Divergence along a steep ecological gradient in lake whitefish (Coregonus sp.)

To understand mechanisms structuring diversity in young adaptive radiations, quantitative and unbiased information about genetic and phenotypic diversity is much needed. Here, we present the first in-depth investigation of whitefish diversity in a Swiss lake, with continuous spawning habitat sampling in both time and space. Our results show a clear cline like pattern in genetics and morphology of populations sampled along an ecological depth gradient in Lake Neuchâtel. Divergent natural selection appears to be involved in shaping this cline given that trait specific P(ST)-values are significantly higher than F(ST)-values when comparing populations caught at different depths. These differences also tend to increase with increasing differences in depth, indicating adaptive divergence along a depth gradient, which persists despite considerable gene flow between adjacent demes. It however remains unclear, whether the observed pattern is a result of currently stable selection-gene flow balance, incipient speciation, or reverse speciation due to anthropogenic habitat alteration causing two formerly divergent species to collapse into a single gene pool.

Reverse total shoulder arthroplasty

The radical changes in prosthetic design made in the mid 1980s transformed the historically poorly performing reverse ball-and-socket total shoulder prosthesis into a highly successful salvage implant for pseudoparalytic, severely rotator cuff-deficient shoulders. Moving the center of rotation more medial and distal as well as implanting a large glenoid hemisphere that articulates with a humeral cup in 155 degrees of valgus are the biomechanical keys to sometimes spectacular short- to mid-term results. Use of the reverse total shoulder arthroplasty device allows salvage of injuries that previously were beyond surgical treatment. However, this technique has a complication rate approximately three times that of conventional arthroplasty. Radiographic and clinical results appear to deteriorate over time. Proper patient selection and attention to technical details are needed to reduce the currently high complication rate.

Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism

Chronic ethanol consumption is a strong risk factor for the development of certain types of cancer including those of the upper aerodigestive tract, the liver, the large intestine and the female breast. Multiple mechanisms are involved in alcohol-mediated carcinogenesis. Among those the action of acetaldehyde (AA), the first metabolite of ethanol oxidation is of particular interest. AA is toxic, mutagenic and carcinogenic in animal experiments. AA binds to DNA and forms carcinogenic adducts. Direct evidence of the role of AA in alcohol-associated carcinogenesis derived from genetic linkage studies in alcoholics. Polymorphisms or mutations of genes coding for AA generation or detoxifying enzymes resulting in elevated AA concentrations are associated with increased cancer risk. Approximately 40% of Japanese, Koreans or Chinese carry the AA dehydrogenase 2*2 (ALDH2*2) allele in its heterozygous form. This allele codes for an ALDH2 enzyme with little activity leading to high AA concentrations after the consumption of even small amounts of alcohol. When individuals with this allele consume ethanol chronically, a significant increased risk for upper alimentary tract and colorectal cancer is noted. In Caucasians, alcohol dehydrogenase 1C*1 (ADH1C*1) allele encodes for an ADH isoenzyme which produces 2.5 times more AA than the corresponding allele ADH1C*2. In studies with moderate to high alcohol intake, ADH1C*1 allele frequency and rate of homozygosity was found to be significantly associated with an increased risk for cancer of the upper aerodigestive tract, the liver, the colon and the female breast. These studies underline the important role of acetaldehyde in ethanol-mediated carcinogenesis.

Novel functional profiling approach combining reverse phase protein microarrays and human 3-D ex vivo tissue cultures: expression of apoptosis-related proteins in human colon cancer

Cancer is caused by a complex pattern of molecular perturbations. To understand the biology of cancer, it is thus important to look at the activation state of key proteins and signaling networks. The limited amount of available sample material from patients and the complexity of protein expression patterns make the use of traditional protein analysis methods particularly difficult. In addition, the only approach that is currently available for performing functional studies is the use of serial biopsies, which is limited by ethical constraints and patient acceptance. The goal of this work was to establish a 3-D ex vivo culture technique in combination with reverse-phase protein microarrays (RPPM) as a novel experimental tool for use in cancer research. The RPPM platform allows the parallel profiling of large numbers of protein analytes to determine their relative abundance and activation level. Cancer tissue and the respective corresponding normal tissue controls from patients with colorectal cancer were cultured ex vivo. At various time points, the cultured samples were processed into lysates and analyzed on RPPM to assess the expression of carcinoembryonic antigen (CEA) and 24 proteins involved in the regulation of apoptosis. The methodology displayed good robustness and low system noise. As a proof of concept, CEA expression was significantly higher in tumor compared with normal tissue (p<0.0001). The caspase 9 expression signal was lower in tumor tissue than in normal tissue (p<0.001). Cleaved Caspase 8 (p=0.014), Bad (p=0.007), Bim (p=0.007), p73 (p=0.005), PARP (p<0.001), and cleaved PARP (p=0.007) were differentially expressed in normal liver and normal colon tissue. We demonstrate here the feasibility of using RPPM technology with 3-D ex vivo cultured samples. This approach is useful for investigating complex patterns of protein expression and modification over time. It should allow functional proteomics in patient samples with various applications such as pharmacodynamic analyses in drug development.

Enriching Reverse Engineering with Annotations

Much of the knowledge about software systems is implicit, and therefore difficult to recover by purely automated techniques. Architectural layers and the externally visible features of software systems are two examples of information that can be difficult to detect from source code alone, and that would benefit from additional human knowledge. Typical approaches to reasoning about data involve encoding an explicit meta-model and expressing analyses at that level. Due to its informal nature, however, human knowledge can be difficult to characterize up-front and integrate into such a meta-model. We propose a generic, annotation-based approach to capture such knowledge during the reverse engineering process. Annotation types can be iteratively defined, refined and transformed, without requiring a fixed meta-model to be defined in advance. We show how our approach supports reverse engineering by implementing it in a tool called Metanool and by applying it to (i) analyzing architectural layering, (ii) tracking reengineering tasks, (iii) detecting design flaws, and (iv) analyzing features.

Enabling the evolution of J2EE applications through reverse engineering and quality assurance

Enterprise Applications are complex software systems that manipulate much persistent data and interact with the user through a vast and complex user interface. In particular applications written for the Java 2 Platform, Enterprise Edition (J2EE) are composed using various technologies such as Enterprise Java Beans (EJB) or Java Server Pages (JSP) that in turn rely on languages other than Java, such as XML or SQL. In this heterogeneous context applying existing reverse engineering and quality assurance techniques developed for object-oriented systems is not enough. Because those techniques have been created to measure quality or provide information about one aspect of J2EE applications, they cannot properly measure the quality of the entire system. We intend to devise techniques and metrics to measure quality in J2EE applications considering all their aspects and to aid their evolution. Using software visualization we also intend to inspect to structure of J2EE applications and all other aspects that can be investigate through this technique. In order to do that we also need to create a unified meta-model including all elements composing a J2EE application.

Genome sequence, comparative analysis, and population genetics of the domestic horse

We report a high-quality draft sequence of the genome of the horse (Equus caballus). The genome is relatively repetitive but has little segmental duplication. Chromosomes appear to have undergone few historical rearrangements: 53% of equine chromosomes show conserved synteny to a single human chromosome. Equine chromosome 11 is shown to have an evolutionary new centromere devoid of centromeric satellite DNA, suggesting that centromeric function may arise before satellite repeat accumulation. Linkage disequilibrium, showing the influences of early domestication of large herds of female horses, is intermediate in length between dog and human, and there is long-range haplotype sharing among breeds.

Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel.

Brugada syndrome (BrS) is a condition defined by ST-segment alteration in right precordial leads and a risk of sudden death. Because BrS is often associated with right bundle branch block and the TRPM4 gene is involved in conduction blocks, we screened TRPM4 for anomalies in BrS cases. The DNA of 248 BrS cases with no SCN5A mutations were screened for TRPM4 mutations. Among this cohort, 20 patients had 11 TRPM4 mutations. Two mutations were previously associated with cardiac conduction blocks and 9 were new mutations (5 absent from ~14'000 control alleles and 4 statistically more prevalent in this BrS cohort than in control alleles). In addition to Brugada, three patients had a bifascicular block and 2 had a complete right bundle branch block. Functional and biochemical studies of 4 selected mutants revealed that these mutations resulted in either a decreased expression (p.Pro779Arg and p.Lys914X) or an increased expression (p.Thr873Ile and p.Leu1075Pro) of TRPM4 channel. TRPM4 mutations account for about 6% of BrS. Consequences of these mutations are diverse on channel electrophysiological and cellular expression. Because of its effect on the resting membrane potential, reduction or increase of TRPM4 channel function may both reduce the availability of sodium channel and thus lead to BrS.

A reverse crystal Engineering approach

The enormous impact of crystal engineering in modern solid state chemistry takes advantage from the connection between a typical basic science field and the word engineering. Regrettably, the engineering aspect of organic or metal organic crystalline materials are limited, so far, to descriptive structural features, sometime entangled with topological aspects, but only rarely with true material design. This should include not only the fabrication and structural description at micro- and nano-scopic level of the solids, but also a proper reverse engineering, a fundamental discipline for engineers. Translated into scientific language, the reverse crystal engineering refers to a dedicated and accurate analysis of how the building blocks contribute to generate a given material property. This would enable a more appropriate design of new crystalline material. We propose here the application of reverse crystal engineering to optical properties of organic and metal organic framework structures, applying the distributed atomic polarizability approach that we have extensively investigated in the past few years[1,2].