Fractional boundary value problems: Analysis and numerical methods

This is the author's PDF of an article published in Fractional calculus and applied analysis 2011. The original publication is available at www.springerlink.comThis journal article discusses nonlinear boundary value problems.Fundacao para a Ciencia e Tecnologi

Protein phosphatase 2a (PP2A) binds within the oligomerization domain of striatin and regulates the phosphorylation and activation of the mammalian Ste20-Like kinase Mst3

<p>Abstract</p> <p>Background</p> <p>Striatin, a putative protein phosphatase 2A (PP2A) B-type regulatory subunit, is a multi-domain scaffolding protein that has recently been linked to several diseases including cerebral cavernous malformation (CCM), which causes symptoms ranging from headaches to stroke. Striatin association with the PP2A A/C (structural subunit/catalytic subunit) heterodimer alters PP2A substrate specificity, but targets and roles of striatin-associated PP2A are not known. In addition to binding the PP2A A/C heterodimer to form a PP2A holoenzyme, striatin associates with cerebral cavernous malformation 3 (CCM3) protein, the mammalian Mps one binder (MOB) homolog, Mob3/phocein, the mammalian sterile 20-like (Mst) kinases, Mst3, Mst4 and STK25, and several other proteins to form a large signaling complex. Little is known about the molecular architecture of the striatin complex and the regulation of these sterile 20-like kinases.</p> <p>Results</p> <p>To help define the molecular organization of striatin complexes and to determine whether Mst3 might be negatively regulated by striatin-associated PP2A, a structure-function analysis of striatin was performed. Two distinct regions of striatin are capable of stably binding directly or indirectly to Mob3--one N-terminal, including the coiled-coil domain, and another more C-terminal, including the WD-repeat domain. In addition, striatin residues 191-344 contain determinants necessary for efficient association of Mst3, Mst4, and CCM3. PP2A associates with the coiled-coil domain of striatin, but unlike Mob3 and Mst3, its binding appears to require striatin oligomerization. Deletion of the caveolin-binding domain on striatin abolishes striatin family oligomerization and PP2A binding. Point mutations in striatin that disrupt PP2A association cause hyperphosphorylation and activation of striatin-associated Mst3.</p> <p>Conclusions</p> <p>Striatin orchestrates the regulation of Mst3 by PP2A. It binds Mst3 likely as a dimer with CCM3 via residues lying between striatin's calmodulin-binding and WD-domains and recruits the PP2A A/C heterodimer to its coiled-coil/oligomerization domain. Residues outside the previously reported coiled-coil domain of striatin are necessary for its oligomerization. Striatin-associated PP2A is critical for Mst3 dephosphorylation and inactivation. Upon inhibition of PP2A, Mst3 activation appears to involve autophosphorylation of multiple activation loop phosphorylation sites. Mob3 can associate with striatin sequences C-terminal to the Mst3 binding site but also with sequences proximal to striatin-associated PP2A, consistent with a possible role for Mob 3 in the regulation of Mst3 by PP2A.</p

Cost‐effectiveness analysis of low‐dose direct oral anticoagulant (DOAC) for the prevention of cancer‐associated thrombosis in the United States

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154607/1/cncr32724.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154607/2/cncr32724_am.pd

Challenges in Representation Learning: A report on three machine learning contests

The ICML 2013 Workshop on Challenges in Representation Learning focused on three challenges: the black box learning challenge, the facial expression recognition challenge, and the multimodal learning challenge. We describe the datasets created for these challenges and summarize the results of the competitions. We provide suggestions for organizers of future challenges and some comments on what kind of knowledge can be gained from machine learning competitions.Comment: 8 pages, 2 figure

F.A.R.O.G. FORUM, Vol. 2 No. 9

https://digitalcommons.library.umaine.edu/francoamericain_forum/1008/thumbnail.jp

KCNK3 mutation causes altered immune function in pulmonary arterial hypertension patients and mouse models

Loss of function KCNK3 mutation is one of the gene variants driving hereditary pulmonary arterial hypertension (PAH). KCNK3 is expressed in several cell and tissue types on both membrane and endoplasmic reticulum and potentially plays a role in multiple pathological process associated with PAH. However, the role of various stressors driving the susceptibility of KCNK3 mutation to PAH is unknown. Hence, we expose

The Advantage of Standing Up to Fight and the Evolution of Habitual Bipedalism in Hominins

BACKGROUND: Many quadrupedal species stand bipedally on their hindlimbs to fight. This posture may provide a performance advantage by allowing the forelimbs to strike an opponent with the range of motion that is intrinsic to high-speed running, jumping, rapid braking and turning; the range of motion over which peak force and power can be produced. METHODOLOGY/PRINCIPAL FINDINGS: To test the hypothesis that bipedal (i.e., orthograde) posture provides a performance advantage when striking with the forelimbs, I measured the force and energy produced when human subjects struck from "quadrupedal" (i.e., pronograde) and bipedal postures. Downward and upward directed striking energy was measured with a custom designed pendulum transducer. Side and forward strikes were measured with a punching bag instrumented with an accelerometer. When subjects struck downward from a bipedal posture the work was 43.70±12.59% (mean ± S.E.) greater than when they struck from a quadrupedal posture. Similarly, 47.49±17.95% more work was produced when subjects struck upward from a bipedal stance compared to a quadrupedal stance. Importantly, subjects did 229.69±44.19% more work in downward than upward directed strikes. During side and forward strikes the force impulses were 30.12±3.68 and 43.04±9.00% greater from a bipedal posture than a quadrupedal posture, respectively. CONCLUSIONS/SIGNIFICANCE: These results indicate that bipedal posture does provide a performance advantage for striking with the forelimbs. The mating systems of great apes are characterized by intense male-male competition in which conflict is resolved through force or the threat of force. Great apes often fight from bipedal posture, striking with both the fore- and hindlimbs. These observations, plus the findings of this study, suggest that sexual selection contributed to the evolution of habitual bipedalism in hominins

Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies

Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs - "4-way", "7-way", and "10-way" - each accommodating a mixing chamber and up to 4, 7, or 10 MPSs. Platforms accommodate multiple different MPS flow configurations, each with internal re-circulation to enhance molecular exchange, and feature on-board pneumatically-driven pumps with independently programmable flow rates to provide precise control over both intra- and inter-MPS flow partitioning and drug distribution. We first developed a 4-MPS system, showing accurate prediction of secreted liver protein distribution and 2-week maintenance of phenotypic markers. We then developed 7-MPS and 10-MPS platforms, demonstrating reliable, robust operation and maintenance of MPS phenotypic function for 3 weeks (7-way) and 4 weeks (10-way) of continuous interaction, as well as PK analysis of diclofenac metabolism. This study illustrates several generalizable design and operational principles for implementing multi-MPS "physiome-on-a-chip" approaches in drug discovery.United States. Army Research Office (Grant W911NF-12-2-0039

Foot Loading Characteristics of Chinese Bound Feet Women: A Comparative Analysis

The custom of bound feet among Chinese women has existed for almost a century. This practice has influenced the daily life of Chinese women, especially during everyday locomotion. The primary aim of this study is to analyze the loading patterns of bound feet. Specifically, the plantar pressure and center of pressure were analyzed for peak pressure, contact area, force time integral, center of pressure displacement velocity and trajectory in the anterior- posterior direction via a comparison with normal feet. The key outcomes from this work were that the forefoot and rearfoot of bound feet bear the whole loading during stance phase. The center of pressure displacement velocity of bound feet was also greatly reduced with the shortening of trajectories. This suggests that the proprioceptive system adjusts motor function to adapt to new loading patterns while maintaining locomotive stability. A biomechanical understanding of bound feet may assist with prevention, treatment and rehabilitation of bound feet disorders