► Comprehensive review of the biochemistry, toxicology and epidemiology of nitrite and nitrate. ► Discusses new paradigm of nitrosation as a fundamental nitric oxide mediated cell signaling pathway. ...► Reviews up to date animal toxicology and epidemiological data to dispute some original findings. ► The emergence of new data on nitrite and nitrate warrant a reconsideration of its safety profile.
Nitrite and nitrate are naturally occurring molecules in vegetables and also added to cured and processed meats to delay spoilage and pathogenic bacteria growth. Research over the past 15years has led to a paradigm change in our ideas about health effects of both nitrite and nitrate. Whereas, historically nitrite and nitrate were considered harmful food additives and listed as probable human carcinogens under conditions where endogenous nitrosation could take place, they are now considered by some as indispensible nutrients essential for cardiovascular health by promoting nitric oxide (NO) production. We provide an update to the literature and knowledge base concerning their safety. Most nitrite and nitrate exposure comes from naturally occurring and endogenous sources and part of the cell signaling effects of NO involve nitrosation. Nitrosation must now be considered broadly in terms of both S- and N-nitrosated species, since S-nitrosation is kinetically favored. Protein S-nitrosation is a significant part of the role of NO in cellular signal transduction and is involved in critical aspects of cardiovascular health. A critical review of the animal toxicology literature of nitrite indicates that in the absence of co-administration of a carcinogenic nitrosamine precursor, there is no evidence for carcinogenesis. Newly published prospective epidemiological cohort studies indicate that there is no association between estimated intake of nitrite and nitrate in the diet and stomach cancer. This new and growing body of evidence calls for a reconsideration of nitrite and nitrate safety.
The UK Biobank is a prospective study of 502,543 individuals, combining extensive phenotypic and genotypic data with streamlined access for researchers around the world
. Here we describe the release ...of exome-sequence data for the first 49,960 study participants, revealing approximately 4 million coding variants (of which around 98.6% have a frequency of less than 1%). The data include 198,269 autosomal predicted loss-of-function (LOF) variants, a more than 14-fold increase compared to the imputed sequence. Nearly all genes (more than 97%) had at least one carrier with a LOF variant, and most genes (more than 69%) had at least ten carriers with a LOF variant. We illustrate the power of characterizing LOF variants in this population through association analyses across 1,730 phenotypes. In addition to replicating established associations, we found novel LOF variants with large effects on disease traits, including PIEZO1 on varicose veins, COL6A1 on corneal resistance, MEPE on bone density, and IQGAP2 and GMPR on blood cell traits. We further demonstrate the value of exome sequencing by surveying the prevalence of pathogenic variants of clinical importance, and show that 2% of this population has a medically actionable variant. Furthermore, we characterize the penetrance of cancer in carriers of pathogenic BRCA1 and BRCA2 variants. Exome sequences from the first 49,960 participants highlight the promise of genome sequencing in large population-based studies and are now accessible to the scientific community.
Abstract The high throughput discovery of new bio materials can be achieved by rapidly screening many different materials synthesised by a combinatorial approach to identify the optimal composition ...that fulfils a particular biomedical application. Here we review the literature in this area and conclude that for polymers this process is best achieved in a microarray format, which enable thousands of cell-material interactions to be monitored on a single chip. Polymer microarrays can be formed by printing pre-synthesised polymers or by printing monomers onto the chip where on-slide polymerisation is initiated. The surface properties of the material can be analysed and correlated to the biological performance using high throughput surface analysis, including time-of-flight secondary ion mass spectrometry (ToF-SIMS), X-ray photoelectron spectroscopy (XPS) and water contact angle (WCA) measurements. This approach enables the surface properties responsible for the success of a material to be understood, which in turn provides the foundations of future material design. The high throughput discovery of materials using polymer microarrays has been explored for many cell-based applications including the isolation of specific cells from heterogeneous populations, the attachment and differentiation of stem cells and the controlled transfection of cells. Further development of polymerisation techniques and high throughput biological assays amenable to the polymer microarray format will broaden the combinatorial space and biological phenomenon that polymer microarrays can explore, and increase their efficacy. This will, in turn, facilitate the discovery of optimised polymeric materials for many biomaterial applications.
White matter tracts of the brain allow neurons and neuronal networks to communicate and function with high efficiency. The aim of this review is to briefly introduce diffusion tensor imaging methods ...that examine white matter tracts and then to give an overview of the studies that have investigated white matter integrity in the brains of individuals with autism spectrum disorder (ASD). From the 48 studies we reviewed, persons with ASD tended to have decreased fractional anisotropy and increased mean diffusivity in white matter tracts spanning many regions of the brain but most consistently in regions such as the corpus callosum, cingulum, and aspects of the temporal lobe. This decrease in fractional anisotropy was often accompanied by increased radial diffusivity. Additionally, the review suggests possible atypical lateralization in some white matter tracts of the brain and a possible atypical developmental trajectory of white matter microstructure in persons with ASD. Clinical implications and future research directions are discussed.
Nanofiltration (NF) membranes have been used previously for the recovery of dyes, salts, and water from textile wastewaters with high salinity. However, commercially available NF membranes have a ...high rejection for divalent salts (i.e., Na2SO4), substantially reducing the salt recovery and membrane flux when treating textile wastewater containing Na2SO4. In this study, a tight ultrafiltration membrane (UH004, Microdyn-Nadir) was proposed to fractionate the dye and Na2SO4 in the textile wastewater. The UH004 membrane with a molecular weight cutoff of 4700Da provided complete passage of monovalent salts, with little rejection of Na2SO4. This significantly increases the filtrate flux that can be achieved with high-salinity wastewater since osmotic pressure and concentration polarization effects are minimized. Furthermore, the retention behavior of four different dyes was evaluated to determine the efficiency of this membrane process. This tight ultrafiltration membrane offered the high retention for direct dyes (i.e., direct red 80, direct red 23, and Congo red) and reactive blue 2. For instance, the UH004 membrane yielded >98.9% rejection for all of the dyes at a pressure of 4bar even in the presence of 60gL−1 Na2SO4. Subsequently, an ultrafiltration-diafiltration process was designed to separate a dye/Na2SO4 aqueous mixture with 98% desalination efficiency and greater than 97% dye recovery after 5 diavolumes. These results clearly demonstrate that tight ultrafiltration membranes can be a stand-alone alternative to NF membranes for the effective fractionation of dye and Na2SO4 in the direct treatment of high-salinity textile wastewater.
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•Tight UF membrane can be an alternative to NF membrane to fractionate the dye/Na2SO4 mixture.•No obvious effect is observed on dye rejection of tight UF membrane after the addition of Na2SO4.•5-diavolume diafiltration by tight UF membrane removes 98% of Na2SO4 from the feed.•Over 97% dye recovery is obtained after diafiltration by UF membrane due to high dye rejection.
Many individuals with autism spectrum disorder (ASD) exhibit motor difficulties, but it is unknown whether manual motor skills improve, plateau, or decline in ASD in the transition from childhood ...into adulthood. Atypical development of manual motor skills could impact the ability to learn and perform daily activities across the life span. This study examined longitudinal grip strength and finger tapping development in individuals with ASD (n = 90) compared to individuals with typical development (n = 56), ages 5 to 40 years old. We further examined manual motor performance as a possible correlate of current and future daily living skills. The group with ASD demonstrated atypical motor development, characterized by similar performance during childhood but increasingly poorer performance from adolescence into adulthood. Grip strength was correlated with current adaptive daily living skills, and Time 1 grip strength predicted daily living skills eight years into the future. These results suggest that individuals with ASD may experience increasingly more pronounced motor difficulties from adolescence into adulthood and that manual motor performance in ASD is related to adaptive daily living skills.
We investigated age‐related changes from early childhood into mid‐adulthood in manual motor skills in individuals with autism spectrum disorder (ASD) compared to typical development. We then examined if manual motor performance correlated with current and future daily living skills. We found evidence for atypical development of grip strength and finger tapping speed in ASD, atypically low grip strength in ~1/3 of the individuals with ASD, and correlations between manual motor performance and both current and future daily living skills.
Combinatorial approaches to materials discovery offer promising potential for the rapid development of novel polymer systems. Polymer microarrays enable the high-throughput comparison of material ...physical and chemical propertiessuch as surface chemistry and properties like cell attachment or protein adsorptionin order to identify correlations that can progress materials development. A challenge for this approach is to accurately discriminate between highly similar polymer chemistries or identify heterogeneities within individual polymer spots. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) offers unique potential in this regard, capable of describing the chemistry associated with the outermost layer of a sample with high spatial resolution and chemical sensitivity. However, this comes at the cost of generating large scale, complex hyperspectral imaging data sets. We have demonstrated previously that machine learning is a powerful tool for interpreting ToF-SIMS images, describing a method for color-tagging the output of a self-organizing map (SOM). This reduces the entire hyperspectral data set to a single reconstructed color similarity map, in which the spectral similarity between pixels is represented by color similarity in the map. Here, we apply the same methodology to a ToF-SIMS image of a printed polymer microarray for the first time. We report complete, single-pixel molecular discrimination of the 70 unique homopolymer spots on the array while also identifying intraspot heterogeneities thought to be related to intermixing of the polymer and the pHEMA coating. In this way, we show that the SOM can identify layers of similarity and clusters in the data, both with respect to polymer backbone structures and their individual side groups. Finally, we relate the output of the SOM analysis with fluorescence data from polymer–protein adsorption studies, highlighting how polymer performance can be visualized within the context of the global topology of the data set.
Cognitive deficits have been reported in children who experienced early neglect, especially children raised in institutionalized settings. Previous research suggests that early neglect may ...differentially affect the directional organization of white matter in the prefrontal cortex (PFC). This may be one mechanism to explain cognitive deficits associated with neglect. To test this idea, properties of white matter and neurocognitive performance were assessed in children who suffered early neglect and those raised in typical environments (n = 63, M
age
= 11.75 years). As predicted, prefrontal white matter microstructure was affected, consistent with more diffuse organization, in children that suffered early neglect and this was related to neurocognitive deficits. Such findings underscore how early adversity may affect the PFC and explain cognitive deficits associated with neglect.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with unknown brain etiology. Our knowledge to date about structural brain development across the lifespan in ASD comes mainly from ...cross-sectional studies, thereby limiting our understanding of true age effects within individuals with the disorder that can only be gained through longitudinal research. The present study describes FreeSurfer-derived volumetric findings from a longitudinal dataset consisting of 607 T1-weighted magnetic resonance imaging (MRI) scans collected from 105 male individuals with ASD (349 MRIs) and 125 typically developing male controls (258 MRIs). Participants were six to forty-five years of age at their first scan, and were scanned up to 5 times over a period of 16 years (average inter-scan interval of 3.7 years). Atypical age-related volumetric trajectories in ASD included enlarged gray matter volume in early childhood that approached levels of the control group by late childhood, an age-related increase in ventricle volume resulting in enlarged ventricles by early adulthood and reduced corpus callosum age-related volumetric increase resulting in smaller corpus callosum volume in adulthood. Larger corpus callosum volume was related to a lower (better) ADOS score at the most recent study visit for the participants with ASD. These longitudinal findings expand our knowledge of volumetric brain-based abnormalities in males with ASD, and highlight the need to continue to examine brain structure across the lifespan and well into adulthood.
IDO2 is implicated in tryptophan catabolism and immunity but its physiological functions are not well established. Here we report the characterization of mice genetically deficient in IDO2, which ...develop normally but exhibit defects in IDO-mediated T-cell regulation and inflammatory responses. Construction of this strain was prompted in part by our discovery that IDO2 function is attenuated in macrophages from Ido1 (-/-) mice due to altered message splicing, generating a functional mosaic with implications for interpreting findings in Ido1 (-/-) mice. No apparent defects were observed in Ido2 (-/-) mice in embryonic development or hematopoietic differentiation, with wild-type profiles documented for kynurenine in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus and bone marrow of naive mice. In contrast, upon immune stimulation we determined that IDO1-dependent T regulatory cell generation was defective in Ido2 (-/-) mice, supporting Ido1-Ido2 genetic interaction and establishing a functional role for Ido2 in immune modulation. Pathophysiologically, both Ido1 (-/-) and Ido2 (-/-) mice displayed reduced skin contact hypersensitivity responses, but mechanistic distinctions were apparent, with only Ido2 deficiency associated with a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-γ, TNF-α, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise indicated by the finding that Ido2 (-/-) mice did not phenocopy Ido1 (-/-) mice in the reduced susceptibility of the latter to inflammatory skin cancer. Taken together, our results offer an initial glimpse into immune modulation by IDO2, revealing its genetic interaction with IDO1 and distinguishing its non-redundant contributions to inflammation.
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