Circular nos. 1-10 (May1, 1912-Jun2 12, 1912); Bulletin nos. 1-9 (April 12, 1912-June 10, 1912); Instructions for use of agent\u27s cash book

The titles of the cirulcars are: No.1 Inventory of Equipment, June 1, 1912, 12 O\u27Clock Noon; No. 2 Agents\u27 Monthly Balance Sheets; No. 3 Fidelity Bonds; No. 4 Foreign Postal Remittances; No. 5 Joint Vouchers, Wells Fargo & Co. and Western Express Company; No. 6 Waybills Reported on Supplementary Statements; No. 7 J.H. Addicks appointed Auditor of Express Receipts; No. 8 Daily Audit of Cash in Hands of Assistant Treasurer; No. 9 Paid Money Orders, Travelers and C.O.D. Checks; No. 10 Analysis of Unadjusted Items. Bulletin titles are: No. 1 Accounting Instructions -- Bulletins and Circulars; No. 2 Subscription lists; No. 3 Initialing of Figures Checked on Balance Sheets; No. 4 Agents\u27 Monthly balance Sheets -- Checking and Distriburion of Miscellaneous Items Reported Thereon; No. 54 Correspondence to be handled in the name of the Comptroller and Correspondence Covering the Establishment of Principles and Methods; No. 6 Mail Received from the President and Officers Reporting to the President, also Communications Received under Personal , Private or Confidential Cover -- Handling of in the Comptoller\u27s Office; No. 7 Method of Agreeing Balance of Outstanding Vouchers; No. 8 Bureau of Agency Accounts -- Organization of; No. 9 (Cancels Bulletin No. 4) Agents\u27 Monthly Balance Sheets -- Distribution of Miscellaneous Items Reported Thereon Including Check of Agents\u27 Remittances, Auditor of Express Receipts and Auditor of Money Orders\u27 Department Consolidation Sheets, etc

The Use of Feedback in Group Counseling in a State Vocational Rehabilitation Setting

This study examined the impact of providing progress feedback to individuals with disabilities receiving services at a state vocational rehabilitation (VR) agency. Thirty individuals were randomly assigned to receive either group therapy (treatment-as-usual, TAU) or group therapy plus feedback (treatment, Fb) during a 10-week counseling program at one of five agency offices. Each week, participants attended a 90-minute session and completed a measure of mental health (Outcome Questionnaire-45). Longitudinal multilevel models were used to evaluate the hypothesis that participation in the Fb group would lead to improved mental health. The effect of the intervention was conditional on receipt of public benefits for three mental health outcomes: interpersonal relationships (p=.025); social role performance (p=.021), and overall mental health functioning (p=.028). Additionally, a significantly greater proportion of participants were employed at the end of the study (p=0.012). Further research is needed to evaluate the efficacy of feedback interventions in VR settings

Glaciovolcanic evidence for a polythermal Neogene East Antarctic Ice Sheet

A paradigm has existed for more than 30 years that the basal thermal regime of the East Antarctic Ice Sheet in Victoria Land made a fundamental transition from wet-based to cold-based either at ca. 14 Ma or after ca. 2.5 Ma. The basal thermal regime is important because it determines the potential for unstable behavior in an ice sheet. We have studied the environmental characteristics of subglacially erupted volcanic centers scattered along 800 km of the Ross Sea fl ank of the Transantarctic Mountains. The volcanoes preserve evidence for the coeval paleo-ice thicknesses and contain features diagnostic of both wet-based and cold-based ice conditions. By dating the sequences we are able to demonstrate that the basal thermal regime varied spatially and with time between ca. 12 Ma and present. It was polythermal overall and probably comprised a coarse temperature patchwork of frozen-bed and thawed-bed ice, similar to the East Antarctic Ice Sheet today. Thus, an important shift is required in the prevailing paradigm describing its temporal evolution

ORIO (Online Resource for Integrative Omics): a web-based platform for rapid integration of next generation sequencing data

Abstract Established and emerging next generation sequencing (NGS)-based technologies allow for genome-wide interrogation of diverse biological processes. However, accessibility of NGS data remains a problem, and few user-friendly resources exist for integrative analysis of NGS data from different sources and experimental techniques. Here, we present Online Resource for Integrative Omics (ORIO; https://orio.niehs.nih.gov/), a web-based resource with an intuitive user interface for rapid analysis and integration of NGS data. To use ORIO, the user specifies NGS data of interest along with a list of genomic coordinates. Genomic coordinates may be biologically relevant features from a variety of sources, such as ChIP-seq peaks for a given protein or transcription start sites from known gene models. ORIO first iteratively finds read coverage values at each genomic feature for each NGS dataset. Data are then integrated using clustering-based approaches, giving hierarchical relationships across NGS datasets and separating individual genomic features into groups. In focusing its analysis on read coverage, ORIO makes limited assumptions about the analyzed data; this allows the tool to be applied across data from a variety of experiments and techniques. Results from analysis are presented in dynamic displays alongside user-controlled statistical tests, supporting rapid statistical validation of observed results. We emphasize the versatility of ORIO through diverse examples, ranging from NGS data quality control to characterization of enhancer regions and integration of gene expression information. Easily accessible on a public web server, we anticipate wide use of ORIO in genome-wide investigations by life scientists

Haploinsufficiency of SIRT1 Enhances Glutamine Metabolism and Promotes Cancer Development

SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and maybe dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development. Heterozygous deletion of Sirt1 induces c-Myc expression, enhancing glutamine metabolism and subsequent proliferation, autophagy, stress resistance and cancer formation. In contrast, homozygous deletion of Sirt1 triggers cellular apoptotic pathways, increases cell death, diminishes autophagy, and reduces cancer formation. Consistent with the observed dose-dependence in cells, intestine-specific Sirt1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific Sirt1 homozygous knockout mice have reduced development of colon cancer. Furthermore, SIRT1 reduction but not deletion is associated with human colorectal tumors, and colorectal cancer patients with low protein expression of SIRT1 have a poor prognosis. Taken together, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contributes to the observed dual roles of SIRT1 in tumorigenesis. Our study highlights the importance of maintenance of a suitable SIRT1 dosage for metabolic and tissue homeostasis, which will have important implications in SIRT1 small molecule activators/inhibitors based therapeutic strategies for cancers

Questionnaire-Based Polyexposure Assessment Outperforms Polygenic Scores for Classification of Type 2 Diabetes in a Multiancestry Cohort

OBJECTIVE Environmental exposures may have greater predictive power for type 2 diabetes than polygenic scores (PGS). Studies examining environmental risk factors, however, have included only individuals with European ancestry, limiting the applicability of results. We conducted an exposome-wide association study in the multiancestry Personalized Environment and Genes Study to assess the effects of environmental factors on type 2 diabetes. RESEARCH DESIGN AND METHODS Using logistic regression for single-exposure analysis, we identified exposures associated with type 2 diabetes, adjusting for age, BMI, household income, and self-reported sex and race. To compare cumulative genetic and environmental effects, we computed an overall clinical score (OCS) as a weighted sum of BMI and prediabetes, hyperten-sion, and high cholesterol status and a polyexposure score (PXS) as a weighted sum of 13 environmental variables. Using UK Biobank data, we developed a multiancestry PGS and calculated it for participants. RESULTS We found 76 significant associations with type 2 diabetes, including novel associations of asbestos and coal dust exposure. OCS, PXS, and PGS were significantly associated with type 2 diabetes. PXS had moderate power to determine associations, with larger effect size and greater power and reclassification improvement than PGS. For all scores, the results differed by race. CONCLUSIONS Our findings in a multiancestry cohort elucidate how type 2 diabetes odds can be at-tributed to clinical, genetic, and environmental factors and emphasize the need for exposome data in disease-risk association studies. Race-based differences in predictive scores highlight the need for genetic and exposome-wide studies in diverse populations. EmR2TaFJ

Brain health: the importance of recognizing cognitive impairment: an IAGG consensus conference

Cognitive impairment creates significant challenges for patients, their families and friends, and clinicians who provide their health care. Early recognition allows for diagnosis and appropriate treatment, education, psychosocial support, and engagement in shared decision-making regarding life planning, health care, involvement in research, and financial matters. An IAGG-GARN consensus panel examined the importance of early recognition of impaired cognitive health. Their major conclusion was that case-finding by physicians and health professionals is an important step toward enhancing brain health for aging populations throughout the world. This conclusion is in keeping with the position of the United States' Centers for Medicare and Medicaid Services that reimburses for detection of cognitive impairment as part the of Medicare Annual Wellness Visit and with the international call for early detection of cognitive impairment as a patient's right. The panel agreed on the following specific findings: (1) validated screening tests are available that take 3 to 7 minutes to administer; (2) a combination of patient- and informant-based screens is the most appropriate approach for identifying early cognitive impairment; (3) early cognitive impairment may have treatable components; and (4) emerging data support a combination of medical and lifestyle interventions as a potential way to delay or reduce cognitive decline

Local Absence of Secondary Structure Permits Translation of mRNAs that Lack Ribosome-Binding Sites

The initiation of translation is a fundamental and highly regulated process in gene expression. Translation initiation in prokaryotic systems usually requires interaction between the ribosome and an mRNA sequence upstream of the initiation codon, the so-called ribosome-binding site (Shine-Dalgarno sequence). However, a large number of genes do not possess Shine-Dalgarno sequences, and it is unknown how start codon recognition occurs in these mRNAs. We have performed genome-wide searches in various groups of prokaryotes in order to identify sequence elements and/or RNA secondary structural motifs that could mediate translation initiation in mRNAs lacking Shine-Dalgarno sequences. We find that mRNAs without a Shine-Dalgarno sequence are generally less structured in their translation initiation region and show a minimum of mRNA folding at the start codon. Using reporter gene constructs in bacteria, we also provide experimental support for local RNA unfoldedness determining start codon recognition in Shine-Dalgarno–independent translation. Consistent with this, we show that AUG start codons reside in single-stranded regions, whereas internal AUG codons are usually in structured regions of the mRNA. Taken together, our bioinformatics analyses and experimental data suggest that local absence of RNA secondary structure is necessary and sufficient to initiate Shine-Dalgarno–independent translation. Thus, our results provide a plausible mechanism for how the correct translation initiation site is recognized in the absence of a ribosome-binding site

A Serial shRNA Screen for Roadblocks to Reprogramming Identifies the Protein Modifier SUMO2

Summary The generation of induced pluripotent stem cells (iPSCs) from differentiated cells following forced expression of OCT4, KLF4, SOX2, and C-MYC (OKSM) is slow and inefficient, suggesting that transcription factors have to overcome somatic barriers that resist cell fate change. Here, we performed an unbiased serial shRNA enrichment screen to identify potent repressors of somatic cell reprogramming into iPSCs. This effort uncovered the protein modifier SUMO2 as one of the strongest roadblocks to iPSC formation. Depletion of SUMO2 both enhances and accelerates reprogramming, yielding transgene-independent, chimera-competent iPSCs after as little as 38 hr of OKSM expression. We further show that the SUMO2 pathway acts independently of exogenous C-MYC expression and in parallel with small-molecule enhancers of reprogramming. Importantly, suppression of SUMO2 also promotes the generation of human iPSCs. Together, our results reveal sumoylation as a crucial post-transcriptional mechanism that resists the acquisition of pluripotency from fibroblasts using defined factors