Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the ...inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers. Our group previously developed a series of orally bioavailable small molecule activators of PP2A, termed SMAPs. We now report that SMAP treatment inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models. Mechanistically, we found that SMAPs act by binding to the PP2A Aα scaffold subunit to drive conformational changes in PP2A. These results show that PP2A can be activated in cancer cells to inhibit proliferation. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases and represents an advancement toward the development of small molecule activators of tumor suppressor proteins.
The Edition 2 (Ed2) cloud property retrieval algorithm system was upgraded and applied to the MODerate-resolution Imaging Spectroradiometer (MODIS) data for the Clouds and the Earth's Radiant Energy ...System (CERES) Edition 4 (Ed4) products. New calibrations for solar channels and the use of the 1.24-<inline-formula> <tex-math notation="LaTeX">\mu \text{m} </tex-math></inline-formula> channel for cloud optical depth (COD) over snow improve the daytime consistency between Terra and Aqua MODIS retrievals. Use of additional spectral channels and revised logic enhanced the cloud-top phase retrieval accuracy. A new ice crystal reflectance model and a CO 2 -channel algorithm retrieved higher ice clouds, while a new regional lapse rate technique produced more accurate water cloud heights than in Ed2. Ice cloud base heights are more accurate due to a new cloud thickness parameterization. Overall, CODs increased, especially over the polar (PO) regions. The mean particle sizes increased slightly for water clouds, but more so for ice clouds in the PO areas. New experimental parameters introduced in Ed4 are limited in utility, but will be revised for the next CERES edition. As part of the Ed4 retrieval evaluation, the average properties are compared with those from other algorithms and the differences between individual reference data and matched Ed4 retrievals are explored. Part II of this article provides a comprehensive, objective evaluation of selected parameters. More accurate interpretation of the CERES radiation measurements has resulted from the use of the Ed4 cloud properties.
Cloud properties are essential for the Clouds and the Earth’s Radiant Energy System (CERES) Project, enabling accurate interpretation of measured broadband radiances, providing a means to understand ...global cloud-radiation interactions, and constituting an important climate record. Producing consistent cloud retrievals across multiple platforms is critical for generating a multidecadal cloud and radiation record. Techniques used by CERES for retrievals from measurements by the MODerate-Resolution Imaging Spectroradiometer (MODIS) on Terra and Aqua platforms are adapted for the application to radiances from the Visible Infrared Imaging Radiometer Suite (VIIRS) on the Suomi National Polar-orbiting Partnership to continue the CERES record beyond the MODIS era. The algorithm adjustments account for spectral and channel differences, use revised reflectance models, and set new thresholds for detecting thin cirrus clouds at night. Cloud amounts from VIIRS are less than their MODIS counterparts by 0.016 during the day and 0.026 at night, but trend consistently over the 2012–2020 period. The VIIRS mean liquid water cloud fraction differs by ~0.01 from the MODIS amount. The average cloud heights from VIIRS differ from the MODIS heights by less than 0.2 km, except the VIIRS daytime ice cloud heights, which are 0.4 km higher. The mean VIIRS nonpolar optical depths are 17% (1%) larger (smaller) than those from MODIS for liquid (ice) clouds. The VIIRS cloud hydrometeor sizes are generally smaller than their MODIS counterparts. Discrepancies between the MODIS and VIIRS properties stem from spectral and spatial resolution differences, new tests at night, calibration inconsistencies, and new reflectance models. Many of those differences will be addressed in future editions.
Reproductive inequality in humans and other mammals Ross, Cody T; Hooper, Paul L; Smith, Jennifer E ...
Proceedings of the National Academy of Sciences - PNAS,
05/2023, Letnik:
120, Številka:
22
Journal Article
Recenzirano
Odprti dostop
To address claims of human exceptionalism, we determine where humans fit within the greater mammalian distribution of reproductive inequality. We show that humans exhibit lower reproductive skew ...(i.e., inequality in the number of surviving offspring) among males and smaller sex differences in reproductive skew than most other mammals, while nevertheless falling within the mammalian range. Additionally, female reproductive skew is higher in polygynous human populations than in polygynous nonhumans mammals on average. This patterning of skew can be attributed in part to the prevalence of monogamy in humans compared to the predominance of polygyny in nonhuman mammals, to the limited degree of polygyny in the human societies that practice it, and to the importance of unequally held rival resources to women's fitness. The muted reproductive inequality observed in humans appears to be linked to several unusual characteristics of our species-including high levels of cooperation among males, high dependence on unequally held rival resources, complementarities between maternal and paternal investment, as well as social and legal institutions that enforce monogamous norms.
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing ...Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers approximately 99% of the euchromatic genome and is accurate to an error rate of approximately 1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human genome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead.
The safety of transesophageal echocardiography (TEE) in elderly patients (aged > or = 70 years) and young patients (aged < or = 50 years) was compared in a retrospective study of 283 examinations in ...each group. A greater percentage of studies was performed in an intensive care unit in the elderly group (22%) as compared with the younger group (13%, p < 0.02). In studies performed in an intensive care unit, 39% (24/61) of patients in the elderly group and 45% (17/38) in the young group were on ventilators. Transient systemic hypotension complicating TEE was 3.5 times more frequent in the elderly (5%) as compared with the young group (1.4%, p < 0.02). Life-threatening complications associated with TEE were rare (< 0.01%) and included third-degree atrioventricular block in one patient and profound vasovagal reaction in one patient in the elderly group and myocardial ischemia in one patient in the young group. Being elderly and on a ventilator were independent predictors of the development of systemic hypotension during TEE. Overall, TEE is a low-risk procedure but is associated with a 3.5 times greater risk of systemic hypotension in elderly patients as compared with younger subjects. The benefit and risk should be assessed in all patients before TEE, particularly in the elderly.
Type-II dens fractures have long been described in the literature as occurring in a bimodal distribution, peaking in young adulthood as well as in older adulthood; however, the origin of this claim ...is unclear. The primary goal of this study was to examine the incidence of type-II dens fractures and assess for bimodality.
This is a retrospective cross-sectional review of the National Trauma Data Bank (NTDB) records on traumatic type-II dens fractures between October 2015 and December 2016. Rates were obtained from the NTDB, and the incidence per 100,000 was ascertained by utilizing U.S. Census data from 2016. Subgroupings by gender and Black or White race were also examined.
Dens fractures occur unimodally, peaking around 89 years of age overall, skewed left by high rates in older White adults. The Black subgroup demonstrated trimodality, with the fracture incidence peaking at 25, 62, and 82 years of age. Rates among Black and White patients were similar until age 65, after which dens fractures occurred disproportionately in White patients. Fractures prior to age 75 occurred predominantly in men.
The evidence derived in this study challenges the common belief that type-II dens fractures occur bimodally across the entire population. However, there remains utility in considering younger and older patients as distinct groups for the purposes of management.
During an eight-week field experience six preservice teachers, under the supervision of their mentor professor, designed and facilitated an integrated inquiry unit for a fifth-grade class. As a part ...of their field experience, the preservice teachers investigated their effectiveness in implementing the inquiry approach to teaching based on the children's learning responses. Reflecting on their own teaching behaviors through reflective classroom research challenged the preservice teachers to explore images of teaching that were often less than ideal but always informative.
The provocative debate about Malcolm X's legacy that emerged after the publication of Manning Marable's 2011 biography raised critical questions about the revolutionary Black Nationalist's importance ...to American and world affairs: What was Malcolm's association with the Nation of Islam? How should we interpret Malcolm's discourses? Was Malcolm antifeminist? What is Malcolm's legacy in contemporary public affairs? How do Malcolm's early childhood experiences in Michigan shape and inform his worldview? Was Malcolm trending toward socialism during his final year? Malcolm X's Michigan Worldviewresponds to these questions by presenting Malcolm's subject as an iconography used to deepen understanding of African descendent peoples' experiences through advanced research and disciplinary study. A Black studies reader that uses the biography of Malcolm X both to interrogate key aspects of the Black world experience and to contribute to the intellectual expansion of the discipline, the book presents Malcolm as a Black subject who represents, symbolizes, and associates meaning with the Black/Africana studies discipline. Through a range of multidisciplinary prisms and themes including discourse, race, culture, religion, gender, politics, and community, this rich volume elicits insights about the Malcolm iconography that contribute to the continuous formulation, deepening, and strengthening of the Black studies discipline.
Titanemia from total knee arthroplasty von Schroeder, Herbert P.; Smith, Dennis C.; Gross, Alan E. ...
The Journal of arthroplasty,
8/1996, Letnik:
11, Številka:
5
Journal Article
Recenzirano
The subject of this case report is a patient with elevated serum levels of titanium (77 parts/billion ppb; normal, 3.3 ppb) and vanadium (0.38 ppb; normal, 0.17 ppb) resulting from excessive wear of ...a metal-backed patellar component in a total knee arthroplasty. The patellar component was worn through both its polyethylene and metal backing as a result of abnormal contact between the patellar and femoral components. Scanning electron microscopic examination of the ingrowth surface of the patellar component indicated that particle debonding occurred as a result of overloading of the sintered neck regions at the particle-substrate interface, suggesting a possible damage during initial insertion of the device, which may have predisposed it to loosening and abnormal contact with the femoral component. Wear particles resulted in staining of the tissues within the knee and an inflammatory and immune response in the synovium consisting of giant cells and T lymphocytes. The serum metal levels were reduced 22 weeks after replacing the patellar component: however, the titanium level was still slightly elevated (8 ppb).
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