Noncytotoxic Roles of Granzymes in Health and Disease

Granzymes are serine proteases previously believed to play exclusive and somewhat redundant roles in lymphocyte-mediated target cell death. However, recent studies have challenged this paradigm. Distinct substrate profiles and functions have since emerged for each granzyme while their dysregulated proteolytic activities have been linked to diverse pathologies

Granzyme K Activates Protease-Activated Receptor-1

Granzyme K (GrK) is a trypsin-like serine protease that is elevated in patients with sepsis and acute lung inflammation. While GrK was originally believed to function exclusively as a pro-apoptotic protease, recent studies now suggest that GrK may possess other non-cytotoxic functions. In the context of acute lung inflammation, we hypothesized that GrK induces pro-inflammatory cytokine release through the activation of protease-activated receptors. The direct effect of extracellular GrK on PAR activation, intracellular signaling and cytokine was assessed using cultured human lung fibroblasts. Extracellular GrK induced secretion of IL-6, IL-8 and MCP-1 in a dose- and time-dependent manner in lung fibroblasts. Heat-inactivated GrK did not induce cytokine release indicating that protease activity is required. Furthermore, GrK induced activation of both the ERK1/2 and p38 MAP kinase signaling pathways, and significantly increased fibroblast proliferation. Inhibition of ERK1/2 abrogated the GrK-mediated cytokine release. Through the use of PAR-1 and PAR-2 neutralizing antibodies, it was determined that PAR-1 is essential for GrK-induced IL-6, IL-8 and MCP-1 release. In summary, extracellular GrK is capable of activating PAR-1 and inducing fibroblast cytokine secretion and proliferation

Principal forms X^2 + nY^2 representing many integers

In 1966, Shanks and Schmid investigated the asymptotic behavior of the number of positive integers less than or equal to x which are represented by the quadratic form X^2+nY^2. Based on some numerical computations, they observed that the constant occurring in the main term appears to be the largest for n=2. In this paper, we prove that in fact this constant is unbounded as n runs through positive integers with a fixed number of prime divisors.Comment: 10 pages, title has been changed, Sections 2 and 3 are new, to appear in Abh. Math. Sem. Univ. Hambur

Tuberculosis in Dr Granville's mummy: a molecular re-examination of the earliest known Egyptian mummy to be scientifically examined and given a medical diagnosis

‘Dr Granville's mummy’ was described to the Royal Society of London in 1825 and was the first ancient Egyptian mummy to be subjected to a scientific autopsy. The remains are those of a woman, Irtyersenu, aged about 50, from the necropolis of Thebes and dated to about 600 BC. Augustus Bozzi Granville (1783–1872), an eminent physician and obstetrician, described many organs still in situ and attributed the cause of death to a tumour of the ovary. However, subsequent histological investigations indicate that the tumour is a benign cystadenoma. Histology of the lungs demonstrated a potentially fatal pulmonary exudate and earlier studies attempted to associate this with particular disease conditions. Palaeopathology and ancient DNA analyses show that tuberculosis was widespread in ancient Egypt, so a systematic search for tuberculosis was made, using specific DNA and lipid biomarker analyses. Clear evidence for Mycobacterium tuberculosis complex DNA was obtained in lung tissue and gall bladder samples, based on nested PCR of the IS6110 locus. Lung and femurs were positive for specific M. tuberculosis complex cell-wall mycolic acids, demonstrated by high-performance liquid chromatography of pyrenebutyric acid–pentafluorobenzyl mycolates. Therefore, tuberculosis is likely to have been the major cause of death of Irtyersenu

Lipids, adiposity and tendinopathy:is there a mechanistic link? Critical review

Being overweight or obese is associated with an elevated risk of tendon pathology. However, for sportspeople the epidemiological data linking weight or adiposity on one hand, and risk of tendon pathology on the other, are less consistent. Indeed, the mechanistic links between diet, adiposity and tendon pathology remain largely unexamined. Recent studies have begun to examine the effects of dietary interventions on outcomes such as tendon biomechanics or pain. Oxidised low-density lipoprotein has been shown to (A) accumulate in the tendon tissues of mice that eat a fatty diet and (B) induce a pathological phenotype in human tendon cells. This paper addresses the current debate: is excessive body mass index (causing increased load and strain on tendon tissue) per se the underlying mechanism? Or do local or systemic influences of fat on tendons predispose to tendon pathology? This narrative review argues that excessive blood lipids may be an important avenue for clinical investigations

The Passive Journalist: How sources dominate the local news

This study explores which sources are “making” local news and whether these sources are simply indicating the type of news that appears, or are shaping newspaper coverage. It provides an empirical record of the extent to which sources are able to dominate news coverage from which future trends in local journalism can be measured. The type and number of sources used in 2979 sampled news stories in four West Yorkshire papers, representing the three main proprietors of local newspapers in the United Kingdom, were recorded for one month and revealed the relatively narrow range of routine sources; 76 per cent of articles cited only a single source. The analysis indicates that journalists are relying less on their readers for news, and that stories of little consequence are being elevated to significant positions, or are filling news pages at the expense of more important stories. Additionally, the reliance on a single source means that alternative views and perspectives relevant to the readership are being overlooked. Journalists are becoming more passive, mere processors of one-sided information or bland copy dictated by sources. These trends indicate poor journalistic standards and may be exacerbating declining local newspaper sales

Towards an 'average' version of the Birch and Swinnerton-Dyer Conjecture

The Birch and Swinnerton-Dyer conjecture states that the rank of the Mordell-Weil group of an elliptic curve E equals the order of vanishing at the central point of the associated L-function L(s,E). Previous investigations have focused on bounding how far we must go above the central point to be assured of finding a zero, bounding the rank of a fixed curve or on bounding the average rank in a family. Mestre showed the first zero occurs by O(1/loglog(N_E)), where N_E is the conductor of E, though we expect the correct scale to study the zeros near the central point is the significantly smaller 1/log(N_E). We significantly improve on Mestre's result by averaging over a one-parameter family of elliptic curves, obtaining non-trivial upper and lower bounds for the average number of normalized zeros in intervals on the order of 1/log(N_E) (which is the expected scale). Our results may be interpreted as providing further evidence in support of the Birch and Swinnerton-Dyer conjecture, as well as the Katz-Sarnak density conjecture from random matrix theory (as the number of zeros predicted by random matrix theory lies between our upper and lower bounds). These methods may be applied to additional families of L-functions.Comment: 20 pages, 2 figures, revised first draft (fixed some typos

A Central Role for Foxp3+ Regulatory T Cells in K-Ras-Driven Lung Tumorigenesis

BACKGROUND: K-Ras mutations are characteristic of human lung adenocarcinomas and occur almost exclusively in smokers. In preclinical models, K-Ras mutations are necessary for tobacco carcinogen-driven lung tumorigenesis and are sufficient to cause lung adenocarcinomas in transgenic mice. Because these mutations confer resistance to commonly used cytotoxic chemotherapies and targeted agents, effective therapies that target K-Ras are needed. Inhibitors of mTOR such as rapamycin can prevent K-Ras-driven lung tumorigenesis and alter the proportion of cytotoxic and Foxp3+ regulatory T cells, suggesting that lung-associated T cells might be important for tumorigenesis. METHODS: Lung tumorigenesis was studied in three murine models that depend on mutant K-Ras; a tobacco carcinogen-driven model, a syngeneic inoculation model, and a transgenic model. Splenic and lung-associated T cells were studied using flow cytometry and immunohistochemistry. Foxp3+ cells were depleted using rapamycin, an antibody, or genetic ablation. RESULTS: Exposure of A/J mice to a tobacco carcinogen tripled lung-associated Foxp3+ cells prior to tumor development. At clinically relevant concentrations, rapamycin prevented this induction and reduced lung tumors by 90%. In A/J mice inoculated with lung adenocarcinoma cells resistant to rapamycin, antibody-mediated depletion of Foxp3+ cells reduced lung tumorigenesis by 80%. Likewise, mutant K-Ras transgenic mice lacking Foxp3+ cells developed 75% fewer lung tumors than littermates with Foxp3+ cells. CONCLUSIONS: Foxp3+ regulatory T cells are required for K-Ras-mediated lung tumorigenesis in mice. These studies support clinical testing of rapamycin or other agents that target Treg in K-Ras driven human lung cancer

Granzyme K mediates IL-23-dependent inflammation and keratinocyte proliferation in psoriasis

Psoriasis is an inflammatory disease with systemic manifestations that most commonly presents as itchy, erythematous, scaly plaques on extensor surfaces. Activation of the IL-23/IL-17 pro-inflammatory signaling pathway is a hallmark of psoriasis and its inhibition is key to clinical management. Granzyme K (GzmK) is an immune cell-secreted serine protease elevated in inflammatory and proliferative skin conditions. In the present study, human psoriasis lesions exhibited elevated GzmK levels compared to non-lesional psoriasis and healthy control skin. In an established murine model of imiquimod (IMQ)-induced psoriasis, genetic loss of GzmK significantly reduced disease severity, as determined by delayed plaque formation, decreased erythema and desquamation, reduced epidermal thickness, and inflammatory infiltrate. Molecular characterization in vitro revealed that GzmK contributed to macrophage secretion of IL-23 as well as PAR-1-dependent keratinocyte proliferation. These findings demonstrate that GzmK enhances IL-23-driven inflammation as well as keratinocyte proliferation to exacerbate psoriasis severity