Mycobacterial Gene cuvA Is Required for Optimal Nutrient Utilization and Virulence

To persist and cause disease in the host, Mycobacterium tuberculosis must adapt to its environment during infection. Adaptations include changes in nutrient utilization and alterations in growth rate. M. tuberculosis Rv1422 is a conserved gene of unknown function that was found in a genetic screen to interact with the mce4 cholesterol uptake locus. The Rv1422 protein is phosphorylated by the M. tuberculosis Ser/Thr kinases PknA and PknB, which regulate cell growth and cell wall synthesis. Bacillus subtilis strains lacking the Rv1422 homologue yvcK grow poorly on several carbon sources, and yvcK is required for proper localization of peptidoglycan synthesis. Here we show that Mycobacterium smegmatis and M. tuberculosis strains lacking Rv1422 have growth defects in minimal medium containing limiting amounts of several different carbon sources. These strains also have morphological abnormalities, including shortened and bulging cells, suggesting a cell wall defect. In both mycobacterial species, the Rv1422 protein localizes uniquely to the growing cell pole, the site of peptidoglycan synthesis in mycobacteria. An M. tuberculosis ΔRv1422 strain is markedly attenuated for virulence in a mouse infection model, where it elicits decreased inflammation in the lungs and shows impaired bacterial persistence. These findings led us to name this gene cuvA (carbon utilization and virulence protein A) and to suggest a model in which deletion of cuvA leads to changes in nutrient uptake and/or metabolism that affect cell wall structure, morphology, and virulence. Its role in virulence suggests that CuvA may be a useful target for novel inhibitors of M. tuberculosis during infection.     

The interplay between chemical speciation and physiology determines the bioaccumulation and toxicity of Cu(II) and Cd(II) to Caenorhabditis elegans

Using the well‐documented model organism Caenorhabditis elegans, a combined analysis of metal speciation in the exposure medium and body burdens of metals (Zn, Cu and Cd) was performed, and factors that are predictive of toxicological endpoints in single metal and mixed metal exposures were identified. Cu, and to a lesser extent Cd, is found to associate with Escherichia coli in the exposure medium (the food source for C. elegans) as evidenced by the observed decrease in both their dissolved and free metal ion concentrations. Together with a critical analysis of literature data, our results suggest that free metal ion concentrations and thus aqueous uptake routes are the best predictor of internal concentrations under all conditions considered, and of metal toxicity in single metal exposures. Additional factors are involved in determining the toxicity of metal mixtures. In general, the eventual adverse effects of metals on biota are expected to be a consequence of the interplay between chemical speciation in the exposure medium, timescale of exposure, exposure route as well as the nature and timescale of the biotic handling pathways.     

A preliminary investigation of the long-term outcome of the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders

Objective

The aim of this study is to conduct a preliminary examination of long-term outcomes on a broad range of affective disorder symptoms treated with a newly developed intervention: The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP).

Method

Maintenance of treatment gains at long-term follow-up (LTFU) were explored in patients (N = 15, mean age = 32.27; 60% female) who completed a clinical trial of the UP.

Results

Treatment gains observed at 6-month follow-up (6MFU) on measures of clinical severity, general symptoms of depression and anxiety, and a measure of symptom interference in daily functioning were largely maintained 12 months later (at an average of 18 months posttreatment), and any significant changes from 6MFU to LTFU reflected small increases in symptoms that remained, on average, in the subclinical range.

Conclusions

These findings provide the first initial support for the durability of broad treatment gains following transdiagnostic treatment.     

Regulation of the Fanconi anemia pathway by a CUE ubiquitin-binding domain in the FANCD2 protein

The Fanconi anemia (FA)-BRCA pathway is critical for the repair of DNA interstrand crosslinks (ICLs) and the maintenance of chromosome stability. A key step in FA-BRCA pathway activation is the covalent attachment of monoubiquitin to FANCD2 and FANCI. Monoubiquitinated FANCD2 and FANCI localize in chromatin-associated nuclear foci where they interact with several well-characterized DNA repair proteins. Importantly, very little is known about the structure, function, and regulation of FANCD2. Herein, we describe the identification and characterization of a CUE (coupling of ubiquitin conjugation to endoplasmic reticulum degradation) ubiquitin-binding domain (UBD) in FANCD2, and demonstrate that the CUE domain mediates noncovalent binding to ubiquitin in vitro. We show that although mutation of the CUE domain destabilizes FANCD2, the protein remains competent for DNA damage-inducible monoubiquitination and phosphorylation. Importantly, we demonstrate that the CUE domain is required for interaction with FANCI, retention of monoubiquitinated FANCD2, and FANCI in chromatin, and for efficient ICL repair. Our results suggest a model by which heterodimerization of monoubiquitinated FANCD2 and FANCI in chromatin is mediated in part through a noncovalent interaction between the FANCD2 CUE domain and monoubiquitin covalently attached to FANCI, and that this interaction shields monoubiquitinated FANCD2 from polyubiquitination and proteasomal degradation.     

Patterns of gaze behavior during an eye-tracking measure of joint attention in typically developing children and children with autism spectrum disorder

This study evaluated whether diagnostic classifications or features of ASD were associated with individual differences in children's gaze pattern during an eye-tracking measure of joint attention. The sample included 21 children with ASD (mean age, 7.3 ± 1.5 years) and 24 typically developing children (mean age, 6.8 ± 1.6 years), matched on receptive language abilities. Results revealed no significant group differences on global measures of gaze allocation (total gaze time allocation). However, significant group differences emerged using a measure evaluating a microstructure of children's gaze (duration of first fixation). In addition, individual differences in children's gaze pattern were reliably predicted by parent report measures of children's social abilities. The majority of children in this sample (including all typically developing children and those children with ASD who scored lowest on the SRS Social Awareness subscale) showed significant modulation in eye-gaze between the two experimental conditions. In contrast, children with ASD who also scored the highest on the SRS Social Awareness subscale consistently failed to modulate their eye gaze in accordance with the experimental condition. This failure to flexibly modulate gaze in the context of a joint attention eye-tracking paradigm may reveal children's limited awareness of social cues that may further limit social learning.     

Alagille syndrome and Wilson disease in siblings: a diagnostic conundrum

The authors describe two siblings, each with a different, rare genetic condition that affects liver function. The index case, the 18-year-old asymptomatic brother of a young man recently diagnosed with Wilson disease, presented for Wilson disease screening and was also found to have abnormal liver function suggestive of cholestasis. However, ceruloplasmin level, 24 h urine copper concentration and liver synthetic function were normal. Further hepatic investigations and genetic mutation analysis were performed, ultimately leading to a diagnosis of Alagille syndrome. He was treated with ursodiol, which resulted in normalization of his liver function tests. Subsequently, he was found to be a carrier for a mutation in the Wilson disease gene, ATP7B. In the present report, the potential implications of being a heterozygote for Wilson disease in the context of Alagille syndrome are discussed. Also stressed is that care must be exercised by the clinician when diagnosing family members who may present with two different disorders closely mimicking one another.     

Perceived information provision and satisfaction among lymphoma and multiple myeloma survivors—results from a Dutch population-based study

To improve posttreatment care for (long-term) lymphoma survivors in the Netherlands, survivorship clinics are being developed. As information provision is an important aspect of survivorship care, our aim was to evaluate the current perceived level of and satisfaction with information received by non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL) and multiple myeloma (MM) survivors, and to identify associations with sociodemographic and clinical characteristics. The population-based Eindhoven Cancer Registry was used to select all patients diagnosed with NHL, HL and MM from 1999 to 2009. In total, 1,448 survivors received a questionnaire, and 1,135 of them responded (78.4?%). The EORTC QLQ-INFO25 was used to evaluate the perceived level of and satisfaction with information. Two thirds of survivors were satisfied with the amount of received information, with HL survivors being most satisfied (74?%). At least 25?% of survivors wanted more information. Young age, having had chemotherapy, having been diagnosed more recently, using internet for information and having no comorbidities were the most important factors associated with higher perceived levels of information provision. Although information provision and satisfaction with information seems relatively good in lymphoma and MM survivors, one third expressed unmet needs. Furthermore, variations between subgroups were observed. Good information provision is known to be associated with better quality of life. Survivorship care plans could be a way to achieve this.