A novel and ancient group of type I keratins with members in bichir, sturgeon and gar

<p>Abstract</p> <p>1. Background</p> <p>Vertebrate epithelial cells typically express a specific set of keratins. In teleosts, keratins are also present in a variety of mesenchymal cells, which usually express vimentin. Significantly, our previous studies revealed that virtually all known teleost keratins evolved independently from those present in terrestrial vertebrates. To further elucidate the evolutionary scenario that led to the large variety of keratins and their complex expression patterns in present day teleosts, we have investigated their presence in bichir, sturgeon and gar.</p> <p>2. Results</p> <p>We have discovered a novel group of type I keratins with members in all three of these ancient ray-finned fish, but apparently no counterparts are present in any other vertebrate class so far investigated, including the modern teleost fish. From sturgeon and gar we sequenced one and from bichir two members of this novel keratin group. By complementary keratin blot-binding assays and peptide mass fingerprinting using MALDI-TOF mass spectrometry, in sturgeon we were able to assign the sequence to a prominent protein spot, present exclusively in a two-dimensionally separated cytoskeletal preparation of skin, thus identifying it as an epidermally expressed type I keratin. In contrast to the other keratins we have so far sequenced from bichir, sturgeon and gar, these new sequences occupy a rather basal position within the phylogenetic tree of type I keratins, in a close vicinity to the keratins we previously cloned from river lamprey.</p> <p>3. Conclusion</p> <p>Thus, this new K14 group seem to belong to a very ancient keratin branch, whose functional role has still to be further elucidated. Furthermore, the exclusive presence of this keratin group in bichir, sturgeon and gar points to the close phylogenetic relationship of these ray- finned fish, an issue still under debate among taxonomists.</p

Blood-based systems biology biomarkers for next-generation clinical trials in Alzheimer's disease

Alzheimer’s disease (AD)—a complex disease showing multiple pathomechanistic alterations—is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomarkers are currently being developed. Specifically, next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use—including proof-of-mechanism, patient selection, assessment of treatment efficacy and safety rates, and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD “signatures” through multifactorial and interindividual variability, allowing us to decipher disease pathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs.Includes MRC fundin

A novel and ancient group of type I keratins with members in bichir, sturgeon and gar-2

<p><b>Copyright information:</b></p><p>Taken from "A novel and ancient group of type I keratins with members in bichir, sturgeon and gar"</p><p>http://www.frontiersinzoology.com/content/4/1/16</p><p>Frontiers in Zoology 2007;4():16-16.</p><p>Published online 6 Jun 2007</p><p>PMCID:PMC1896152.</p><p></p>nce. *For three type I keratin sequences the Ensembl database gene IDs are given

A novel and ancient group of type I keratins with members in bichir, sturgeon and gar-0

<p><b>Copyright information:</b></p><p>Taken from "A novel and ancient group of type I keratins with members in bichir, sturgeon and gar"</p><p>http://www.frontiersinzoology.com/content/4/1/16</p><p>Frontiers in Zoology 2007;4():16-16.</p><p>Published online 6 Jun 2007</p><p>PMCID:PMC1896152.</p><p></p> and gar. Thick black lines mark the four helical subdomains (coils 1A to 2B), which are typical for the central rod domain of all known IF-proteins. Asterisks indicate identical amino acids; double dots indicate a high and single dots a lower degree of amino acid conservation. Pse, (bichir); Aba, (sturgeon); Loc, (gar). Note that only AbaK14 comprises the complete amino acid sequence. From PseK14a at least a section and from LocK14 the complete head sequence is still missing. From PseK14b we still have to recover both, the complete head and tail sequence

A novel and ancient group of type I keratins with members in bichir, sturgeon and gar-3

<p><b>Copyright information:</b></p><p>Taken from "A novel and ancient group of type I keratins with members in bichir, sturgeon and gar"</p><p>http://www.frontiersinzoology.com/content/4/1/16</p><p>Frontiers in Zoology 2007;4():16-16.</p><p>Published online 6 Jun 2007</p><p>PMCID:PMC1896152.</p><p></p>14 sequences from bichir, sturgeon and gar to the other type I keratins known from vertebrates. The tree was rooted with the lancelet type I keratin sequences. It clearly shows that the K14 sequences form a separate branch (boxed in violet) close to the sequences we cloned from the river lamprey. They even branch off prior to the twig formed by the gnathostomian K18 sequences (boxed in green) that apparently emerged before the separation of cartilaginous and bony fish. The tree, furthermore, suggests that most of the ray-finned fish type I keratins (boxed in blue) evolved independently from those present in lungfish, frog or man and that early in actinopterygian evolution gene duplications already gave rise to at least two different type I keratin groups with members in both, ancient and modern ray-finned fish. Importantly, within the tetrapod lineage the Bayesian analysis revealed four highly supported keratin subgroups, each with members in both, frog and man (encircled by dotted lines and coloured orange). Bar, 0.1 substitutions per site

A novel and ancient group of type I keratins with members in bichir, sturgeon and gar-4

<p><b>Copyright information:</b></p><p>Taken from "A novel and ancient group of type I keratins with members in bichir, sturgeon and gar"</p><p>http://www.frontiersinzoology.com/content/4/1/16</p><p>Frontiers in Zoology 2007;4():16-16.</p><p>Published online 6 Jun 2007</p><p>PMCID:PMC1896152.</p><p></p> and gar. Thick black lines mark the four helical subdomains (coils 1A to 2B), which are typical for the central rod domain of all known IF-proteins. Asterisks indicate identical amino acids; double dots indicate a high and single dots a lower degree of amino acid conservation. Pse, (bichir); Aba, (sturgeon); Loc, (gar). Note that only AbaK14 comprises the complete amino acid sequence. From PseK14a at least a section and from LocK14 the complete head sequence is still missing. From PseK14b we still have to recover both, the complete head and tail sequence

Blood-based systems biology biomarkers for next-generation clinical trials in Alzheimer's disease .

Alzheimer's disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomarkers are currently being developed. Specifically, next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use-including proof-of-mechanism, patient selection, assessment of treatment efficacy and safety rates, and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD "signatures" through multifactorial and interindividual variability, allowing us to decipher disease pathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs.


Blood-based systems biology biomarkers for next-generation clinical trials in Alzheimers disease .

Alzheimers disease (AD)-a complex disease showing multiple pathomechanistic alterations-is triggered by nonlinear dynamic interactions of genetic/epigenetic and environmental risk factors, which, ultimately, converge into a biologically heterogeneous disease. To tackle the burden of AD during early preclinical stages, accessible blood-based biomarkers are currently being developed. Specifically, next-generation clinical trials are expected to integrate positive and negative predictive blood-based biomarkers into study designs to evaluate, at the individual level, target druggability and potential drug resistance mechanisms. In this scenario, systems biology holds promise to accelerate validation and qualification for clinical trial contexts of use-including proof-of-mechanism, patient selection, assessment of treatment efficacy and safety rates, and prognostic evaluation. Albeit in their infancy, systems biology-based approaches are poised to identify relevant AD signatures through multifactorial and interindividual variability, allowing us to decipher disease pathophysiology and etiology. Hopefully, innovative biomarker-drug codevelopment strategies will be the road ahead towards effective disease-modifying drugs.