New Evidence of a Post-Laurentide Local Cirque Glacier on Mount Washington, New Hampshire

As global temperatures warmed and the last North American continental ice sheet receded there were several climate reversals during which time mean temperatures in New England were significantly reduced. Decreased temperatures in combination with increased precipitation may have supported the formation or reactivation of local mountain glaciers in pre-existing cirques on Mt. Washington, New Hampshire. Evidence supporting the existence of a local cirque glacier would provide important constraints on climatic conditions during the late-glacial Holocene transition. Preliminary mapping done in the area has identified a potential terminal moraine associated with a local valley glacier in the Great Gulf, the largest cirque-like feature on Mount Washington. The presence of this landform is significant because any pre-Wisconsin evidence of valley glaciers in the Great Gulf would likely have been expunged by the presence of continental ice. In order to determine the origins of the terminal moraine, representative samples of the till composing the moraine were collected by digging five test pits across the feature, sampling ~50 hand-sized stones from each pit, and determining the provenence of individual stones. Results indicate that the landform is composed of unsorted clasts with provenances of both local and regional origin. Clasts sourced within the Great Gulf support the interpretation that they were deposited by processes dependent on the presence of a local mountain glacier during a post-Wisconsin climate reversal. Stones of more distant origins may be attributed to residual till, associated with a continental ice mass that occupied the cirque at the time of local glacier reactivation. This data shows that the landform was deposited from processes taking place within the Great Gulf, and the pronounced topography and volume of the landform would support its interpretation as a terminal moraine. By reconstructing the glacier using the feature as terminus, a paleo-ELA was calculated and climate conditions necessary to promote the growth of an icemass were ascertained. Comparing this climate to the contemporary allows us to evaluate the magnitude of late-Pleistocene climate reversals in the White Mountains

Reducing Printed Circuit Board Emissions with Low-Noise Design Practices

This paper presents the results of an experiment designed to determine the effectiveness of adopting several low-noise printed circuit board (PCB) design practices. Two boards were designed and fabricated, each consisting of identical mixed signal circuitry. Several important differences were introduced between the board layouts: one board was constructed using recommended low-noise practices and the other constructed without such attention. The emissions from the two boards were then measured and compared, demonstrating an improvement in radiated emissions of up to 22 dB

Emerging Multidrug Resistance of Methicillin-Resistant Staphylococcus aureus in Hand Infections.

BACKGROUND: Methicillin-resistant Staphylococcus aureus has been the most commonly identified pathogen in hand infections at urban centers, but the evolving antibiotic sensitivity profiles of methicillin-resistant Staphylococcus aureus are not known. The purposes of this study are to determine if multidrug resistance in methicillin-resistant Staphylococcus aureus is emerging and to provide current recommendations for empiric antibiotic selection for hand infections in endemic regions. METHODS: An eight-year longitudinal, retrospective chart review was performed on all culture-positive hand infections encountered by an urban hospital from 2005 to 2012. The proportions of all major organisms were calculated for each year. Methicillin-resistant Staphylococcus aureus infections were additionally analyzed for antibiotic sensitivity. RESULTS: A total of 683 culture-positive hand infections were identified. Overall, methicillin-resistant Staphylococcus aureus grew on culture in 49% of cases; the annual incidence peaked at 65% in 2007. Over the study period, methicillin-resistant Staphylococcus aureus was universally resistant to penicillin, oxacillin, and ampicillin. Clindamycin resistance significantly increased, approaching 20% by 2012 (p = 0.02). Levofloxacin resistance linearly increased from 12% to 50% (p \u3c 0.01). Resistance to trimethoprim-sulfamethoxazole, tetracycline, gentamicin, and moxifloxacin was only sporadically observed. Resistance to vancomycin, daptomycin, linezolid, and rifampin was not observed. CONCLUSIONS: Significant increases in resistance to clindamycin and levofloxacin were observed in recent years, and empiric therapy with these drugs may have limited efficacy, especially in urban centers. CLINICAL RELEVANCE: Hand infections caused by methicillin-resistant Staphylococcus aureus may be developing increasing resistance to clindamycin and levofloxacin in recent years. This longitudinal study examines the effectiveness of a variety of antibiotics to methicillin-resistant Staphylococcus aureus

Genome-wide gene expression analysis supports a developmental model of low temperature tolerance gene regulation in wheat (Triticum aestivum L.)

<p>Abstract</p> <p>Background</p> <p>To identify the genes involved in the development of low temperature (LT) tolerance in hexaploid wheat, we examined the global changes in expression in response to cold of the 55,052 potentially unique genes represented in the Affymetrix Wheat Genome microarray. We compared the expression of genes in winter-habit (winter Norstar and winter Manitou) and spring-habit (spring Manitou and spring Norstar)) cultivars, wherein the locus for the vernalization gene <it>Vrn-A1 </it>was swapped between the parental winter Norstar and spring Manitou in the derived near-isogenic lines winter Manitou and spring Norstar. Global expression of genes in the crowns of 3-leaf stage plants cold-acclimated at 6°C for 0, 2, 14, 21, 38, 42, 56 and 70 days was examined.</p> <p>Results</p> <p>Analysis of variance of gene expression separated the samples by genetic background and by the developmental stage before or after vernalization saturation was reached. Using gene-specific ANOVA we identified 12,901 genes (at <it>p </it>< 0.001) that change in expression with respect to both genotype and the duration of cold-treatment. We examined in more detail a subset of these genes (2,771) where expression was highly influenced by the interaction between these two main factors. Functional assignments using GO annotations showed that genes involved in transport, oxidation-reduction, and stress response were highly represented. Clustering based on the pattern of transcript accumulation identified genes that were up or down-regulated by cold-treatment. Our data indicate that the cold-sensitive lines can up-regulate known cold-responsive genes comparable to that of cold-hardy lines. The levels of expression of these genes were highly influenced by the initial rate and the duration of the gene's response to cold. We show that the <it>Vrn-A1 </it>locus controls the duration of gene expression but not its initial rate of response to cold treatment. Furthermore, we provide evidence that <it>Ta.Vrn-A1 </it>and <it>Ta.Vrt1 </it>originally hypothesized to encode for the same gene showed different patterns of expression and therefore are distinct.</p> <p>Conclusion</p> <p>This study provides novel insight into the underlying mechanisms that regulate the expression of cold-responsive genes in wheat. The results support the developmental model of LT tolerance gene regulation and demonstrate the complex genotype by environment interactions that determine LT adaptation in winter annual cereals.</p

In-Patient Evolution of a High-Persister Escherichia coli Strain With Reduced In Vivo Antibiotic Susceptibility

Gram-negative bacterial bloodstream infections (GNB-BSI) are common and frequently lethal. Despite appropriate antibiotic treatment, relapse of GNB-BSI with the same bacterial strain is common and associated with poor clinical outcomes and high healthcare costs. The role of persister cells, which are sub-populations of bacteria that survive for prolonged periods in the presence of bactericidal antibiotics, in relapse of GNB-BSI is unclear. Using a cohort of patients with relapsed GNB-BSI, we aimed to determine how the pathogen evolves within the patient between the initial and subsequent episodes of GNB-BSI and how these changes impact persistence. Usin

Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia

The cblG and cblC disorders of cobalamin (Cbl) metabolism are two inherited causes of megaloblastic anaemia. In cblG, mutations in methionine synthase (MTR) decrease conversion of hydroxocobalamin (HOCbl) to methylcobalamin, while in cblC, mutations in MMACHC disrupt formation of cob(II)alamin (detected as HOCbl). Cases with undetectable methionine synthase (MS) activity are extremely rare and classified as ‘cblG-variant'. In four ‘cblG-variant' cases, we observed a decreased conversion of cyanocobalamin to HOCbl that is also seen in cblC cases. To explore this observation, we studied the gene defects, splicing products and expression of MS, as well as MS/MMACHC protein interactions in cblG-variant, cblG, cblC and control fibroblasts. We observed a full-size MS encoded by MTR-001 and a 124 kDa truncated MS encoded by MTR-201 in cblG, cblC, control fibroblasts and HEK cells, but only the MTR-201 transcript and inactive truncated MS in cblG-variant cells. Co-immunoprecipitation and proximity ligation assay showed interaction between truncated MS and MMACHC in cblG-variant cells. This interaction decreased 2.2, 1.5 and 5.0-fold in the proximity ligation assay of cblC cells with p.R161Q and p.R206W mutations, and HEK cells with knock down expression of MS by siRNA, respectively, when compared with control cells. In 3D modelling and docking analysis, both truncated and full-size MS provide a loop anchored to MMACHC, which makes contacts with R-161 and R-206 residues. Our data suggest that the interaction of MS with MMACHC may play a role in the regulation of the cellular processing of Cbls that is required for Cbl cofactor synthesi

Single-cell RNA-seq reveals dynamic paracrine control of cellular variation

High-throughput single-cell transcriptomics offers an unbiased approach for understanding the extent, basis and function of gene expression variation between seemingly identical cells. Here we sequence single-cell RNA-seq libraries prepared from over 1,700 primary mouse bone-marrow-derived dendritic cells spanning several experimental conditions. We find substantial variation between identically stimulated dendritic cells, in both the fraction of cells detectably expressing a given messenger RNA and the transcript’s level within expressing cells. Distinct gene modules are characterized by different temporal heterogeneity profiles. In particular, a ‘core’ module of antiviral genes is expressed very early by a few ‘precocious’ cells in response to uniform stimulation with a pathogenic component, but is later activated in all cells. By stimulating cells individually in sealed microfluidic chambers, analysing dendritic cells from knockout mice, and modulating secretion and extracellular signalling, we show that this response is coordinated by interferon-mediated paracrine signalling from these precocious cells. Notably, preventing cell-to-cell communication also substantially reduces variability between cells in the expression of an early-induced ‘peaked’ inflammatory module, suggesting that paracrine signalling additionally represses part of the inflammatory program. Our study highlights the importance of cell-to-cell communication in controlling cellular heterogeneity and reveals general strategies that multicellular populations can use to establish complex dynamic responses.National Human Genome Research Institute (U.S.). Centers of Excellence in Genomic Science (1P50HG006193-01)National Institutes of Health (U.S.). Pioneer Award (DP1OD003958-01)Howard Hughes Medical InstituteBroad Institute of MIT and Harvard. Klarman Cell Observator

Single cell RNA Seq reveals dynamic paracrine control of cellular variation

High-throughput single-cell transcriptomics offers an unbiased approach for understanding the extent, basis, and function of gene expression variation between seemingly identical cells. Here, we sequence single-cell RNA-Seq libraries prepared from over 1,700 primary mouse bone marrow derived dendritic cells (DCs) spanning several experimental conditions. We find substantial variation between identically stimulated DCs, in both the fraction of cells detectably expressing a given mRNA and the transcript’s level within expressing cells. Distinct gene modules are characterized by different temporal heterogeneity profiles. In particular, a “core” module of antiviral genes is expressed very early by a few “precocious” cells, but is later activated in all cells. By stimulating cells individually in sealed microfluidic chambers, analyzing DCs from knockout mice, and modulating secretion and extracellular signaling, we show that this response is coordinated via interferon-mediated paracrine signaling. Surprisingly, preventing cell-to-cell communication also substantially reduces variability in the expression of an early-induced “peaked” inflammatory module, suggesting that paracrine signaling additionally represses part of the inflammatory program. Our study highlights the importance of cell-to-cell communication in controlling cellular heterogeneity and reveals general strategies that multicellular populations use to establish complex dynamic responses