Cell Signaling by Receptor Tyrosine Kinases

Recent structural studies of receptor tyrosine kinases (RTKs) have revealed unexpected diversity in the mechanisms of their activation by growth factor ligands. Strategies for inducing dimerization by ligand binding are surprisingly diverse, as are mechanisms that couple this event to activation of the intracellular tyrosine kinase domains. As our understanding of these details becomes increasingly sophisticated, it provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases. Much remains to be learned, however, about the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses

United States Food Law Update: Shrouded by Election-Year Politics, State Initiatives and Private Lawsuits Fill in the Gaps Created by Congressional and Agency Ossification

Observers of food law in the 2012 presidential election year witnessed a dramatic slowing of federal initiatives-perhaps arising from a desire by both Congress and the administration to avoid upsetting critical constituent groups during a year seemingly dominated by campaigns and endless talking points. For example, Congress failed to take action on a unique compromise between what some had considered mortal enemies-the Humane Society of the United States and United Egg Producers-that would implement a federal animal welfare standard for laying hens in return for abandoning ballot measures in various states. Similarly, the FDA waited until the early days of 2013 to issue the proposed rules implementing the FDA Food Safety Modernization Act. Recall that Congress passed this landmark statute not in 2012, but January of 2011. Despite this apparent reluctance to tackle some big issues in 2012, the FDA did decide two significant food law issues: a refusal of a request seeking to rebrand high fructose corn syrup as corn sugar, as well as promulgation of a long overdue rule on salmonella testing in shell egg production

Universal deformation rings of modules over Frobenius algebras

Let $k$ be a field, and let $\Lambda$ be a finite dimensional $k$-algebra. We prove that if $\Lambda$ is a self-injective algebra, then every finitely generated $\Lambda$-module $V$ whose stable endomorphism ring is isomorphic to $k$ has a universal deformation ring $R(\Lambda,V)$ which is a complete local commutative Noetherian $k$-algebra with residue field $k$. If $\Lambda$ is also a Frobenius algebra, we show that $R(\Lambda,V)$ is stable under taking syzygies. We investigate a particular Frobenius algebra $\Lambda_0$ of dihedral type, as introduced by Erdmann, and we determine $R(\Lambda_0,V)$ for every finitely generated $\Lambda_0$-module $V$ whose stable endomorphism ring is isomorphic to $k$.Comment: 25 pages, 2 figures. Some typos have been fixed, the outline of the paper has been changed to improve readabilit

Signature of strange dibaryon in kaon-induced reaction

We examine how the signature of the strange-dibaryon resonances in the barKNN-piSigmaN system shows up in the scattering amplitude on the physical real energy axis within the framework of Alt-Grassberger-Sandhas (AGS) equations. The so-called point method is applied to handle the three-body unitarity cut in the amplitudes. We also discuss the possibility that the strange-dibaryon production reactions can be used for discriminating between existing models of the two-body barKN-piSigma system with Lambda(1405).Comment: 4 pages, 6 figures, talk given at The Fifth Asia-Pacific Conference on Few-Body Problems in Physics 2011 (APFB2011), held in Seoul, Korea, August 22-26, 201

Carotid beta stiffness association with thyroid function

Background: Thyroid hormone modulation of cardiovascular function has been associated with cardiovascular disease. Recent evidence suggests that free thyroxine (FT4) levels are associated with an increase in systemic arterial stiffness, but little is known about the effects of FT4 at the local level of the common carotid artery. β-stiffness index is a local elastic parameter usually determined by carotid ultrasound imaging. Methods: We conducted a cross-sectional analysis in the ProgeNIA cohort, including 4846 subjects across a broad age range. For the purpose of this study, we excluded subjects with increased thyrotropin (TSH) levels and those treated with levothyroxine or thyrostatic. We assessed β stiffness, strain, wall–lumen ratio, carotid cross-sectional area (CSA), and stress and flow in the right common carotid artery. We tested whether FT4, heart rate, and their interactions were associated with carotid parameters. Results: FT4 was positively and independently associated with β stiffness index (β = 0.026, p = 0.041), and had a negative association with strain (β = −0.025, p = 0.009). After adding heart rate and the interaction between FT4 and heart rate to the model, FT4 was still associated with the β stiffness index (β = 0.186, p = 0.06), heart rate was positively associated with the stiffness index (β = 0.389, p < 0.001) as well as their interaction (β = 0.271, p = 0.007). Conclusion: This study suggests that higher FT4 levels increase arterial stiffness at the common carotid level, consistent with a detrimental effect on elastic arteries. The effect of FT4 is likely to be primarily attributable to its effect on heart rate

Population history from the Neolithic to present on the Mediterranean island of Sardinia: an ancient DNA perspective

Recent ancient DNA studies of western Eurasia have revealed a dynamic history of admixture, with evidence for major migrations during the Neolithic and Bronze Age. The population of the Mediterranean island of Sardinia has been notable in these studies –} Neolithic individuals from mainland Europe cluster more closely with Sardinian individuals than with all other present-day Europeans. The current model to explain this result is that Sardinia received an initial influx of Neolithic ancestry and then remained relatively isolated from expansions in the later Neolithic and Bronze Age that took place in continental Europe. To test this model, we generated genome-wide capture data (approximately 1.2 million variants) for 43 ancient Sardinian individuals spanning the Neolithic through the Bronze Age, including individuals from Sardinia{’}s Nuragic culture, which is known for the construction of numerous large stone towers throughout the island. We analyze these new samples in the context of previously generated genome-wide ancient DNA data from 972 ancient individuals across western Eurasia and whole-genome sequence data from approximately 1,500 modern individuals from Sardinia. The ancient Sardinian individuals show a strong affinity to western Mediterranean Neolithic populations and we infer a high degree of genetic continuity on the island from the Neolithic (around fifth millennium BCE) through the Nuragic period (second millennium BCE). In particular, during the Bronze Age in Sardinia, we do not find significant levels of the {“}Steppe{” ancestry that was spreading in many other parts of Europe at that time. We also characterize subsequent genetic influx between the Nuragic period and the present. We detect novel, modest signals of admixture between 1,000 BCE and present-day, from ancestry sources in the eastern and northern Mediterranean. Within Sardinia, we confirm that populations from the more geographically isolated mountainous provinces have experienced elevated levels of genetic drift and that northern and southwestern regions of the island received more gene flow from outside Sardinia. Overall, our genetic analysis sheds new light on the origin of Neolithic settlement on Sardinia, reinforces models of genetic continuity on the island, and provides enhanced power to detect post-Bronze-Age gene flow. Together, these findings offer a refined demographic model for future medical genetic studies in Sardinia

Relative impact of indels versus SNPs on complex disease

It is unclear whether insertions and deletions (indels) are more likely to influence complex traits than abundant single‐nucleotide polymorphisms (SNPs). We sought to understand which category of variation is more likely to impact health. Using the SardiNIA study as an exemplar, we characterized 478,876 common indels and 8,246,244 common SNPs in up to 5,949 well‐phenotyped individuals from an isolated valley in Sardinia. We assessed association between 120 traits, resulting in 89 nonoverlapping‐associated loci.We evaluated whether indels were enriched among credible sets of potential causal variants. These credible sets included 1,319 SNPs and 88 indels. We did not find indels to be significantly enriched. Indels were the most likely causal variant in seven loci, including one locus associated with monocyte count where an indel with causality and mechanism previously demonstrated (rs200748895:TGCTG/T) had a 0.999 posterior probability. Overall, our results show a very modest and nonsignificant enrichment for common indels in associated loci.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/1/gepi22175_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/2/gepi22175-sup-0001-Gagliano-Supplementary.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147866/3/gepi22175.pd

Lymphotoxin-β regulates periderm differentiation during embryonic skin development

Lymphotoxin-beta (LTbeta) is a key regulator of immune system development, but also affects late stages in hair development. In addition, high expression of LTbeta at an early stage in epidermis hinted at a further function in hair follicle induction or epithelial development. We report that hair follicles were normally induced in LTbeta(-/-) skin, but the periderm detached from the epidermis earlier, accompanied by premature appearance of keratohyalin granules. Expression profiling revealed dramatic down-regulation of a gene cluster encoding periderm-specific keratin-associated protein 13 and four novel paralogs in LTbeta(-/-) skin prior to periderm detachment. Epidermal differentiation markers, including small proline-rich proteins, filaggrins and several keratins, were also affected, but transiently in LTbeta(-/-) skin at the time of abnormal periderm detachment. As expected, Tabby mice, which lack the EDA gene, the putative upstream regulator of LTbeta in skin, showed similar though milder periderm histopathology and alterations in gene expression. Overall, LTbeta shows a primary early function in periderm differentiation, with later transient effects on epidermal and hair follicle differentiation

On operad structures of moduli spaces and string theory

Recent algebraic structures of string theory, including homotopy Lie algebras, gravity algebras and Batalin-Vilkovisky algebras, are deduced from the topology of the moduli spaces of punctured Riemann spheres. The principal reason for these structures to appear is as simple as the following. A conformal field theory is an algebra over the operad of punctured Riemann surfaces, this operad gives rise to certain standard operads governing the three kinds of algebras, and that yields the structures of such algebras on the (physical) state space naturally.Comment: 33 pages (An elaboration of minimal area metrics and new references are added