Familial DiGeorge syndrome and associated partial monosomy of chromosome 22

Summary Partial monosomy of 22q due to an unbalanced 4;22 translocation was seen in a 2-month-old male with Type I truncus arterious, dysmorphic features, and T-cell abnormalities. The family history revealed a previous sib with Type I truncus arteriosus, thymic aplasia, and parathyroid hypoplasia noted on postmortem examination, consistent with DiGeorge syndrome. Evaluation of the asymptomatic mother of these two patients revealed partial T-cell deficiency and the same unbalanced translocation with deletion of proximal 22qll. These findings provide further evidence that some cases of complete or partial DiGeorge syndrome are associated with monosomy of the proximal long arm of chromosome 22, and they may explain many, if not all, familial cases of the syndrome.Supported in part by National Foundation-March of Dimes Grant No. 2-161/C-331. Funds from the Texas Department of Health through PL94-278 National Genetic Diseases Act, from the Robert J. Kleberg, Jr. Center for Human Genetics, and USPHS Grant No. RR-05425.     

A novel hypothalamic peptide, pituitary adenylate cyclase activating peptide, modulates Sertoli cell function in vitro.

Pituitary adenylate cyclase-activating peptide (PACAP), a novel hypothalamic peptide that has been shown to exist in several tissues including the testis, was examined for its effects on cultured rat Sertoli cells. PACAP stimulates cAMP accumulation in Sertoli cells cultured from 15-day-old rats in the presence or absence of methylisobutylxanthine, a phosphodiesterase inhibitor, and in the presence of pertussis toxin, a blocker of the adenylate cyclase inhibitory pathway. Maximal stimulation, which is 20-40% of that attainable with FSH, occurs at PACAP concentrations of 10 nM: the ED50 is approximately 100 pM. The ability of PACAP to stimulate Sertoli cell cAMP declines with increasing age of donor animals (15-60 days of age) in a fashion similar to the FSH effect. PACAP stimulation of Sertoli cell cAMP accumulation is additive with submaximal, but not maximal, concentrations of FSH or forskolin. PACAP also stimulates the secretion of lactate, estradiol, and inhibin in a concentration-dependent manner. The stimulation of Sertoli cell cAMP accumulation by PACAP is not altered by a vasoactive intestinal peptide antagonist, and vasoactive intestinal peptide alone does not stimulate cAMP accumulation, indicating that PACAP is not acting via vasoactive intestinal peptide receptors. Further experiments are needed to determine whether PACAP is synthesized within the testis and if so, in which cell types; however, the present data clearly demonstrate that PACAP can modulate Sertoli cell function in vitro.     

Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer

Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that accumulate in response to tumor progression. Compelling data from mouse models and human cancer patients showed that tumor-induced inflammatory mediators induce MDSC differentiation. However, the mechanisms underlying MDSC persistence is largely unknown. Here, we demonstrated that tumor-induced MDSCs exhibit significantly decreased spontaneous apoptosis as compared with myeloid cells with the same phenotypes from tumor-free mice. Consistent with the decreased apoptosis, cell surface Fas receptor decreased significantly in tumor-induced MDSCs. Screening for changes of key apoptosis mediators downstream the Fas receptor revealed that expression levels of IRF8 and Bax are diminished, whereas expression of Bcl-xL is increased in tumor-induced MDSCs. We further determined that IRF8 binds directly to Bax and Bcl-x promoter in primary myeloid cells in vivo, and IRF8-deficient MDSC-like cells also exhibit increased Bcl-xL and decreased Bax expression. Analysis of CD69 and CD25 levels revealed that cytotoxic T lymphocytes (CTLs) are partially activated in tumor-bearing hosts. Strikingly, FasL but not perforin and granzymes were selectively activated in CTLs in the tumor-bearing host. ABT-737 significantly increased the sensitivity of MDSCs to Fas-mediated apoptosis in vitro. More importantly, ABT-737 therapy increased MDSC spontaneous apoptosis and decreased MDSC accumulation in tumor-bearing mice. Our data thus determined that MDSCs use down-regulation of IRF8 to alter Bax and Bcl-xL expression to deregulate the Fas-mediated apoptosis pathway to evade elimination by host CTLs. Therefore, targeting Bcl-xL is potentially effective in suppression of MDSC persistence in cancer therapy.     

SPEED: a molecular-evolution-based database of mammalian orthologous groups

MOTIVATION: The abundance of nucleotide sequence information available has expanded horizons of inquiry for molecular evolution; however, the full potential of whole-genome analysis has not been realized because of inadequate tools. Here, we present one of the first toolkits to aid multidisciplinary high-throughput analysis. SUMMARY: SPEED was created to integrate molecular evolutionary data with existing genetic resources and provide a straightforward user interface to 17,352 orthologous gene groups, containing representatives from eight mammalian species and an avian outgroup. AVAILABILITY: See http://bioinfobase.umkc.edu/speed/ for access.     

Regulated specific proteolysis of the Cajal body marker protein coilin

Cajal bodies (CB) are subnuclear domains that contain various proteins with diverse functions including the CB marker protein coilin. In this study, we investigate the proteolytic activity of calpain on coilin. Here, we report a 28-kDa cleaved coilin fragment detected by two coilin antibodies that is cell cycle regulated, with levels that are consistently reduced during mitosis. We further show that an in vitro calpain assay with full-length or C-terminal coilin recombinant protein releases the same size cleaved fragment. Furthermore, addition of exogenous RNA to purified coilin induces proteolysis by calpain. We also report that the relative levels of this cleaved coilin fragment are susceptible to changes induced by various cell stressors, and that coilin localization is affected by inhibition or knockdown of calpain both under normal and stressed conditions. Collectively, our data suggest that coilin is subjected to regulated specific proteolysis by calpain, and this processing may play a role in the regulation of coilin activity and CB formation.     

The Escherichia coli clamp loader can actively pry open the β-sliding clamp

Clamp loaders load ring-shaped sliding clamps onto DNA. Once loaded onto DNA, sliding clamps bind to DNA polymerases to increase the processivity of DNA synthesis. To load clamps onto DNA, an open clamp loader-clamp complex must form. An unresolved question is whether clamp loaders capture clamps that have transiently opened or whether clamp loaders bind closed clamps and actively open clamps. A simple fluorescence-based clamp opening assay was developed to address this question and to determine how ATP binding contributes to clamp opening. A direct comparison of real time binding and opening reactions revealed that the Escherichia coli γ complex binds β first and then opens the clamp. Mutation of conserved "arginine fingers" in the γ complex that interact with bound ATP decreased clamp opening activity showing that arginine fingers make an important contribution to the ATP-induced conformational changes that allow the clamp loader to pry open the clamp.     

Malnutrition and Childhood Disability in Turkana,Kenya: Results from a Case-Control Study

Background

Children with disabilities may be particularly vulnerable to malnutrition, as a result of exclusions and feeding difficulties. However, there is limited evidence currently available on this subject.

Methods

A population-based case-control study was conducted in Turkana County, Kenya, between July and August 2013. Key informants in the community identified children aged 6 months to 10 years who they believed may have a disability. These children were screened by a questionnaire (UNICEF-Washington Group) and assessed by a paediatrician to confirm whether they had a disability and the type. Two controls without disabilities were selected per case: A sibling control (sibling nearest in age) and a neighbourhood control (nearest neighbour within one year of age). The caregiver completed a questionnaire on behalf of the child (e.g. information on feeding, poverty, illness, education), and anthropometric measures were taken. We undertook multivariable logistic and linear regression analyses to estimate the relationship between disability and malnutrition.

Results

The study included 311 cases with disabilities, 196 sibling controls and 300 neighbour controls. Children with disabilities were more likely to report a range of feeding difficulties. They were 1.6–2.9 times more likely to have malnutrition in comparison to neighbour controls or family controls, including general malnutrition (low weight for age), stunting (low height for age), low body mass index (BMI) or low mid upper arm circumference (MUAC) for age. Children with disabilities were almost twice as likely to have wasting (low weight for height) in comparison to neighbour controls (OR = 1.9, 95% CI 1.1–3.2), but this difference was not apparent compared with siblings (OR = 1.5, 95% CI 0.8–2.7). Children with disabilities also faced other exclusions. For instance those aged 5+ were much more likely not to attend school than neighbour controls (OR = 8.5, 95% CI 4.3–16.9).

Conclusions

Children with disabilities were particularly vulnerable to malnutrition, even within this area of food insecurity and widespread malnutrition. Efforts need to be made to include children with disabilities within food supplementation programmes, and school based programmes alone may be inadequate to meet this need. Exclusion of children with disabilities from education is also a priority area to be addressed.     

Disentangling Ethnicity and Context as Predictors of Parenting Within Rural African American Families

This study will address the initial question: Are there ethnic differences in parenting that remain when contextual variables are controlled and are related to culture, focusing on two samples of rural African American families. This study is part of a series of coordinated studies presented in this special issue (Le et al., 2008). Specific attention was given to ascertaining whether these differences were explained by contextual factors, such as socioeconomic factors (i.e., parents' educational level, homeownership, family structure, and number of children in the household). Finally, this study examined whether any differences in parenting (warmth, monitoring, communication) were attributed to cultural factors, after controlling for the contributions of contextual factors. Results indicate that parental education, family size, negative life events, racial discrimination, neighborhood characteristics, and religiosity were significantly associated with various domains of parenting among rural African Americans.