Can out‐of‐sample forecast comparisons help prevent overfitting?

This paper shows that out‐of‐sample forecast comparisons can help prevent data mining‐induced overfitting. The basic results are drawn from simulations of a simple Monte Carlo design and a real data‐based design similar to those used in some previous studies. In each simulation, a general‐to‐specific procedure is used to arrive at a model. If the selected specification includes any of the candidate explanatory variables, forecasts from the model are compared to forecasts from a benchmark model that is nested within the selected model. In particular, the competing forecasts are tested for equal MSE and encompassing. The simulations indicate most of the post‐sample tests are roughly correctly sized. Moreover, the tests have relatively good power, although some are consistently more powerful than others. The paper concludes with an application, modelling quarterly US inflation. Copyright © 2004 John Wiley & Sons, Ltd.     

An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis

Using advanced gene targeting methods, generating mouse models of cancer that accurately reproduce the genetic alterations present in human tumors is now relatively straightforward. The challenge is to determine to what extent such models faithfully mimic human disease with respect to the underlying molecular mechanisms that accompany tumor progression. Here we describe a method for comparing mouse models of cancer with human tumors using gene-expression profiling. We applied this method to the analysis of a model of Kras2-mediated lung cancer and found a good relationship to human lung adenocarcinoma, thereby validating the model. Furthermore, we found that whereas a gene-expression signature of KRAS2 activation was not identifiable when analyzing human tumors with known KRAS2 mutation status alone, integrating mouse and human data uncovered a gene-expression signature of KRAS2 mutation in human lung cancer. We confirmed the importance of this signature by gene-expression analysis of short hairpin RNA-mediated inhibition of oncogenic Kras2. These experiments identified both a pattern of gene expression indicative of KRAS2 mutation and potential effectors of oncogenic KRAS2 activity in human cancer. This approach provides a strategy for using genomic analysis of animal models to probe human disease.     

MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.

Acute lymphoblastic leukemias carrying a chromosomal translocation involving the mixed-lineage leukemia gene (MLL, ALL1, HRX) have a particularly poor prognosis. Here we show that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms reveal that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. We propose that they constitute a distinct disease, denoted here as MLL, and show that the differences in gene expression are robust enough to classify leukemias correctly as MLL, acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets.     

Regulation of Arabidopsis cryptochrome 2 by blue-light-dependent phosphorylation

Cryptochromes are blue/ultraviolet-A light receptors that mediate various light responses in plants and animals. But the initial photochemical reaction of cryptochrome is still unclear. For example, although most photoreceptors are known to undergo light-dependent protein modification such as phosphorylation, no blue-light dependent phosphorylation has been reported for a cryptochrome. Arabidopsis cryptochrome 2 (cry2) mediates light regulation of seedling development and photoperiodic flowering. The physiological activity and cellular level of cry2 protein are light-dependent, and protein protein interactions are important for cry2 function. Here we report that cry2 undergoes a blue-light-dependent phosphorylation, and that cry2 phosphorylation is associated with its function and regulation. Our results suggest that, in the absence of light, cry2 remains unphosphorylated, inactive and stable; absorption of blue light induces the phosphorylation of cry2, triggering photomorphogenic responses and eventually degradation of the photoreceptor.     

Antipredator defence mechanism in the amphidromous shrimp Xiphocaris elongata (Decapoda: Xiphocarididae): rostrum length

Predators may affect prey through inducible defences that can alter prey phenotype. The shrimp Xiphocaris elongata exhibits a short rostrum (SR) in the absence of fish predators and a long rostrum (LR) in their presence. The long rostrum in X. elongata is inducible by the predatory fish Agonostomus monticola (mountain mullet). Our objective was to test whether the long rostrum is an effective antipredator defence against A. monticola in different stages of predator–prey interactions (i.e. choice, attacks, bites, rejections, handling time and survival). We conducted behavioural experiments in fish tanks in which we fed A. monticola simultaneously with (1) one LR shrimp and one SR shrimp, or (2) one LR shrimp and one shrimp which originally had a long rostrum but whose rostrum was cut (LR[S]). We scored the fish behaviours in terms of choice, unsuccessful attacks, bites, rejections and handling time. We also conducted mortality experiments in closed artificial pools in which we exposed (1) 10 LR and 10 SR shrimp or (2) 10 LR and 10 LR[S] shrimp to A. monticola, and quantified shrimp survival after 24 h. In the trials with LR and SR shrimp, A. monticola tended to attack SR shrimp first. LR shrimp were unsuccessfully attacked, bitten and rejected more than SR individuals. Handling time was higher for LR shrimp. The mortality experiments show higher survival of LR shrimp. In the trials with LR and LR[S] shrimp, A. monticola tended to attack LR[S] shrimp first. Unsuccessful attacks were similar for LR and LR[S]. There were more bites and rejections and longer handling time for LR shrimp. Survival was similar for LR and LR[S] shrimp in the mortality experiments. This study provides evidence in support of the hypothesis that the long rostrum in X. elongata is an effective antipredator defence against A. monticola by conferring benefits in most stages of the predator–prey interactions.     

Tertiary structural similarity between a class A beta-lactamase and a penicillin-sensitive D-alanyl carboxypeptidase-transpeptidase

beta-Lactam antibiotics--the penicillins, cephalosporins and related compounds--act by inhibiting enzymes that catalyse the final stages of the synthesis of bacterial cell walls. Recent crystallographic studies of representative enzymes are beginning to reveal the structural bases of antibiotic specificity and mechanism of action, while intensive efforts are being made to understand the beta-lactamase enzymes that are largely responsible for bacterial resistance to these antibiotics. It has been suggested that the beta-lactamases and beta-lactam target enzymes may be evolutionarily related and some similarity of amino-acid sequence around a common active-site serine residue supports this idea. We present here the first evidence from a comparison of three-dimensional structures in support of this hypothesis: the structure of beta-lactamase I from Bacillus cereus is similar to that of the penicillin-sensitive D-alanyl-D-alanine carboxypeptidase-transpeptidase from Streptomyces R61.     

Die Farbstoffe der Blattläuse(Aphididae)

Summary Many dark-coloured species ofAphididae contain a colouring matter (protoaphin) of unusual structure in the haemolymph. After death of the insect this undergoes a remarkable series of changes by enzymic action yielding successively the pigments xanthoaphin, chrysoaphin and erythroaphin. Recent investigations leading to the complete structural elucidation of all these pigments is described.

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ViertePaul-Karrer-Vorlesung von Lord A. R. Todd F. R. S., gehalten an der Universität Zürich am 4, Juli 1962.     

A technique for successful 20 h kidney storage at 4°C

Zusammenfassung Es gelingt die normale Nierenfunktion des 20 h bei 4°C tiefgekühlten Organs durch Perfusion mit Novocain und Reomacrodex von 40°C wieder herzustellen.     

Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.