Nuclear localization of clathrin involves a labile helix outside the trimerization domain

AbstractClathrin is a trimeric protein involved in receptor-mediated-endocytosis, but can function as a non-trimer outside of endocytosis. We have discovered that the subcellular distribution of a clathrin cysteine mutant we previously studied is altered and a proportion is also localized to nuclear spaces. MALS shows C1573A hub is a mixture of trimer-like and detrimerized molecules. The X-ray structure of the trimerization domain reveals that without light chains, a helix harboring cysteine-1573 is reoriented. We propose clathrin has a detrimerization switch, which suggests clathrin topology can be altered naturally for new functions

The rise of the three-spined stickleback – eco-evolutionary consequences of a mesopredator release

Declines of large predatory fish due to overexploitation are restructuring food webs across the globe. It is now becoming evident that restoring these altered food webs requires addressing not only ecological processes, but evolutionary ones as well, because human-induced rapid evolution may in turn affect ecological dynamics. In the central Baltic Sea, abundances of the mesopredatory fish, the three-spined stickleback (Gasterosteus aculeatus), have increased dramatically during the past decades. Time-series data covering 22 years show that this increase coincides with a decline in the number of juvenile perch (Perca fluviatilis), the most abundant predator of stickleback along the coast. We studied the interaction between evolutionary and ecological effects of this mesopredator take-over, by surveying the armour plate morphology of stickleback and the structure of the associated food web. First, we investigated the distribution of different stickleback phenotypes depending on predator abundances and benthic production; and described the stomach content of the stickleback phenotypes using metabarcoding. Second, we explored differences in the relation between different trophic levels and benthic production, between bays where the relative abundance of fish was dominated by stickleback or not; and compared this to previous cage-experiments to support causality of detected correlations. We found two distinct lateral armour plate phenotypes of stickleback, incompletely and completely plated. The proportion of incompletely plated individuals increased with increasing benthic production and decreasing abundances of adult perch. Stomach content analyses showed that the completely plated individuals had a stronger preference for invertebrate herbivores (amphipods) than the incompletely plated ones. In addition, predator dominance interacted with ecosystem production to determine food web structure and the propagation of a trophic cascade: with increasing production, biomass accumulated on the first (macroalgae) and third (stickleback) trophic levels in stickleback-dominated bays, but on the second trophic level (invertebrate herbivores) in perch-dominated bays. Since armour plates are defence structures favoured by natural selection in the presence of fish predators, the phenotype distribution suggest that a novel low-predation regime favours sticklebacks with less armour. Our results indicate that an interaction between evolutionary and ecological effects of the stickleback take-over has the potential to affect food web dynamics

Habitat segregation of plate phenotypes in a rapidly expanding population of three-spined stickleback

Declines of large predatory fish due to overexploitation are restructuring food webs across the globe. It is now becoming evident that restoring these altered food webs requires addressing not only ecological processes, but evolutionary ones as well, because human-induced rapid evolution may in turn affect ecological dynamics. We studied the potential for niche differentiation between different plate armor phenotypes in a rapidly expanding population of a small prey fish, the three-spined stickleback (Gasterosteus aculeatus). In the central Baltic Sea, three-spined stickleback abundance has increased dramatically during the past decades. The increase in this typical mesopredator has restructured near-shore food webs, increased filamentous algal blooms, and threatens coastal biodiversity. Time-series data covering 22 years show that the increase coincides with a decline in the number of juvenile perch (Perca fluviatilis), the most abundant predator of stickleback along the coast. We investigated the distribution of different stickleback plate armor phenotypes depending on latitude, environmental conditions, predator and prey abundances, nutrients, and benthic production; and described the stomach content of the stickleback phenotypes using metabarcoding. We found two distinct lateral armor plate phenotypes of stickleback, incompletely and completely plated. The proportion of incompletely plated individuals increased with increasing benthic production and decreasing abundances of adult perch. Metabarcoding showed that the stomach content of the completely plated individuals more often contained invertebrate herbivores (amphipods) than the incompletely plated ones. Since armor plates are defense structures favored by natural selection in the presence of fish predators, the phenotype distribution suggests that a novel low-predation regime favors stickleback with less armor. Our results suggest that morphological differentiation of the three-spined stickleback has the potential to affect food web dynamics and influence the persistence and resilience of the stickleback take-over in the Baltic Sea.Peer reviewe

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562

Aberrant \u3ci\u3eAZIN2\u3c/i\u3e and Polyamine Metabolism Precipitates Tau Neuropathology

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell’s response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer’s disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Rise of oceanographic barriers in continuous populations of a cetacean: the genetic structure of harbour porpoises in Old World waters

<p>Abstract</p> <p>Background</p> <p>Understanding the role of seascape in shaping genetic and demographic population structure is highly challenging for marine pelagic species such as cetaceans for which there is generally little evidence of what could effectively restrict their dispersal. In the present work, we applied a combination of recent individual-based landscape genetic approaches to investigate the population genetic structure of a highly mobile extensive range cetacean, the harbour porpoise in the eastern North Atlantic, with regards to oceanographic characteristics that could constrain its dispersal.</p> <p>Results</p> <p>Analyses of 10 microsatellite loci for 752 individuals revealed that most of the sampled range in the eastern North Atlantic behaves as a 'continuous' population that widely extends over thousands of kilometres with significant isolation by distance (IBD). However, strong barriers to gene flow were detected in the south-eastern part of the range. These barriers coincided with profound changes in environmental characteristics and isolated, on a relatively small scale, porpoises from Iberian waters and on a larger scale porpoises from the Black Sea.</p> <p>Conclusion</p> <p>The presence of these barriers to gene flow that coincide with profound changes in oceanographic features, together with the spatial variation in IBD strength, provide for the first time strong evidence that physical processes have a major impact on the demographic and genetic structure of a cetacean. This genetic pattern further suggests habitat-related fragmentation of the porpoise range that is likely to intensify with predicted surface ocean warming.</p

Measurement of the prompt J/psi and psi(2S) polarizations in pp collisions at sqrt(s) = 7 TeV

The polarizations of prompt J/psi and psi(2S) mesons are measured in proton-proton collisions at sqrt(s) = 7 TeV, using a dimuon data sample collected by the CMS experiment at the LHC, corresponding to an integrated luminosity of 4.9 inverse femtobarns. The prompt J/psi and psi(2S) polarization parameters lambda[theta], lambda[phi], and lambda[theta, phi], as well as the frame-invariant quantity lambda(tilde), are measured from the dimuon decay angular distributions in three different polarization frames. The J/psi results are obtained in the transverse momentum range 14 &lt; pt &lt; 70 GeV, in the rapidity intervals abs(y) &lt; 0.6 and 0.6 &lt; abs(y) &lt; 1.2. The corresponding psi(2S) results cover 14 &lt; pt &lt; 50 GeV and include a third rapidity bin, 1.2 &lt; abs(y) &lt; 1.5. No evidence of large transverse or longitudinal polarizations is seen in these kinematic regions, which extend much beyond those previously explored

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.