Reflections On Contributing To “Big Discoveries” About The Fly Clock: Our Fortunate Paths As Post-Docs With 2017 Nobel Laureates Jeff Hall, Michael Rosbash, And Mike Young

In the early 1980s Jeff Hall and Michael Rosbash at Brandeis University and Mike Young at Rockefeller University set out to isolate the period (per) gene, which was recovered in a revolutionary genetic screen by Ron Konopka and Seymour Benzer for mutants that altered circadian behavioral rhythms. Over the next 15 years the Hall, Rosbash and Young labs made a series of groundbreaking discoveries that defined the molecular timekeeping mechanism and formed the basis for them being awarded the 2017 Nobel Prize in Physiology or Medicine. Here the authors recount their experiences as post-docs in the Hall, Rosbash and Young labs from the mid-1980s to the mid-1990s, and provide a perspective of how basic research conducted on a simple model system during that era profoundly influenced the direction of the clocks field and established novel approaches that are now standard operating procedure for studying complex behavior

Parsing Heterogeneity in the Brain Connectivity of Depressed and Healthy Adults During Positive Mood

There is well-known heterogeneity in affective mechanisms in depression that may extend to positive affect. We used data-driven parsing of neural connectivity to reveal subgroups present across depressed and healthy individuals during positive processing, informing targets for mechanistic intervention

A Post-AGB Star in the Small Magellanic Cloud Observed with the Spitzer Infrared Spectrograph

We have observed an evolved star with a rare combination of spectral features, MSX SMC 029, in the Small Magellanic Cloud (SMC) using the low-resolution modules of the Infrared Spectrograph on the Spitzer Space Telescope. A cool dust continuum dominates the spectrum of MSX SMC 029. The spectrum also shows both emission from polycyclic aromatic hydrocarbons (PAHs) and absorption at 13.7 micron from C2H2, a juxtaposition seen in only two other sources, AFGL 2688 and IRAS 13416-6243, both post-asymptotic giant branch (AGB) objects. As in these sources, the PAH spectrum has the unusual trait that the peak emission in the 7-9 micron complex lies beyond 8.0 micron. In addition, the 8.6 micron feature has an intensity as strong as the C-C modes which normally peak between 7.7 and 7.9 micron. The relative flux of the feature at 11.3 micron to that at 8 micron suggests that the PAHs in MSX SMC 029 either have a low ionization fraction or are largely unprocessed. The 13-16 micron wavelength region shows strong absorption features similar to those observed in the post-AGB objects AFGL 618 and SMP LMC 11. This broad absorption may arise from the same molecules which have been identified in those sources: C2H2, C4H2, HC3N, and C6H6. The similarities between MSX SMC 029, AFGL 2688, and AFGL 618 lead us to conclude that MSX SMC 029 has evolved off the AGB in only the past few hundred years, making it the third post-AGB object identified in the SMC.Comment: 4 figures, Fig. 4 color; to appear in the 20 November 2006 Astrophysical Journal Letter

Molecular and Phenotypic Characteristics of Healthcare- and Community-Associated Methicillin-Resistant Staphylococcus aureus at a Rural Hospital

BACKGROUND: While methicillin-resistant Staphylococcus aureus (MRSA) originally was associated with healthcare, distinct strains later emerged in patients with no prior hospital contact. The epidemiology of MRSA continues to evolve. METHODS: To characterize the current epidemiology of MRSA-colonized patients entering a hospital serving both rural and urban communities, we interviewed patients with MRSA-positive admission nasal swabs between August 2009 and March 2010. We applied hospitalization risk factor, antimicrobial resistance phenotype, and multi-locus sequence genotype (MLST) classification schemes to 94 case-patients. RESULTS: By MLST analysis, we identified 15 strains with two dominant clonal complexes (CCs)-CC5 (51 isolates), historically associated with hospitals, and CC8 (27 isolates), historically of community origin. Among patients with CC5 isolates, 43% reported no history of hospitalization within the past six months; for CC8, 67% reported the same. Classification by hospitalization risk factor did not correlate strongly with genotypic classification. Sensitivity of isolates to ciprofloxacin, clindamycin, or amikacin was associated with the CC8 genotype; however, among CC8 strains, 59% were resistant to ciprofloxacin, 15% to clindamycin, and 15% to amikacin. CONCLUSIONS: Hospitalization history was not a strong surrogate for the CC5 genotype. Conversely, patients with a history of hospitalization were identified with the CC8 genotype. Although ciprofloxacin, clindamycin, and amikacin susceptibility distinguished CC8 strains, the high prevalence of ciprofloxacin resistance limited its predictive value. As CC8 strains become established in healthcare settings and CC5 strains disseminate into the community, community-associated MRSA definitions based on case-patient hospitalization history may prove less valuable in tracking community MRSA strains

Slow progressors to type 1 diabetes lose islet autoantibodies over time, have few islet antigen-specific CD8+ T cells and exhibit a distinct CD95hi B cell phenotype

ims/hypothesis The aim of this study was to characterise islet autoantibody profiles and immune cell phenotypes in slow progressors to type 1 diabetes. Methods Immunological variables were compared across peripheral blood samples obtained from slow progressors to type 1 diabetes, individuals with newly diagnosed or long-standing type 1 diabetes, and healthy individuals. Polychromatic flow cytometry was used to characterise the phenotypic attributes of B and T cells. Islet autoantigen-specific B cells were quantified using an enzyme-linked immunospot (ELISpot) assay and islet autoantigen-specific CD8+ T cells were quantified using peptide–HLA class I tetramers. Radioimmunoassays were used to detect islet autoantibodies. Sera were assayed for various chemokines, cytokines and soluble receptors via ELISAs. Results Islet autoantibodies were lost over time in slow progressors. Various B cell subsets expressed higher levels of CD95 in slow progressors, especially after polyclonal stimulation, compared with the corresponding B cell subsets in healthy donors (p < 0.05). The phenotypic characteristics of CD4+ and CD8+ T cells were similar in slow progressors and healthy donors. Lower frequencies of CD4+ T cells with a central memory phenotype (CD27int, CD127+, CD95int) were observed in slow progressors compared with healthy donors (mean percentage of total CD4+ T cells was 3.00% in slow progressors vs 4.67% in healthy donors, p < 0.05). Autoreactive B cell responses to proinsulin were detected at higher frequencies in slow progressors compared with healthy donors (median no. of spots was 0 in healthy donors vs 24.34 in slow progressors, p < 0.05) in an ELISpot assay. Islet autoantigen-specific CD8+ T cell responses were largely absent in slow progressors and healthy donors. Serum levels of DcR3, the decoy receptor for CD95L, were elevated in slow progressors compared with healthy donors (median was 1087 pg/ml in slow progressors vs 651 pg/ml in healthy donors, p = 0.06). Conclusions/interpretation In this study, we found that slow progression to type 1 diabetes was associated with a loss of islet autoantibodies and a distinct B cell phenotype, consistent with enhanced apoptotic regulation of peripheral autoreactivity via CD95. These phenotypic changes warrant further studies in larger cohorts to determine their functional implications

Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases.

Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases

Circumstellar Structure around Evolved Stars in the Cygnus-X Star Formation Region

We present observations of newly discovered 24 micron circumstellar structures detected with the Multiband Imaging Photometer for Spitzer (MIPS) around three evolved stars in the Cygnus-X star forming region. One of the objects, BD+43 3710, has a bipolar nebula, possibly due to an outflow or a torus of material. A second, HBHA 4202-22, a Wolf-Rayet candidate, shows a circular shell of 24 micron emission suggestive of either a limb-brightened shell or disk seen face-on. No diffuse emission was detected around either of these two objects in the Spitzer 3.6-8 micron Infrared Array Camera (IRAC) bands. The third object is the luminous blue variable candidate G79.29+0.46. We resolved the previously known inner ring in all four IRAC bands. The 24 micron emission from the inner ring extends ~1.2 arcmin beyond the shorter wavelength emission, well beyond what can be attributed to the difference in resolutions between MIPS and IRAC. Additionally, we have discovered an outer ring of 24 micron emission, possibly due to an earlier episode of mass loss. For the two shell stars, we present the results of radiative transfer models, constraining the stellar and dust shell parameters. The shells are composed of amorphous carbon grains, plus polycyclic aromatic hydrocarbons in the case of G79.29+0.46. Both G79.29+0.46 and HBHA 4202-22 lie behind the main Cygnus-X cloud. Although G79.29+0.46 may simply be on the far side of the cloud, HBHA 4202-22 is unrelated to the Cygnus-X star formation region.Comment: Accepted by A

Social, cultural and economic aspects of antimicrobial resistance.

Although often considered only a medical problem, antimicrobial resistance is an evolutionary challenge accelerated by social, cultural and economic factors that lead to the misuse, overuse and abuse of life-saving antimicrobial medicines. The antimicrobial resistance challenge is compounded by inadequate attention to disease prevention and response, global circulation of people and products, differences in industry and market regulations across countries, and a fragile pipeline of new antibiotics and their alternatives. While the discovery of new antimicrobials will provide temporary solutions, sustainable success requires rigorous social science research that explores the drivers of antimicrobial resistance. These solutions should promote balance between equitable access to, conservation of, and innovation for antimicrobials, adapted to local conditions across the globe

Sensitive Detection of Chromosomal Segments of Distinct Ancestry in Admixed Populations

Identifying the ancestry of chromosomal segments of distinct ancestry has a wide range of applications from disease mapping to learning about history. Most methods require the use of unlinked markers; but, using all markers from genome-wide scanning arrays, it should in principle be possible to infer the ancestry of even very small segments with exquisite accuracy. We describe a method, HAPMIX, which employs an explicit population genetic model to perform such local ancestry inference based on fine-scale variation data. We show that HAPMIX outperforms other methods, and we explore its utility for inferring ancestry, learning about ancestral populations, and inferring dates of admixture. We validate the method empirically by applying it to populations that have experienced recent and ancient admixture: 935 African Americans from the United States and 29 Mozabites from North Africa. HAPMIX will be of particular utility for mapping disease genes in recently admixed populations, as its accurate estimates of local ancestry permit admixture and case-control association signals to be combined, enabling more powerful tests of association than with either signal alone

Developing Compassionate Self Care Skills in Persons Living with HIV: a Pilot Study to Examine Mindful Awareness in Body-oriented Therapy Feasibility and Acceptability

Background: Self-care skills for persons living with HIV (PLWH) are needed to better cope with the common symptoms and emotional challenges of living with this chronic illness. Purpose: The purpose of this study was to examine the feasibility and acceptability of Mindful Awareness in Body-oriented Therapy (MABT) for individuals receiving medical management for HIV at an outpatient program. Setting: A nonprofit outpatient day program that provided medical management to low-income individuals with HIV. Research Design: A one group pre–post study design, nine participants were recruited to receive eight weekly MABT sessions of 1.25 hours each. Intervention: MABT is designed to facilitate emotion regulation through teaching somaticallybased self-care skills to respond to daily stressors. Main Outcome Measures: To assess participant characteristics and study feasibility, a battery of health questionnaires and one week of wrist actigraphy was administered pre- and postintervention. A satisfaction survey and written questionnaire was administered postintervention to assess MABT acceptability. Results: The results demonstrated recruitment and retention feasibility. The sample had psychological and physical health symptoms that are characteristic of PLWH. MABT acceptability was high, and participants perceived that they learned new mind-body self-care skills that improved HIV symptoms and their ability to manage symptoms. Conclusion: The positive findings support a larger future study to examine MABT efficacy to improve coping with HIV symptoms among PLWH