Summary
When the Lyme disease spirochete, Borrelia burgdorferi, transfers from a feeding tick into a human or other vertebrate host, the bacterium produces vertebrate‐specific proteins and represses ...factors needed for arthropod colonization. Previous studies determined that the B. burgdorferi BpuR protein binds to its own mRNA and autoregulates its translation, and also serves as co‐repressor of erp transcription. Here, we demonstrate that B. burgdorferi controls transcription of bpuR, expressing high levels of bpuR during tick colonization but significantly less during mammalian infection. The master regulator of chromosomal replication, DnaA, was found to bind specifically to a DNA sequence that overlaps the bpuR promoter. Cultured B. burgdorferi that were genetically manipulated to produce elevated levels of BpuR exhibited altered levels of several proteins, although BpuR did not impact mRNA levels. Among these was the SodA superoxide dismutase, which is essential for mammalian infection. BpuR bound to sodA mRNA in live B. burgdorferi, and a specific BpuR‐binding site was mapped 5′ of the sodA open reading frame. Recognition of posttranscriptional regulation of protein levels by BpuR adds another layer to our understanding of the B. burgdorferi regulome, and provides further evidence that bacterial protein levels do not always correlate directly with mRNA levels.
Borrelia burgdorferi differentially transcribes bpuR during its natural infectious cycle, expressing substantially greater levels of bpuR during colonization of unfed ticks than it does when infecting vertebrate hosts. The Lyme spirochete also alters bpuR transcription in response to changes in bacterial replication rate, producing greater levels of the mRNA and protein under conditions of slow replication that it does during rapid replication. DnaA, the master regulator of chromsomal replication, was found to bind specifically to the bpuR promoter region, and could thereby connect replication rate with bpuR transcript levels. The BpuR protein binds with high affinity to several RNAs, including its own mRNA and that of sodA, which inhibits translation of BpuR and SodA. It is hypothesized that B. burgdorferi utilizes DnaA and BpuR to sense bacterial replication levels during the bacteria's mammal‐tick infectious cycle, which coordinates production of virulence factors such as SodA.
Background: Drinking during pregnancy has been associated with learning disabilities in affected offspring. At present, there are no clinically effective pharmacotherapeutic interventions for these ...learning deficits. Here, we examined the effects of ABT‐239, a histamine H3 receptor antagonist, on fetal ethanol‐induced fear conditioning and spatial memory deficits.
Methods and Results: Long‐Evans rat dams stably consumed a mean of 2.82 g ethanol/kg during a 4‐hour period each day during pregnancy. This voluntary drinking pattern produced a mean peak serum ethanol level of 84 mg/dl. Maternal weight gain, litter size and birth weights were not different between the ethanol‐consuming and control groups. Female adult offspring from the control and fetal alcohol‐exposed (FAE) groups received saline or 1 mg ABT‐239/kg 30 minutes prior to fear conditioning training. Three days later, freezing time to the context was significantly reduced in saline‐treated FAE rats compared to control. Freezing time in ABT‐239‐treated FAE rats was not different than that in controls. In the spatial navigation study, adult male offspring received a single injection of saline or ABT‐239 30 minutes prior to 12 training trials on a fixed platform version of the Morris Water Task. All rats reached the same performance asymptote on Trials 9 to 12 on Day 1. However, 4 days later, first‐trial retention of platform location was significantly worse in the saline‐treated FAE rats compared control offspring. Retention by ABT‐239‐treated FAE rats was similar to that by controls. ABT‐239’s effect on spatial memory retention in FAE rats was dose dependent.
Conclusions: These results suggest that ABT‐239 administered prior to training can improve retention of acquired information by FAE offspring on more challenging versions of hippocampal‐sensitive learning tasks. Further, the differential effects of ABT‐239 in FAE offspring compared to controls raises questions about the impact of fetal ethanol exposure on histaminergic neurotransmission in affected offspring.
Biallelic mutations in G‐Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify ...disease causing GRK1 variants and use in‐depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients’ genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure‐based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease‐causing variants may impede protein function in‐silico.
In this study, Poulter et al. expand the number of mutations in Rhodopsin Kinase (GRK1), associated with Oguchi disease, from 13 to 21. The authors compare disease associated mutations with likely nonpathogenic variants in a range of bioinformatic prediction software. In silico analyses of the mutations, using a homology model, suggest mutations result in one of three potential mechanisms of disease: loss of protein, loss of kinase function or a failure of prenylation leading to mislocalisation of the protein.
To evaluate the effects of participation in a memory group intervention focusing on internal strategy use on persons with traumatic brain injury-related memory impairment.
Ninety-four adults with ...traumatic brain injury (54 in the experimental group and 40 controls) and resulting memory impairment, with severities ranging from mild to severe. All participants were at least 18 years of age at the time of injury and at least 1 year post injury at the time of study.
Non randomized pre/posttest group comparison design.
Hopkins Verbal Learning Test-Revised and Rivermead Behavioral Memory Test II.
Participation in the memory group intervention was associated with improved memory performance immediately postintervention, and improvements were maintained 1 month postintervention. Severe injury was associated with less improvement in memory outcomes than mild and moderate injuries. Age and preinjury education were not related to outcome.
Individuals with traumatic brain injury may benefit from memory group intervention focusing on internal strategy use. Study hypotheses should be retested using a randomized, controlled design, and further research is needed to better delineate influences on intervention candidacy and outcomes.
Past efforts to synthesize and quantify the magnitude and change in carbon dioxide (CO2) fluxes in terrestrial ecosystems across the rapidly warming Arctic–boreal zone (ABZ) have provided valuable ...information but were limited in their geographical and temporal coverage. Furthermore, these efforts have been based on data aggregated over varying time periods, often with only minimal site ancillary data, thus limiting their potential to be used in large-scale carbon budget assessments. To bridge these gaps, we developed a standardized monthly database of Arctic–boreal CO2 fluxes (ABCflux) that aggregates in situ measurements of terrestrial net ecosystem CO2 exchange and its derived partitioned component fluxes: gross primary productivity and ecosystem respiration. The data span from 1989 to 2020 with over 70 supporting variables that describe key site conditions (e.g., vegetation and disturbance type), micrometeorological and environmental measurements (e.g., air and soil temperatures), and flux measurement techniques. Here, we describe these variables, the spatial and temporal distribution of observations, the main strengths and limitations of the database, and the potential research opportunities it enables. In total, ABCflux includes 244 sites and 6309 monthly observations; 136 sites and 2217 monthly observations represent tundra, and 108 sites and 4092 observations represent the boreal biome. The database includes fluxes estimated with chamber (19 % of the monthly observations), snow diffusion (3 %) and eddy covariance (78 %) techniques. The largest number of observations were collected during the climatological summer (June–August; 32 %), and fewer observations were available for autumn (September–October; 25 %), winter (December–February; 18 %), and spring (March–May; 25 %). ABCflux can be used in a wide array of empirical, remote sensing and modeling studies to improve understanding of the regional and temporal variability in CO2 fluxes and to better estimate the terrestrial ABZ CO2 budget. ABCflux is openly and freely available online (Virkkala et al., 2021b, https://doi.org/10.3334/ORNLDAAC/1934).
Past efforts to synthesize and quantify the magnitude and change in carbon dioxide (CO.sub.2) fluxes in terrestrial ecosystems across the rapidly warming Arctic-boreal zone (ABZ) have provided ...valuable information but were limited in their geographical and temporal coverage. Furthermore, these efforts have been based on data aggregated over varying time periods, often with only minimal site ancillary data, thus limiting their potential to be used in large-scale carbon budget assessments. To bridge these gaps, we developed a standardized monthly database of Arctic-boreal CO.sub.2 fluxes (ABCflux) that aggregates in situ measurements of terrestrial net ecosystem CO.sub.2 exchange and its derived partitioned component fluxes: gross primary productivity and ecosystem respiration. The data span from 1989 to 2020 with over 70 supporting variables that describe key site conditions (e.g., vegetation and disturbance type), micrometeorological and environmental measurements (e.g., air and soil temperatures), and flux measurement techniques. Here, we describe these variables, the spatial and temporal distribution of observations, the main strengths and limitations of the database, and the potential research opportunities it enables. In total, ABCflux includes 244 sites and 6309 monthly observations; 136 sites and 2217 monthly observations represent tundra, and 108 sites and 4092 observations represent the boreal biome. The database includes fluxes estimated with chamber (19 % of the monthly observations), snow diffusion (3 %) and eddy covariance (78 %) techniques. The largest number of observations were collected during the climatological summer (June-August; 32 %), and fewer observations were available for autumn (September-October; 25 %), winter (December-February; 18 %), and spring (March-May; 25 %). ABCflux can be used in a wide array of empirical, remote sensing and modeling studies to improve understanding of the regional and temporal variability in CO.sub.2 fluxes and to better estimate the terrestrial ABZ CO.sub.2 budget. ABCflux is openly and freely available online (Virkkala et al., 2021b,
Immune aberrations in schizophrenia and bipolar disorder have led to the hypotheses that infectious agents or corresponding immune responses might contribute to psychiatric etiopathogeneses. We ...investigated case-control differences in exposure to the opportunistic fungal pathogen, Candida albicans, and examined associations with cognition, medication, lifestyle, and somatic conditions. We quantified C. albicans IgG antibodies in two cohorts totaling 947 individuals and evaluated odds ratios (OR) of exposure with psychiatric disorder using multivariate regressions. The case-control cohort included 261 with schizophrenia, 270 with bipolar disorder, and 277 non-psychiatric controls; the second included 139 with first-episode schizophrenia, 78 of whom were antipsychotic naive. No differences in C. albicans exposures were found until diagnostic groups were stratified by sex. In males, C. albicans seropositivity conferred increased odds for a schizophrenia diagnosis (OR 2.04-9.53, P⩽0.0001). In females, C. albicans seropositivity conferred increased odds for lower cognitive scores on Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in schizophrenia (OR 1.12, P⩽0.004), with significant decreases on memory modules for both disorders (P⩽0.0007-0.03). C. albicans IgG levels were not impacted by antipsychotic medications. Gastrointestinal (GI) disturbances were associated with elevated C. albicans in males with schizophrenia and females with bipolar disorder (P⩽0.009-0.02). C. albicans exposure was associated with homelessness in bipolar males (P⩽0.0015). In conclusion, sex-specific C. albicans immune responses were evident in psychiatric disorder subsets. Inquiry regarding C. albicans infection or symptoms may expedite amelioration of this treatable comorbid condition. Yeast exposure as a risk factor for schizophrenia and its associated cognitive and GI effects require further investigation including the possible contribution of gut-brain mechanisms.
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