Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes.

Serine/threonine protein phosphatase 5 (PP5) is ubiquitously expressed in eukaryotic cells; however, its function in cardiomyocytes is unknown. Under basal conditions, PP5 is autoinhibited, but enzymatic activity rises upon binding of specific factors, such as the chaperone Hsp90. Here we show that PP5 binds and dephosphorylates the elastic N2B-unique sequence (N2Bus) of titin in cardiomyocytes. Using various binding and phosphorylation tests, cell-culture manipulation, and transgenic mouse hearts, we demonstrate that PP5 associates with N2Bus in vitro and in sarcomeres and is antagonistic to several protein kinases, which phosphorylate N2Bus and lower titin-based passive tension. PP5 is pathologically elevated and likely contributes to hypo-phosphorylation of N2Bus in failing human hearts. Furthermore, Hsp90-activated PP5 interacts with components of a sarcomeric, N2Bus-associated, mechanosensor complex, and blocks mitogen-activated protein-kinase signaling in this complex. Our work establishes PP5 as a compartmentalized, well-controlled phosphatase in cardiomyocytes, which regulates titin properties and kinase signaling at the myofilaments

Impact of Long‐Term Alcohol Consumption and Relapse on Genome‐Wide DNA Methylation Changes in Alcohol‐Dependent Subjects: A Longitudinal Study

Background: Genetic factors play an important role in the development and maintenance of alcohol use disorder (AUD). Significant and widespread differences in methylation levels of multiple regions within the genome have been reported between AUD patients and healthy controls in large epigenome-wide association studies (EWASs). Also, within patient populations, methylation changes over time (both during and after withdrawal) have been identified as sensitive indicators for disease activity. The detection of changes in methylation levels is a powerful tool to further explore and understand the biological correlates and underpinnings of AUD. Although there is strong and convincing evidence for differences in methylation of various sites between AUD patients and controls, only few studies assessed changes within patients over longer periods of time while taking into account alcohol consumption, relapse, and abstinence. So far, the longest period assessed as a within-subject design using EWASs was 4 weeks. Methods: Here, we investigated changes in whole-genome methylation levels within a sample of 69 detoxified AUD patients over a period as long as 12 months for the first time, comparing patients that relapsed within the follow-up period to those that remained abstinent. Results: Whole-genome methylation patterns of individual CpG sites over time did not differ between abstinent and relapsing patients. However, there was a negative association between global mean methylation at the 12-month follow-up and alcohol consumption within our sample. Conclusion: Although the present study represents the largest study of methylation levels in a sample of AUD patients with a follow-up period of 1 year and accounting for alcohol consumption and relapse to date, the sample size might still not be large enough to detect genome-wide significant effects. Therefore, large-scale, long-term studies with AUD subjects are needed to determine the utility of DNA methylation for the assessment and monitoring of persons with alcohol use disorders

Effects of strontium ranelate and alendronate on bone microstructure in women with osteoporosis: Results of a 2-year study

Summary: Strontium ranelate appears to influence more than alendronate distal tibia bone microstructure as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), and biomechanically relevant parameters as assessed by micro-finite element analysis (μFEA), over 2years, in postmenopausal osteoporotic women. Introduction: Bone microstructure changes are a target in osteoporosis treatment to increase bone strength and reduce fracture risk. Methods: Using HR-pQCT, we investigated the effects on distal tibia and radius microstructure of strontium ranelate (SrRan; 2g/day) or alendronate (70mg/week) for 2years in postmenopausal osteoporotic women. This exploratory randomized, double-blind trial evaluated HR-pQCT and FEA parameters, areal bone mineral density (BMD), and bone turnover markers. Results: In the intention-to-treat population (n = 83, age: 64 ± 8years; lumbar T-score: −2.8 ± 0.8 [DXA]), distal tibia Cortical Thickness (CTh) and Density (DCort), and cancellous BV/TV increased by 6.3%, 1.4%, and 2.5%, respectively (all P < 0.005), with SrRan, but not with alendronate (0.9%, 0.4%, and 0.8%, NS) (P < 0.05 for all above between-group differences). Difference for CTh evaluated with a distance transformation method was close to significance (P = 0.06). The estimated failure load increased with SrRan (+2.1%, P < 0.005), not with alendronate (−0.6%, NS) (between-group difference, P < 0.01). Cortical stress was lower with SrRan (P < 0.05); both treatments decreased trabecular stress. At distal radius, there was no between-group difference other than DCort (P < 0.05). Bone turnover markers decreased with alendronate; bALP increased (+21%) and serum-CTX-I decreased (−1%) after 2years of SrRan (between-group difference at each time point for both markers, P < 0.0001). Both treatments were well tolerated. Conclusions: Within the constraints of HR-pQCT method, and while a possible artefactual contribution of strontium cannot be quantified, SrRan appeared to influence distal tibia bone microstructure and FEA-determined biomechanical parameters more than alendronate. However, the magnitude of the differences is unclear and requires confirmation with another metho

Circulating interleukin-6 receptor in patients with sepsis syndrome

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P11 promoter methylation predicts the antidepressant effect of electroconvulsive therapy

Although electroconvulsive therapy (ECT) is among the most effective treatment options for pharmacoresistant major depressive disorder (MDD), some patients still remain refractory to standard ECT practise. Thus, there is a need for markers reliably predicting ECT non/response. In our study, we have taken a novel translational approach for discovering potential biomarkers for the prediction of ECT response. Our hypothesis was that the promoter methylation of p11, a multifunctional protein involved in both depressive-like states and antidepressant treatment responses, is differently regulated in ECT responders vs. nonresponders and thus be a putative biomarker of ECT response. The chronic mild stress model of MDD was adapted with the aim to obtain rats that are resistant to conventional antidepressant drugs (citalopram). Subsequently, electroconvulsive stimulation (ECS) was used to select responders and nonresponders, and compare p11 expression and promoter methylation. In the rat experiments we found that the gene promoter methylation and expression of p11 significantly correlate with the antidepressant effect of ECS. Next, we investigated the predictive properties of p11 promoter methylation in two clinical cohorts of patients with pharmacoresistant MDD. In a proof-of-concept clinical trial in 11 patients with refractory MDD, higher p11 promoter methylation was found in responders to ECT. This finding was replicated in an independent sample of 65 patients with pharmacoresistant MDD. This translational study successfully validated the first biomarker reliably predicting the responsiveness to ECT. Prescreening of this biomarker could help to identify patients eligible for first-line ECT treatment and also help to develop novel antidepressant treatment procedures for depressed patients resistant to all currently approved antidepressant treatments.Peer reviewe

Pre-breakup magmatism on the Vøring margin: Insight from new sub-basalt imaging and results from Ocean Drilling program hole 642E

Highlights • Sub-basalt imaging improvement on the Vøring Margin • Definition of a new seismic facies unit: the Lower Series Flows • Significant organic carbon content within the melting crustal segment • Apectodinium augustum marker for the PETM is reworked into the Lower Series Flows • The Lower Series Flows, early Eocene in age, predate the Vøring Margin breakup Abstract Improvements in sub-basalt imaging combined with petrological and geochemical observations from the Ocean Drilling Program (ODP) Hole 642E core provide new constraints on the initial breakup processes at the Vøring Margin. New and reprocessed high quality seismic data allow us to identify a new seismic facies unit which we define as the Lower Series Flows. This facies unit is seismically characterized by wavy to continuous subparallel reflections with an internal disrupted and hummocky shape. Drilled lithologies, which we correlate to this facies unit, have been interpreted as subaqueous flows extruding and intruding into wet sediments. Locally, the top boundary of this facies unit is defined as a negative in polarity reflection, and referred as the K-Reflection. This reflection can be correlated with the spatial extent of pyroclastic deposits, emplaced during transitional shallow marine to subaerial volcanic activities during the rift to drift transition. The drilled Lower Series Flows consist of peraluminous, cordierite bearing peperitic basaltic andesitic to dacitic flows interbedded with thick volcano-sedimentary deposits and intruded sills. The peraluminous geochemistry combined with available C (from calcite which fills vesicles and fractures), Sr, Nd, and Pb isotopes data point towards upper crustal rock-mantle magma interactions with a significant contribution of organic carbon rich pelagic sedimentary material during crustal anatexis. From biostratigraphic analyses, Apectodinium augustum was found in the The Lower Series Flows. This species is a marker for the Paleocene – Eocene Thermal Maximum (PETM). However, the absence of very low carbon isotope values (from bulk organic matter), that characterize the PETM, imply that A.augustum was reworked into the early Eocene sediments of this facies unit which predate the breakup time of the Vøring Margin. Finally, a plausible conceptual emplacement model for the Lower Series Flows facies unit is proposed. This model comprises several stages: (1) the emplacement of subaqueous peperitic basaltic andesitic flows intruding and/or extruding wet sediments; (2) a subaerial to shallow marine volcanism and extrusion of dacitic flows; (3) a proto-breakup phase with intense shallow marine to subaerial explosive volcanism responsible for pyroclastic flow deposits which can be correlated with the seismic K-Reflection and (4) the main breakup stage with intense transitional tholeiitic MORB-type volcanism and large subsidence concomitant with the buildup of the Seaward Dipping Reflector wedge

The similarity problem for JJ-nonnegative Sturm-Liouville operators

Sufficient conditions for the similarity of the operator $A := 1/r(x) (-d^2/dx^2 +q(x))$ with an indefinite weight r(x)=(\sgn x)|r(x)| are obtained. These conditions are formulated in terms of Titchmarsh-Weyl $m$-coefficients. Sufficient conditions for the regularity of the critical points 0 and $\infty$ of $J$-nonnegative Sturm-Liouville operators are also obtained. This result is exploited to prove the regularity of 0 for various classes of Sturm-Liouville operators. This implies the similarity of the considered operators to self-adjoint ones. In particular, in the case r(x)=\sgn x and $q\in L^1(R, (1+|x|)dx)$, we prove that $A$ is similar to a self-adjoint operator if and only if $A$ is $J$-nonnegative. The latter condition on $q$ is sharp, i.e., we construct $q\in \cap_{\gamma <1} L^1(R, (1+|x|)^\gamma dx)$ such that $A$ is $J$-nonnegative with the singular critical point 0. Hence $A$ is not similar to a self-adjoint operator. For periodic and infinite-zone potentials, we show that $J$-positivity is sufficient for the similarity of $A$ to a self-adjoint operator. In the case $q\equiv 0$, we prove the regularity of the critical point 0 for a wide class of weights $r$. This yields new results for "forward-backward" diffusion equations.Comment: 36 pages, LaTeX2e, version 2; addresses of the authors added, the reference [38] update

Early Jurassic large igneous province carbon emissions constrained by sedimentary mercury

This is the final version. Available on open access from Nature Research via the DOI in this recordData availability: All data generated or analysed during this study are included in this published paper (and its Supplementary Information) and are available at https://doi.org/10.6084/m9.figshare.23301311.Code availability: The R script to calculate residual Hg for the Mochras dataset is available within the Supplementary Information.Large igneous province eruptions and their carbon emissions often coincide with, and are hypothesized to have driven, severe environmental perturbations in the geological past. However, the vast scale of large igneous provinces and uncertainties in magmatic volatile contents and radioisotopic dates limit our ability to resolve gas emissions in detail over time. Here we employ high-resolution (~5–200 kyr) sedimentary mercury data from the Llanbedr (Mochras Farm) borehole, Wales, to derive quantitative large igneous province degassing estimates over a 20-million-year-long Early Jurassic interval (195–175 million years ago). Intervals of relatively elevated sedimentary mercury coincide with episodes of carbon-cycle change, including the Toarcian Oceanic Anoxic Event (183–182 million years ago). We use excess mercury loading to estimate large igneous province-associated carbon emissions, revealing that multi-millennial episodes of activity plausibly drove recognized pCO2 and temperature increases. However, previous carbon-cycle model-based carbon emission scenarios require faster and larger carbon inputs than our proposed emissions. Resolving this discrepancy may require climate–carbon-cycle feedbacks or co-emitted gases to substantially exacerbate the carbon-cycle response, processes potentially underestimated in current models. Our long and near-continuous record of Early Jurassic large igneous province activity demonstrates mercury’s potential as a tool to resolve past carbon fluxes.European Research Council (ERC)Natural Environment Research Council (NERC

Neuropathological and Reelin Deficiencies in the Hippocampal Formation of Rats Exposed to MAM; Differences and Similarities with Schizophrenia

Adult rats exposed to methylazoxymethanol (MAM) at embryonic day 17 (E17) consistently display behavioral characteristics similar to that observed in patients with schizophrenia and replicate neuropathological findings from the prefrontal cortex of psychotic individuals. However, a systematic neuropathological analysis of the hippocampal formation and the thalamus in these rats is lacking. It is also unclear if reelin, a protein consistently associated with schizophrenia and potentially involved in the mechanism of action of MAM, participates in the neuropathological effects of this compound. Therefore, a thorough assessment including cytoarchitectural and neuromorphometric measurements of eleven brain regions was conducted. Numbers of reelin positive cells and reelin expression and methylation levels were also studied.Compared to untreated rats, MAM-exposed animals showed a reduction in the volume of entorhinal cortex, hippocampus and mediodorsal thalamus associated with decreased neuronal soma. The entorhinal cortex also showed laminar disorganization and neuronal clusters. Reelin methylation in the hippocampus was decreased whereas reelin positive neurons and reelin expression were unchanged.Our results indicate that E17-MAM exposure reproduces findings from the hippocampal formation and the mediodorsal thalamus of patients with schizophrenia while providing little support for reelin's involvement. Moreover, these results strongly suggest MAM-treated animals have a diminished neuropil, which likely arises from abnormal neurite formation; this supports a recently proposed pathophysiological hypothesis for schizophrenia

Neutrophils are Mediators of Metastatic Prostate Cancer Progression in Bone

Bone metastatic prostate cancer (BM-PCa) significantly reduces overall patient survival and is currently incurable. Current standard immunotherapy showed promising results for PCa patients with metastatic, but less advanced, disease (i.e., fewer than 20 bone lesions) suggesting that PCa growth in bone contributes to response to immunotherapy. We found that: (1) PCa stimulates recruitment of neutrophils, the most abundant immune cell in bone, and (2) that neutrophils heavily infiltrate regions of prostate tumor in bone of BM-PCa patients. Based on these findings, we examined the impact of direct neutrophil-prostate cancer interactions on prostate cancer growth. Bone marrow neutrophils directly induced apoptosis of PCa in vitro and in vivo, such that neutrophil depletion in bone metastasis models enhanced BM-PCa growth. Neutrophil-mediated PCa killing was found to be mediated by suppression of STAT5, a transcription factor shown to promote PCa progression. However, as the tumor progressed in bone over time, neutrophils from late-stage bone tumors failed to elicit cytotoxic effector responses to PCa. These findings are the first to demonstrate that bone-resident neutrophils inhibit PCa and that BM-PCa are able to progress via evasion of neutrophil-mediated killing. Enhancing neutrophil cytotoxicity in bone may present a novel therapeutic option for bone metastatic prostate cancer