechanical pick-up/transfer assembly -- atomic scale registrations and structures can be readily tuned over distances smaller than characteristic electronic length-scales (such as electron wavelength, screening length, and electron mean free path). Yet electronic metamaterials promise far richer categories of behavior than those found in conventional optical metamaterial technologies. This is because unlike photons that scarcely interact with each other, electrons in subwavelength structured metamaterials are charged, and strongly interact. As a result, an enormous variety of emergent phenomena can be expected, and radically new classes of interacting quantum metamaterials designed

Movements of Wolves at the Northern Extreme of the Species' Range, Including during Four Months of Darkness

Information about wolf (Canis lupus) movements anywhere near the northern extreme of the species' range in the High Arctic (>75°N latitude) are lacking. There, wolves prey primarily on muskoxen (Ovibos moschatus) and must survive 4 months of 24 hr/day winter darkness and temperatures reaching −53 C. The extent to which wolves remain active and prey on muskoxen during the dark period are unknown, for the closest area where information is available about winter wolf movements is >2,250 km south. We studied a pack of ≥20 wolves on Ellesmere Island, Nunavut, Canada (80°N latitude) from July 2009 through mid-April 2010 by collaring a lead wolf with a Global Positioning System (GPS)/Argos radio collar. The collar recorded the wolf's precise locations at 6:00 a.m. and 6:00 p.m. daily and transmitted the locations by satellite to our email. Straight-line distances between consecutive 12-hr locations varied between 0 and 76 km. Mean (SE) linear distance between consecutive locations (n = 554) was 11 (0.5) km. Total minimum distance traveled was 5,979 km, and total area covered was 6,640 km2, the largest wolf range reported. The wolf and presumably his pack once made a 263-km (straight-line distance) foray to the southeast during 19–28 January 2010, returning 29 January to 1 February at an average of 41 km/day straight-line distances between 12-hr locations. This study produced the first detailed movement information about any large mammal in the High Arctic, and the average movements during the dark period did not differ from those afterwards. Wolf movements during the dark period in the highest latitudes match those of the other seasons and generally those of wolves in lower latitudes, and, at least with the gross movements measurable by our methods, the 4-month period without direct sunlight produced little change in movements

Is the maturity of hospitals' quality improvement systems associated with measures of quality and patient safety?

UNLABELLED: ABSTRACT: BACKGROUND: Previous research addressed the development of a classification scheme for quality improvement systems in European hospitals. In this study we explore associations between the 'maturity' of the hospitals' quality improvement system and clinical outcomes. METHODS: The maturity classification scheme was developed based on survey results from 389 hospitals in eight European countries. We matched the hospitals from the Spanish sample (113 hospitals) with those hospitals participating in a nation-wide, voluntary hospital performance initiative. We then compared sample distributions and explored associations between the 'maturity' of the hospitals' quality improvement system and a range of composite outcomes measures, such as adjusted hospital-wide mortality, -readmission, -complication and -length of stay indices. Statistical analysis includes bivariate correlations for parametrically and non-parametrically distributed data, multiple robust regression models and bootstrapping techniques to obtain confidence-intervals for the correlation and regression estimates. RESULTS: Overall, 43 hospitals were included. Compared to the original sample of 113, this sample was characterized by a higher representation of university hospitals. Maturity of the quality improvement system was similar, although the matched sample showed less variability. Analysis of associations between the quality improvement system and hospital-wide outcomes suggests significant correlations for the indicator adjusted hospital complications, borderline significance for adjusted hospital readmissions and non-significance for the adjusted hospital mortality and length of stay indicators. These results are confirmed by the bootstrap estimates of the robust regression model after adjusting for hospital characteristics. CONCLUSIONS: We assessed associations between hospitals' quality improvement systems and clinical outcomes. From this data it seems that having a more developed quality improvement system is associated with lower rates of adjusted hospital complications. A number of methodological and logistic hurdles remain to link hospital quality improvement systems to outcomes. Further research should aim at identifying the latent dimensions of quality improvement systems that predict quality and safety outcomes. Such research would add pertinent knowledge regarding the implementation of organizational strategies related with quality of care outcomes

Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis

Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia

The effect of early pregnancy following chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours

Little literature exists on the safety of early pregnancy following chemotherapy. Here we assess the rate of relapse and foetal outcome in women who have completed single and multi-agent chemotherapy for gestational trophoblastic tumours. The records of 1532 patients treated for persistent gestational trophoblastic tumours at Charing Cross Hospital between 1969 and 1998 were reviewed. Patients were defined as receiving single agent or multi-agent treatment. Relapse rates and foetal outcome were reviewed in the 230 patients who became pregnant within 12 months of completing chemotherapy. In the single agent group 153 (22%) of 691 patients conceived early. Three subsequently relapsed. In the multi-agent group, 77 (10%) of 779 patients conceived early, two then relapsed. Relapse rates were 2% (3 out of 153) and 2.5% (2 out of 77) for each group compared to 5% and 5.6% in the comparative non-pregnant groups. Outcomes of 230 early pregnancies: 164 (71%) delivered at full term, 35 (15%) terminations, 26 (11%) spontaneous abortions, three (1.3%) new hydatidiform moles and two (1%) stillbirths. Early pregnancies were more common in the single agent group (P<0.001), but spontaneous miscarriages and terminations were more likely to occur in the multi-agent group (P=0.04 and 0.03, respectively). Of the full-term pregnancies, three (1.8%) babies were born with congenital abnormalities. Patients in either group who conceive within 12 months of completing chemotherapy are not at increased risk of relapse. Though, we still advise avoiding pregnancy within 12 months of completing chemotherapy, those that do conceive can be reassured of a likely favourable outcome

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Degenerate and Other Neutrino Mass Scenarios and Dark Matter

I discuss in this talk mainly three topics related with dark matter motivated neutrino mass spectrum and a generic issue of mass pattern, the normal versus the inverted mass hierarchies. In the first part, by describing failure of a nontrivial potential counter example, I argue that the standard 3 $\nu$ mixing scheme with the solar and the atmospheric $\Delta m^2$'s is robust. In the second part, I discuss the almost degenerate neutrino (ADN) scenario as the unique possibility of accommodating dark matter mass neutrinos into the 3 $\nu$ scheme. I review a cosmological bound and then reanalyze the constraints imposed on the ADN scenario with the new data of double beta decay experiment. In the last part, I discuss the 3 $\nu$ flavor transformation in supernova (SN) and point out the possibility that neutrinos from SN may distinguish the normal versus inverted hierarchies of neutrino masses. By analyzing the neutrino data from SN1987A, I argue that the inverted mass hierarchy is disfavored by the data