bluuebunny/crossref_metadata_2025 huggingface dataset:
“Only the National Socialist”: Postwar US and West German Approaches to Nazi “Euthanasia” Crimes, 1946–1953
Authors: Bryant Michael
Published: October 2009

In Western historical consciousness, National Socialist mass murder has become permanently identified with the Jewish Holocaust, Adolf Hitler's maniacal project to annihilate European Jewry. From its earliest days, the Nazi Party sought to exclude Jews from German public life, and when the Nazis came to power in January 1933, their anti-Jewish animus became official policy. What followed was legal disemancipation of German Jews, physical attacks on their persons, ghettoization, deportation, and physical extermination in the East. The story of the Holocaust is well known and generally accepted. Yet two years before German Jewish policy swerved from persecution and harassment to genocide, the Nazis were already involved in state-organized killing of another disfavored minority. Unlike the destruction of European Jews, the murder of this group—the mentally disabled—occurred within the Reich's own borders. Launched with the signing of a “Hitler decree” in October 1939 (backdated to 1 September), the centrally organized program targeted so-called “incurable” patients, whose lives were to be ended by a doctor-administered “mercy death” (Gnadentod). The Nazis attached the term “euthanasia” to their program of destruction, bolstering their rationale for it with humanitarian arguments and cost-based justifications, the latter legitimizing euthanasia as a means to free up scarce resources for use by “valuable” Germans. Over time, the restrictive use of euthanasia just for incurable patients ended; thereafter, the Nazis extended the killing program to healthier patients, sick concentration camp inmates, Jewish patients, and a variety of “asocials” (juvenile delinquents, beggars, tramps, prostitutes). The technology of murder developed in the “euthanasia” program—carbon monoxide asphyxiation in gas chambers camouflaged as shower rooms—would become the model for the first death camps in Poland. Many of the “euthanasia” personnel were likewise transferred to the Polish extermination centers, where they applied the techniques of mass death—refined in murdering the disabled—to the murder of the European Jews.
“The Last Bullet for the Last Serb”:1 The Ustaša Genocide against Serbs: 1941–19452
Authors: Levy Michele Frucht
Published: October 2009

While participating in Hitler's Holocaust against Jews and Roma, wartime Croatia's collaborationist government, the Ustaša (Insurgent), conducted its own genocide against the Serbs within its territories. As the title of Marco Rivelli's 1978 text, Le Génocide occulté, makes clear, this phenomenon remained largely unknown in the West until the 1990s. Of the principal external actors, post-war German attention focused on the Holocaust. Italy still resists fully confronting its less than pristine role in the Balkans, so that Rivelli's work, completed in 1978, was not published in Italy until 1999. The Vatican, meanwhile, has yet to release its documents on the subject.
Effectiveness of a Self-Instruction Program for Microcounseling Skills Training
Authors: Schönrock-Adema Johanna , Van der Molen Henk T. , van der Zee Karen I.
Published: October 2009

This article describes the effects of self-instruction training (SIT) in microcounseling skills compared to those of a traditional trainer-guided program (TT) in a pretest–posttest comparison group design. A sample of 193 undergraduate psychology students participated in this study: 97 students followed SIT and 96 students followed TT. We used video tests and behavioral role-play tests to measure the learning effects. Both SIT and TT generated large learning effects. An important conclusion of this study is that it is possible to realize the same training effectiveness with trainer time reduced by about 50%.
Problem-Based Group Activities for Teaching Sensation and Perception
Authors: Kreiner David S.
Published: October 2009

This article describes 14 problem-based group activities for a sensation and perception course. The intent was to provide opportunities for students to practice applying their knowledge to real-world problems related to course content. Student ratings of how effectively the activities helped them learn were variable but relatively high. Students rated their ability to apply their knowledge of sensation and perception to real-world issues substantially higher at the end of the course than at the beginning. Furthermore, student performance on an objective assessment of knowledge was significantly higher at the end of the semester than at the beginning. The results provide preliminary evidence that it is possible to develop an effective sensation and perception course that incorporates problem-based learning activities.
Examining Self-Determination in a Service Learning Course
Authors: Levesque-Bristol Chantal , Stanek Layla R.
Published: October 2009

This article examines students' perceptions of the learning environment in a service learning research course and increases in student motivation and skill development. According to self-determination theory (Deci & Ryan, 1985), positive learning environments increase levels of student motivation and learning outcomes. Survey responses revealed that students perceived the learning environment as positive and that their level of motivation, including intrinsic motivation, increased over the semester. Students also self-reported significant gains in knowledge and skills. Service learning appears to be an autonomy-supportive teaching tool that can enhance classroom environment and student engagement.
Evaluating the Effectiveness of a Personal Response System in the Classroom
Authors: Shaffer Dennis M. , Collura Michael J.
Published: October 2009

We evaluated the effectiveness of the use of an electronic personal response system (or “clickers”) during an introductory psychology lecture on perceptual constancy. We graphed and projected student responses to questions during the lecture onto a large-screen display in Microsoft PowerPoint. The distributions of answers corresponded well to results found in the literature. Students rated the lecture as more interactive, interesting, and entertaining. Students in the clicker lecture also performed significantly better on exam questions concerning the lecture compared to another group of students who did not use the clickers.
Object appearance and picture-specific viewpoint are not integrated in long-term memory
Authors: Varakin D. Alexander , Loschky Lester
Published: October 2009

Previous work has demonstrated that visual long-term memory (VLTM) stores detailed information about object appearance. The current experiments investigate whether object appearance information in VLTM is integrated within representations that contain picture-specific viewpoint information. In three experiments using both incidental and intentional encoding instructions, participants were unable to perform above chance on recognition tests that required recognizing the conjunction of object appearance and viewpoint information (Experiments 1a, 1b, 2, and 3). However, performance was better when object appearance information (Experiments 1a, 1b, and 2) or picture-specific viewpoint information (Experiment 3) alone was sufficient to succeed on the memory test. These results replicate previous work demonstrating good memory for object appearance and viewpoint. However the current results suggest that object appearance and viewpoint are not episodically integrated in VLTM.
Myosin IXa Regulates Epithelial Differentiation and Its Deficiency Results in Hydrocephalus
Authors: Abouhamed Marouan , Grobe Kay , Leefa Chong San Isabelle V. , Thelen Sabine , Honnert Ulrike , Balda Maria S. , Matter Karl , Bähler Martin
Published: October 2009

The ependymal multiciliated epithelium in the brain restricts the cerebrospinal fluid to the cerebral ventricles and regulates its flow. We report here that mice deficient for myosin IXa (Myo9a), an actin-dependent motor molecule with a Rho GTPase–activating (GAP) domain, develop severe hydrocephalus with stenosis and closure of the ventral caudal 3rd ventricle and the aqueduct. Myo9a is expressed in maturing ependymal epithelial cells, and its absence leads to impaired maturation of ependymal cells. The Myo9a deficiency further resulted in a distorted ependyma due to irregular epithelial cell morphology and altered organization of intercellular junctions. Ependymal cells occasionally delaminated, forming multilayered structures that bridged the CSF-filled ventricular space. Hydrocephalus formation could be significantly attenuated by the inhibition of the Rho-effector Rho-kinase (ROCK). Administration of ROCK-inhibitor restored maturation of ependymal cells, but not the morphological distortions of the ependyma. Similarly, down-regulation of Myo9a by siRNA in Caco-2 adenocarcinoma cells increased Rho-signaling and induced alterations in differentiation, cell morphology, junction assembly, junctional signaling, and gene expression. Our results demonstrate that Myo9a is a critical regulator of Rho-dependent and -independent signaling mechanisms that guide epithelial differentiation. Moreover, Rho-kinases may represent a new target for therapeutic intervention in some forms of hydrocephalus.
The CORVET Subunit Vps8 Cooperates with the Rab5 Homolog Vps21 to Induce Clustering of Late Endosomal Compartments
Authors: Markgraf Daniel F. , Ahnert Franziska , Arlt Henning , Mari Muriel , Peplowska Karolina , Epp Nadine , Griffith Janice , Reggiori Fulvio , Ungermann Christian
Published: October 2009

Membrane tethering, the process of mediating the first contact between membranes destined for fusion, requires specialized multisubunit protein complexes and Rab GTPases. In the yeast endolysosomal system, the hexameric HOPS tethering complex cooperates with the Rab7 homolog Ypt7 to promote homotypic fusion at the vacuole, whereas the recently identified homologous CORVET complex acts at the level of late endosomes. Here, we have further functionally characterized the CORVET-specific subunit Vps8 and its relationship to the remaining subunits using an in vivo approach that allows the monitoring of late endosome biogenesis. In particular, our results indicate that Vps8 interacts and cooperates with the activated Rab5 homolog Vps21 to induce the clustering of late endosomal membranes, indicating that Vps8 is the effector subunit of the CORVET complex. This clustering, however, requires Vps3, Vps16, and Vps33 but not the remaining CORVET subunits. These data thus suggest that the CORVET complex is built of subunits with distinct activities and potentially, their sequential assembly could regulate tethering and successive fusion at the late endosomes.
Requirements for Recruitment of a G Protein-coupled Receptor to Clathrin-coated Pits in Budding Yeast
Authors: Toshima Junko Y. , Nakanishi Jun-ichi , Mizuno Kensaku , Toshima Jiro , Drubin David G.
Published: October 2009

Endocytic internalization of G protein-coupled receptors (GPCRs) plays a critical role in down-regulation of GPCR signaling. The yeast mating pheromone receptor Ste2p has been used as a model to investigate mechanisms of signal transduction, modification, and endocytic internalization of GPCRs. We previously used a fluorescently labeled mating pheromone derivative to reveal unappreciated molecular and spatiotemporal features of GPCR endocytosis in budding yeast. Here, we identify recruitment of Ste2p to preexisting clathrin-coated pits (CCPs) as a key step regulated by receptor phosphorylation and subsequent ubiquitination upon ligand binding. The yeast casein kinase I homologue Yck2p directly phosphorylates six serine residues located in the C-terminal tail of Ste2p, and mutation of these serine residues to alanine significantly decreased recruitment of Ste2p to CCPs. We also found that the clathrin adaptors Ent1p, Ent2p, and Ede1p work cooperatively to recruit ubiquitinated Ste2p to CCPs. In addition, ubiquitination has a role in ligand-independent constitutive recruitment of Ste2p to CCPs, although this process is much slower than ligand-induced recruitment. These results suggest that ubiquitination of Ste2p is indispensable for recruiting Ste2p to CCPs in both ligand-dependent and ligand-independent endocytosis.
ABWGAT: anchor-based whole genome analysis tool
Authors: Das Sarbashis , Vishnoi Anchal , Bhattacharya Alok
Published: October 2009

Summary: Large numbers of genomes are being sequenced regularly and the rate will go up in future due to availability of new genome sequencing techniques. In order to understand genotype to phenotype relationships, it is necessary to identify sequence variations at the genomic level. Alignment of a pair of genomes and parsing the alignment data is an accepted approach for identification of variations. Though there are a number of tools available for whole-genome alignment, none of these allows automatic parsing of the alignment and identification of different kinds of genomic variants with high degree of sensitivity. Here we present a simple web-based interface for whole genome comparison named ABWGAT (Anchor-Based Whole Genome Analysis Tool) that is simple to use. The output is a list of variations such as SNVs, indels, repeat expansion and inversion.

Availability: The web server is freely available to non-commercial users at the following address http://abwgc.jnu.ac.in/_sarba. Supplementary data are available at http://abwgc.jnu.ac.in/_sarba/cgi-bin/abwgc_retrival.cgi using job id 524, 526 and 528.

Contact:  dsarbashis@gmail.com; alok.bhattacharya@gmail.com
Integrated analysis of copy number alterations and gene expression: a bivariate assessment of equally directed abnormalities
Authors: Schäfer Martin , Schwender Holger , Merk Sylvia , Haferlach Claudia , Ickstadt Katja , Dugas Martin
Published: October 2009

Motivation: The analysis of a number of different genetic features like copy number (CN) variation, gene expression (GE) or loss of heterocygosity has considerably increased in recent years, as well as the number of available datasets. This is particularly due to the success of microarray technology. Thus, to understand mechanisms of disease pathogenesis on a molecular basis, e.g. in cancer research, the challenge of analyzing such different data types in an integrated way has become increasingly important. In order to tackle this problem, we propose a new procedure for an integrated analysis of two different data types that searches for genes and genetic regions which for both inputs display strong equally directed deviations from the reference median. We employ this approach, based on a modified correlation coefficient and an explorative Wilcoxon test, to find DNA regions of such abnormalities in GE and CN (e.g. underexpressed genes accompanied by a loss of DNA material).

Results: In an application to acute myeloid leukemia, our procedure is able to identify various regions on different chromosomes with characteristic abnormalities in GE and CN data and shows a higher sensitivity to differences in abnormalities than standard approaches. While the results support various findings of previous studies, some new interesting DNA regions can be identified. In a simulation study, our procedure also shows more reliable results than standard approaches.

Availability: Code and data available as R packages edira and ediraAMLdata from http://www.statistik.tu-dortmund.de/~schaefer/

Contact:  martin.schaefer@udo.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Sperm competition and sperm length influence the rate of mammalian spermatogenesis
Authors: Ramm Steven A. , Stockley Paula
Published: October 2009

Sperm competition typically favours an increased investment in testes, because larger testes can produce more sperm to provide a numerical advantage in competition with rival ejaculates. However, interspecific variation in testis size cannot be equated directly with variation in sperm production rate—which is the trait ultimately selected under sperm competition—because there are also differences between species in the proportion of spermatogenic tissue contained within the testis and in the time it takes to produce each sperm. Focusing on the latter source of variation, we provide phylogenetically controlled evidence for mammals that species with relatively large testes (and hence a high level of sperm competition) have a shorter duration of the cycle of the seminiferous epithelium and consequently a faster rate of spermatogenesis, enabling males to produce more sperm per unit testis per unit time. Moreover, we identify an independent negative relationship between sperm length and the rate of spermatogenesis, such that spermatogenesis takes longer in species with longer sperm. We conclude that sperm competition selects for both larger testes and a faster rate of spermatogenesis to increase overall sperm production, and that an evolutionary trade-off between sperm size and numbers may be mediated via constraints on the rate of spermatogenesis imposed by selection for longer sperm.
Food availability differentially influences young males' and females' cognitive processes in accordance with sexual selection theory
Authors: Benenson Joyce F. , Rivard Ryan , Markovits Henry
Published: October 2009

Sexual selection theory predicts that additional resources will have a greater impact on males’ compared with females’ reproductive success. Consequently, we expected that strong cues signalling increased resource availability should augment cognitive functioning associated with long-term maximization of reproductive outcomes (inhibition, working memory) in human males. In human females, who can rely on assistance in resource-rich environments, we expected the opposite effect. We tested this prediction in lower socio-economic status children, since their poverty increased the relative salience of the cues available in a limited experimental situation. We show that cues indicative of food availability increased impoverished young males’ inhibitory and working memory capacities compared with males who viewed photographs of food. By contrast, cues indicating food availability exerted the opposite effect on females. These results indicate that cues related to resource availability have differential effects on basic cognitive functions associated with strategic behaviour in males and females. The findings also demonstrate remarkable plasticity in fundamental cognitive processes in young children, even those from impoverished backgrounds.
Preventable H5N1 avian influenza epidemics in the British poultry industry network exhibit characteristic scales
Authors: Jonkers A. R. T. , Sharkey K. J. , Christley R. M.
Published: October 2009

Epidemics are frequently simulated on redundantly wired contact networks, which have many more links between sites than are minimally required to connect all. Consequently, the modelled pathogen can travel numerous alternative routes, complicating effective containment strategies. These networks have moreover been found to exhibit ‘scale-free’ properties and percolation, suggesting resilience to damage. However, realistic H5N1 avian influenza transmission probabilities and containment strategies, here modelled on the British poultry industry network, show that infection dynamics can additionally express characteristic scales. These system-preferred scales constitute small areas within an observed power law distribution that exhibit a lesser slope than the power law itself, indicating a slightly increased relative likelihood. These characteristic scales are here produced by a network-pervading intranet of so-called hotspot sites that propagate large epidemics below the percolation threshold. This intranet is, however, extremely vulnerable; targeted inoculation of a mere 3–6% (depending on incorporated biosecurity measures) of the British poultry industry network prevents large and moderate H5N1 outbreaks completely, offering an order of magnitude improvement over previously advocated strategies affecting the most highly connected ‘hub’ sites. In other words, hotspots and hubs are separate functional entities that do not necessarily coincide, and hotspots can make more effective inoculation targets. Given the ubiquity and relevance of networks (epidemics, Internet, power grids, protein interaction), recognition of this spreading regime elsewhere would suggest a similar disproportionate sensitivity to such surgical interventions.
A novel biomimetic approach to the design of high-performance ceramic–metal composites
Authors: Launey Maximilien E. , Munch Etienne , Alsem Daan Hein , Saiz Eduardo , Tomsia Antoni P. , Ritchie Robert O.
Published: October 2009

The prospect of extending natural biological design to develop new synthetic ceramic–metal composite materials is examined. Using ice-templating of ceramic suspensions and subsequent metal infiltration, we demonstrate that the concept of ordered hierarchical design can be applied to create fine-scale laminated ceramic–metal (bulk) composites that are inexpensive, lightweight and display exceptional damage-tolerance properties. Specifically, Al
2
O
3
/Al–Si laminates with ceramic contents up to approximately 40 vol% and with lamellae thicknesses down to 10 µm were processed and characterized. These structures achieve an excellent fracture toughness of 40 MPa√m at a tensile strength of approximately 300 MPa. Salient toughening mechanisms are described together with further toughening strategies.
The control systems structures of energy metabolism
Authors: Cloutier Mathieu , Wellstead Peter
Published: October 2009

The biochemical regulation of energy metabolism (EM) allows cells to modulate their energetic output depending on available substrates and requirements. To this end, numerous biomolecular mechanisms exist that allow the sensing of the energetic state and corresponding adjustment of enzymatic reaction rates. This regulation is known to induce dynamic systems properties such as oscillations or perfect adaptation. Although the various mechanisms of energy regulation have been studied in detail from many angles at the experimental and theoretical levels, no framework is available for the systematic analysis of EM from a control systems perspective. In this study, we have used principles well known in control to clarify the basic system features that govern EM. The major result is a subdivision of the biomolecular mechanisms of energy regulation in terms of widely used engineering control mechanisms: proportional, integral, derivative control, and structures: feedback, cascade and feed-forward control. Evidence for each mechanism and structure is demonstrated and the implications for systems properties are shown through simulations. As the equivalence between biological systems and control components presented here is generic, it is also hypothesized that our work could eventually have an applicability that is much wider than the focus of the current study.
Airborne transmission of disease in hospitals
Authors: Eames I. , Tang J. W. , Li Y. , Wilson P.
Published: October 2009

Hospital-acquired infection (HAI) is an important public health issue with unacceptable levels of morbidity and mortality, over the last 5 years. Disease can be transmitted by air (over large distances), by direct/indirect contact or a combination of both routes. While contact transmission of disease forms the majority of HAI cases, transmission through the air is harder to control, but one where the engineering sciences can play an important role in limiting the spread. This forms the focus of this themed volume.

In this paper, we describe the current hospital environment and review the contributions from microbiologists, mechanical and civil engineers, and mathematicians to this themed volume on the airborne transmission of infection in hospitals. The review also points out some of the outstanding scientific questions and possible approaches to mitigating transmission.
James Joule, William Thomson and the concept of a perfect gas
Authors: Rowlinson J. S.
Published: October 2009

In the early 1850s Joule and Thomson measured the cooling experienced by a flowing gas on passing an obstacle that caused a decrease in pressure. The mythical ‘perfect gas’, which conforms exactly to Boyle's and Charles's laws, would show no such cooling. They used their results to put the new theory of thermodynamics on a more secure foundation and to establish a practical route for converting the measurement of temperature on a gas scale to an absolute temperature based on the second law of thermodynamics. Their experiments were sound but their calculations were in error. Later in the century William Hampson and Carl von Linde independently devised a simple method of liquefying air based on Joule–Thomson cooling, but whereas Linde understood the theory, Hampson, and many chemists, confused the process with the cooling of a gas doing external work, which is an effect that would occur also with a perfect gas. James Dewar copied Hampson's process, without acknowledgement, in his work on the liquefaction of air and hydrogen at the Royal Institution. He, too, did not at first understand the theoretical basis of the apparatus. In the twentieth century the effect was exploited to investigate intermolecular forces, but it is now rarely used.
A wavelet-based model of one-dimensional periodic structure for wave-propagation analysis
Authors: Sonekar Parikshit , Mitra Mira
Published: October 2009

In this paper, a wavelet-based method is developed for wave-propagation analysis of a generic multi-coupled one-dimensional periodic structure (PS). The formulation is based on the periodicity condition and uses the dynamic stiffness matrix of the periodic cell obtained from finite-element (FE) or other numerical methods. Here, unlike its conventional definition, the dynamic stiffness matrix is obtained in the wavelet domain through a Daubechies wavelet transform. The proposed numerical scheme enables both time- and frequency-domain analysis of PSs under arbitrary loading conditions. This is in contrast to the existing Fourier-transform-based analysis that is restricted to frequency-domain study. Here, the dispersion characteristics of PSs, especially the band-gap features, are studied. In addition, the method is implemented to simulate time-domain wave response under impulse loading conditions. The two examples considered are periodically simply supported beam and periodic frame structures. In all cases, the responses obtained using the present periodic formulation are compared with the response simulated using the FE model without the periodicity assumption, and they show an exact match. This validates the accuracy of the periodic assumption to obtain the time- and frequency-domain wave responses up to a high-frequency range. Apart from this, the proposed method drastically reduces the computational cost and can be implemented for homogenization of PSs.
Vertical transmission as the key to the colonization of Madagascar by fungus-growing termites?
Authors: Nobre T. , Eggleton P. , Aanen D. K.
Published: October 2009

The mutualism between fungus-growing termites (Macrotermitinae) and their mutualistic fungi (
Termitomyces
) began in Africa. The fungus-growing termites have secondarily colonized Madagascar and only a subset of the genera found in Africa is found on this isolated island. Successful long-distance colonization may have been severely constrained by the obligate interaction of the termites with fungal symbionts and the need to acquire these symbionts secondarily from the environment for most species (horizontal symbiont transmission). Consistent with this hypothesis, we show that all extant species of fungus-growing termites of Madagascar are the result of a single colonization event of termites belonging to one of the only two groups with vertical symbiont transmission, and we date this event at approximately 13 Mya (Middle/Upper Miocene). Vertical symbiont transmission may therefore have facilitated long-distance dispersal since both partners disperse together. In contrast to their termite hosts, the fungal symbionts have colonized Madagascar multiple times, suggesting that the presence of fungus-growing termites may have facilitated secondary colonizations of the symbiont. Our findings indicate that the absence of the right symbionts in a new environment can prevent long-distance dispersal of symbioses relying on horizontal symbiont acquisition.
Impacts of climate change and environmental factors on reproduction and development in wildlife
Authors: Milligan Stuart R. , Holt William V. , Lloyd Rhiannon
Published: October 2009

The robustness of the growth of the human population in the face of environmental impacts is in contrast to the sensitivity of wildlife. There is a danger that the success of reproduction of humans provides a false sense of security for the public, media and politicians with respect to wildlife survival, the maintenance of viable ecosystems and the capacity for recovery of damaged ecosystems and endangered species. In reality, the success of humans to populate the planet has been dependent on the combination of the ability to reproduce successfully and to minimize loss of offspring through controlling and manipulating their own micro-environment. In contrast, reproduction in wildlife is threatened by environmental changes operating at many different physiological levels.
Nutritional effects on oocyte and embryo development in mammals: implications for reproductive efficiency and environmental sustainability
Authors: Ashworth Cheryl J. , Toma Luiza M. , Hunter Morag G.
Published: October 2009

The environment in which a breeding female lives prior to conception and during the early stages of her pregnancy has striking effects on oocytes developing in the ovarian follicle and on early embryos in the reproductive tract. Of the various environmental factors known to affect oocyte and embryo development, altered nutrition during this critical period has been particularly well studied. Alterations in the quantity of food consumed or the composition of the diet imposed solely during the pre-mating period affect oocyte maturity, blastocyst yield, prenatal survival and the number of offspring born alive. Importantly, nutrition at this time also affects the quality of embryos and resultant offspring, with increasing evidence from a variety of species showing that peri-conception nutrition can alter behaviour, cardiovascular function and reproductive function throughout post-natal life. In livestock species, it is important to devise nutritional strategies that improve reproductive efficiency and the quality of offspring but that do not add to the environmental footprint of the production system and which recognize likely changes in feedstuff availability arising from predicted changes in climate.
HARPing on about the DNA damage response during replication: Figure 1.
Authors: Driscoll Robert , Cimprich Karlene A.
Published: October 2009

In this issue of Genes & Development, four papers report that the annealing helicase HepA-related protein (HARP, also known as SMARCAL1 [SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1]) binds directly to the ssDNA-binding protein Replication protein A (RPA) and is recruited to sites of replicative stress. Knockdown of HARP results in hypersensitivity to multiple DNA-damaging agents and defects in fork stability or restart. These exciting insights reveal a key new player in the S-phase DNA damage response.
Developmental trajectories in early hematopoiesis: Figure 1.
Authors: Murre Cornelis
Published: October 2009

The paths that hematopoietic stem cells take to develop from multipotent, self-renewing cells into committed lymphocytes has been a topic of debate for some time. During early hematopoiesis, multiple branchpoints have been described in which progeny cells segregate into cell lineages with distinct developmental potentials. In this issue of Genes & Development, Inlay and colleagues (pp. 2376–2381) identify novel intermediate stages through which hematopoietic progenitor cells travel.
Promoter recognition by bacterial alternative σ factors: the price of high selectivity?: Figure 1.
Authors: Feklistov Andrey , Darst Seth A.
Published: October 2009

A key step in bacterial transcription initiation is melting of the double-stranded promoter DNA by the RNA polymerase holoenzyme. Primary σ factors mediate the melting of thousands of promoters through a conserved set of aromatic amino acids. Alternative σs, which direct transcription of restricted regulons, lack the full set of melting residues. In this issue of Genes & Development, Koo and colleagues (pp. 2426–2436) show that introducing the primary σ melting residues into alternative σs relaxes their promoter specificity, pointing to a trade-off of reduced promoter melting capacity for increased promoter stringency.
Dietary supplementation with branched‐chain amino acids suppresses diethylnitrosamine‐induced liver tumorigenesis in obese and diabetic C57BL/KsJ‐db/db mice
Authors: Iwasa Junpei , Shimizu Masahito , Shiraki Makoto , Shirakami Yohei , Sakai Hiroyasu , Terakura Yoichi , Takai Koji , Tsurumi Hisashi , Tanaka Takuji , Moriwaki Hisataka
Published: October 2009

Obesity and related metabolic abnormalities, including insulin resistance, are risk factors for hepatocellular carcinoma in non‐alcoholic steatohepatitis as well as in chronic viral hepatitis. Branched‐chain amino acids (BCAA), which improve insulin resistance, inhibited obesity‐related colon carcinogenesis in a rodent model, and also reduced the incidence of hepatocellular carcinoma in obese patients with liver cirrhosis. In the present study, we determined the effects of BCAA on the development of diethylnitrosamine (DEN)‐induced liver tumorigenesis in obese C57BL/KsJ‐db/db (db/db) mice with diabetes mellitus. Male db/db mice were given tap water containing 40 ppm DEN for an initial 2 weeks and thereafter they received a basal diet containing 3.0% of BCAA or casein, which served as a nitrogen content‐matched control of BCAA, throughout the experiment. Supplementation with BCAA significantly reduced the total number of foci of cellular alteration, a premalignant lesion of the liver, and the expression of insulin‐like growth factor (IGF)‐1, IGF‐2, and IGF‐1 receptor in the liver when compared to the casein supplementation. BCAA supplementation for 34 weeks also significantly inhibited both the development of hepatocellular neoplasms and the proliferation of hepatocytes in comparison to the basal diet or casein‐fed groups. Supplementation with BCAA improved liver steatosis and fibrosis and inhibited the expression of α‐smooth muscle actin in the DEN‐treated db/db mice. The serum levels of glucose and leptin decreased by dietary BCAA, whereas the value of the quantitative insulin sensitivity check index increased by this agent, indicating the improvement of insulin resistance and hyperleptinemia. In conclusion, oral BCAA supplementation improves insulin resistance and prevents the development of liver tumorigenesis in obese and diabetic mice. (Cancer Sci 2009)
Cannabis and crime: findings from a longitudinal study
Authors: Pedersen Willy , Skardhamar Torbjørn
Published: October 2009

Aim  To examine the association between cannabis use during adolescence and young adulthood, and subsequent criminal charges.

Methods  Data were obtained from the Young in Norway Longitudinal Study. A population‐based sample (n = 1353) was followed from 13 to 27 years of age. Data were gathered on cannabis use, alcohol consumption and alcohol problems, and use of other illegal substances such as amphetamines, cocaine and opiates. In addition, extensive information on socio‐demographic, family and personal factors was collected. This data set was linked to individual‐level information from official Norwegian crime statistics.

Findings  We found robust associations between cannabis use and later registered criminal charges, both in adolescence and in young adulthood. These associations were adjusted for a range of confounding factors, such as family socio‐economic background, parental support and monitoring, educational achievement and career, previous criminal charges, conduct problems and history of cohabitation and marriage. In separate models, we controlled for alcohol measures and for use of other illegal substances. After adjustment, we still found strong associations between cannabis use and later criminal charges. However, when eliminating all types of drug‐specific charges from our models, we no longer observed any significant association with cannabis use.

Conclusions  The study suggests that cannabis use in adolescence and early adulthood may be associated with subsequent involvement in criminal activity. However, the bulk of this involvement seems to be related to various types of drug‐specific crime. Thus, the association seems to rest on the fact that use, possession and distribution of drugs such as cannabis is illegal. The study strengthens concerns about the laws relating to the use, possession and distribution of cannabis.
Relationship of abdominal obesity with cardiovascular disease, diabetes and hyperlipidaemia in Spain
Authors: Casanueva Felipe F. , Moreno Basilio , Rodríguez‐Azeredo Rosario , Massien Christine , Conthe Pedro , Formiguera Xavier , Barrios Vivencio , Balkau Beberly
Published: October 2009

Objectives  To evaluate the relevance of obesity and abdominal obesity in the prevalence of cardiovascular disease (CVD), diabetes mellitus, hyperlipidaemia and hypertension in primary care patients and to ascertain whether waist circumference (WC) measurement should be included in routine clinical practice in addition to body mass index (BMI).

Methods  As part of the IDEA study, primary care physicians from Spain recruited patients aged 18–80 years. WC and BMI and the presence of CVD, diabetes mellitus, hyperlipidaemia and hypertension were recorded. Finally, 17 980 were analysed.

An age‐related increase in adiposity was observed. Overall 33% were obese by BMI, and 51% of subjects presented abdominal obesity by the National Cholesterol Education Program Adult Treatment Panel III (NCEP‐ATPIII) (WC > 102 cm for men and > 88 cm for women). Although there was a correlation between BMI and WC, they presented different distribution patterns. Women, but not men, with a high level of education, professional activity and smoking were associated with a lower WC. Abdominal obesity was significantly associated with CVD. Some subjects with abdominal obesity but lean by BMI, showed an increased prevalence of CVD and diabetes. Furthermore, abdominal obesity was strongly associated with dyslipidaemia and hypertension.

Conclusions  Half of the primary care patients studied showed abdominal obesity as measured by WC, whereas one‐third was obese by BMI. Abdominal obesity was strongly associated with CVD and diabetes, even in patients lean by BMI. WC should be included in the routine clinical practice in addition to BMI.
Maternal thyroid function during gestation is related to breech presentation at term
Authors: Kuppens S. M. I. , Kooistra L. , Wijnen H. A. , Crawford S. , Vader H. L. , Hasaart T. H. M. , Oei S. G. , Pop V. J.
Published: October 2009

Objective  To study the relationship between suboptimal maternal thyroid function during gestation and breech presentation at term.

Design  Prospective follow‐up study during three trimesters of gestation.

Patients  A total of 1058 Dutch Caucasian healthy pregnant women were prospectively followed from 12 weeks gestation until term (≥37 weeks) delivery.

Measurements  Maternal thyroid parameters [TSH, free T4 (FT4) and auto‐antibodies to thyroid peroxidase] were assessed at 12, 24 and 36 weeks gestation as well as foetal presentation at term.

Results  At term, 58 women (5·5%) presented in breech. Compared with women with foetuses in the cephalic position, those women who presented in breech at term had significantly higher TSH concentrations, but only at 36 weeks gestation (P = 0·007). No between group differences were obtained for FT4 level at any assessment. The prevalence of breech presentation in the subgroup of women with TSH ≥ 2·5 mIU/l (90th percentile) at 36 weeks gestation was 11%, compared with 4·8% in the women with TSH < 2·50 mIU/l (P = 0·006). Women with TSH below the 5th percentile had no breech presentations. Breech position was significantly and independently related to high maternal TSH concentration (≥2·5 mIU/l) at 36 weeks gestation (O.R.: 2·23, 95% CI: 1·14–4·39), but not at 12 and 24 weeks gestation.

Conclusions  Women with TSH levels above 2·5 mIU/l during end gestation are at risk for breech presentation, and as such for obstetric complications.
An audit of liquid‐based cervical cytology screening samples (ThinPrep and SurePath) reported as glandular neoplasia
Authors: Thiryayi S. A. , Marshall J. , Rana D. N.
Published: October 2009

S. A. Thiryayi, J. Marshall and D. N. Rana An audit of liquid‐based cervical cytology screening samples (ThinPrep and SurePath) reported as glandular neoplasia

Objectives:  The aims of this study were to assess the number of cases diagnosed as glandular neoplasia (national report code 6) of cervical (6A) and non‐cervical (6B) types on ThinPrep (TP) and SurePath (SP) liquid‐based cytology (LBC) samples and to calculate the positive predictive value (PPV) of these diagnoses for significant glandular and/or squamous pathology for local audit and as a contribution to national data on glandular neoplasia.

Methods:  A computerized search identified all screening LBC samples reported as glandular neoplasia during the 24‐month period from January 2006 to December 2007. Corresponding histology samples were identified, with a minimum follow‐up period of 6 months for each case.

Results:  A total of 70 samples, representing 70 patients, were reported as glandular neoplasia, 39 TP (55.7%) and 31 SP (44.3%), with 46 samples (31 TP, 15 SP) reported as 6A and 24 samples (eight TP, 16 SP) as 6B. PPV of glandular neoplasia was calculated for a biopsy diagnosis of cervical glandular intraepithelial neoplasia/adenocarcinoma and/or cervical intraepithelial neoplasia (CIN) 2 or worse. The PPV of 6A was 100% for both TP and SP. The PPV of 6B for adenocarcinoma was 62.5% for TP and 66.7% for SP. The combined PPV for 6A + 6B was 92.3% for TP, 83.3% for SP and 88.4% combined. The overall pick‐up rates for the two methods were significantly different (TP 0.031%, SP 0.052%; P = 0.014). Histology showed only CIN3 with endocervical crypt involvement in nine TP cases and one SP case.
Modified Papanicolaou staining protocol with minimum alcohol use: a cost‐cutting measure for resource‐limited settings
Authors: Gupta S. , Chachra K. L. , Bhadola P. , Sodhani P.
Published: October 2009

S. Gupta, K. L. Chachra, P. Bhadola and P. Sodhani Modified Papanicolaou staining protocol with minimum alcohol use: a cost‐cutting measure for resource‐limited settings

Objective:  To devise a simple, cost‐effective protocol for Papanicolaou (Pap) staining of cervicovaginal smears.

Methods:  Five hundred coded paired cervical smears were collected from women as part of routine cervical cancer screening. One set of smears was stained by conventional Pap staining protocol (CP) and the other by a modified protocol (MP) in which alcohol was replaced by 1% acetic acid in all the steps except during fixation and prior to mounting; in addition, one alcohol‐based counterstain, OG, was omitted. The smears were examined blindly by the pathologists and then decoded. Each pair of smears was compared and the two protocols were analysed for staining quality and diagnoses by McNemar and chi‐square tests.

Results:  The staining quality in the MP was satisfactory. The nuclear and cytoplasmic features were comparable to the CP. Cytoplasmic transparency was maintained in the MP and the differential staining of blue/green and pink was acceptable to the pathologists and technicians. The diagnoses agreed in all cases and there was no compromise in interpreting the smears. With MP it took only 3–4 minutes to stain a batch of 50 slides. in contrast to the 20 minutes taken by CP. The MP used almost one‐seventh of the amount of alcohol compared with CP, which translated into a significant cost reduction per smear.

Conclusions:  The improvised Pap staining protocol with minimum alcohol use is a simple, cost‐effective and technician‐friendly procedure that can be easily adopted in high‐volume, resource‐limited laboratories for mass cervical cancer screening.
Activated complement is more extensively present in diseased aortic valves than naturally occurring complement inhibitors: a sign of ongoing inflammation
Authors: Ter Weeme M. , Vonk A. B. A. , Kupreishvili K. , Van Ham M. , Zeerleder S. , Wouters D. , Stooker W. , Eijsman L. , Van Hinsbergh V. W. M. , Krijnen P. A. J. , Niessen H. W. M.
Published: October 2009

Eur J Clin Invest 2010; 40 (1): 4–10

Background  Recent studies indicate a role for complement in the pathogenesis of aortic valve disease. However, the role of naturally occurring anti‐complement mediators in this context is unknown. In this study, we have analysed this in three different pathological conditions of the aortic valve: degeneration, atherosclerosis and bacterial endocarditis.

Materials and methods  Human aortic valves were obtained at autopsy (n = 30): 5 control valves, 10 aortic valves with atherosclerotic changes, 10 aortic valves with degenerative changes and 5 degenerative changed aortic valves with bacterial infection. These valves were analysed immunohistochemically for the presence of activated complement (C3d and C5b9) and the complement inhibitors C1‐inh and clusterin. Areas of positivity were then quantified.

Results  C3d, C5b9 and the complement inhibitors C1‐inh and clusterin depositions were mainly found in the endothelium and extracellular matrix in aortic valves. All these mediators were already present in control valves, but the area of positivity increased significantly in response to the different diseases, with the highest increase in response to bacterial endocarditis. Interestingly, in all three aortic diseases, the depositions of complement were significantly more widespread than that of their inhibitors.

Conclusions  Our study indicates that anti‐complement mediators (C1‐inh and clusterin) are deposited in diseased aortic valves together with activated complement, indicating an existing counter response against complement locally in the valve. However, deposition of activated complement is significantly more widespread than that of its inhibitors, which could explain ongoing inflammation in those diseased aortic valves.
Sperm chromatin structure assay as an independent predictor of fertility in vivo: a case–control study
Authors: Giwercman Aleksander , Lindstedt Lars , Larsson Mattias , Bungum Mona , Spano Marcello , Levine Richard J. , Rylander Lars
Published: October 2009

Standard sperm parameters have a limited power for prediction of the chance of natural conception. Recent studies have indicated that the sperm chromatin structure assay (SCSA) DNA fragmentation index (DFI), a measure for the fraction of sperms with DNA damage, is associated with fertility in vivo. The aim of this study was to evaluate the value of this parameter for prediction of infertility. One hundred and twenty‐seven men from infertile couples with no known female factor and 137 men with proven fertility were included. Semen analysis was performed as recommended by the WHO. DFI was assessed using SCSA. Logistic binary regression was used to compute the odds ratios (OR) for infertility. As compared with men with a DFI <10%, men with a DFI between 10% and 20% had an increased risk for infertility (OR 2.5, 95% CI: 1.0–6.1). This was also true for men with a DFI >20% (OR 8.4; 95% CI: 3.0–23). In men with normal standard semen parameters (sperm concentration, motility and morphology) the OR for infertility was increased with DFI >20% (OR 5.1, 95% CI: 1.2–23), whereas if one of the standard semen parameters was abnormal, the OR for infertility was increased already at DFI above 10% (OR 16, 95% CI: 4.2–60). We conclude that SCSA DFI adds to the value of semen analysis in prediction of the chance of natural conception.