No abstract

The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night1–3. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and while rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes4, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism, and insulin signaling is delayed in circadian mutant mice, and both Clock5,6 and Bmal17 mutants exhibit impaired glucose tolerance, reduced insulin secretion, and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival, and synaptic vesicle assembly. Remarkably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective β-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the β-cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger onset of diabetes mellitus.

Although pneumonic plague is the deadliest manifestation of disease caused by the bacterium Yersinia pestis, there is surprisingly little information on the cellular and molecular mechanisms responsible for Y. pestis-triggered pathology in the lung. Therefore, to understand the progression of this unique disease, we characterized an intranasal mouse model of primary pneumonic plague. Mice succumbed to a purulent multifocal severe exudative bronchopneumonia that closely resembles the disease observed in humans. Analyses revealed a strikingly biphasic syndrome, in which the infection begins with an antiinflammatory state in the first 24 -36 h that rapidly progresses to a highly proinflammatory state by 48 h and death by 3 days. To assess the adaptation of Y. pestis to a mammalian environment, we used DNA microarray technology to analyze the transcriptional responses of the bacteria during interaction with the mouse lung. Included among the genes up-regulated in vivo are those comprising the yop-ysc type III secretion system and genes contained within the chromosomal pigmentation locus, validating the use of this technology to identify loci essential to the virulence of Y. pestis.inflammation ͉ microarray ͉ Yersinia pestis P neumonic plague is the deadliest manifestation of disease caused by the bacterium Yersinia pestis. Although rare compared with the bubonic form of plague, which is acquired by skin penetration, primary pneumonic plague is highly contagious and almost always fatal. The current worldwide incidence of plague is low by historical standards, but the possible combination of widespread aerosol dissemination and rapid disease progression are of particular concern for defense against bioterrorism (1).In cases of primary pneumonic plague in humans, microscopic examination of lung tissue reveals multiple histological patterns, including acute pneumonia, intraalveolar hemorrhage and edema, and the presence of extracellular bacteria in the alveoli but not the interstitium (2). In addition, extensive neutrophilic infiltrate and fibrin deposition have been observed, and in some cases a complete loss of recognizable alveolar architecture results from the infection (3, 4). Studies of experimental primary pneumonic plague in monkeys, mice, and guinea pigs showed similar pathologic effects, including extensive intraalveolar edema, massive bacterial proliferation in the small airways, and numerous neutrophils in the alveoli (5-8).How Y. pestis triggers pulmonary pathology is largely unexplored, as are the bacterial responses to this dramatically changing host environment. DNA microarray technology has been widely used to assess transcriptional changes in bacterial gene expression in vitro, but analyses of the bacterial transcriptome during host infection have been hampered by two significant problems (9). These include the excess amounts of copurified eukaryotic RNA that may produce nonspecific hybridization signals on the microarray, and the oftenlimiting amounts of bacterial RNA extracted from an animal, which w...

Background-The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation.

Epidermal keratinocytes form a highly organized stratified epithelium and sustain a competent barrier function together with dermal and hematopoietic cells. The Notch signaling pathway is a critical regulator of epidermal integrity. Here, we show that keratinocyte-specific deletion of total Notch signaling triggered a severe systemic B-lymphoproliferative disorder, causing death. RBP-j is the DNA binding partner of Notch, but both RBP-j–dependent and independent Notch signaling were necessary for proper epidermal differentiation and lipid deposition. Loss of both pathways caused a persistent defect in skin differentiation/barrier formation. In response, high levels of thymic stromal lymphopoietin (TSLP) were released into systemic circulation by Notch-deficient keratinocytes that failed to differentiate, starting in utero. Exposure to high TSLP levels during neonatal hematopoiesis resulted in drastic expansion of peripheral pre- and immature B-lymphocytes, causing B-lymphoproliferative disorder associated with major organ infiltration and subsequent death, a previously unappreciated systemic effect of TSLP. These observations demonstrate that local skin perturbations can drive a lethal systemic disease and have important implications for a wide range of humoral and autoimmune diseases with skin manifestations.