Measurement of radioactive contamination in the high-resistivity silicon CCDs of the DAMIC experiment

We present measurements of radioactive contamination in the high-resistivity silicon charge-coupled devices (CCDs) used by the DAMIC experiment to search for dark matter particles. Novel analysis methods, which exploit the unique spatial resolution of CCDs, were developed to identify $\alpha$ and $\beta$ particles. Uranium and thorium contamination in the CCD bulk was measured through $\alpha$ spectroscopy, with an upper limit on the $^{238}$U ($^{232}$Th) decay rate of 5 (15) kg$^{-1}$ d$^{-1}$ at 95% CL. We also searched for pairs of spatially correlated electron tracks separated in time by up to tens of days, as expected from $^{32}$Si-$^{32}$P or $^{210}$Pb-$^{210}$Bi sequences of $\beta$ decays. The decay rate of $^{32}$Si was found to be $80^{+110}_{-65}$ kg$^{-1}$ d$^{-1}$ (95% CI). An upper limit of $\sim$35 kg$^{-1}$ d$^{-1}$ (95% CL) on the $^{210}$Pb decay rate was obtained independently by $\alpha$ spectroscopy and the $\beta$ decay sequence search. These levels of radioactive contamination are sufficiently low for the successful operation of CCDs in the forthcoming 100 g DAMIC detector.Comment: 18 pages, 20 figure

Acute nongonococcal infectious arthritis

A retrospective analysis of 71 nongonococcal joint infections in 63 patients in reported. Staphylococcus aureus was isolated from 59% of the patients. Five patients died as a result of infections. The outcome in Gram-n egative joint infections was similar to the overall outcome in the entire series of patients. All 11 joints with infected prostheses ultimately required removal of the prostheses. All patients were treated with appropriate parenteral antibiotics, and surgical intervention was used in 40 joints. Six patients underwent surgical treatment because of inability to sterilize the joint with antibiotics and because of repeated joint aspirations. The outcome with surgical intervention was good only in patients younger than 16 years of age. Medical therapy (parenteral antibiotics and frequent joint aspirations) led to good results in 74% of the patients. Outcome of joint infection was also influenced by factors which contribute to imparied host resistance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/37749/1/1780230803_ftp.pd

Circadian Rhythm and Sleep Disruption: Causes, Metabolic Consequences and Countermeasures.

Circadian (∼ 24 hour) timing systems pervade all kingdoms of life, and temporally optimize behaviour and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behaviour and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these too are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally-driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioural and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis

Prolactin Receptor Signaling Is Essential for Perinatal Brown Adipocyte Function: A Role for Insulin-like Growth Factor-2

BACKGROUND: The lactogenic hormones prolactin (PRL) and placental lactogens (PL) play central roles in reproduction and mammary development. Their actions are mediated via binding to PRL receptor (PRLR), highly expressed in brown adipose tissue (BAT), yet their impact on adipocyte function and metabolism remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: PRLR knockout (KO) newborn mice were phenotypically characterized in terms of thermoregulation and their BAT differentiation assayed for gene expression studies. Derived brown preadipocyte cell lines were established to evaluate the molecular mechanisms involved in PRL signaling on BAT function. Here, we report that newborn mice lacking PRLR have hypotrophic BAT depots that express low levels of adipocyte nuclear receptor PPARgamma2, its coactivator PGC-1alpha, uncoupling protein 1 (UCP1) and the beta3 adrenoceptor, reducing mouse viability during cold challenge. Immortalized PRLR KO preadipocytes fail to undergo differentiation into mature adipocytes, a defect reversed by reintroduction of PRLR. That the effects of the lactogens in BAT are at least partly mediated by Insulin-like Growth Factor-2 (IGF-2) is supported by: i) a striking reduction in BAT IGF-2 expression in PRLR KO mice and in PRLR-deficient preadipocytes; ii) induction of cellular IGF-2 expression by PRL through JAK2/STAT5 pathway activation; and iii) reversal of defective differentiation in PRLR KO cells by exogenous IGF-2. CONCLUSIONS: Our findings demonstrate that the lactogens act in concert with IGF-2 to control brown adipocyte differentiation and growth. Given the prominent role of brown adipose tissue during the perinatal period, our results identified prolactin receptor signaling as a major player and a potential therapeutic target in protecting newborn mammals against hypothermia