The presumptions in favour of marriage

This is the author accepted manuscript. The final version is available from Cambridge University Press via the DOI in this record.Eighteenth-century courts needed to rely on presumptions in favour of marriage for a number of reasons, some practical and some legal, but the misleading reporting of one leading nineteenth-century case, followed by institutional changes and a stronger focus on precedent, led to the original evidential assumptions being obscured. A further blurring of the different strands of the presumption occurred in the twenty-first century, leading to confusion in recent cases. Understanding how the much-misunderstood presumptions have developed reveals why they were needed, when they became decoupled from their evidential underpinnings, and how, when and why they should operate today

State and Law

This is the author accepted manuscript. The final version is available in print format only from Bloombsbury

The transportation of bigamists in early nineteenth-century England and Wales

This is the author accepted manuscript. The final version is available from Taylor & Francis via the DOI in this recordBetween 1795 and 1853, over 250 men and women were sentenced to transportation for committing the crime of bigamy. This harsh treatment is at odds with the assumption that the sentences handed down to bigamists were generally light. This article provides the first in-depth study of the use of transportation in this context, drawing on the criminal registers, the Proceedings of the Old Bailey, and local and national newspaper reports in order to ascertain who was transported for bigamy, and why. Analysing a range of aggravating and mitigating factors, it shows why certain cases were deemed to merit the harshest form of punishment, while others, despite exhibiting some of the same factors, were treated more leniently. The sheer greed, deceit and nastiness demonstrated by many of these bigamists provides a significant counter-narrative to the depiction of bigamy as a substitute for divorce and raises broader questions about its incidence

Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex

Citation: Garcia, B. L., Zhi, H., Wager, B., Hook, M., & Skare, J. T. (2016). Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex. Plos Pathogens, 12(1), 28. doi:10.1371/journal.ppat.1005404Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems

RNAseq Analyses Identify Tumor Necrosis Factor-Mediated Inflammation as a Major Abnormality in ALS Spinal Cord

ALS is a rapidly progressive, devastating neurodegenerative illness of adults that produces disabling weakness and spasticity arising from death of lower and upper motor neurons. No meaningful therapies exist to slow ALS progression, and molecular insights into pathogenesis and progression are sorely needed. In that context, we used high-depth, next generation RNA sequencing (RNAseq, Illumina) to define gene network abnormalities in RNA samples depleted of rRNA and isolated from cervical spinal cord sections of 7 ALS and 8 CTL samples. We aligned \u3e50 million 2X150 bp paired-end sequences/sample to the hg19 human genome and applied three different algorithms (Cuffdiff2, DEseq2, EdgeR) for identification of differentially expressed genes (DEG’s). Ingenuity Pathways Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA) identified inflammatory processes as significantly elevated in our ALS samples, with tumor necrosis factor (TNF) found to be a major pathway regulator (IPA) and TNFα-induced protein 2 (TNFAIP2) as a major network “hub” gene (WGCNA). Using the oPOSSUM algorithm, we analyzed transcription factors (TF) controlling expression of the nine DEG/hub genes in the ALS samples and identified TF’s involved in inflammation (NFkB, REL, NFkB1) and macrophage function (NR1H2::RXRA heterodimer). Transient expression in human iPSC-derived motor neurons of TNFAIP2 (also a DEG identified by all three algorithms) reduced cell viability and induced caspase 3/7 activation. Using high-density RNAseq, multiple algorithms for DEG identification, and an unsupervised gene co-expression network approach, we identified significant elevation of inflammatory processes in ALS spinal cord with TNF as a major regulatory molecule. Overexpression of the DEG TNFAIP2 in human motor neurons, the population most vulnerable to die in ALS, increased cell death and caspase 3/7 activation. We propose that therapies targeted to reduce inflammatory TNFα signaling may be helpful in ALS patients

Serum amyloid A primes microglia for ATP-dependent interleukin-1\u3b2 release

Acute-phase response is a systemic reaction to environmental/inflammatory insults and involves production of acute-phase proteins, including serum amyloid A (SAA). Interleukin-1\u3b2 (IL-1\u3b2), a master regulator of neuroinflammation produced by activated inflammatory cells of the myeloid lineage, in particular microglia, plays a key role in the pathogenesis of acute and chronic diseases of the peripheral nervous system and CNS. IL-1\u3b2 release is promoted by ATP acting at the purinergic P2X7 receptor (P2X7R) in cells primed with toll-like receptor (TLR) ligands

Medium-term seed storage of 50 genera of forage legumes and evidence-based genebank monitoring intervals

Genebanks maintaining seeds for long-term genetic resources conservation monitor seed lots to detect early loss in viability. Monitoring is costly and depletes valuable seed. Three decades of genebank seed germination test results of diverse forage species from 50 legume genera in the International Livestock Research Institute’s medium-term store (circa 8° C with 5 % moisture content) were analysed to determine whether advice on seed monitoring intervals could be derived. Cumulative normal distributions were fitted by probit analysis for each seed lot and compared within each genus. Six patterns of within-genus variation were identified: no detectable trend in germination test results during storage (4 genera); detectable trends, but variable (positive to negative) amongst lots (5); consistent slope of loss in viability amongst lots (17); consistent slope of increase in ability to germinate amongst lots (21); common loss in viability amongst lots (2); common increase in ability to germinate amongst lots (1). Seed lot monitoring intervals for the medium-term store were derived for each of 19 genera with consistent loss in viability across seed lots: three genera provided comparatively rapid deterioration, five met the general expectations for a medium-term store (2-10 years’ maintenance of high viability), whilst 11 provided much better survival. Moreover, 26 further genera provided no evidence as yet of seed deterioration; of these, 22 improved in ability to germinate during storage indicating confounding of hardseededness with viability in germination tests

Distant metastases of a squamous cell carcinoma of the tongue in peripheral skeletal muscles and adjacent soft tissues

A 66-year-old female patient was admitted to our department with a large tumor of the tongue measuring 10 cm in diameter. The tumor occupied nearly the entire oral cavity and showed exophytic and ulcerative areas. Histological analysis revealed a low grade squamous cell carcinoma (SCC) of the tongue. Bilateral enlarged cervical lymphatic masses were also present. The extent of the tumor infiltration was assessed by fluoro-2-deoxy-glucose-positron emission tomography (PET) scans showing an elevated activity of the tracer corresponding to the assumed cervical metastases. Additionally, pulmonary metastases were identified. Contrast enhanced computed tomography (CT) scans showed metastases in the soft tissues of the abdomen, legs and arms. Foci of distant metastases were found in the left upper anterior thoracal wall, near the intraabdominal portion of the aorta, near the right iliac crest and in both the right vastus medialis- and adductor magnus muscles. The final diagnosis was a T4N3M1(G3)(C3) SCC of the tongue with multiple distant thoracal, abdominal and intramuscular metastases. The survival expectancy was five weeks, and the patient finally deceased by cardiopulmonary complications

Progress towards high-performance, steady-state spherical torus

Research on the spherical torus (or spherical tokamak) (ST) is being pursued to explore the scientific benefits of modifying the field line structue fro that in more moderate aspect ratio devices. The ST experiments are being conducted in various US research facilities. The area of power and particle handling is expected to be challenging because of the higher power density expected in the ST relative to that in conventional aspect-ratio tokamaks

Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways

Background: Genetic studies of human lung function and Chronic Obstructive Pulmonary Disease have identified a highly significant and reproducible signal on 4q24. It remains unclear which of the two candidate genes within this locus may regulate lung function: GSTCD, a gene with unknown function, and/or INTS12, a member of the Integrator Complex which is currently thought to mediate 3'end processing of small nuclear RNAs.Results: We found that, in lung tissue, 4q24 polymorphisms associated with lung function correlate with INTS12 but not neighbouring GSTCD expression. In contrast to the previous reports in other species, we only observed a minor alteration of snRNA processing following INTS12 depletion. RNAseq analysis of knockdown cells instead revealed dysregulation of a core subset of genes relevant to airway biology and a robust downregulation of protein synthesis pathways. Consistent with this, protein translation was decreased in INTS12 knockdown cells. In addition, ChIPseq experiments demonstrated INTS12 binding throughout the genome, which was enriched in transcriptionally active regions. Finally, we defined the INTS12 regulome which includes genes belonging to the protein synthesis pathways.Conclusion: INTS12 has functions beyond the canonical snRNA processing. We show that it regulates translation by regulating the expression of genes belonging to protein synthesis pathways. This study provides a detailed analysis of INTS12 activities on a genome-wide scale and contributes to the biology behind the genetic association for lung function at 4q24.</p