Identification of a Novel Response Regulator, Crr1, That Is Required for Hydrogen Peroxide Resistance in Candida albicans

Candida albicans colonises numerous niches within humans and thus its success as a pathogen is dependent on its ability to adapt to diverse growth environments within the host. Two component signal transduction is a common mechanism by which bacteria respond to environmental stimuli and, although less common, two component-related pathways have also been characterised in fungi. Here we report the identification and characterisation of a novel two component response regulator protein in C. albicans which we have named CRR1 (Candida Response Regulator 1). Crr1 contains a receiver domain characteristic of response regulator proteins, including the conserved aspartate that receives phosphate from an upstream histidine kinase. Significantly, orthologues of CRR1 are present only in fungi belonging to the Candida CTG clade. Deletion of the C. albicans CRR1 gene, or mutation of the predicted phospho-aspartate, causes increased sensitivity of cells to the oxidising agent hydrogen peroxide. Crr1 is present in both the cytoplasm and nucleus, and this localisation is unaffected by oxidative stress or mutation of the predicted phospho-aspartate. Furthermore, unlike the Ssk1 response regulator, Crr1 is not required for the hydrogen peroxide-induced activation of the Hog1 stress-activated protein kinase pathway, or for the virulence of C. albicans in a mouse model of systemic disease. Taken together, our data suggest that Crr1, a novel response regulator restricted to the Candida CTG clade, regulates the response of C. albicans cells to hydrogen peroxide in a Hog1-independent manner that requires the function of the conserved phospho-aspartate

The Gene Ontology knowledgebase in 2023

The Gene Ontology (GO) knowledgebase (http://geneontology.org) is a comprehensive resource concerning the functions of genes and gene products (proteins and noncoding RNAs). GO annotations cover genes from organisms across the tree of life as well as viruses, though most gene function knowledge currently derives from experiments carried out in a relatively small number of model organisms. Here, we provide an updated overview of the GO knowledgebase, as well as the efforts of the broad, international consortium of scientists that develops, maintains, and updates the GO knowledgebase. The GO knowledgebase consists of three components: (1) the GO-a computational knowledge structure describing the functional characteristics of genes; (2) GO annotations-evidence-supported statements asserting that a specific gene product has a particular functional characteristic; and (3) GO Causal Activity Models (GO-CAMs)-mechanistic models of molecular "pathways" (GO biological processes) created by linking multiple GO annotations using defined relations. Each of these components is continually expanded, revised, and updated in response to newly published discoveries and receives extensive QA checks, reviews, and user feedback. For each of these components, we provide a description of the current contents, recent developments to keep the knowledgebase up to date with new discoveries, and guidance on how users can best make use of the data that we provide. We conclude with future directions for the project

Alternative option labeling impacts decision‐making in noninvasive prenatal screening

Prenatal genetic screening should be an informed, autonomous patient choice. Extrinsic factors which influence patient decision- making threaten the ethical basis of prenatal genetic screening. Prior research in the area of medical decision- making has identified that labeling may have unanticipated effects on patient perceptions and decision- making processes. This Internet- administered study explored the impact of option labeling on the noninvasive prenatal screening (NIPS) selections of US adults. A total of 1,062 participants were recruited through Amazon Mechanical Turk (MTurk) and randomly assigned to one of three possible label sets reflecting provider- derived and industry- derived option labels used in prenatal screening. Multinomial logistic regression analysis showed option labeling had a statistically significant impact on the NIPS selections of study participants (p = .0288). Outcomes of the Satisfaction with Decision Scale (SWD) indicated option labels did not play a role in participant satisfaction with screening selection. The results of this study indicate a need for further evaluation of the impact NIPS option labeling has on patient screening decisions in real- world clinical interactions. Clinical providers and testing laboratories offering NIPS should give careful consideration to the option labels used with prenatal screening so as to minimize influence on patient screening selection and decision- making processes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163878/1/jgc41191_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163878/2/jgc41191.pd

Alternative option labeling impacts decision- making in noninvasive prenatal screening

Prenatal genetic screening should be an informed, autonomous patient choice. Extrinsic factors which influence patient decision- making threaten the ethical basis of prenatal genetic screening. Prior research in the area of medical decision- making has identified that labeling may have unanticipated effects on patient perceptions and decision- making processes. This Internet- administered study explored the impact of option labeling on the noninvasive prenatal screening (NIPS) selections of US adults. A total of 1,062 participants were recruited through Amazon Mechanical Turk (MTurk) and randomly assigned to one of three possible label sets reflecting provider- derived and industry- derived option labels used in prenatal screening. Multinomial logistic regression analysis showed option labeling had a statistically significant impact on the NIPS selections of study participants (p = .0288). Outcomes of the Satisfaction with Decision Scale (SWD) indicated option labels did not play a role in participant satisfaction with screening selection. The results of this study indicate a need for further evaluation of the impact NIPS option labeling has on patient screening decisions in real- world clinical interactions. Clinical providers and testing laboratories offering NIPS should give careful consideration to the option labels used with prenatal screening so as to minimize influence on patient screening selection and decision- making processes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163878/1/jgc41191_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163878/2/jgc41191.pd

A novel TRPC6mutation in a family with podocytopathy and clinical variability

BACKGROUND: Mutation in several podocyte-specific genes have been noted to result in phenotypic heterogeneity. Herein, we report a novel, autosomal dominant TRPC6 mutation in a family with disease ranging from asymptomatic minimal change disease to end-stage kidney disease. CASE PRESENTATION: A 35 year old woman developed asymptomatic, nephrotic range proteinuria during pregnancy that did not resolve after delivery. Her mother had end-stage kidney disease of unknown etiology and her brother had asymptomatic proteinuria. Kidney biopsy revealed minimal change disease in both the proband and her brother. Genetic testing was performed in the proband and mother, revealing a novel frameshift mutation in TRPC6, D873fsX878. The proband continues to have subnephrotic range proteinuria and normal creatinine but her brother has since developed progressive chronic kidney disease. CONCLUSIONS: The current case report underscores the heterogeneity of disease in podocytopathies and related genes. Genetic testing of podocyte genes is useful in order to understand the pathophysiologic processes underlying these overlapping diseases

Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings.

The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data