Renin and renin blockade have no role in complement activity.

Renin, an aspartate protease, regulates the renin-angiotensin system by cleaving its only known substrate angiotensinogen to angiotensin. Recent studies have suggested that renin may also cleave complement component C3 to activate complement or contribute to its dysregulation. Typically, C3 is cleaved by C3 convertase, a serine protease that uses the hydroxyl group of a serine residue as a nucleophile. Here, we provide seven lines of evidence to show that renin does not cleave C3. First, there is no association between renin plasma levels and C3 levels in patients with C3 Glomerulopathies (C3G) and atypical Hemolytic Uremic Syndrome (aHUS), implying that serum C3 consumption is not increased in the presence of high renin. Second, in vitro tests of C3 conversion to C3b do not detect differences when sera from patients with high renin levels are compared to sera from patients with normal/low renin levels. Third, aliskiren, a renin inhibitor, does not block abnormal complement activity introduced by nephritic factors in the fluid phase. Fourth, aliskiren does not block dysregulated complement activity on cell surfaces. Fifth, recombinant renin from different sources does not cleave C3 even after 24 hours of incubation at 37 °C. Sixth, direct spiking of recombinant renin into sera samples of patients with C3G and aHUS does not enhance complement activity in either the fluid phase or on cell surfaces. And seventh, molecular modeling and docking place C3 in the active site of renin in a position that is not consistent with a productive ground state complex for catalytic hydrolysis. Thus, our study does not support a role for renin in the activation of complement.

Mechanistic modeling of climate effects on redistribution and population growth in a community of fish species.

Understanding community responses to climate is critical for anticipating the future impacts of global change. However, despite increased research efforts in this field, models that explicitly include important biological mechanisms are lacking. Quantifying the potential impacts of climate change on species is complicated by the fact that the effects of climate variation may manifest at several points in the biological process. To this end, we extend a dynamic mechanistic model that combines population dynamics, such as species interactions, with species redistribution by allowing climate to affect both processes. We examine their relative contributions in an application to the changing biomass of a community of eight species in the Gulf of Maine using over 30 years of fisheries data from the Northeast Fishery Science Center. Our model suggests that the mechanisms driving biomass trends vary across space, time, and species. Phase space plots demonstrate that failing to account for the dynamic nature of the environmental and biologic system can yield theoretical estimates of population abundances that are not observed in empirical data. The stock assessments used by fisheries managers to set fishing targets and allocate quotas often ignore environmental effects. At the same time, research examining the effects of climate change on fish has largely focused on redistribution. Frameworks that combine multiple biological reactions to climate change are particularly necessary for marine researchers. This work is just one approach to modeling the complexity of natural systems and highlights the need to incorporate multiple and possibly interacting biological processes in future models.

Complement Factor I Variants in Complement-Mediated Renal Diseases.

C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) are two rare diseases caused by dysregulated activity of the alternative pathway of complement secondary to the presence of genetic and/or acquired factors. Complement factor I (FI) is a serine protease that downregulates complement activity in the fluid phase and/or on cell surfaces in conjunction with one of its cofactors, factor H (FH), complement receptor 1 (CR1/CD35), C4 binding protein (C4BP) or membrane cofactor protein (MCP/CD46). Because altered FI activity is causally related to the pathogenesis of C3G and aHUS, we sought to test functional activity of select CFI missense variants in these two patient cohorts. We identified 65 patients (16, C3G; 48, aHUS; 1 with both) with at least one rare variant in CFI (defined as a MAF < 0.1%). Eight C3G and eleven aHUS patients also carried rare variants in either another complement gene, ADAMTS13 or THBD. We performed comprehensive complement analyses including biomarker profiling, pathway activity and autoantibody testing, and developed a novel FI functional assay, which we completed on 40 patients. Seventy-eight percent of rare CFI variants (31/40) were associated with FI protein levels below the 25th percentile; in 22 cases, FI levels were below the lower limit of normal (type 1 variants). Of the remaining nine variants, which associated with normal FI levels, two variants reduced FI activity (type 2 variants). No patients carried currently known autoantibodies (including FH autoantibodies and nephritic factors). We noted that while rare variants in CFI predispose to complement-mediated diseases, phenotypes are strongly contingent on the associated genetic background. As a general rule, in isolation, a rare CFI variant most frequently leads to aHUS, with the co-inheritance of a CD46 loss-of-function variant driving the onset of aHUS to the younger age group. In comparison, co-inheritance of a gain-of-function variant in C3 alters the phenotype to C3G. Defects in CFH (variants or fusion genes) are seen with both C3G and aHUS. This variability underscores the complexity and multifactorial nature of these two complement-mediated renal diseases.

Jointly modeling marine species to inform the effects of environmental change on an ecological community in the Northwest Atlantic.

Single species distribution models (SSDMs) are typically used to understand and predict the distribution and abundance of marine fish by fitting distribution models for each species independently to a combination of abiotic environmental variables. However, species abundances and distributions are influenced by abiotic environmental preferences as well as biotic dependencies such as interspecific competition and predation. When species interact, a joint species distribution model (JSDM) will allow for valid inference of environmental effects. We built a joint species distribution model of marine fish and invertebrates of the Northeast US Continental Shelf, providing evidence on species relationships with the environment as well as the likelihood of species to covary. Predictive performance is similar to SSDMs but the Bayesian joint modeling approach provides two main advantages over single species modeling: (1) the JSDM directly estimates the significance of environmental effects; and (2) predicted species richness accounts for species dependencies. An additional value of JSDMs is that the conditional prediction of species distributions can use not only the environmental associations of species, but also the presence and abundance of other species when forecasting future climatic associations.

Shifting seas, shifting boundaries: Dynamic marine protected area designs for a changing climate.

Marine protected areas (MPAs) are valuable tools for marine conservation that aim to limit human impacts on marine systems and protect valuable species or habitats. However, as species distributions shift due to ocean warming, acidification, and oxygen depletion from climate change, the areas originally designated under MPAs may bear little resemblance to their past state. Different approaches have been suggested for coping with species on the move in conservation. Here, we test the effectiveness of different MPA designs, including dynamic, network, and different directional orientations on protecting shifting species under climate change through ecosystem modeling in a theoretical ecosystem. Our findings suggest that dynamic MPAs may benefit some species (e.g., whiting and anchovy) and fishing fleets, and these benefits can inform the design or adaptation of MPAs worldwide. In addition, we find that it is important to design MPAs with specific goals and to account for the effects of released fishing pressure and species interactions in MPA design.

Substrate-dependent fish have shifted less in distribution under climate change.

Analyses of the impacts of climate change on fish species have primarily considered dynamic oceanographic variables that are the output of predictive models, yet fish species distributions are determined by much more than just variables such as ocean temperature. Functionally diverse species are differentially influenced by oceanographic as well as physiographic variables such as bottom substrate, thereby influencing their ability to shift distributions. Here, we show that fish species distributions that are more associated with bottom substrate than other dynamic environmental variables have shifted significantly less over the last 30 years than species whose distributions are associated with bottom salinity. Correspondingly, species whose distributions are primarily determined by bottom temperature or ocean salinity have shifted their mean centroid and southern and northern range boundaries significantly more than species whose distributions are determined by substrate or depth. The influence of oceanographic versus static variables differs by species functional group, as benthic species distributions are more associated with substrate and they have shifted significantly less than pelagic species whose distributions are primarily associated with ocean temperatures. In conclusion, benthic fish, that are more influenced by substrate, may prove much less likely to shift distributions under future climate change.