An evaluation of wetland no net loss and mitigation under section 404 of the Clean Water Act on the Santa Rosa Plain, Sonoma County, California.

The Santa Rosa Plain (Plain), Sonoma County, California, has lost 85% of its vernal pools, affecting the survival of four threatened and endangered species. The ability of Section 404 of the Clean Water Act to achieve the goal of no net loss is a particular importance in areas, such as the Plain, where wetland resources have become severely impacted. The objective of the study was to determine if a no net loss of wetland area occurred on the Plain, to evaluate the implementation of the Santa Rosa Plain programmatic permit, and to examine trends associated with compensatory medication. Fifty-two Section 404 permits affecting seasonal wetlands on the Santa Rosa Plain between July 17th, 1998 and December 31st, 2004 were examined. The no net loss based on required mitigation was determined and adjusted for loss due to mitigation failure and loss resulting from enhancement. The medication acreage That could be verified was determined in the acreage appended to the programmatic permit was totaled. The frequency of the type of mitigation (on-site, off-site, bank) selected was evaluated by type of proponent (public or private). The location of impacts and mitigation sites were evaluated to assess the effects of geographic displacement. Required mitigation resulted in a net gain of 3.512 acres; however, the combined effects of failure in enhancement resulted in a net loss of 0.504 acre. Only 53% of the mitigation was verified. In most cases the programmatic permit was properly applied and maximum acreage limits had not been exceeded. Mitigation banking was the most frequently used type of mitigation; however, banks were found to result in greater geographic displacement. A majority of the impacts were due to private developers occurred within urban boundaries, while a majority of the mitigation sites were located outside of urban areas. Mitigation banks were found to play an important role in mitigation on the Plain

Biomarkers of Extracellular Matrix Metabolism (MMP-9 and TIMP-1) and Risk of Stroke, Myocardial Infarction, and Cause-Specific Mortality: Cohort Study

Objective: Turnover of the extracellular matrix in all solid organs is governed mainly by a balance between the degrading matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). An altered extracellular matrix metabolism has been implicated in a variety of diseases. We investigated relations of serum levels of MMP-9 and TIMP-1 to mortality risk from an etiological perspective. Design: The prospective Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, followed from 1991–1995 for up to 18.1 years. A random population-based sample of 1,082 71-year-old men, no loss to follow-up. Endpoints were all-cause (n = 628), cardiovascular (n = 230), non-cardiovascular (n = 398) and cancer mortality (n = 178), and fatal or non-fatal myocardial infarction (n = 138) or stroke (n = 163). Results: Serum MMP-9 and TIMP-1 levels were associated with risk of all-cause mortality (Cox proportional hazard ratio [HR] per standard deviation 1.10, 95% confidence interval [CI] 1.03–1.19; and 1.11, 1.02–1.20; respectively). TIMP-1 levels were mainly related to risks of cardiovascular mortality and stroke (HR per standard deviation 1.22, 95% CI 1.09–1.37; and 1.18, 1.04–1.35; respectively). All relations except those of TIMP-1 to stroke risk were attenuated by adjustment for cardiovascular disease risk factors. Relations in a subsample without cardiovascular disease or cancer were similar to those in the total sample. Conclusion: In this community-based cohort of elderly men, serum MMP-9 and TIMP-1 levels were related to mortality risk. An altered extracellular matrix metabolism may be involved in several detrimental pathways, and circulating MMP-9 or TIMP-1 levels may be relevant markers thereof

Smoke and Mirrors: U.K. Newspaper Representations of Intimate Partner Domestic Violence

This is a pre-copyedited, author-produced pdf of an article accepted for publication in Violence Against Women following peer review. The final, definitive version of this paper has been published in Violence Against Women, Vol 23 (1): 114-139, first published April 2016 by SAGE Publishing, and is available on line at doi: 10.1177/1077801216634468. All rights reserved.News media are in a position to project certain perspectives on domestic violence while marginalizing others, which has implications for public understanding and policy development. This study applies discourse analysis to articles on domestic violence in two U.K. national daily newspapers published in 2001-2002 and 2011-2012 to evaluate evidence of change over a 10-year time span. The research examines how discourses of domestic violence are constructed through newspaper representations of victims, predominantly women, and perpetrators, predominantly men. Although one of the newspapers adopts a respectful position toward women, the textual and visual techniques adopted by the other reveal a tendency for blaming the victim and sexualizing violence related to perceptions of “deserving” or “undeserving” women victims.Peer reviewe

Development and characterization of agonistic antibodies targeting the Ig-like 1 domain of MuSK

Muscle-specific kinase (MuSK) is crucial for acetylcholine receptor (AChR) clustering and thereby neuromuscular junction (NMJ) function. NMJ dysfunction is a hallmark of several neuromuscular diseases, including MuSK myasthenia gravis. Aiming to restore NMJ function, we generated several agonist monoclonal antibodies targeting the MuSK Ig-like 1 domain. These activated MuSK and induced AChR clustering in cultured myotubes. The most potent agonists partially rescued myasthenic effects of MuSK myasthenia gravis patient IgG autoantibodies in vitro. In an IgG4 passive transfer MuSK myasthenia model in NOD/SCID mice, MuSK agonists caused accelerated weight loss and no rescue of myasthenic features. The MuSK Ig-like 1 domain agonists unexpectedly caused sudden death in a large proportion of male C57BL/6 mice (but not female or NOD/SCID mice), likely caused by a urologic syndrome. In conclusion, these agonists rescued pathogenic effects in myasthenia models in vitro, but not in vivo. The sudden death in male mice of one of the tested mouse strains revealed an unexpected and unexplained role for MuSK outside skeletal muscle, thereby hampering further (pre-) clinical development of these clones. Future research should investigate whether other Ig-like 1 domain MuSK antibodies, binding different epitopes, do hold a safe therapeutic promise

Anti-C2 Antibody ARGX-117 Inhibits Complement in a Disease Model for Multifocal Motor Neuropathy

BACKGROUND AND OBJECTIVES: To determine the role of complement in the disease pathology of multifocal motor neuropathy (MMN), we investigated complement activation, and inhibition, on binding of MMN patient-derived immunoglobulin M (IgM) antibodies in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model for MMN. METHODS: iPSC-derived MNs were characterized for the expression of complement receptors and membrane-bound regulators, for the binding of circulating IgM anti-GM1 from patients with MMN, and for subsequent fixation of C4 and C3 on incubation with fresh serum. The potency of ARGX-117, a novel inhibitory monoclonal antibody targeting C2, to inhibit fixation of complement was assessed. RESULTS: iPSC-derived MNs moderately express the complement regulatory proteins CD46 and CD55 and strongly expressed CD59. Furthermore, MNs express C3aR, C5aR, and complement receptor 1. IgM anti-GM1 antibodies in serum from patients with MMN bind to MNs and induce C3 and C4 fixation on incubation with fresh serum. ARGX-117 inhibits complement activation downstream of C4 induced by patient-derived anti-GM1 antibodies bound to MNs. DISCUSSION: Binding of IgM antibodies from patients with MMN to iPSC-derived MNs induces complement activation. By expressing complement regulatory proteins, particularly CD59, MNs are protected against complement-mediated lysis. Yet, because of expressing C3aR, the function of these cells may be affected by complement activation upstream of membrane attack complex formation. ARGX-117 inhibits complement activation upstream of C3 in this disease model for MMN and therefore represents an intervention strategy to prevent harmful effects of complement in MMN

CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia.

Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand-receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb-induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells inhibited cell growth and colony formation and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML

CD70-restricted specific activation of TRAILR1 or TRAILR2 using scFv-targeted TRAIL mutants

To combine the CD27 stimulation inhibitory effect of blocking CD70 antibodies with an antibody-dependent cellular cytotoxicity (ADCC)-independent, cell death-inducing activity for targeting of CD70-expressing tumors, we evaluated here fusion proteins of the apoptosis-inducing TNF family member TRAIL and a single-chain variable fragment (scFv) derived from a high-affinity llama-derived anti-human CD70 antibody (lαhCD70). A fusion protein of scFv:lαhCD70 with TNC-TRAIL, a stabilized form of TRAIL, showed strongly enhanced apoptosis induction upon CD70 binding and furthermore efficiently interfered with CD70-CD27 interaction. Noteworthy, introduction of recently identified mutations that discriminate between TRAILR1 and TRAILR2 binding into the TRAIL part of scFv:lαhCD70-TNC-TRAIL resulted in TRAIL death receptor-specific fusion proteins with CD70-restricted activity

Interactions between epibenthos and meiobenthos in a high intertidal <i>Avicennia marina</i> mangrove forest

Many studies in the muddy intertidal zone of temperate regions have indicated meiofaunal communities to be mainly affected by epibenthic predation and disturbance rather than competition. Few studies, however, have dealt with mangrove sediments of tropical areas. In addition to a parallel study in a Ceriops tagal (Perr.) Rob. zone, a manipulative exclusion technique was used to trace the dominant biological interactions structuring the meiobenthos of an East African Avicennia marina (Forsk.) Vierh. mangrove forest. The densities of the major meiobenthic taxa and nematode genera and a broad range of environmental factors were monitored over a depth profile for one year of caging. Cages (1m²) excluded all epibenthos (>2mm) for one year and were procedurally controlled. Procedural and exclusion effects were traced, using a factorial and mixed ANOVA design. Significant exclusion effects were indicated for oligochaetes and for one of the dominant epistratal feeding nematode genera. They are discussed in terms of epibenthic composition and density, feeding behaviour, food resources, and the abiotic environment. The conclusion is that the observed meiobenthos (especially oligochaetes and nematodes) is influenced mainly by exploitative or resource competition with the epibenthos. The common food source was indicated to be muddy detritus and microalgae. Consequently, the role of the meiobenthos is mainly situated in an isolated, detrital food web with only minor energy fluxes to the epibenthos