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Pyrrolysine, the 22nd amino acid, is found in few proteins. One, the trimethylamine methyltransferase MttB, forms a small portion of a large family of proteins. Most in this family lack pyrrolysine and have no known activity. We show that one such protein, MtgB, is a glycine betaine methyltransferase, providing functional context that may explain the relationship between family members with and without pyrrolysine. Close relatives of MtgB are encoded in many of the abundant bacteria in the oceans, as well as different microbes undertaking symbioses ranging from plants to humans. This finding implies that MtgB might partake in a widespread and underappreciated pathway of GB metabolism contributing significantly to global carbon and nitrogen cycling as well as human health. COG5598 comprises a large number of proteins related to MttB, the trimethylamine:corrinoid methyltransferase. MttB has a genetically encoded pyrrolysine residue proposed essential for catalysis. MttB is the only known trimethylamine methyltransferase, yet the great majority of members of COG5598 lack pyrrolysine, leaving the activity of these proteins an open question. Here, we describe the function of one of the nonpyrrolysine members of this large protein family. Three nonpyrrolysine MttB homologs are encoded in Desulfitobacterium hafniense , a Gram-positive strict anaerobe present in both the environment and human intestine. D. hafniense was found capable of growth on glycine betaine with electron acceptors such as nitrate or fumarate, producing dimethylglycine and CO 2 as products. Examination of the genome revealed genes for tetrahydrofolate-linked oxidation of a methyl group originating from a methylated corrinoid protein, but no obvious means to carry out corrinoid methylation with glycine betaine. DSY3156, encoding one of the nonpyrrolysine MttB homologs, was up-regulated during growth on glycine betaine. The recombinant DSY3156 protein converts glycine betaine and cob(I)alamin to dimethylglycine and methylcobalamin. To our knowledge, DSY3156 is the first glycine betaine:corrinoid methyltransferase described, and a designation of MtgB is proposed. In addition, DSY3157, an adjacently encoded protein, was shown to be a methylcobalamin:tetrahydrofolate methyltransferase and is designated MtgA. Homologs of MtgB are widely distributed, especially in marine bacterioplankton and nitrogen-fixing plant symbionts. They are also found in multiple members of the human microbiome, and may play a beneficial role in trimethylamine homeostasis, which in recent years has been directly tied to human cardiovascular health.

The human gut microbiome has been shown to contribute to atherosclerotic cardiovascular disease with adverse health effects throughout the world. Gut microbes canonically metabolize quaternary amines into proatherogenic TMA. In this study, a gut bacterium, CJ25, metabolizes choline and carnitine to a non-atherogenic product, glycine betaine, potentially using novel dehydrogenase homologs for their oxidation. Notably, the ability of CJ25 to metabolize choline and carnitine in a non-atherogenic manner establishes its potential as a beneficial human gut bacterium. Additionally, enzymes identified in CJ25 for choline and carnitine breakdown may be present in other gut microbes, which could amplify the effects of these pathways and reduce the risk of atherosclerotic cardiovascular disease more universally.

Two novel strains of methanogens were isolated from an estuarine sediment with the capability to utilize quaternary amines. Based on the 16S rRNA analysis, strain B1d shared 99 % sequence identity with Methanolobus vulcani PL-12/Mᵀand strain Q3c shared 99 % identity with Methanococcoides sp. PM1 and PM2, but our current isolates display clearly different capabilities of growth on quaternary amines and were isolated based on these capabilities. Strain Q3c was capable of growth on tetramethylammonium and choline, while strain B1d was capable of growth on glycine betaine. Ml. vulcani PL-12/Mᵀwas incapable of growth on glycine betaine, indicating an obvious distinction between strains B1d and PL-12/Mᵀ. Strain Q3c now represents the only known tetramethylammonium-utilizing methanogen in isolation. Strain B1d is the first quaternary amine-utilizing methanogen from the genus Methanolobus. This study suggests that quaternary amines may serve as ready precursors of biological methane production in marine environments.

BackgroundPatient quality of life (QoL) during orthodontic treatment is an important consideration that requires greater academic investigation as greater focus is placed on enhancing patient experience. Quality of life (QoL) was assessed in three orthodontic appliance groups, i.e., vestibular, lingual, and aligners during the initial stages of treatment. The sample was comprised of 117 adult patient-subjects distributed into 3 groups: vestibular (n = 41), lingual (n = 37), and aligner (n = 39). A WHOQOL-BREF questionnaire surveyed four domains (physical health, psychological health, social relationships, and environment).ResultsMean scores for domain 1, physical health, showed that the aligner group (28.1) had significantly greater scores than that of the vestibular (22.7) or lingual (22) groups. Domain 2, psychological health, demonstrated significant differences (P < 0.001) between all groups, with the aligner group scoring the highest (23.2), followed by the lingual (18.4) and vestibular (15.2) groups. Domain 3, social relationship, showed that aligner (10.9) and lingual (10.2) scores were significantly greater (P < 0.001) than those of the vestibular group (7.8). Domain 4, environment, displayed significant differences between all groups, with the aligner group scoring highest (32.1), followed by the lingual group (29.3), and lastly the vestibular group (26.4). Overall, the highest mean score was obtained by the aligner group (23.1) and the lowest mean score was by the vestibular group (18). The mean domain scores for all three groups were significantly different (P ≤ 0.005) from each other (Table 2).ConclusionsOverall, patients undergoing Aligner therapy reported the overall highest QoL scores, followed by lingual and vestibular groups.

Ni-dependent carbon monoxide dehydrogenases (Ni-CODHs) are a diverse family of enzymes that catalyze reversible CO:CO₂ oxidoreductase activity in acetogens, methanogens, and some CO-using bacteria. Crystallography of Ni-CODHs from CO-using bacteria and acetogens has revealed the overall fold of the Ni-CODH core and has suggested structures for the C cluster that mediates CO:CO₂ interconversion. Despite these advances, the mechanism of CO oxidation has remained elusive. Herein, we report the structure of a distinct class of Ni-CODH from methanogenic archaea: the α₂ε₂ component from the α₈β₈γ₈δ₈ε₈ CODH/acetyl-CoA decarbonylase/synthase complex, an enzyme responsible for the majority of biogenic methane production on Earth. The structure of this Ni-CODH component provides support for a hitherto unobserved state in which both CO and H₂O/OH⁻ bind to the Ni and the exogenous FCII iron of the C cluster, respectively, and offers insight into the structures and functional roles of the ε-subunit and FeS domain not present in nonmethanogenic Ni-CODHs.

Purpose. The aim of this study was to investigate arch parameters and dentoalveolar changes from pretreatment to posttreatment by comparing the Miniscrew Assisted Rapid Palatal Expansion (MARPE), Periodontally Accelerated Osteogenic Orthodontics (PAOO), and Damon self-ligating bracket therapies. Materials and Methods. Seventy-nine patients underwent maxillary expansion followed by or in conjunction with Damon (n=23), PAOO (n=28), and MARPE (n=28) therapies. Nine maxillary dental arch parameters were compared at pretreatment, posttreatment as well as, increments of treatment change. Measurements were made on STL study casts using 3Shape Ortho Analyzer 3D scanner software. Results. All groups showed significant posterior width increase in the molar area. The mean increase in inter-molar distance was more than 8X greater in MARPE group compared to Damon and more than 4X greater compared to PAOO. MARPE showed significantly greater increments of change in inter-molar width and palatal vault area Conclusions. All groups showed a significant width increase in the canine and molar area. MARPE showed the greatest increase in inter-molar width, followed by PAOO and Damon. MARPE was the only group to show a significant increase in palatal vault area.

Sepsis is a frequent complication in critical illness. The mechanisms that are involved in initiation and propagation of the disease are not well understood. Scavenger receptor A (SRA) is a membrane receptor that binds multiple polyanions such as oxidized LDL and endotoxin. Recent studies suggest that SRA acts as a pattern recognition receptor in the innate immune response. The goal of the present study was to determine the role of SRA in polymicrobial sepsis. SRA deficient (SRA(-/-)) and C57BL/6JB/6J (WT) male mice were subjected to cecal ligation and puncture (CLP) to induce polymicrobial sepsis. NFκB activity, myeloperoxidase activity, and co-association of SRA with toll like receptor (TLR) 4 and TLR2 was analyzed in the lungs. Spleens were analyzed for apoptosis. Serum cytokines and chemokines were assayed. Blood and peritoneal fluid were cultured for aerobic and anaerobic bacterial burdens. Long-term survival was significantly increased in SRA(-/-) septic mice (53.6% vs. 3.6%, p < 0.05) when compared to WT mice. NFκB activity was 45.5% lower in the lungs of SRA(-/-) septic mice versus WT septic mice (p < 0.05). Serum levels of interleukin (IL)-5, IL-6, IL-10 and monocyte chemoattractant protein -1 were significantly lower in septic SRA(-/-) mice when compared to septic WT mice (p < 0.05). We found that SRA immuno-precipitated with TLR4, but not TLR2, in the lungs of WT septic mice. We also found that septic SRA(-/-) mice had lower bacterial burdens than WT septic mice. SRA deficiency had no effect on pulmonary neutrophil infiltration or splenocyte apoptosis during sepsis. We conclude that SRA plays a pivotal, and previously unknown, role in mediating the pathophysiology of sepsis/septic shock in a murine model of polymicrobial sepsis. Mechanistically, SRA interacts with TLR4 to enhance the development of the pro-inflammatory phenotype and mediate the morbidity and mortality of sepsis/septic shock.

ABSTRACT Objective: The objective of this article was to evaluate the effect of alpha binaural beat music on pain level after initial placement of a maxillary fixed appliance, compared to music without binaural beats (placebo) and no music (control). Methods: 60 patients undergoing maxillary fixed orthodontic appliance and initial archwire placement were randomly allocated into the three aforementioned groups. The pain level experienced was monitored for the following seven days, using the short-form McGill pain questionnaire (SF-MPQ). Results / Descriptors: Intensity of both sensory and psychological aspects of pain reduced significantly in the binaural beat music (BBM) group, compared to the control, after the 5th day. Statistically significant lower affective and total pain scores were also found on day 6 for the placebo group, compared to the control. Present Pain Intensity (PPI): Statistically significant lower scores were found between the BBM group and the control group from days 3 to 7. Statistically significant lower scores were also found between the placebo and the control groups on days 4, 5 and 6. Visual Analog Scale (VAS): Compared to the control group, the placebo group had a lower VAS score on day 4, and the BBM group had lower scores on days 6 and 7. Conclusions: There was a significant reduction of pain demonstrated in the BBM group, compared to the control, toward the end of the first week of treatment. There was no difference in reported pain between the BBM and placebo groups for any of the scores. RESUMO Objetivo: O objetivo deste artigo foi avaliar o efeito da música alfa com ritmo binaural sobre o nível de dor após a instalação de um aparelho fixo superior com arco inicial, em comparação com a música sem ritmos binaurais (placebo) e sem música (controle). Métodos: 60 pacientes submetidos a instalação de aparelho ortodôntico fixo superior e do arco inicial foram alocados aleatoriamente nos três grupos acima mencionados. O nível de dor experimentado foi monitorado durante os sete dias seguintes, usando a forma curta do questionário de dor McGill (SF-MPQ). Resultados: Após o quinto dia, a intensidade dos aspectos sensoriais e psicológicos da dor foi significativamente reduzida no grupo de música com ritmo binaural (BBM), em comparação com o grupo controle. Escores significativamente menores de dor afetiva e total também foram encontrados no dia 6 para o grupo placebo, comparado ao controle. Intensidade da Dor Presente (PPI): escores significativamente menores foram encontrados para o grupo BBM, em comparação ao grupo controle, nos dias 3 a 7. Escores significativamente menores também foram encontrados para o grupo placebo, em comparação ao grupo controle, nos dias 4, 5 e 6. Escala Visual Analógica (VAS): comparado ao grupo controle, o grupo placebo teve um escore VAS menor no dia 4, e o grupo BBM teve escores menores nos dias 6 e 7. Conclusões: No final da primeira semana de tratamento, houve redução significativa da dor no grupo BBM, em comparação ao grupo controle. Não houve diferença entre a dor relatada nos grupos BBM e placebo para qualquer um dos escores.

Within hours after its initiation, the severe systemic inflammatory response of sepsis shifts to an adaptive anti‐inflammatory state with coincident immunosuppression. This anti‐inflammatory phenotype is characterized by diminished proinflammatory cytokine gene expression in response to toll‐like receptor (TLR) stimulation with bacterial endotoxin/lipopolysaccharide (LPS), also known as endotoxin tolerance/adaptation. Our and other studies have established that gene‐specific reprogramming following TLR4 responses independently represses transcription and translation of proinflammatory genes such as tumor necrosis factor alpha (TNFα). We also previously demonstrated that TNFα and interleukin (IL)‐6 mRNA translation is repressed in endotoxin‐adapted THP‐1 human monocytes by an miRNA‐based mechanism involving the argonaute family protein argonaute 2 (Ago2). Here, we further define the molecular nature of reprogramming translation by showing that TLR4‐induced microRNA‐146 promotes a feed‐forward loop that modifies the subcellular localization of the RNA‐binding protein RBM4 (RNA‐binding motif protein 4) and promotes its interaction with Ago2. This interaction results in the assembly of a translation‐repressor complex that disrupts TNFα and IL‐6 cytokine synthesis in endotoxin‐adapted THP‐1 monocytes. This novel molecular path prevents the phosphorylation of RBM4 on serine‐309 by p38 MAPK (mitogen‐activated protein kinase), which leads to RBM4 accumulation in the cytosol and interaction with Ago2. We further find that microRNA‐146a knockdown by antagomirs or protein phosphatase inhibition by okadaic acid increases p38 MAPK phosphorylation and results in RBM4 serine‐309 phosphorylation and nuclear relocalization, which disrupts RBM4 and Ago2 interactions and restores TLR4‐dependent synthesis of TNFα and IL‐6. We conclude that miR‐146a has a diverse and critical role in limiting an excessive acute inflammatory reaction.

In his many tears of teaching and writing about music Professor Ferguson has given much thought to the question of the why of music -- why does music affect us as it does, why are we deeply moved by some music by not by other music, what is it about music that “sends” us, and where does it send us? In this book he explores such questions in depth and provides intriguing answers. The discussions are presented in the form of dialogues between the author and several friends. As Professor Ferguson explains, the book is intended to take the reader on a guided tour, a tour which follows, in part, the familiar roads of formal music appreciation but which leads more often into byways where, almost hidden by the brilliant Hows that line the more familiar roads, lurks the essential Why of music. He describes this Why as the fertilizing commerce between music and human experience -- a portrayal, not of the tangible facts of experience, but of the concern aroused by our encounter with those facts. He explains that while avant-garde abstractionism is concerned only with music as art -- a concern too specialized for the general music lover to grasp and too narrow to sustain interest -- the Why of enduring music lies in its endeavor to portray experience as it lives in Everyman’s mind.