Structure of a putative NTP pyrophosphohydrolase: YP_001813558.1 from Exiguobacterium sibiricum 255-15.

The crystal structure of a putative NTPase, YP_001813558.1 from Exiguobacterium sibiricum 255-15 (PF09934, DUF2166) was determined to 1.78 Å resolution. YP_001813558.1 and its homologs (dimeric dUTPases, MazG proteins and HisE-encoded phosphoribosyl ATP pyrophosphohydrolases) form a superfamily of all-α-helical NTP pyrophosphatases. In dimeric dUTPase-like proteins, a central four-helix bundle forms the active site. However, in YP_001813558.1, an unexpected intertwined swapping of two of the helices that compose the conserved helix bundle results in a `linked dimer' that has not previously been observed for this family. Interestingly, despite this novel mode of dimerization, the metal-binding site for divalent cations, such as magnesium, that are essential for NTPase activity is still conserved. Furthermore, the active-site residues that are involved in sugar binding of the NTPs are also conserved when compared with other α-helical NTPases, but those that recognize the nucleotide bases are not conserved, suggesting a different substrate specificity

Structure of the γ-D-glutamyl-L-diamino acid endopeptidase YkfC from Bacillus cereus in complex with L-Ala-γ-D-Glu: insights into substrate recognition by NlpC/P60 cysteine peptidases.

Dipeptidyl-peptidase VI from Bacillus sphaericus and YkfC from Bacillus subtilis have both previously been characterized as highly specific γ-D-glutamyl-L-diamino acid endopeptidases. The crystal structure of a YkfC ortholog from Bacillus cereus (BcYkfC) at 1.8 Å resolution revealed that it contains two N-terminal bacterial SH3 (SH3b) domains in addition to the C-terminal catalytic NlpC/P60 domain that is ubiquitous in the very large family of cell-wall-related cysteine peptidases. A bound reaction product (L-Ala-γ-D-Glu) enabled the identification of conserved sequence and structural signatures for recognition of L-Ala and γ-D-Glu and, therefore, provides a clear framework for understanding the substrate specificity observed in dipeptidyl-peptidase VI, YkfC and other NlpC/P60 domains in general. The first SH3b domain plays an important role in defining substrate specificity by contributing to the formation of the active site, such that only murein peptides with a free N-terminal alanine are allowed. A conserved tyrosine in the SH3b domain of the YkfC subfamily is correlated with the presence of a conserved acidic residue in the NlpC/P60 domain and both residues interact with the free amine group of the alanine. This structural feature allows the definition of a subfamily of NlpC/P60 enzymes with the same N-terminal substrate requirements, including a previously characterized cyanobacterial L-alanine-γ-D-glutamate endopeptidase that contains the two key components (an NlpC/P60 domain attached to an SH3b domain) for assembly of a YkfC-like active site

The structure of BVU2987 from Bacteroides vulgatus reveals a superfamily of bacterial periplasmic proteins with possible inhibitory function.

Proteins that contain the DUF2874 domain constitute a new Pfam family PF11396. Members of this family have predominantly been identified in microbes found in the human gut and oral cavity. The crystal structure of one member of this family, BVU2987 from Bacteroides vulgatus, has been determined, revealing a β-lactamase inhibitor protein-like structure with a tandem repeat of domains. Sequence analysis and structural comparisons reveal that BVU2987 and other DUF2874 proteins are related to β-lactamase inhibitor protein, PepSY and SmpA_OmlA proteins and hence are likely to function as inhibitory proteins

Multi-level evidence of an allelic hierarchy of USH2A variants in hearing, auditory processing and speech/language outcomes.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems

Associations Between Food Insecurity and Psychotropic Medication Use Among Women Living With HIV in the United States

AIMS: Psychotropic prescription rates continue to increase in the United States (USA). Few studies have investigated whether social-structural factors may play a role in psychotropic medication use independent of mental illness. Food insecurity is prevalent among people living with HIV in the USA and has been associated with poor mental health. We investigated whether food insecurity was associated with psychotropic medication use independent of the symptoms of depression and anxiety among women living with HIV in the USA. METHODS: We used cross-sectional data from the Women\u27s Interagency HIV Study (WIHS), a nationwide cohort study. Food security (FS) was the primary explanatory variable, measured using the Household Food Security Survey Module. First, we used multivariable linear regressions to test whether FS was associated with symptoms of depression (Center for Epidemiologic Studies Depression [CESD] score), generalised anxiety disorder (GAD-7 score) and mental health-related quality of life (MOS-HIV Mental Health Summary score; MHS). Next, we examined associations of FS with the use of any psychotropic medications, including antidepressants, sedatives and antipsychotics, using multivariable logistic regressions adjusting for age, race/ethnicity, income, education and alcohol and substance use. In separate models, we additionally adjusted for symptoms of depression (CESD score) and anxiety (GAD-7 score). RESULTS: Of the 905 women in the sample, two-thirds were African-American. Lower FS (i.e. worse food insecurity) was associated with greater symptoms of depression and anxiety in a dose-response relationship. For the psychotropic medication outcomes, marginal and low FS were associated with 2.06 (p \u3c 0.001; 95% confidence interval [CI] = 1.36-3.13) and 1.99 (p \u3c 0.01; 95% CI = 1.26-3.15) times higher odds of any psychotropic medication use, respectively, before adjusting for depression and anxiety. The association of very low FS with any psychotropic medication use was not statistically significant. A similar pattern was found for antidepressant and sedative use. After additionally adjusting for CESD and GAD-7 scores, marginal FS remained associated with 1.93 (p \u3c 0.05; 95% CI = 1.16-3.19) times higher odds of any psychotropic medication use. Very low FS, conversely, was significantly associated with lower odds of antidepressant use (adjusted odds ratio = 0.42; p \u3c 0.05; 95% CI = 0.19-0.96). CONCLUSIONS: Marginal FS was associated with higher odds of using psychotropic medications independent of depression and anxiety, while very low FS was associated with lower odds. These complex findings may indicate that people experiencing very low FS face barriers to accessing mental health services, while those experiencing marginal FS who do access services are more likely to be prescribed psychotropic medications for distress arising from social and structural factors

The structure of Haemophilus influenzae prephenate dehydrogenase suggests unique features of bifunctional TyrA enzymes

The crystal structure of the prephenate dehydrogenase component of the bifunctional H. influenzae TyrA reveals unique structural differences between bifunctional and monofunctional TyrA enzymes

Structures of the first representatives of Pfam family PF06938 (DUF1285) reveal a new fold with repeated structural motifs and possible involvement in signal transduction

The crystal structures of SPO0140 and Sbal_2486 revealed a two-domain structure that adopts a novel fold. Analysis of the interdomain cleft suggests a nucleotide-based ligand with a genome context indicating signaling as a possible role for this family

Open and closed conformations of two SpoIIAA-like proteins (YP_749275.1 and YP_001095227.1) provide insights into membrane association and ligand binding

The crystal structures of two orthologous proteins from different Shewanella species have uncovered a resemblance to CRAL-TRIO carrier proteins, which suggest that they function as transporters of small nonpolar molecules. One protein adopts an open conformation, while the other adopts a closed structure that may act as a conformational switch in the transport of ligands at the membrane surface

Structure of LP2179, the first representative of Pfam family PF08866, suggests a new fold with a role in amino-acid metabolism

The first structural representative of the PF08866 (DUF1831) protein family reveals a potential new α+β fold and indicates a possible involvement in amino-acid metabolism