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ational Biotec Group Company.d-serine is synthesized by serine racemase (SR), a fold type II class of pyridoxal-5'-phosphate (PLP)-dependent enzyme. Whereas X-ray crystallography reveals that SR can be monomeric, reversible dimers having the highest racemase activity, or stable SR dimers resistant to both denaturation and reductive treatment, showing reduced racemase activity have been detected in microglia and astrocytes; the latter especially in oxidative or inflammatory environments. The microglial inflammatory environment depends largely on the TGFβ1-mediated regulation of inflammatory cytokines such as TNFα and IL1β. Here we evaluated the participation of TGFβ1 in the regulation of SR, and whether that regulation is associated with the induction of stable SR dimers in the microglia from adult mice. In contrast to the effect of lipopolysaccharide (LPS), TGFβ1 increased the formation of stable SR dimers and reduced the detection of monomers in microglia in culture. LPS or TGFβ1 did not change the amount of total SR. The increase of stable SR dimer was abolished when TGFβ1 treatment was done in the presence of the Smad inhibitor SIS3, showing that Smad3 has a role in the induction of stable dimers. Treatment with TGFβ1 + SIS3 also reduced total SR, indicating that the canonical TGFβ1 pathway participates in the regulation of the synthesis or degradation of SR. In addition, the decrease of IL1β, but not the decrease of TNFα induced by TGFβ1, was mediated by Smad3. Our results reveal a mechanism for the regulation of d-serine through the induction of stable SR dimers mediated by TGFβ1-Smad3 signaling in microglia.α-Crystallin, comprising 40-50 subunits of αA- and αB-subunits, is a long-lived major soluble chaperone protein in lens. During aging, α-crystallin forms aggregates of high molecular weight (HMW) protein and eventually becomes water-insoluble (WI). Isomerization of Asp in α-crystallin has been proposed as a trigger of protein aggregation, ultimately leading to cataract formation. Here, we have investigated the relationship between protein aggregation and Asp isomerization of αA-crystallin by a series of analyses of the soluble α-crystallin, HMW and WI fractions from human lens samples of different ages (10-76 years). Analytical ultracentrifugation showed that the HMW fraction had a peak sedimentation coefficient of 40 S and a wide distribution of values (10-450 S) for lens of all ages, whereas the α-crystallin had a much smaller peak sedimentation coefficient (10-20 S) and was less heterogeneous, regardless of lens age. Measurement of the ratio of isomers (Lα-, Lβ-, Dα-, Dβ-) at Asp58, Asp91/92 and Asp151 in αA-crystallin by liquid chromatography-mass spectrometry showed that the proportion of isomers at all three sites increased in order of aggregation level (α-crystallin less then HMW less then WI fractions). Among the abnormal isomers of Asp58 and Asp151, Dβ-isomers were predominant with a very few exceptions. Notably, the chaperone activity of HMW protein was minimal for lens of all ages, whereas that of α-crystallin decreased with increasing lens age. Thus, abnormal aggregation caused by Asp isomerization might contribute to the loss of chaperone activity of α-crystallin in aged human lens.Background context While burst fracture is a well-known cause of spinal canal occlusion with dynamic, axial spinal compression, it is unclear how such loading mechanisms might cause occlusion without fracture. Purpose To determine how spinal canal occlusion during dynamic compression of the lumbar spine is differentially caused by fracture or mechanisms without fracture and to examine the influence of spinal level on occlusion. Study design A cadaveric biomechanical study. Methods Twenty sets of three-vertebrae specimens from all spinal levels between T12 and S1 were subjected to dynamic compression using a hydraulic loading apparatus up to a peak velocity between 0.1 and 0.9 m/s. The presence of canal occlusion was measured optically with a high-speed camera. This was repeated with incremental increases of 4% compressive strain until a vertebral fracture was detected using acoustic emission measurements and computed tomographic imaging. Results For axial compression without fracture, the peak occlusion (Omax) was 29.9±10.0%, which was deduced to be the result of posterior bulging of the intervertebral disc into the spinal canal. Omax correlated significantly with lumbar spinal level (p less then 0.001), the compressive displacement (p less then 0.001) and the cross-sectional area of the vertebra (p=0.031). Conclusions Spinal canal occlusion observed without vertebral fracture involves intervertebral disc bulging. The lower lumbar spine tended to be more severely occluded than more proximal levels. Clinical significance Clinically, intermittent canal occlusion from disc bulging during dynamic compression may not show any radiographic features. The lower lumbar spine should be a focus of injury prevention intervention in cases of high-rate axial compression.The 'Geophagus' brasiliensis complex is one of the most abundant groups of cichlids from eastern coastal basins in South America. Traditionally, this fish group has been recognized as incertae sedis because of phylogenetic uncertainties and unclear taxonomy. In addition, the remarkable morphological, chromosomal, and DNA variation reported over recent years in several populations of these cichlids has increased the debate about their species richness and their distributional range. Here, we tested the presence of independent evolutionary lineages within the 'G.' brasiliensis complex, addressing their taxonomic status and evolutionary relationships, including a comparative analysis of genetic and morphological patterns, based on an extensive dataset, comprising 172 sampling sites along most of their known range using a mitochondrial marker, RADseq data and geometric morphometrics. The number of putative species in the present study varied from 9 to 11 depending on the molecular species delimitation methods used. Our results revealed at least two putative new taxa ('Geophagus' sp. Doce and 'Geophagus' sp. Upper Contas). Morphometric analyses, particularly those based on Canonical Variate Analysis (CVA), revealed significant morphological differentiation between species within the main clades. On the other hand, analyses of morphological phylogenetic signal and phylomorphospace provided no evidence of adaptive differentiation among these species. Thus, diversification in the 'G.' brasiliensis complex seems to have been influenced by hydrogeological events that promoted allopatry, such as the presence of paleodrainages and distributional reconfiguration through river captures. We propose major changes in the known distribution of some species within the complex and conservatively suggest the recognition of 10 species within the 'Geophagus' brasiliensis complex, with the potential for further dividing 'G.' rufomarginatus after additional taxonomic evaluation.Ketone bodies can become a major source of adenosine triphosphate (ATP) production during stress to maintain bioenergetic homeostasis in the brain, heart and skeletal muscles. In the normal heart, ketone bodies contribute from 10 to 15% of the cardiac ATP production, while their contribution during pathological stress is still not well characterized and currently represents an exciting area of cardiovascular research. This review focuses on the mechanisms which regulate circulating ketone levels under physiological and pathological conditions and how this impacts cardiac ketone metabolism. We also review the current understanding of the role of augmented ketone metabolism as an adaptive response in different types and stages of heart failure. This includes the emerging experimental and clinical evidence of the potential favourable effects of boosting ketone metabolism in the failing heart and the possible mechanisms of action through which these interventions may mediate their cardioprotective effects. We also critically appraise the emerging data from animal and human studies which characterize the role of ketones in mediating the cardioprotection established by the new class of anti-diabetic drugs, namely sodium-glucose co-transporter inhibitors (SGLT2i).Chest pain is a common presenting complaint in the primary care setting. Imaging plays a key role in the evaluation of the multiple organ systems that can be responsible for chest pain. With numerous imaging modalities available, determination of the most appropriate test and interpretation of the findings can be a challenge for the clinician. In this 2-part series, we offer resources to guide primary care physicians in the selection of imaging studies and present the imaging findings of various causes of non-emergent chest pain. INCB054329 concentration In Part 2, we focus on the radiologic appearance of common non-cardiac sources of chest pain, including gastrointestinal, pulmonary, and musculoskeletal etiologies.Chest pain is a common presenting complaint in the primary care setting. Imaging plays a key role in the evaluation of the multiple organ systems that can be responsible for chest pain. With numerous imaging modalities available, determination of the most appropriate test and interpretation of the findings can be a challenge for the clinician. In this 2-part series, we offer resources to guide primary care physicians in the selection of imaging studies and present the imaging findings of various causes of non-emergent chest pain. In Part 1, we focus on a discussion of the basic concepts of each imaging technique and the appearance of common cardiovascular etiologies.Synthetic biology has promised and delivered on an impressive array of applications based on genetically modified microorganisms. While novel biotechnology undoubtedly offers benefits, like all new technology, precautions should be considered during implementation to reduce the risk of both known and unknown adverse effects. To achieve containment of transgenic microorganisms, confidence to a near-scientific certainty that they cannot transfer their transgenic genes to other organisms, and that they cannot survive to propagate in unintended environments, is a priority. Here, we present an in-depth summary of biological containment systems for micro-organisms published to date, including the production of a genetic firewall through genome recoding and physical containment of microbes using auxotrophies, regulation of essential genes, and expression of toxic genes. The level of containment required to consider a transgenic organism suitable for deployment is discussed, as well as standards of practice for developing new containment systems.Co-evolution of gut commensal bacteria and humans has ensured that the micronutrient needs of both parties are met. This minireview summarizes the known molecular mechanisms of iron, zinc, and B vitamin processing by human-associated bacteria, comparing gut pathogens and commensals, and highlights the tension between their roles as competitors versus collaborators with the human host.Athukoralage et al. (2020) identify a new anti-CRISPR (Acr) that degrades cA4, a cyclic oligo-adenylate second messenger produced during the type III CRISPR immune response. This provides an effective way by which invaders can bypass downstream CRISPR effectors that rely on this signaling molecule.