An Early Transcriptional Analysis of Fracture Hematoma in Rat

Among other stressors, age and mechanical constraints significantly influence regeneration cascades in bone healing. Here, our aim was to identify genes and, through their functional annotation, related biological processes that are influenced by an interaction between the effects of mechanical fixation stability and age. Therefore, at day three post-osteotomy, chip-based whole- genome gene expression analyses of fracture hematoma tissue were performed for four groups of Sprague-Dawley rats with a 1.5-mm osteotomy gap in the femora with varying age (12 vs. 52 weeks - biologically challenging) and external fixator stiffness (mechanically challenging). From 31099 analysed genes, 1103 genes were differentially expressed between the six possible combinations of the four groups and from those 144 genes were identified as statistically significantly influenced by the interaction between age and fixation stability. Functional annotation of these differentially expressed genes revealed an association with extracellular space, cell migration or vasculature development. The chip-based whole-genome gene expression data was validated by q-RT-PCR at days three and seven post-osteotomy for MMP-9 and MMP-13, members of the mechanosensitive matrix metalloproteinase family and key players in cell migration and angiogenesis. Furthermore, we observed an interaction of age and mechanical stimuli in vitro on cell migration of mesenchymal stromal cells. These cells are a subpopulation of the fracture hematoma and are known to be key players in bone regeneration. In summary, these data correspond to and might explain our previously described biomechanical healing outcome after six weeks in response to fixation stiffness variation. In conclusion, our data highlight the importance of analysing the influence of risk factors of fracture healing (e.g. advanced age, suboptimal fixator stability) in combination rather than alone

High-contrast Computational Caustic Design

We present a new algorithm for computational caustic design. Our algorithm solves for the shape of a transparent object such that the refracted light paints a desired caustic image on a receiver screen. We introduce an optimal transport formulation to establish a correspondence between the input geometry and the unknown target shape. A subsequent 3D optimization based on an adaptive discretization scheme then finds the target surface from the correspondence map. Our approach supports piecewise smooth surfaces and non-bijective mappings, which eliminates a number of shortcomings of previous methods. This leads to a significantly richer space of caustic images, including smooth transitions, singularities of infinite light density, and completely black areas. We demonstrate the effectiveness of our approach with several simulated and fabricated examples

A Randomized, Controlled Trial of Financial Incentives for Smoking Cessation.

BACKGROUND: Smoking is the leading preventable cause of premature death in the United States. Previous studies of financial incentives for smoking cessation in work settings have not shown that such incentives have significant effects on cessation rates, but these studies have had limited power, and the incentives used may have been insufficient. METHODS: We randomly assigned 878 employees of a multinational company based in the United States to receive information about smoking-cessation programs (442 employees) or to receive information about programs plus financial incentives (436 employees). The financial incentives were $100 for completion of a smoking-cessation program,$250 for cessation of smoking within 6 months after study enrollment, as confirmed by a biochemical test, and $400 for abstinence for an additional 6 months after the initial cessation, as confirmed by a biochemical test. Individual participants were stratified according to work site, heavy or nonheavy smoking, and income. The primary end point was smoking cessation 9 or 12 months after enrollment, depending on whether initial cessation was reported at 3 or 6 months. Secondary end points were smoking cessation within the first 6 months after enrollment and rates of participation in and completion of smoking-cessation programs. RESULTS: The incentive group had significantly higher rates of smoking cessation than did the information-only group 9 or 12 months after enrollment (14.7% vs. 5.0%, P CONCLUSIONS: In this study of employees of one large company, financial incentives for smoking cessation significantly increased the rates of smoking cessation. (ClinicalTrials.gov number, NCT00128375.

Proyecto de restauración de la casa del bosque, Buitrago de Lozoya

Proyecto de restauración de la casa del bosque, Buitrago de Lozoy

Knowing the past to improve the future: Estimating historical fishing catches to improve fisheries management in the Western Mediterranean Sea

We developed for the first time the commercial fishing catches reconstruction of the Balearic Islands (Western Mediterranean) between 1950 and 2010, by adding non-reported components, including unreported landings and discards, to the official reported landing data. To back‑estimate historical unreported landings and discards, collaboration and information acquired from fishermen were essential, as gathered through interviews and observer programs of the Spanish Oceanographic Institute (IEO) on board commercial bottom trawling fleet. We estimated a total catch of 511,500 t over the period 1950‑2010, of which official landings represented 49% (around 248,000 t), followed by unreported catches (32%) and discards (20%). A decrease in unreported catches was observed during the period 1950-2010 (from 58% to 38%) due to a reduction of unreported landings, but substantial efforts are still required to improve the recordings of actual fishing catches. This work contributes to the global assessment of fisheries removals led by the Sea Around Us and aims to provide the basis for an improved management of the Balearic Islands and Mediterranean Sea fisheries

Activity-Dependent Shedding of the NMDA Receptor Glycine Binding Site by Matrix Metalloproteinase 3: A PUTATIVE Mechanism of Postsynaptic Plasticity

Functional and structural alterations of clustered postsynaptic ligand gated ion channels in neuronal cells are thought to contribute to synaptic plasticity and memory formation in the human brain. Here, we describe a novel molecular mechanism for structural alterations of NR1 subunits of the NMDA receptor. In cultured rat spinal cord neurons, chronic NMDA receptor stimulation induces disappearance of extracellular epitopes of NMDA receptor NR1 subunits, which was prevented by inhibiting matrix metalloproteinases (MMPs). Immunoblotting revealed the digestion of solubilized NR1 subunits by MMP-3 and identified a fragment of about 60 kDa as MMPs-activity-dependent cleavage product of the NR1 subunit in cultured neurons. The expression of MMP-3 in the spinal cord culture was shown by immunoblotting and immunofluorescence microscopy. Recombinant NR1 glycine binding protein was used to identify MMP-3 cleavage sites within the extracellular S1 and S2-domains. N-terminal sequencing and site-directed mutagenesis revealed S542 and L790 as two putative major MMP-3 cleavage sites of the NR1 subunit. In conclusion, our data indicate that MMPs, and in particular MMP-3, are involved in the activity dependent alteration of NMDA receptor structure at postsynaptic membrane specializations in the CNS

Parameterized Games and Parameterized Automata

We introduce a way to parameterize automata and games on finite graphs with natural numbers. The parameters are accessed essentially by allowing counting down from the parameter value to 0 and branching depending on whether 0 has been reached. The main technical result is that in games, a player can win for some values of the parameters at all, if she can win for some values below an exponential bound. For many winning conditions, this implies decidability of any statements about a player being able to win with arbitrary quantification over the parameter values.While the result seems broadly applicable, a specific motivation comes from the study of chains of strategies in games. Chains of games were recently suggested as a means to define a rationality notion based on dominance that works well with quantitative games by Bassett, Jecker, P., Raskin and Van den Boogard. From the main result of this paper, we obtain generalizations of their decidability results with much simpler proofs.As both a core technical notion in the proof of the main result, and as a notion of potential independent interest, we look at boolean functions defined via graph game forms. Graph game forms have properties akin to monotone circuits, albeit are more concise. We raise some open questions regarding how concise they are exactly, which have a flavour similar to circuit complexity. Answers to these questions could improve the bounds in the main theorem

Marine reserves can mitigate and promote adaptation to climate change

Strong decreases in greenhouse gas emissions are required to meet the reduction trajectory resolved within the 2015 Paris Agreement. However, even these decreases will not avert serious stress and damage to life on Earth, and additional steps are needed to boost the resilience of ecosystems, safeguard their wildlife, and protect their capacity to supply vital goods and services. We discuss how well-managed marine reserves may help marine ecosystems and people adapt to five prominent impacts of climate change: acidification, sea-level rise, intensification of storms, shifts in species distribution, and decreased productivity and oxygen availability, as well as their cumulative effects. We explore the role of managed ecosystems in mitigating climate change by promoting carbon sequestration and storage and by buffering against uncertainty in management, environmental fluctuations, directional change, and extreme events. We highlight both strengths and limitations and conclude that marine reserves are a viable low-tech, cost-effective adaptation strategy that would yield multiple cobenefits from local to global scales, improving the outlook for the environment and people into the future

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia

Objective: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. Methods: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients. Results: We identified a heterozygous variant, c.388G&gt;A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G&gt;A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G&gt;C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A&gt;C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia. Interpretation: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485–497.</p