When Torts Met Civil Procedure: A Curricular Coupling

Law students must become adept at understanding how various bodies of law interact-supporting, balancing, and even conflicting with each other. This article describes an attempt to achieve these goals by merging two canonical first-year courses, civil procedure and torts, into an integrated class titled ‘Introduction to Civil Litigation’. Our most pressing motivation was concern that students who study civil procedure and torts in isolation develop a skewed, unrealistic view of how law works in the real world. By combining these courses, we hoped to teach students early in their careers to approach problems more like practicing lawyers, who must deal with multiple bodies of law simultaneously. And while the course did yield a higher level of practice readiness, the experience also brought unexpected rewards to both students and faculty. As we developed and refined the course, we discovered that we were not just merging two courses. We were bringing together two different perspectives on how the law functions. We came to believe that more can be gained by viewing torts and civil procedure together than by studying them apart. Torts and Civil Procedure tell different sides of the same story

Heads of alternative provision: committed to realising young peoples’ potential in an unregulated market

Alternative provision (AP) caters for pupils marginalised and excluded from mainstream schooling. In England, it is conceptualised in policy as providing education to support behavioural improvements (pupils are directed off-site to improve behaviour). There is limited research on the experiences of those who work in AP settings. That which does exist tends to report the commitment of these professionals to the young people with whom they work. Young people who attend these schools frequently talk positively about the relationships they experience there. As such, there is a need to better understand the motivations of those working with these young people if we are to understand the key relationships that make AP work. This article fills a gap by focusing on the experiences of those managing AP settings across a geographical area. The findings are based on 3 interviews and 20 surveys and develop significantly our understanding of the motivations of those working in and managing AP settings. Interesting divergences in practice are highlighted and findings show managers both see and work to realise the potential of young people in AP. These findings suggest staff commitment should be conceptualised as belief in the potential of the young people who attend AP

Gentamicin induces LAMB3 nonsense mutation readthrough and restores functional laminin 332 in junctional epidermolysis bullosa

Herlitz junctional epidermolysis bullosa (H-JEB) is an incurable, devastating, and mostly fatal inherited skin disease for which there is only supportive care. H-JEB is caused by loss-of-function mutations in LAMA3, LAMB3, or LAMC2, leading to complete loss of laminin 332, the major component of anchoring filaments, which mediate epidermal-dermal adherence. LAMB3 (laminin \u3b23) mutations account for 80% of patients with H-JEB, and 3c95% of H-JEB\u2013associated LAMB3 mutations are nonsense mutations leading to premature termination codons (PTCs). In this study, we evaluated the ability of gentamicin to induce PTC readthrough in H-JEB laminin \u3b23-null keratinocytes transfected with expression vectors encoding eight different LAMB3 nonsense mutations. We found that gentamicin induced PTC readthrough in all eight nonsense mutations tested. We next used lentiviral vectors to generate stably transduced H-JEB cells with the R635X and C290X nonsense mutations. Incubation of these cell lines with various concentrations of gentamicin resulted in the synthesis and secretion of full-length laminin \u3b23 in a dose-dependent and sustained manner. Importantly, the gentamicin-induced laminin \u3b23 led to the restoration of laminin 332 assembly, secretion, and deposition within the dermal/epidermal junction, as well as proper polarization of \u3b16\u3b24 integrin in basal keratinocytes, as assessed by immunoblot analysis, immunofluorescent microscopy, and an in vitro 3D skin equivalent model. Finally, newly restored laminin 332 corrected the abnormal cellular phenotype of H-JEB cells by reversing abnormal cell morphology, poor growth potential, poor cell-substratum adhesion, and hypermotility. Therefore, gentamicin may offer a therapy for H-JEB and other inherited skin diseases caused by PTC mutations

Optical and IR Photometry of Globular Clusters in NGC1399: Evidence for Color-Metallicity Nonlinearity

We combine new Wide Field Camera~3 IR Channel (WFC3/IR) F160W (H) imaging data for NGC1399, the central galaxy in the Fornax cluster, with archival F475W (g), F606W (V), F814W (I), and F850LP (z) optical data from the Advanced Camera for Surveys (ACS). The purely optical g-I, V-I, and g-z colors of NGC1399's rich globular cluster (GC) system exhibit clear bimodality, at least for magnitudes $I_814 > 21.5$. The optical-IR I-H color distribution appears unimodal, and this impression is confirmed by mixture modeling analysis. The V-H colors show marginal evidence for bimodality, consistent with bimodality in V-I and unimodality in I-H. If bimodality is imposed for I-H with a double Gaussian model, the preferred blue/red split differs from that for optical colors; these "differing bimodalities" mean that the optical and optical-IR colors cannot both be linearly proportional to metallicity. Consistent with the differing color distributions, the dependence of I-H on g-I for the matched GC sample is significantly nonlinear, with an inflection point near the trough in the g-I color distribution; the result is similar for the I-H dependence on g-z colors taken from the ACS Fornax Cluster Survey. These g-z colors have been calibrated empirically against metallicity; applying this calibration yields a continuous, skewed, but single-peaked metallicity distribution. Taken together, these results indicate that nonlinear color-metallicity relations play an important role in shaping the observed bimodal distributions of optical colors in extragalactic GC systems.Comment: 15 pages, 12 figures, accepted for publication in the Astrophysical Journa

Zinc isotopic compositions of breast cancer tissue

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. https://creativecommons.org/licenses/by-nc-nd/3.0/ The attached file is the published version of the article.An early diagnostic biomarker for breast cancer is essential to improve outcome. High precision isotopic analysis, originating in Earth sciences, can detect very small shifts in metal pathways. For the first time, the natural intrinsic Zn isotopic compositions of various tissues in breast cancer patients and controls were determined. Breast cancer tumours were found to have a significantly lighter Zn isotopic composition than the blood, serum and healthy breast tissue in both groups. The Zn isotopic lightness in tumours suggests that sulphur rich metallothionein dominates the isotopic selectivity of a breast tissue cell, rather than Zn-specific proteins. This reveals a possible mechanism of Zn delivery to Zn-sequestering vesicles by metallothionein, and is supported by a similar signature observed in the copper isotopic compositions of one breast cancer patient. This change in intrinsic isotopic compositions due to cancer has the potential to provide a novel early biomarker for breast cancer.This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. https://creativecommons.org/licenses/by-nc-nd/3.0/ The attached file is the published version of the article

Snakebite drug discovery: high-throughput screening to identify novel snake venom metalloproteinase toxin inhibitors

Snakebite envenoming results in ∼100,000 deaths per year, with close to four times as many victims left with life-long sequelae. Current antivenom therapies have several limitations including high cost, variable cross-snake species efficacy and a requirement for intravenous administration in a clinical setting. Next-generation snakebite therapies are being widely investigated with the aim to improve cost, efficacy, and safety. In recent years several small molecule drugs have shown considerable promise for snakebite indication, with oral bioavailability particularly promising for community delivery rapidly after a snakebite. However, only two such drugs have entered clinical development for snakebite. To offset the risk of attrition during clinical trials and to better explore the chemical space for small molecule venom toxin inhibitors, here we describe the first high throughput drug screen against snake venom metalloproteinases (SVMPs)—a pathogenic toxin family responsible for causing haemorrhage and coagulopathy. Following validation of a 384-well fluorescent enzymatic assay, we screened a repurposed drug library of 3,547 compounds against five geographically distinct and toxin variable snake venoms. Our drug screen resulted in the identification of 14 compounds with pan-species inhibitory activity. Following secondary potency testing, four SVMP inhibitors were identified with nanomolar EC50s comparable to the previously identified matrix metalloproteinase inhibitor marimastat and superior to the metal chelator dimercaprol, doubling the current global portfolio of SVMP inhibitors. Following analysis of their chemical structure and ADME properties, two hit-to-lead compounds were identified. These clear starting points for the initiation of medicinal chemistry campaigns provide the basis for the first ever designer snakebite specific small molecules.</jats:p

Antimicrobial Resistance Genes, Cassettes, and Plasmids Present in Salmonella enterica Associated With United States Food Animals

The ability of antimicrobial resistance (AR) to transfer, on mobile genetic elements (MGEs) between bacteria, can cause the rapid establishment of multidrug resistance (MDR) in bacteria from animals, thus creating a foodborne risk to human health. To investigate MDR and its association with plasmids in Salmonella enterica, whole genome sequence (WGS) analysis was performed on 193 S. enterica isolated from sources associated with United States food animals between 1998 and 2011; 119 were resistant to at least one antibiotic tested. Isolates represented 86 serotypes and variants, as well as diverse phenotypic resistance profiles. A total of 923 AR genes and 212 plasmids were identified among the 193 strains. Every isolate contained at least one AR gene. At least one plasmid was detected in 157 isolates. Genes were identified for resistance to aminoglycosides (n = 472), β-lactams (n = 84), tetracyclines (n = 171), sulfonamides (n = 91), phenicols (n = 42), trimethoprim (n = 8), macrolides (n = 5), fosfomycin (n = 48), and rifampicin (n = 2). Plasmid replicon types detected in the isolates were A/C (n = 32), ColE (n = 76), F (n = 43), HI1 (n = 4), HI2 (n = 20), I1 (n = 62), N (n = 4), Q (n = 7), and X (n = 35). Phenotypic resistance correlated with the AR genes identified in 95.4% of cases. Most AR genes were located on plasmids, with many plasmids harboring multiple AR genes. Six antibiotic resistance cassette structures (ARCs) and one pseudo-cassette were identified. ARCs contained between one and five resistance genes (ARC1: sul2, strAB, tetAR; ARC2: aac3-iid; ARC3: aph, sph; ARC4: cmy-2; ARC5: floR; ARC6: tetB; pseudo-ARC: aadA, aac3-VIa, sul1). These ARCs were present in multiple isolates and on plasmids of multiple replicon types. To determine the current distribution and frequency of these ARCs, the public NCBI database was analyzed, including WGS data on isolates collected by the USDA Food Safety and Inspection Service (FSIS) from 2014 to 2018. ARC1, ARC4, and ARC5 were significantly associated with cattle isolates, while ARC6 was significantly associated with chicken isolates. This study revealed that a diverse group of plasmids, carrying AR genes, are responsible for the phenotypic resistance seen in Salmonella isolated from United States food animals. It was also determined that many plasmids carry similar ARCs