Bockkarstensen3544
But most function prediction tools do not take these key residues into account. We developed interactive tools for identifying functional residues in a protein sequence by comparing it to proteins with known functional residues. Our tools also make it easy to compare key residues across many similar proteins. This should help biologists check if a protein's function is predicted correctly, or to predict if groups of similar proteins have conserved functions.Gene transfer agents (GTAs) are virus-like elements that are encoded by some bacterial and archaeal genomes. The production of GTAs can be induced by carbon depletion and results in host lysis and the release of virus-like particles that contain mostly random fragments of the host DNA. The remaining members of a GTA-producing population act as GTA recipients by producing proteins needed for GTA-mediated DNA acquisition. Here, we detected a codon usage bias toward codons with more readily available tRNAs in the RcGTA-like GTA genes of alphaproteobacterial genomes. Such bias likely improves the translational efficacy during GTA gene expression. While the strength of codon usage bias fluctuates substantially among individual GTA genes and across taxonomic groups, it is especially pronounced in Sphingomonadales, whose members are known to inhabit nutrient-depleted environments. By screening genomes for gene families with trends in codon usage biases similar to those in GTA genes, we found a gene that likely encodiruses. We show that GTA genes are under selection to improve the efficiency of their translation when the host activates GTA production. The selection is especially pronounced in bacteria that occupy nutrient-depleted environments. Intriguingly, several genes involved in incorporation of DNA into a genome are under similar selection pressure, suggesting that they may facilitate the integration of GTA-delivered DNA into the host genome. Our findings underscore the potential importance of GTAs as a mechanism of HGT under nutrient-limited conditions, which are widespread in microbial habitats.There is considerable debate about the benefits and trade-offs for colony formation in a major marine nitrogen fixer, Trichodesmium. selleck chemical To quantitatively analyze the trade-offs, we developed a metabolic model based on carbon fluxes to compare the performance of Trichodesmium colonies and free trichomes under different scenarios. Despite reported reductions in carbon fixation and nitrogen fixation rates for colonies relative to free trichomes, we found that model colonies can outperform individual cells in several cases. The formation of colonies can be advantageous when respiration rates account for a high proportion of the carbon fixation rate. Negative external influence on vital rates, such as mortality due to predation or micronutrient limitations, can also create a net benefit for colony formation relative to individual cells. In contrast, free trichomes also outcompete colonies in many scenarios, such as when respiration rates are equal for both colonies and individual cells or when there is a net positiveTrichodesmium? To answer this question, we developed a carbon flux model that utilizes existing published rates to evaluate whether and when colony formation can be sustained. Enhanced respiration rates, influential external factors such as environmental conditions and ecological interactions, and variable carbon and nitrogen fixation rates can all create scenarios for colony formation to be a viable strategy. Our results show that colony formation is an ecologically beneficial strategy under specific conditions, enabling Trichodesmium to be a globally significant organism.
Drug development strategies for genetic diseases depend critically on accurate knowledge of how pathogenic variants cause disease. For some well-studied genes, the direct effects of pathogenic variants are well documented as loss-of-function, gain-of-function or hypermorphic, or a combination of the two. For many genes, however, even the direction of effect of variants remains unclear. Classification of Mendelian disease genes in terms of whether pathogenic variants are loss- or gain-of-function would directly inform drug development strategies.
We leveraged the recent dramatic increase in reported pathogenic variants to provide a novel approach to inferring the direction of effect of pathogenic variants. Specifically, we quantify the ratio of reported pathogenic variants that are missense compared to loss-of-function.
We first show that for many genes that cause dominant Mendelian disease, the ratio of reported pathogenic missense variants is diagnostic of whether the gene causes disease through loss- or gain-of-function, or a combination. Second, we identify a set of genes that appear to cause disease largely or entirely through gain-of-function or hypermorphic pathogenic variants.
We suggest a set of 16 genes suitable for drug developmental efforts utilizing direct inhibition.
We suggest a set of 16 genes suitable for drug developmental efforts utilizing direct inhibition.
Mechanically ventilated emergency department (ED) patients experience high morbidity and mortality. In a prior trial at our center, ED-based lung-protective ventilation was associated with improved care delivery and outcomes. Whether this strategy has persisted in the years after the trial remains unclear. The objective was to assess practice change and clinical outcomes associated with ED lung-protective ventilation.
Secondary analysis of individual patient-level data from prior clinical trials and cohort studies.
ED and ICUs of a single academic center.
Mechanically ventilated adults.
A lung-protective ventilator protocol used as the default approach in the ED.
The primary ventilator-related outcome was tidal volume, and the primary clinical outcome was hospital mortality. Secondary outcomes included ventilator-, hospital-, and ICU-free days. Multivariable logistic regression, propensity score (PS)-adjustment, and multiple a priori subgroup analyses were used to evaluate outcome as a function ofeans to improve outcome.
ED lung-protective ventilation has persisted in the years since implementation and was associated with improved outcomes. These data suggest the use of ED-based lung-protective ventilation as a means to improve outcome.Azole drugs represent the primary means of treating infections associated with the filamentous fungal pathogen Aspergillus fumigatus. A central player in azole resistance is the Zn2Cys6 zinc cluster-containing transcription factor AtrR. This factor stimulates expression of both the cyp51A gene, which encodes the azole drug target enzyme, as well as an ATP-binding cassette transporter-encoding gene called abcG1 (cdr1B). We used a fusion protein between AtrR and the tandem affinity purification (TAP) moiety to purify proteins that associated with AtrR from A. fumigatus. Protein fractions associated with AtrR-TAP were subjected to multidimensional protein identification technology mass spectrometry, and one of the proteins identified was encoded by the AFUA_6g08010 gene. We have designated this protein NcaA (for nuclear coactivator of AtrR). Loss of ncaA caused a reduction in voriconazole resistance and drug-induced abcG1 expression, although it did not impact induction of cyp51A transcription. We confirmed the tle of the regulation of this transcription factor. Using a biochemical approach, we identified a new protein called NcaA that is involved in regulation of AtrR at certain target gene promoters. Understanding the mechanisms controlling AtrR function is an important goal in preventing or reversing azole resistance in this pathogen.Anelloviruses are the most common viruses infecting humans. Every human carries a nonpathogenic personal anellovirus virome (anellome), yet it is unknown which mechanisms contribute to its stability. Here, we assessed the dynamics and impact of a host antiviral defense mechanism-cytidine deaminase activity leading to C to U editing in anelloviruses-on the stability of the anellome. We investigated anellome sequence data obtained from serum samples collected every 6 months from two healthy subjects followed for more than 30 years. The subjects were infected by a total of 64 anellovirus lineages. Minus-stranded C to U editing was observed in lineages belonging to the Alpha-, Beta-, and Gammatorquevirus genera. The edited genomes were present within virus particles, therefore editing must have occurred at the late stages of the virus life cycle. Editing was favored by 5'-TC contexts in the virus genome, indicating that apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like, catalytic subunit 3 or A3 (A results expand our knowledge of anellovirus-host interactions, which may be important for the design of gene therapies.Dispersion is an active process exhibited by Pseudomonas aeruginosa during the late stages of biofilm development or in response to various cues, including nitric oxide and glutamate. Upon cue sensing, biofilm cells employ enzymes that actively degrade the extracellular matrix, thereby allowing individual cells to become liberated. While the mechanism by which P. aeruginosa senses and relays dispersion cues has been characterized, little is known about how dispersion cue sensing mechanisms result in matrix degradation. Considering that the alginate and motility regulator AmrZ has been reported to regulate genes that play a role in dispersion, including those affecting virulence, c-di-GMP levels, Pel and Psl abundance, and motility, we asked whether AmrZ contributes to the regulation of dispersion. amrZ was found to be significantly increased in transcript abundance under dispersion-inducing conditions, with the inactivation of amrZ impairing dispersion by P. aeruginosa biofilms in response to glutamate and ni to many of the phenotypic changes ascribed to dispersion, including the modulation of motility and matrix production, little is known about the regulatory mechanisms leading to matrix degradation and cells actively leaving the biofilm. In this study, we report for the first time an essential role of the transcriptional regulator AmrZ and two AmrZ-dependent genes, napB, and PA1891, in the dispersion response, thereby linking dispersion cue sensing via BdlA to the regulation of matrix degradation and to the ultimate liberation of bacterial cells from the biofilm.We investigated the temporal profile of multiple components of the serological response after asymptomatic or mildly symptomatic SARS-CoV-2 infection, in a cohort of 67 previously SARS-CoV-2 naive young adults, up to 8.5 months after infection. We found a significant decrease of spike IgG and neutralization antibody titers from early (11 to 56 days) to late (4 to 8.5 months) time points postinfection. Over the study period, S1-specific IgG levels declined significantly faster than that of the S2-specific IgG. Further, serum antibodies from PCR-confirmed participants cross-recognized S2, but not S1, of the betacoronaviruses HKU1 and OC43, suggesting a greater degree of cross-reactivity of S2 among betacoronaviruses. Antibody-Dependent Natural Killer cell Activation (ADNKA) was detected at the early time point but significantly decreased at the late time point. Induction of serum Antibody-Dependent Monocyte Phagocytosis (ADMP) was detected in all the infected participants, and its levels remained stable over time.
