Crime and criminality in County Durham 1840 - 1855

Between 1840 and 1855 the population of County Durham rose markedly in response to the needs of industry, especially the coal mines. Throughout this period there was a widely held assumption that an increase in industrial population would automatically result in a startling increase in crime. It is argued that despite the growing number of workers (especially colliers) this assumption cannot be sustained for County Durham. To substantiate this contention, several factors affecting criminality are reviewed: the introduction and development of the Durham County Constabulary; the awkward criminal litigation procedure; and the regimen of the Durham Gaol. These are examined in light of their functions as institutional restraints on the working class. In addition, the colliers are examined with a view to establishing the reasons for their surprisingly low rate of crime. Further, the quarterly returns of the Chief Constable, the County Treasurer’s Annual Report and the Quarter Sessions Indictment Rolls are analysed by a computer to establish certain patterns such as the increasing efficiency of the police and the growing number of cases payed for by the county. Finally, each bill of indictment from 1840 to 1855 was reduced to a 'computer readable’ form and then analysed to supply information on issues such as the number of criminals and types of crime; the resident parish of the offender; the plea, verdict, particulars; and (where applicable) the sentence incurred in each case

The Federal Reserve's Primary Dealer Credit Facility

As liquidity conditions in the "repo market"--the market where broker-dealers obtain financing for their securities--deteriorated following the near-bankruptcy of Bear Stearns in March 2008, the Federal Reserve took the step of creating a special facility to provide overnight loans to dealers that have a trading relationship with the Federal Reserve Bank of New York. Six months later, in the wake of new strains in the repo market, the Fed expanded the facility by broadening the types of collateral accepted for loans. Both initiatives were designed to help restore the orderly functioning of the market and to prevent the spillover of distress to other financial firms.Federal Reserve Bank of New York ; Loans ; Financial crises ; Brokers

A Human Torque Teno Virus Encodes a MicroRNA That Inhibits Interferon Signaling

Rodney P. Kincaid, James M. Burke, Jennifer C. Cox, Christopher S. Sullivan, The University of Texas at Austin, Molecular Genetics and Microbiology, Austin, Texas, United States of AmericaEthel-Michele de Villiers, Division for the Characterization of Tumorviruses, Deutsches Krebsforschungszentrum, Heidelberg, GermanyTorque teno viruses (TTVs) are a group of viruses with small, circular DNA genomes. Members of this family are thought to ubiquitously infect humans, although causal disease associations are currently lacking. At present, there is no understanding of how infection with this diverse group of viruses is so prevalent. Using a combined computational and synthetic approach, we predict and identify miRNA-coding regions in diverse human TTVs and provide evidence for TTV miRNA production in vivo. The TTV miRNAs are transcribed by RNA polymerase II, processed by Drosha and Dicer, and are active in RISC. A TTV mutant defective for miRNA production replicates as well as wild type virus genome; demonstrating that the TTV miRNA is dispensable for genome replication in a cell culture model. We demonstrate that a recombinant TTV genome is capable of expressing an exogenous miRNA, indicating the potential utility of TTV as a small RNA vector. Gene expression profiling of host cells identifies N-myc (and STAT) interactor (NMI) as a target of a TTV miRNA. NMI transcripts are directly regulated through a binding site in the 3′UTR. SiRNA knockdown of NMI contributes to a decreased response to interferon signaling. Consistent with this, we show that a TTV miRNA mediates a decreased response to IFN and increased cellular proliferation in the presence of IFN. Thus, we add Annelloviridae to the growing list of virus families that encode miRNAs, and suggest that miRNA-mediated immune evasion can contribute to the pervasiveness associated with some of these viruses.This work was supported by grants RO1AI077746 from the National Institutes of Health, RP110098 from the Cancer Prevention and Research Institute of Texas, a Burroughs Wellcome Investigators in Pathogenesis Award to CSS, a UT Austin Powers Graduate Fellowship to RPK, a UT Austin Institute for Cellular and Molecular Biology fellowship, and the DKFZ for EMdV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Molecular BiosciencesMicrobiologyEmail: [email protected]

Effectiveness of short-term heat acclimation on intermittent exercise in thermoneutral and hot environments

It is well-established that repetition of heat stress exposure has been shown to facilitate adaptations to the heat but these protocols have tended to be of a fixed work intensity, continuous exercise, long-term in duration (>7 days) and use hydration. Secondly, there is limited information on the potential use of heat acclimation as a training method for human performance in thermoneutral conditions. Therefore, the aims of this study were to investigate the effectiveness of short-term heat acclimation (STHA) for 5 days, using the controlled hyperthermia technique with dehydration, on intermittent exercise in thermoneutral and hot environments

Thermography Inspection for Early Detection of Composite Damage in Structures During Fatigue Loading

Advanced composite structures are commonly tested under controlled loading. Understanding the initiation and progression of composite damage under load is critical for validating design concepts and structural analysis tools. Thermal nondestructive evaluation (NDE) is used to detect and characterize damage in composite structures during fatigue loading. A difference image processing algorithm is demonstrated to enhance damage detection and characterization by removing thermal variations not associated with defects. In addition, a one-dimensional multilayered thermal model is used to characterize damage. Lastly, the thermography results are compared to other inspections such as non-immersion ultrasonic inspections and computed tomography X-ray

Neighbor-directed histidine N (τ)-alkylation: A route to imidazolium-containing phosphopeptide macrocycles

Our recently discovered, selective, on-resin route to N(τ)-alkylated imidazolium-containing histidine residues affords new strategies for peptide mimetic design. In this, we demonstrate the use of this chemistry to prepare a series of macrocyclic phosphopeptides, in which imidazolium groups serve as ring-forming junctions. Interestingly, these cationic moieties subsequently serve to charge-mask the phosphoamino acid group that directed their formation. Neighbor-directed histidine N(τ)-alkylation opens the door to new families of phosphopeptidomimetics for use in a range of chemical biology contexts.National Institutes of Health (U.S.) (Grants ES015339 and GM104047

Validation of the Family Inpatient Communication Survey

CONTEXT: Although many family members who make surrogate decisions report problems with communication, there is no validated instrument to accurately measure surrogate/clinician communication for older adults in the acute hospital setting. OBJECTIVES: The objective of this study was to validate a survey of surrogate-rated communication quality in the hospital that would be useful to clinicians, researchers, and health systems. METHODS: After expert review and cognitive interviewing (n = 10 surrogates), we enrolled 350 surrogates (250 development sample and 100 validation sample) of hospitalized adults aged 65 years and older from three hospitals in one metropolitan area. The communication survey and a measure of decision quality were administered within hospital days 3 and 10. Mental health and satisfaction measures were administered six to eight weeks later. RESULTS: Factor analysis showed support for both one-factor (Total Communication) and two-factor models (Information and Emotional Support). Item reduction led to a final 30-item scale. For the validation sample, internal reliability (Cronbach's alpha) was 0.96 (total), 0.94 (Information), and 0.90 (Emotional Support). Confirmatory factor analysis fit statistics were adequate (one-factor model, comparative fit index = 0.981, root mean square error of approximation = 0.62, weighted root mean square residual = 1.011; two-factor model comparative fit index = 0.984, root mean square error of approximation = 0.055, weighted root mean square residual = 0.930). Total score and subscales showed significant associations with the Decision Conflict Scale (Pearson correlation -0.43, P < 0.001 for total score). Emotional Support was associated with improved mental health outcomes at six to eight weeks, such as anxiety (-0.19 P < 0.001), and Information was associated with satisfaction with the hospital stay (0.49, P < 0.001). CONCLUSION: The survey shows high reliability and validity in measuring communication experiences for hospital surrogates. The scale has promise for measurement of communication quality and is predictive of important outcomes, such as surrogate satisfaction and well-being

Development of a novel secondary phenotypic screen to identify hits within the mycobacterial protein synthesis pipeline

Background Whole‐cell phenotypic screening is the driving force behind modern anti‐tubercular drug discovery efforts. Focus has shifted from screening for bactericidal scaffolds to screens incorporating target deconvolution. Target‐based screening aims to direct drug discovery toward known effective targets and avoid investing resources into unproductive lines of enquiry. The protein synthesis pipeline, including RNA polymerase and the ribosome, is a clinically proven target in Mycobacterium tuberculosis. Screening for new hits of this effective target pathway is an invaluable tool in the drug discovery arsenal. Methods Using M. tuberculosis H37Rv augmented with anhydrotetracycline‐inducible expression of mCherry, a phenotypic screen was developed for the identification of protein synthesis inhibitors in a medium throughput screening format. Results The assay was validated using known inhibitors of protein synthesis to show a dose‐dependent reduction in mCherry fluorescence. This was expanded to a proprietary screen of hypothetical protein synthesis hits and modified to include quantitative viability measurement of cells using resazurin. Conclusion Following the success of the proprietary screen, a larger scale screen of the GlaxoSmithKline anti‐tubercular library containing 2799 compounds was conducted. Combined single shot and dose‐response screening yielded 18 hits, 0.64% of all screened compounds

Mono-anionic phosphopeptides produced by unexpected histidine alkylation exhibit high plk1 polo-box domain-binding affinities and enhanced antiproliferative effects in hela cells

Binding of polo-like kinase 1 (Plk1) polo-box domains (PBDs) to phosphothreonine (pThr)/phosphoserine (pSer)-containing sequences is critical for the proper function of Plk1. Although high-affinity synthetic pThr-containing peptides provide starting points for developing PBD-directed inhibitors, to date the efficacy of such peptides in whole cell assays has been poor. This potentially reflects limited cell membrane permeability arising, in part, from the di-anionic nature of the phosphoryl group or its mimetics. In our current article we report the unanticipated on-resin N(τ)-alkylation of histidine residues already bearing a N(π)- alkyl group. This resulted in cationic imidazolium-containing pThr peptides, several of which exhibit single-digit nanomolar PBD-binding affinities in extracellular assays and improved antimitotic efficacies in intact cells. We enhanced the cellular efficacies of these peptides further by applying bio-reversible pivaloyloxymethyl (POM) phosphoryl protection. New structural insights presented in our current study, including the potential utility of intramolecular charge masking, may be useful for the further development of PBD-binding peptides and peptide mimetics.National Institutes of Health (U.S.) (Grants ES015339 and GM104047

64Cu PET Imaging of the CXCR4 Chemokine Receptor Using a Cross-Bridged Cyclam Bis-Tetraazamacrocyclic Antagonist

© 2020 by the Society of Nuclear Medicine and Molecular Imaging. Expression of the chemokine receptor chemokine C-X-C motif receptor 4 (CXCR4) plays an important role in cancer metastasis, in autoimmune diseases, and during stem cell-based repair processes after stroke and myocardial infarction. Previously reported PET imaging agents targeting CXCR4 suffer from either high nonspecific uptake or bind only to the human form of the receptor. The objective of this study was to develop a high-stability 64Cu-labeled small-molecule PET agent for imaging both human and murine CXCR4 chemokine receptors. Methods: Synthesis, radiochemistry, stability and radioligand binding assays were performed for the novel tracer 64Cu-CuCB-bicyclam. In vivo dynamic PET studies were performed on mice bearing U87 (CXCR4 low-expressing) and U87.CXCR4 (human-CXCR4 high-expressing) tumors. Biodistribution and receptor blocking studies were performed on CD1-IGS immunocompetent mice. CXCR4 expression on tumor and liver disaggregates was confirmed using a combination of immunohistochemistry, quantitative polymerase chain reaction, and Western blot. Results:64Cu-CuCB-bicyclam has a high affinity for both the human and the murine variants of the CXCR4 receptor (half-maximal inhibitory concentration, 8 nM [human]/2 nM [murine]) and can be obtained from the parent chelator that has low affinity. In vitro and in vivo studies demonstrate specific uptake in CXCR4-expressing cells that can be blocked by more than 90% using a higher-affinity antagonist, with limited uptake in non-CXCR4-expressing organs and high in vivo stability. The tracer was also able to selectively displace the CXCR4 antagonists AMD3100 and AMD3465 from the liver. Conclusion: The tetraazamacrocyclic small molecule 64Cu-CuCB-bicyclam has been shown to be an imaging agent for the CXCR4 receptor that is likely to be applicable across a range of species. It has high affinity and stability and is suitable for preclinical research in immunocompetent murine models