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.

Antitumor effect of SIRT1 inhibition in human HCC tumor models in vitro and in vivo

Sirtuins (SIRT1-7) are a highly conserved family of NAD(+)-dependent enzymes that control the activity of histone and nonhistone regulatory proteins. SIRT1 is purposed to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared with normal liver or surrounding tumor tissue, SIRT1 is strongly overexpressed in human hepatocellular carcinoma (HCC). In addition, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared with normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing short hairpin RNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation, an increased expression of differentiation markers, and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data show that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy.

Relating Crevassing to Non-Linear Strain in the Floating Part of Jakobshavn Isbrae, West Greenland

Jakobshavn Isbrae is a major ice stream that drains the west-central Greenland ice sheet and becomes afloat in Jakobshavn Isfiord (69degreesN, 49degreesW), where it has maintained the world's fastest-known sustained velocity and calving rate (7 km a(-1)) for at least four decades. The floating portion is approximately 12 km long and 6 km wide. Surface elevations and motion vectors were determined photogrammetrically for about 500 crevasses on the floating ice, and adjacent grounded ice, using aerial photographs obtained 2 weeks apart in July 1985. Surface strain rates were computed from a mesh of 399 quadrilateral elements having velocity measurements at each corner. It is shown that heavy crevassing of floating ice invalidates the assumptions of linear strain theory that (i) surface strain in the floating ice is homogeneous in both space and time, (ii) the squares and products of strain components are nil, and (iii) first- and second-order rotation components are small compared to strain components. Therefore, strain rates and rotation rates were also computed using non-linear strain theory. The percentage difference between computed linear and non-linear second invariants of strain rate per element were greatest (mostly in the range 40-70%) where crevassing is greatest. Isopleths of strain rate parallel and transverse to flow and elevation isopleths relate crevassing to known and inferred pinning points.

The arguments advanced against the enfranchisement of the Jews considered in a series of letters

by Francis Henry Goldsmid

Replications of fundamental research models in ultra high dilutions 1994 and 2015 - update on a bibliometric study

INTRODUCTION This paper focuses exclusively on experimental models with ultra high dilutions (i.e. beyond 10(-23)) that have been submitted to replication scrutiny. It updates previous surveys, considers suggestions made by the research community and compares the state of replication in 1994 with that in 2015. METHODS Following literature research, biochemical, immunological, botanical, cell biological and zoological studies on ultra high dilutions (potencies) were included. Reports were grouped into initial studies, laboratory-internal, multicentre and external replications. Repetition could yield either comparable, or zero, or opposite results. The null-hypothesis was that test and control groups would not be distinguishable (zero effect). RESULTS A total of 126 studies were found. From these, 28 were initial studies. When all 98 replicative studies were considered, 70.4% (i.e. 69) reported a result comparable to that of the initial study, 20.4% (20) zero effect and 9.2% (9) an opposite result. Both for the studies until 1994 and the studies 1995-2015 the null-hypothesis (dominance of zero results) should be rejected. Furthermore, the odds of finding a comparable result are generally higher than of finding an opposite result. Although this is true for all three types of replication studies, the fraction of comparable studies diminishes from laboratory-internal (total 82.9%) to multicentre (total 75%) to external (total 48.3%), while the fraction of opposite results was 4.9%, 10.7% and 13.8%. Furthermore, it became obvious that the probability of an external replication producing comparable results is bigger for models that had already been further scrutinized by the initial researchers. CONCLUSIONS We found 28 experimental models which underwent replication. In total, 24 models were replicated with comparable results, 12 models with zero effect, and 6 models with opposite results. Five models were externally reproduced with comparable results. We encourage further replications of studies in order to learn more about the model systems used.

Psychological inquiries : in an series of essays, intended to illustrate the mutual relations of the physical organization and the mental faculties

by Sir Benjamin C. Brodie

The wine hedonic price models in the "Old and New World": : state of the art

The basic hedonic hypothesis is that goods are valued for their utility-bearing characteristics and not for the good itself. Each attribute can be evaluated by consumers when making a purchasing decision and an implicit price can be identified for each of them. Thus, the observed price of a certain good can be analyzed as the sum of the implicit prices paid for each quality attribute. Literature has reported hedonic models estimates in the case of wines, which are excellent examples of differentiated goods worldwide.The impact of different wine attributes (intrinsic or extrinsic) on consumers’ willingness to pay has been analyzed with dissimilar results. Wines coming from "New World" producers seem to be appreciated for different attributes than wines produced in the "Old World". Moreover, "Old and New World" consumers seem to value differently the wine’s characteristics. To our knowledge, no cross country analysis has been done dealing with "New World" wines in "Old World" countries, leaving an important gap in understanding underlying attributes influencing buying decisions.

Distributed models in P-Systems architectures to reduce computation time

Membrane systems are computational equivalent to Turing machines. However, their distributed and massively parallel nature obtains polynomial solutions opposite to traditional non-polynomial ones. At this point, it is very important to develop dedicated hardware and software implementations exploiting those two membrane systems features. Dealing with distributed implementations of P systems, the bottleneck communication problem has arisen. When the number of membranes grows up, the network gets congested. The purpose of distributed architectures is to reach a compromise between the massively parallel character of the system and the needed evolution step time to transit from one configuration of the system to the next one, solving the bottleneck communication problem. The goal of this paper is twofold. Firstly, to survey in a systematic and uniform way the main results regarding the way membranes can be placed on processors in order to get a software/hardware simulation of P-Systems in a distributed environment. Secondly, we improve some results about the membrane dissolution problem, prove that it is connected, and discuss the possibility of simulating this property in the distributed model. All this yields an improvement in the system parallelism implementation since it gets an increment of the parallelism of the external communication among processors. Proposed ideas improve previous architectures to tackle the communication bottleneck problem, such as reduction of the total time of an evolution step, increase of the number of membranes that could run on a processor and reduction of the number of processors.

Comparison of methods for downscaling runoff from regional climate models in Spanish basins

At present there is much literature that refers to the advantages and disadvantages of different methods of statistical and dynamical downscaling of climate variables projected by climate models. Less attention has been paid to other indirect variables, like runoff, which play a significant role in evaluating the impact of climate change on hydrological systems. Runoff presents a much greater bias in climate models than other climate variables, like temperature or precipitation. It is very important to identify the methods that minimize bias while downscaling runoff from the gridded results of climate models to the basin scale

The Analysis of Airline Business Models in the Development of Possible Future Business Options

Innovations in the current interconnected world of organizations have lead to a focus on business models as a fundamental statement of direction and identity. Although industry transformations generally emanate from technological changes, recent examples suggest they may also be due to the introduction of new business models. In the past, different types of airline business models could be clearly separated from each other. However, this has changed in recent years partly due to the concentration process and partly to reaction caused by competitive pressure. At least it can be concluded that in future the distinction of different business models will remain less clear. To advance the use of business models as a concept, it is essential to be able to compare and perform analyses to identify the business models that may have the highest potential. This can essentially contribute to understanding the synergies and incompatibilities in the case of two airlines that are going in for a merger. This is illustrated by the example of Swiss Air-Lufthansa merger analysis. The idea is to develop quantitative methods and tools for comparing and analyzing Aeronautical/Airline business models. The paper identifies available methods of comparing airline business models and lays the ground work for a quantitative model of comparing airline business models. This can be a useful tool for business model analysis when two airlines are merged

A review on probabilistic graphical models in evolutionary computation

Thanks to their inherent properties, probabilistic graphical models are one of the prime candidates for machine learning and decision making tasks especially in uncertain domains. Their capabilities, like representation, inference and learning, if used effectively, can greatly help to build intelligent systems that are able to act accordingly in different problem domains. Evolutionary algorithms is one such discipline that has employed probabilistic graphical models to improve the search for optimal solutions in complex problems. This paper shows how probabilistic graphical models have been used in evolutionary algorithms to improve their performance in solving complex problems. Specifically, we give a survey of probabilistic model building-based evolutionary algorithms, called estimation of distribution algorithms, and compare different methods for probabilistic modeling in these algorithms.