The Role of Wnt Signaling in Bone Mechanotransduction

Indiana University-Purdue University Indianapolis (IUPUI)The aging US population is experiencing a growing incidence of osteoporosis, characterized by increased fracture risk and low bone mass. In skeletal tissue, canonical Wnt signaling is a critical regulator of bone mass, and dysregulation of the Wnt pathway has been implicated in numerous skeletal displasias. Some components of the Wnt signaling pathway have a clear role in bone homeostasis, particularly in the response of bone to altered mechanical environment. Other pathway components are more poorly defined. One important intracellular signal transduction node in the Wnt cascade is β- catenin, which modulates gene expression and cell-cell junctions, among other functions. During periods of disuse, β-catenin is degraded, leading to inhibition of Wnt targets. Here, I characterize the role of β-catenin in bone during a disuse challenge, using a genetic mouse model expressing an inducible constitively-active mutant form of β- catenin in the osteocyte population. I hypothesize that prevention of β-catenin degradation during disuse will prevent the bone wasting effects of mechanodeprivation. As a second goal, I focus on upstream (membrane-bound) modulation of Wnt. Here, I investigate the low-density lipoprotein receptor-related receptor 4 (Lrp4), in the regulation of bone mass and mechanotransduction. I generated an Lrp4 knockin mouse model harboring a missense mutation found among human patients with abnormally high bone mass. I hypothesize that the mutation compromises sclerostin action on bone cells. Understanding how each of these components of the Wnt signaling pathway interact, may lead to novel therapeutic targets for treatment of bone diseases

Letters from Governor Ann Richards, Lieutenant Governor Bob Bullock, and Dr. James Young: 1994

Letters from Governor Ann Richards, Lieutenant Governor Bob Bullock, and Dr. James Young regarding the expansion of medical school facilities in the Rio Grande Valley.https://scholarworks.utrgv.edu/hcard/1010/thumbnail.jp

A Wide Field Survey of Satellite Galaxies around the Spiral Galaxy M106

We present a wide field survey of satellite galaxies in M106 (NGC 4258) covering a 1.7\degr \times 2\degr field around M106 using Canada-France-Hawaii Telescope/MegaCam. We find 16 satellite galaxy candidates of M106. Eight of these galaxies are found to be dwarf galaxies that are much smaller and fainter than the remaining galaxies. Four of these galaxies are new findings. Surface brightness profiles of 15 out of 16 satellite galaxies can be represented well by an exponential disk profile with varying scale length. We derive the surface number density distribution of these satellite galaxies. The central number density profile (d $<100$ kpc) is well fitted by a power-law with a power index of $-2.1\pm0.5$, similar to the expected power index of isothermal distribution. The luminosity function of these satellites is represented well by the Schechter function with a faint end slope of $-1.19^{+0.03}_{-0.06}$. Integrated photometric properties (total luminosity, total colour, and disk scale length) and the spatial distribution of these satellite galaxies are found to be roughly similar to those of the Milky Way and M31.Comment: Accepted by MNRA

Crystal Structure of the PIM2 Kinase in Complex with an Organoruthenium Inhibitor

BACKGROUND: The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2. PRINCIPAL FINDINGS: Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level). Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases. SIGNIFICANCE: The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Satellite abundances around bright isolated galaxies

We study satellite galaxy abundances in SDSS by counting photometric galaxies around isolated bright primaries. We present results as a function of the luminosity, stellar mass and colour of the satellites, and of the stellar mass and colour of the primaries. For massive primaries the luminosity and stellar mass functions of satellites are similar in shape to those of field galaxies, but for lower mass primaries they are significantly steeper. The steepening is particularly marked for the stellar mass function. Satellite abundance increases strongly with primary stellar mass, approximately in proportion to expected dark halo mass. Massive red primaries have up to a factor of 2 more satellites than blue ones of the same stellar mass. Satellite galaxies are systematically redder than field galaxies of the same stellar mass. Satellites are also systematically redder around more massive primaries. At fixed primary mass, they are redder around red primaries. We select similarly isolated galaxies from mock catalogues based on the simulations of Guo et al.(2011) and analyze them in parallel with the SDSS data. The simulation reproduces all the above trends qualitatively, except for the steepening of the satellite luminosity and stellar mass functions. Model satellites, however, are systematically redder than in the SDSS, particularly at low mass and around low-mass primaries. Simulated haloes of a given mass have satellite abundances that are independent of central galaxy colour, but red centrals tend to have lower stellar masses, reflecting earlier quenching of their star formation by feedback. This explains the correlation between satellite abundance and primary colour in the simulation. The correlation between satellite colour and primary colour arises because red centrals live in haloes which are more massive, older and more gas-rich, so that satellite quenching is more efficient.Comment: 29 pages, 24 figure

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.United States. National Institutes of Health (HG002668)United States. National Institutes of Health (CA109901

Social capital and HIV-serodiscordance: Disparities in access to personal and professional resources for HIV-positive and HIV-negative partners.

As people living with HIV are living longer lives, they have a correspondingly greater opportunity to enjoy long-term romantic and sexual partnerships, including with persons who do not live with HIV ("serodiscordant" relationships). In these dyads, asymmetries may emerge in access to social resources between partners. In this paper we examined how serodiscordant couples access informal (interpersonal, such as family and friends) and formal (practitioner, such as doctor or social worker) social resources for health. We recruited 540 participants in current serodiscordant relationships, working with 150 AIDS service organizations and HIV clinics across Canada from 2016 to 2018. Our findings demonstrate that partners with HIV have greater access to formal resources than their partners (through health care professionals, therapists/counselors/support workers), while both persons have similar access to resources through informal social relationships (family and friends). Furthermore, the findings indicated that HIV positive partners accessed more varied forms of support through formal ties, compared to HIV negative persons. We offer recommendations for changes to how HIV-negative partners in a serodiscordant relationship are served and cared for, and particularly, the importance of moving toward dyad-focused policies and practices

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.United States. National Institutes of Health (HG002668)United States. National Institutes of Health (CA109901

Alcohol use among university students in Sweden measured by an electronic screening instrument

<p>Abstract</p> <p>Background</p> <p>Electronic-based alcohol screening and brief interventions for university students with problem drinking behaviours forms an important means by which to identify risky drinkers.</p> <p>Methods</p> <p>In this study an e-SBI project was implemented to assess drinking patterns, and to provide personalised feedback about alcohol consumption and related health problems, to students in a Swedish university. In this study, third semester university students (n = 2858) from all faculties (colleges) at the University were invited to participate in e-SBI screenings. This study employed a randomised controlled trial, with respondents having a equal chance of being assigned to a limited, or full-feedback response.</p> <p>Results</p> <p>The study shows that high risk drinkers tend to underestimate their own consumption compared to others, and that these high risk drinkers experience more negative consequences after alcohol intake, than other respondents. There was a strong belief, for both high- and low-risk drinkers, that alcohol helped celebrations be more festive. This study also confirms findings from other study locations that while males drank more than females in our study population; females reached the same peak alcohol blood concentrations as males.</p> <p>Conclusion</p> <p>Obtaining clear and current information on drinking patterns demonstrated by university students can help public health officials, university administration, and local health care providers develop appropriate prevention and treatment strategies.</p

A national recruitment strategy for HIV-serodiscordant partners living in Canada for the Positive Plus One study: a mixed-methods study.

BACKGROUND: With the recent shift in focus to addressing HIV risk within relationships and couple-based interventions to prevent HIV transmission, successful recruitment of individuals involved in HIV-serodiscordant relationships is crucial. This paper evaluates methods used by the Positive Plus One (PP1) study to recruit and collect data on a diverse national sample of dyads and individuals involved in current or past HIV-serodiscordant relationships, discusses the strengths and limitations of the recruitment approach, and makes recommendations to inform the interpretation of study results and the design of future studies. METHODS: PP1 used a multi-pronged approach to recruit adults involved in a current or past HIV-serodiscordant relationship in Canada from 2016 to 2018 to complete a survey and an interview. Upon survey completion, index (first recruited) partners were invited to recruit their primary current HIV-serodiscordant partner. We investigated participant enrollment by recruitment source, participant-, relationship-, and dyad-level sociodemographic characteristics, missing data, and correlates of participation for individuals recruited by their partners. RESULTS: We recruited 613 participants (355 HIV-positive; 258 HIV-negative) across 10 Canadian provinces, including 153 complete dyads and 307 individuals who participated alone, and representing 460 HIV-serodiscordant relationships. Among those in current relationships, HIV-positive participants were more likely than HIV-negative participants to learn of the study through an ASO staff member (36% v. 20%, p < 0.001), ASO listserv/newsletter (12% v. 5%, p = 0.007), or physician/staff at a clinic (20% v. 11%, p = 0.006). HIV-negative participants involved in current relationships were more likely than HIV-positive participants to learn of the study through their partner (46% v. 8%, p < 0.001). Seventy-eight percent of index participants invited their primary HIV-serodiscordant partner to participate, and 40% were successful. Successful recruitment of primary partners was associated with longer relationship duration, higher relationship satisfaction, and a virally suppressed HIV-positive partner. CONCLUSIONS: Our findings provide important new information on and support the use of a multi-pronged approach to recruit HIV-positive and HIV-negative individuals involved in HIV-serodiscordant relationships in Canada. More creative strategies are needed to help index partners recruit their partner in relationships with lower satisfaction and shorter duration and further minimize the risk of "happy couple" bias