Myelin bilayer mapping in the human brain in vivo

PURPOSE To quantitatively map the myelin lipid-protein bilayer in the live human brain. METHODS This goal was pursued by integrating a multi-TE acquisition approach targeting ultrashort T$_{2}$ signals with voxel-wise fitting to a three-component signal model. Imaging was performed at 3 T in two healthy volunteers using high-performance RF and gradient hardware and the HYFI sequence. The design of a suitable imaging protocol faced substantial constraints concerning SNR, imaging volume, scan time, and RF power deposition. Model fitting to data acquired using the proposed protocol was made feasible through simulation-based optimization, and filtering was used to condition noise presentation and overall depiction fidelity. RESULTS A multi-TE protocol (11 TEs of 20-780 μs) for in vivo brain imaging was developed in adherence with applicable safety regulations and practical scan time limits. Data acquired using this protocol produced accurate model fitting results, validating the suitability of the protocol for this purpose. Structured, grainy texture of myelin bilayer maps was observed and determined to be a manifestation of correlated image noise resulting from the employed acquisition strategy. Map quality was significantly improved by filtering to uniformize the k-space noise distribution and simultaneously extending the k-space support. The final myelin bilayer maps provided selective depiction of myelin, reconciling competitive resolution (1.4 mm) with adequate SNR and benign noise texture. CONCLUSION Using the proposed technique, quantitative maps of the myelin bilayer can be obtained in vivo. These maps offer unique information content with potential applications in basic research, diagnosis, disease monitoring, and drug development

Development of engineered cementitious composites with limestone powder and blast furnace slag

Nowadays limestone powder and blast furnace slag (BFS) are widely used in concrete as blended materials in cement. The replacement of Portland cement by limestone powder and BFS can lower the cost and enhance the greenness of concrete, since the production of these two materials needs less energy and causes less CO(2) emission than Portland cement. Moreover, the use of limestone powder and BFS improves the properties of fresh and hardened concrete, such as workability and durability. Engineered cementitious composites (ECC) is a class of ultra ductile fiber reinforced cementitious composites, characterized by high ductility, tight crack width control and relatively low fiber content. The limestone powder and BFS are used to produce ECC in this research. The mix proportion is designed experimentally by adjusting the amount of limestone powder and BFS, accompanied by four-point bending test and uniaxial tensile test. This study results in an ECC mix proportion with the Portland cement content as low as 15% of powder by weight. This mixture, at 28 days, exhibits a high tensile strain capacity of 3.3%, a tight crack width of 57 mu m and a moderate compressive strength of 38 MPa. In order to promote a wide use of ECC, it was tried to simplify the mixing of ECC with only two matrix materials, i.e. BFS cement and limestone powder, instead of three matrix materials. By replacing Portland cement and BFS in the aforementioned ECC mixture with BFS cement, the ECC with BFS cement and limestone powder exhibits a tensile strain capacity of 3.1%, a crack width of 76 mu m and a compressive strength of 40 MPa after 28 days of curing

TNFa and IL2 Encoding Oncolytic Adenovirus Activates Pathogen and Danger-Associated Immunological Signaling

In order to break tumor resistance towards traditional treatments, we investigate the response of tumor and immune cells to a novel, cytokine-armed oncolytic adenovirus: Ad5/3-d24-E2F-hTNFa-IRES-hIL2 (also known as TILT-123 and OAd.TNFa-IL2). There are several pattern recognition receptors (PRR) that might mediate adenovirus-infection recognition. However, the role and specific effects of each PRR on the tumor microenvironment and treatment outcome remain unclear. Hence, the aim of this study was to investigate the effects of OAd.TNFa-IL2 infection on PRR-mediated danger- and pathogen-associated molecular pattern (DAMP and PAMP, respectively) signaling. In addition, we wanted to see which PRRs mediate an antitumor response and are therefore relevant for optimizing this virotherapy. We determined that OAd.TNFa-IL2 induced DAMP and PAMP release and consequent tumor microenvironment modulation. We show that the AIM2 inflammasome is activated during OAd.TNFa-IL2 virotherapy, thus creating an immunostimulatory antitumor microenvironment.Peer reviewe

Evaluation of diffuse reflectance spectroscopy for predicting age, species, and cuticular resistance of Anopheles gambiae s.l under laboratory conditions

Mid-infrared spectroscopy (MIRS) combined with machine learning analysis has shown potential for quick and efficient identification of mosquito species and age groups. However, current technology to collect spectra is destructive to the sample and does not allow targeting specific tissues of the mosquito, limiting the identification of other important biological traits such as insecticide resistance. Here, we assessed the use of a non-destructive approach of MIRS for vector surveillance, micro diffuse reflectance spectroscopy (µDRIFT) using mosquito legs to identify species, age and cuticular insecticide resistance within the Anopheles gambiae s.l. complex. These mosquitoes are the major vectors of malaria in Africa and the focus on surveillance in malaria control programs. Legs required significantly less scanning time and showed more spectral consistence compared to other mosquito tissues. Machine learning models were able to identify An. gambiae and An. coluzzii with an accuracy of 0.73, two ages groups (3 and 10 days old) with 0.77 accuracy and we obtained accuracy of 0.75 when identifying cuticular insecticide resistance. Our results highlight the potential of different mosquito tissues and µDRIFT as tools for biological trait identification on mosquitoes that transmit malaria. These results can guide new ways of identifying mosquito traits which can help the creation of innovative surveillance programs by adapting new technology into mosquito surveillance and control tools

Role of macrophage sialoadhesin in host defense against the sialylated pathogen group B <em>Streptococcus</em>

ABSTRACT: Several bacterial pathogens decorate their surfaces with sialic acid (Sia) residues within cell wall components or capsular exopolysaccharides. Sialic acid expression can promote bacterial virulence by blocking complement activation or by engagement of inhibitory sialic acid-binding immunoglobulin-like lectins (Siglecs) on host leukocytes. Expressed at high levels on splenic and lymph node macrophages, sialoadhesin (Sn) is a unique Siglec with an elongated structure that lacks intracellular signaling motifs. Sialoadhesin allows macrophage to engage certain sialylated pathogens and stimulate inflammatory responses, but the in vivo significance of sialoadhesin in infection has not been shown. We demonstrate that macrophages phagocytose the sialylated pathogen group B Streptococcus (GBS) and increase bactericidal activity via sialoadhesin-sialic-acid-mediated recognition. Sialoadhesin expression on marginal zone metallophillic macrophages in the spleen trapped circulating GBS and restricted the spread of the GBS to distant organs, reducing mortality. Specific IgM antibody responses to GBS challenge were also impaired in sialoadhesin-deficient mice. Thus, sialoadhesin represents a key bridge to orchestrate innate and adaptive immune defenses against invasive sialylated bacterial pathogens. KEY MESSAGE: Sialoadhesin is critical for macrophages to phagocytose and clear GBS. Increased GBS organ dissemination in the sialoadhesin-deficient mice. Reduced anti-GBS IgM production in the sialoadhesin-deficient mice. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00109-014-1157-y) contains supplementary material, which is available to authorized users

Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide

Abstract Background Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. Objective We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition. Results 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100–800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions. Conclusion AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing

Remarkable structural resistance of a nanoflagellatedominated plankton community to iron fertilization during the Southern Ocean experiment LOHAFEX

The genesis of phytoplankton blooms and the fate of their biomass in iron-limited, high-nutrient−low-chlorophyll regions can be studied under natural conditions with ocean iron fertilization (OIF) experiments. The Indo-German OIF experiment LOHAFEX was carried out over 40 d in late summer 2009 within the cold core of a mesoscale eddy in the productive southwest Atlantic sector of the Southern Ocean. Silicate concentrations were very low, and phytoplankton biomass was dominated by autotrophic nanoflagellates (ANF) in the size range 3−10 μm. As in all previous OIF experiments, the phytoplankton responded to iron fertilization by increasing the maximum quantum yield (Fv/Fm) and cellular chlorophyll levels. Within 3 wk, chlorophyll levels tripled and ANF biomass doubled. With the exception of some diatoms and dinoflagellates, the biomass levels of all other groups of the phyto- and protozooplankton (heterotrophic nanoflagellates, dinoflagellates and ciliates) remained remarkably stable throughout the experiment both inside and outside the fertilized patch. We attribute the unusually high biomass attained and maintained by ANF to the absence of their grazers, the salps, and to constraints on protozooplankton grazers by heavy predation exerted by the large copepod stock. The resistance to change of the ecosystem structure over 38 d after fertilization, indicated by homogeneity at regional and temporal scales, suggests that it was locked into a stable, mature state that had evolved in the course of the seasonal cycle. The LOHAFEX bloom provides a case study of a resistant/robust dynamic equilibrium between auto- and heterotrophic ecosystem components resulting in low vertical flux both inside and outside the patch despite high biomass levels

Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GR beta) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GR(iKO)) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker