Postnatal β-catenin deletion from Dmp1-expressing osteocytes/osteoblasts reduces structural adaptation to loading, but not periosteal load-induced bone formation

Mechanical signal transduction in bone tissue begins with load-induced activation of several cellular pathways in the osteocyte population. A key pathway that participates in mechanotransduction is Wnt/Lrp5 signaling. A putative downstream mediator of activated Lrp5 is the nucleocytoplasmic shuttling protein β-catenin (βcat), which migrates to the nucleus where it functions as a transcriptional co-activator. We investigated whether osteocytic βcat participates in Wnt/Lrp5-mediated mechanotransduction by conducting ulnar loading experiments in mice with or without chemically induced βcat deletion in osteocytes. Mice harboring βcat floxed loss-of-function alleles (βcat(f/f)) were bred to the inducible osteocyte Cre transgenic (10)(kb)Dmp1-CreERt2. Adult male mice were induced to recombine the βcat alleles using tamoxifen, and intermittent ulnar loading sessions were applied over the following week. Although adult-onset deletion of βcat from Dmp1-expressing cells reduced skeletal mass, the bone tissue was responsive to mechanical stimulation as indicated by increased relative periosteal bone formation rates in recombined mice. However, load-induced improvements in cross sectional geometric properties were compromised in recombined mice. The collective results indicate that the osteoanabolic response to loading can occur on the periosteal surface when β-cat levels are significantly reduced in Dmp1-expressing cells, suggesting that either (i) only low levels of β-cat are required for mechanically induced bone formation on the periosteal surface, or (ii) other additional downstream mediators of Lrp5 might participate in transducing load-induced Wnt signaling

Allosteric effects of E. coli SSB and RecR proteins on RecO protein binding to DNA

Escherichia coli single stranded (ss) DNA binding protein (SSB) plays essential roles in DNA maintenance. It binds ssDNA with high affinity through its N-terminal DNA binding core and recruits at least 17 different SSB interacting proteins (SIPs) that are involved in DNA replication, recombination, and repair via its nine amino acid acidic tip (SSB-Ct). E. coli RecO, a SIP, is an essential recombination mediator protein in the RecF pathway of DNA repair that binds ssDNA and forms a complex with E. coli RecR protein. Here, we report ssDNA binding studies of RecO and the effects of a 15 amino acid peptide containing the SSB-Ct monitored by light scattering, confocal microscope imaging, and analytical ultracentrifugation (AUC). We find that one RecO monomer can bind the oligodeoxythymidylate, (dT)15, while two RecO monomers can bind (dT)35 in the presence of the SSB-Ct peptide. When RecO is in molar excess over ssDNA, large RecO-ssDNA aggregates occur that form with higher propensity on ssDNA of increasing length. Binding of RecO to the SSB-Ct peptide inhibits RecO-ssDNA aggregation. RecOR complexes can bind ssDNA via RecO, but aggregation is suppressed even in the absence of the SSB-Ct peptide, demonstrating an allosteric effect of RecR on RecO binding to ssDNA. Under conditions where RecO binds ssDNA but does not form aggregates, SSB-Ct binding enhances the affinity of RecO for ssDNA. For RecOR complexes bound to ssDNA, we also observe a shift in RecOR complex equilibrium towards a RecR4O complex upon binding SSB-Ct. These results suggest a mechanism by which SSB recruits RecOR to facilitate loading of RecA onto ssDNA gaps

Higgs Structures of Dyonic Instantons

We study Higgs field configurations of dyonic instantons in spontaneously broken (4+1)-dimensional Yang-Mills theory. The adjoint scalar field solutions to the covariant Laplace equation in the ADHM instanton background are constructed in general noncanonical basis, and they are used to study explicitly the Higgs field configurations of dyonic instantons when the gauge fields are taken by Jackiw-Nohl-Rebbi instanton solutions. For these solutions corresponding to small instanton number we then consider in some detail the zero locus of the Higgs field, which describes the cross section of supertubes connecting parallel D4-branes in string theory. Also the information on the Higgs zeroes is used to discuss the residual gauge freedom concerning the Jackiw-Nohl-Rebbi solutions.Comment: 1+27 pages, 6 figure

Are the intrinsically disordered linkers involved in SSB binding to accessory proteins

Tuesday, February 18, 2020, 12:30 p.m., 1130 Eck Hall of Law Speakers: Josh Divine and Marah Stith McLeod Federal law regularly incorporates state law as its own, but meaningful use of such dynamic incorporation in criminal law is very rare. Its use in the criminal law context could reduce the political inertia that makes reforming criminal laws exceptionally difficult. It could also serve federalism by giving state legislatures the opportunity to exercise greater oversight of enforcement discretion, thereby enhancing enforcement accountability.https://scholarship.law.nd.edu/ndls_posters/1472/thumbnail.jp

Induction of Lrp5 HBM-causing mutations in Cathepsin-K expressing cells alters bone metabolism

High-bone-mass (HBM)-causing missense mutations in the low density lipoprotein receptor-related protein-5 (Lrp5) are associated with increased osteoanabolic action and protection from disuse- and ovariectomy-induced osteopenia. These mutations (e.g., A214V and G171V) confer resistance to endogenous secreted Lrp5/6 inhibitors, such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). Cells in the osteoblast lineage are responsive to canonical Wnt stimulation, but recent work has indicated that osteoclasts exhibit both indirect and direct responsiveness to canonical Wnt. Whether Lrp5-HBM receptors, expressed in osteoclasts, might alter osteoclast differentiation, activity, and consequent net bone balance in the skeleton, is not known. To address this, we bred mice harboring heterozygous Lrp5 HBM-causing conditional knock-in alleles to Ctsk-Cre transgenic mice and studied the phenotype using DXA, μCT, histomorphometry, serum assays, and primary cell culture. Mice with HBM alleles induced in Ctsk-expressing cells (TG) exhibited higher bone mass and architectural properties compared to non-transgenic (NTG) counterparts. In vivo and in vitro measurements of osteoclast activity, population density, and differentiation yielded significant reductions in osteoclast-related parameters in female but not male TG mice. Droplet digital PCR performed on osteocyte enriched cortical bone tubes from TG and NTG mice revealed that ~8–17% of the osteocyte population (depending on sex) underwent recombination of the conditional Lrp5 allele in the presence of Ctsk-Cre. Further, bone formation parameters in the midshaft femur cortex show a small but significant increase in anabolic action on the endocortical but not periosteal surface. These findings suggest that Wnt/Lrp5 signaling in osteoclasts affects osteoclastogenesis and activity in female mice, but also that some of the changes in bone mass in TG mice might be due to Cre expression in the osteocyte population

Correlation between temperature and the timing of arrival of geese in South Korea

The impact of climate change on animals has been globally documented. Especially, migration of birds has been extensively monitored as migratory birds are susceptible to any changes occurring both on breeding grounds and on wintering grounds. However, in contrast to spring migration, the patterns and the factors for autumn migration have not been well documented. In this study, we investigated the relationship with climate condition and the first arrival dates (FADs) of bean geese (Anser fabalis) and white-fronted geese (A. albifrons), the representative group of wintering birds in South Korea, using the data collected by Korean Meteorological Association during 1995–2016. Average temperature of September in wintering grounds has increased, and the FADs of the geese have advanced over the 22 years. Even when the influence of autumn temperature was statistically controlled for, the FADs of the geese have significantly advanced. This suggests that warming has hastened the completion of breeding, which speeded up the arrival of the geese at the wintering grounds. In order to assess the effect of climate condition on the arrival of the wintering migratory birds such as the geese in more detail, extensive data collection over many sampling sites and with long-term monitoring is needed.Funding was provided from NRF grants 2017R1D1A1B03029300 and 2018R1A6A3A01012729

Valuing Climate Impacts in Integrated Assessment Models: The MIT IGSM

http://globalchange.mit.edu/research/publications/reports/allWe discuss a strategy for investigating the impacts of climate change on Earth’s physical, biological and human resources and links to their socio-economic consequences. The features of the integrated global system framework that allows a comprehensive evaluation of climate change impacts are described with particular examples of effects on agriculture and human health. We argue that progress requires a careful understanding of the chain of physical changes—global and regional temperature, precipitation, ocean acidification and polar ice melting. We relate those changes to other physical and biological variables that help people understand risks to factors relevant to their daily lives—crop yield, food prices, premature death, flooding or drought events, land use change. Finally, we investigate how societies may adapt, or not, to these changes and how the combination of measures to adapt or to live with losses will affect the economy. Valuation and assessment of market impacts can play an important role, but we must recognize the limits of efforts to value impacts where deep uncertainty does not allow a description of the causal chain of effects that can be described, much less assigned a likelihood. A mixed approach of valuing impacts, evaluating physical and biological effects, and working to better describe uncertainties in the earth system can contribute to the social dialogue needed to achieve consensus—where it is needed—on the level and type of mitigation and adaptation actions that are required.The MIT Integrated Global System Model (IGSM) and its economic component used in the analysis, the MIT Emissions Prediction and Policy Analysis (EPPA) model, is supported by a consortium of government, industry, and foundation sponsors of the MIT Joint Program on the Science and Policy of Global Change. (For a complete list of sponsors, see: http://globalchange.mit.edu)

Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex.

Bioresorbable silicon electronics technology offers unprecedented opportunities to deploy advanced implantable monitoring systems that eliminate risks, cost and discomfort associated with surgical extraction. Applications include postoperative monitoring and transient physiologic recording after percutaneous or minimally invasive placement of vascular, cardiac, orthopaedic, neural or other devices. We present an embodiment of these materials in both passive and actively addressed arrays of bioresorbable silicon electrodes with multiplexing capabilities, which record in vivo electrophysiological signals from the cortical surface and the subgaleal space. The devices detect normal physiologic and epileptiform activity, both in acute and chronic recordings. Comparative studies show sensor performance comparable to standard clinical systems and reduced tissue reactivity relative to conventional clinical electrocorticography (ECoG) electrodes. This technology offers general applicability in neural interfaces, with additional potential utility in treatment of disorders where transient monitoring and modulation of physiologic function, implant integrity and tissue recovery or regeneration are required