Hebbian analysis of the transformation of medial entorhinal grid-cell inputs to hippocampal place fields.

The discovery of grid cells in the medial entorhinal cortex (MEC) permits the characterization of hippocampal computation in much greater detail than previously possible. The present study addresses how an integrate-and-fire unit driven by grid-cell spike trains may transform the multipeaked, spatial firing pattern of grid cells into the single-peaked activity that is typical of hippocampal place cells. Previous studies have shown that in the absence of network interactions, this transformation can succeed only if the place cell receives inputs from grids with overlapping vertices at the location of the place cell's firing field. In our simulations, the selection of these inputs was accomplished by fast Hebbian plasticity alone. The resulting nonlinear process was acutely sensitive to small input variations. Simulations differing only in the exact spike timing of grid cells produced different field locations for the same place cells. Place fields became concentrated in areas that correlated with the initial trajectory of the animal; the introduction of feedback inhibitory cells reduced this bias. These results suggest distinct roles for plasticity of the perforant path synapses and for competition via feedback inhibition in the formation of place fields in a novel environment. Furthermore, they imply that variability in MEC spiking patterns or in the rat's trajectory is sufficient for generating a distinct population code in a novel environment and suggest that recalling this code in a familiar environment involves additional inputs and/or a different mode of operation of the network.

A cladistic analysis of apolipoprotein B gene variation and plasma lipid and apolipoprotein B levels, using familial data

Any functionally important mutation is embedded in an evolutionary matrix of other mutations. Cladistic analysis, based on this, is a method of investigating gene effects using a haplotype phylogeny to define a set of tests which localize causal mutations to branches of the phylogeny. Previous implementations of cladistic analysis have not addressed the issue of analyzing data from related individuals, though in human studies, family data are usually needed to obtain unambiguous haplotypes. In this study, a method of cladistic analysis is described in which haplotype effects are parameterized in a linear model which accounts for familial correlations. The method was used to study the effect of apolipoprotein (Apo) B gene variation on total-, LDL-, and HDL-cholesterol, triglyceride, and Apo B levels in 121 French families. Five polymorphisms defined Apo B haplotypes: the signal peptide Insertion/deletion, Bsp 1286I, XbaI, MspI, and EcoRI. Eleven haplotypes were found, and a haplotype phylogeny was constructed and used to define a set of tests of haplotype effects on lipid and apo B levels.^ This new method of cladistic analysis, the parametric method, found significant effects for single haplotypes for all variables. For HDL-cholesterol, 3 clusters of evolutionarily-related haplotypes affecting levels were found. Haplotype effects accounted for about 10% of the genetic variance of triglyceride and HDL-cholesterol levels. The results of the parametric method were compared to those of a method of cladistic analysis based on permutational testing. The permutational method detected fewer haplotype effects, even when modified to account for correlations within families. Simulation studies exploring these differences found evidence of systematic errors in the permutational method due to the process by which haplotype groups were selected for testing.^ The applicability of cladistic analysis to human data was shown. The parametric method is suggested as an improvement over the permutational method. This study has identified candidate haplotypes for sequence comparisons in order to locate the functional mutations in the Apo B gene which may influence plasma lipid levels. ^

Implementation analysis of the Texas Vendor Drug Program

An agency is accountable to a legislative body in the implementation of public policy. It has a responsibility to ensure that the implementation of that policy is consistent with its statutory objectives.^ The analysis of the effectiveness of implementation of the Vendor Drug Program proceeded in the following manner. The federal and state roles and statutes pursuant to the formulation of the Vendor Drug Program were reviewed to determine statutory intent and formal provisions. The translation of these into programmatic details was examined focusing on the factors impacting the implementation process. Lastly, the six conditions outlined by Mazmanian and Sabatier as criteria for effective implementation, were applied to the implementation of the Vendor Drug Program to determine if the implementation was effective in relation to consistency with statutory objectives.^ The implementation of the statutes clearly met four of the six conditions for effective implementation: (1) clear and consistent objectives; (2) a valid causal theory; (3) structured the process to maximize agency and target compliance with the objectives; and (4) had continued support of constituency groups and sovereigns.^ The implementation was basically consistent with the statutory objectives, although the determination of vendor reimbursement has had and continues to have problems. ^

Genetic analysis of tumor progression susceptibility in the mouse skin model

In the field of chemical carcinogenesis the use of animal models has proved to be a useful tool in dissecting the multistage process of tumor formation. In this regard the outbred SENCAR mouse has been the strain of choice in the analysis of skin carcinogenesis given its high sensitivity to the chemically induced acquisition of premalignant lesions, papillomas, and the later progression of these lesions into squamous cell carcinomas (SCC).^ The derivation of an inbred strain from the SENCAR stock called SSIN, that in spite of a high sensitivity to the development of papillomas lack the ability to transform these premalignant lesions into SCC, suggested that tumor promotion and progression were under the genetic control of different sets of genes.^ In the present study the nature of susceptibility to tumor progression was investigated. Analysis of F1 hybrids between the outbred SENCAR and SSIN mice suggested that there is at least one dominant gene responsible for susceptibility to tumor progression.^ Later development of another inbred strain from the outbred SENCAR stock, that had sensitivity to both tumor promotion and progression, allowed the formulation of a more accurate genetic model. Using this newly derived line, SENCAR B/Pt. and SSIN it was determined that there is one dominant tumor progression susceptibility gene. Linkage analysis showed that this gene maps to mouse chromosome 14 and it was possible to narrow the region to a 16 cM interval.^ In order to better characterize the nature of the progression susceptibility differences between these two strains, their proliferative pattern was investigated. It was found that SENCAR B/Pt, have an enlarged proliferative compartment with overexpression of cyclin D1, p16 and p21. Further studies showed an aberrant overexpression of TGF-$\beta$ in the susceptible strain, an increase in apoptosis, p53 protein accumulation and early loss of connexin 26. These results taken together suggest that papillomas in the SENCAR B/Pt. mice have higher proliferation and may have an increase in genomic instability, these two factors would contribute to a higher sensitivity to tumor progression. ^

Transcriptional regulation and functional analysis of the human Wilms' tumor 1 gene

The Wilms' tumor 1 gene (WT1) encodes a zinc-finger transcription factor and is expressed in urogenital, hematopoietic and other tissues. It is expressed in a temporal and spatial manner in both embryonic and adult stages. To obtain a better understanding of the biological function of WT1, we studied two aspects of WT1 regulation: one is the identification of tissue-specific cis-regulatory elements that regulate its expression, the other is the downstream genes which are modulated by WT1.^ My studies indicate that in addition to the promoter, other regulatory elements are required for the tissue specific expression of this gene. A 259-bp hematopoietic specific enhancer in intron 3 of the WT1 gene increased the transcriptional activity of the WT1 promoter by 8- to 10-fold in K562 and HL60 cells. Sequence analysis revealed both GATA and c-Myb motifs in the enhancer fragment. Mutation of the GATA motif decreased the enhancer activity by 60% in K562 cells. Electrophoretic mobility shift assays showed that both GATA-1 and GATA-2 proteins in K562 nuclear extracts bind to this motif. Cotransfection of the enhancer containing reporter construct with a GATA-1 or GATA-2 expression vector showed that both GATA-1 and GATA-2 transactivated this enhancer, increasing the CAT reporter activity 10-15 fold and 5-fold respectively. Similar analysis of the c-Myb motif by cotransfection with the enhancer CAT reporter construct and a c-Myb expression vector showed that c-Myb transactivated the enhancer by 5-fold. A DNase I-hypersensitive site has been identified in the 258 bp enhancer region. These data suggest that GATA-1 and c-Myb are responsible for the activity of this enhancer in hematopoietic cells and may bind to the enhancer in vivo. In the process of searching for cis-regulatory elements in transgenic mice, we have identified a 1.0 kb fragment that is 50 kb downstream from the promoter and is required for the central nervous system expression of WT1.^ In the search for downstream target genes of WT1, we noted that the proto-oncogene N-myc is coexpressed with the tumor suppressor gene WT1 in the developing kidney and is overexpressed in many Wilms' tumors. Sequence analysis revealed eleven consensus WT1 binding sites located in the 1 kb mouse N-myc promoter. We further showed that the N-myc promoter was down-regulated by WT1 in transient transfection assays. Electrophoretic mobility shift assays showed that oligonucleotides containing the WT1 motifs could bind WT1 protein. Furthermore, a Denys-Drash syndrome mutant of WT1, R394W, that has a mutation in the DNA binding domain, failed to repress the N-myc promoter. This suggests that the repression of the N-myc promoter is mediated by DNA binding of WT1. This finding helps to elucidate the relationship of WT1 and N-myc in tumorigenesis and renal development. ^

ANALYSIS OF THE CORYNEBACTERIUM PARVUM-INDUCED DECLINE OF MURINE NATURAL KILLER CELL-MEDIATED CYTOTOXICITY

Treatment of mice with the immunomodulating agent, Corynebacterium parvum (C. parvum), was shown to result in a severe and long-lasting depression of splenic natural killer (NK) cell-mediated cytotoxicity 5-21 days post-inoculation. Because NK cells have been implicated in immunosurveillance against malignancy (due to their spontaneous occurrence and rapid reactivity to a variety of histological types of tumors), as well as in resistance to established tumors, this decreased activity was of particular concern, since this effect is contrary to that which would be considered therapeutically desirable in cancer treatment (i.e. a potentiation of antitumor effector functions, including NK cell activity, would be expected to lead to a more effective destruction of malignant cells). Therefore, an analysis of the mechanism of this decline of splenic NK cell activity in C.parvum treated mice was undertaken.^ From in vitro co-culturing experiments, it was found that low NK-responsive C. parvum splenocytes were capable of reducing the normally high-reactivity of cells from untreated syngeneic mice to YAC-1 lymphoma, suggesting the presence of NK-directed suppressor cells in C. parvum treated animals. This was further supported by the demonstration of normal levels of cytotoxicity in C. parvum splenocyte preparations following Ficoll-Hypaque separation, which coincided with removal of the NK-suppressive capabilities of these cells. The T cell nature of these regulatory cells was indicated by (1) the failure of C. parvum to cause a reduction of NK cell activity, or the generation of NK-directed suppressor cells in T cell-deficient athymic mice, (2) the removal of C. parvum-induced suppression by T cell-depleting fractionation procedures or treatments, and (3) demonstration of suppression of NK cell activity by T cell-enriched C. parvum splenocytes. These studies suggest, therefore, that the eventual reduction of suppression by T cell elimination and/or inhibition, may result in a promotion of the antitumor effectiveness of C. parvum due to the contribution of "freed" NK effector cell activity.^ However, the temporary suppression of NK cell activity induced by C. parvum (reactivity of treated mice returns to normal levels within 28 days after C. parvum injection), may in fact be favorable in some situations, e.g. in bone marrow transplantation cases, since NK cells have been suggested to play a role also in the process of bone marrow graft rejection.^ Therefore, the discriminate use of agents such as C. parvum may allow for the controlled regulation of NK cell activity suggested to be necessary for the optimalization of therapeutic regimens. ^

Retrospective analysis of a nonforecasted rain-on-snow flood in the Alps – a matter of model limitations or unpredictable nature?

A rain-on-snow flood occurred in the Bernese Alps, Switzerland, on 10 October 2011, and caused significant damage. As the flood peak was unpredicted by the flood forecast system, questions were raised concerning the causes and the predictability of the event. Here, we aimed to reconstruct the anatomy of this rain-on-snow flood in the Lötschen Valley (160 km2) by analyzing meteorological data from the synoptic to the local scale and by reproducing the flood peak with the hydrological model WaSiM-ETH (Water Flow and Balance Simulation Model). This in order to gain process understanding and to evaluate the predictability. The atmospheric drivers of this rain-on-snow flood were (i) sustained snowfall followed by (ii) the passage of an atmospheric river bringing warm and moist air towards the Alps. As a result, intensive rainfall (average of 100 mm day-1) was accompanied by a temperature increase that shifted the 0° line from 1500 to 3200 m a.s.l. (meters above sea level) in 24 h with a maximum increase of 9 K in 9 h. The south-facing slope of the valley received significantly more precipitation than the north-facing slope, leading to flooding only in tributaries along the south-facing slope. We hypothesized that the reason for this very local rainfall distribution was a cavity circulation combined with a seeder-feeder-cloud system enhancing local rainfall and snowmelt along the south-facing slope. By applying and considerably recalibrating the standard hydrological model setup, we proved that both latent and sensible heat fluxes were needed to reconstruct the snow cover dynamic, and that locally high-precipitation sums (160 mm in 12 h) were required to produce the estimated flood peak. However, to reproduce the rapid runoff responses during the event, we conceptually represent likely lateral flow dynamics within the snow cover causing the model to react "oversensitively" to meltwater. Driving the optimized model with COSMO (Consortium for Small-scale Modeling)-2 forecast data, we still failed to simulate the flood because COSMO-2 forecast data underestimated both the local precipitation peak and the temperature increase. Thus we conclude that this rain-on-snow flood was, in general, predictable, but requires a special hydrological model setup and extensive and locally precise meteorological input data. Although, this data quality may not be achieved with forecast data, an additional model with a specific rain-on-snow configuration can provide useful information when rain-on-snow events are likely to occur.

Quantitative morphometric analysis of lakes using GIS: rectangularity R , ellipticity E , orientation O , and the rectangularity vs. ellipticity index, REi

Quantitative measures of polygon shapes and orientation are important elements of geospatial analysis. These kinds of measures are particularly valuable in the case of lakes, where shape and orientation patterns can help identifying the geomorphological agents behind lake formation and evolution. However, the lack of built-in tools in commercial geographic information system (GIS) software packages designed for this kind of analysis has meant that many researchers often must rely on tools and workarounds that are not always accurate. Here, an easy-to-use method to measure rectangularity R, ellipticity E, and orientation O is developed. In addition, a new rectangularity vs. ellipticity index, REi, is defined. Following a step-by-step process, it is shown how these measures and index can be easily calculated using a combination of GIS built-in functions. The identification of shapes and estimation of orientations performed by this method is applied to the case study of the geometric and oriented lakes of the Llanos de Moxos, in the Bolivian Amazon, where shape and orientation have been the two most important elements studied to infer possible formation mechanisms. It is shown that, thanks to these new indexes, shape and orientation patterns are unveiled, which would have been hard to identify otherwise.

Organ donation in Switzerland - an analysis of factors associated with consent rate

BACKGROUND AND AIM Switzerland has a low post mortem organ donation rate. Here we examine variables that are associated with the consent of the deceased's next of kin (NOK) for organ donation, which is a prerequisite for donation in Switzerland. METHODS AND ANALYSIS During one year, we registered information from NOK of all deceased patients in Swiss intensive care units, who were approached for consent to organ donation. We collected data on patient demographics, characteristics of NOK, factors related to the request process and to the clinical setting. We analyzed the association of collected predictors with consent rate using univariable logistic regression models; predictors with p-values <0.2 were selected for a multivariable logistic regression. RESULTS Of 266 NOK approached for consent, consent was given in 137 (51.5%) cases. In multivariable analysis, we found associations of consent rates with Swiss nationality (OR 3.09, 95% CI: 1.46-6.54) and German language area (OR 0.31, 95% CI: 0.14-0.73). Consent rates tended to be higher if a parent was present during the request (OR 1.76, 95% CI: 0.93-3.33) and if the request was done before brain death was formally declared (OR 1.87, 95% CI: 0.90-3.87). CONCLUSION Establishing an atmosphere of trust between the medical staff putting forward a request and the NOK, allowing sufficient time for the NOK to consider donation, and respecting personal values and cultural differences, could be of importance for increasing donation rates. Additional measures are needed to address the pronounced differences in consent rates between language regions.

Proteomic analysis of porcine bone-conditioned medium.

PURPOSE Autografts are considered to support bone regeneration. Paracrine factors released from cortical bone might contribute to the overall process of graft consolidation. The aim of this study was to characterize the paracrine factors by means of proteomic analysis. MATERIALS AND METHODS Bone-conditioned medium (BCM) was prepared from fresh bone chips of porcine mandibles and subjected to proteomic analysis. Proteins were categorized and clustered using the bioinformatic tools UNIPROT and PANTHER, respectively. RESULTS Proteomic analysis showed that BCM contains more than 150 proteins, of which 43 were categorized into "secreted" and "extracellular matrix." Growth factors that are not only detectable in BCM, but potentially also target cellular processes involved in bone regeneration, eg, pleiotrophin, galectin-1, transforming growth factor beta (TGF-β)-induced gene (TGFBI), lactotransferrin, insulin-like growth factor (IGF)-binding protein 5, latency-associated peptide forming a complex with TGF-β1, and TGF-β2, were discovered. CONCLUSION The present results demonstrate that cortical bone chips release a large spectrum of proteins with the possibility of modulating cellular aspects of bone regeneration. The data provide the basis for future studies to understand how these paracrine factors may contribute to the complex process of graft consolidation.

Bone dimensions in the posterior mandible: a retrospective radiographic study using cone beam computed tomography. Part 2- analysis of edentulous sites.

A precise radiographic evaluation of the local bone dimensions and morphology is important for preoperative planning of implant placement. The purpose of this retrospective study was to analyze dimensions and morphology of edentulous sites in the posterior mandible using cone beam computed tomography (CBCT) images. This retrospective radiographic study measured the bone width (BW) of the mandible at three locations on CBCT scans for premolars (PM1, PM2) and molars (M1, M2): at 1 mm and 4 mm below the most cranial point of the alveolar crest (BW1, BW2) and at the superior border of the mandibular canal (BW3). Furthermore, the height (H) of the alveolar process (distance between the measuring points BW1 and BW3), as well as the presence of lingual undercuts, were analyzed. A total of 56 CBCTs met the inclusion criteria, resulting in a sample size of 127 cross sections. There was a statistically significant increase from PM1 to M2 for the BW2 (P < .001), which was not present for BW1 and BW3 values. For the height of the alveolar process, the values exhibited a decrease from PM1 to M2 sites. Sex was a statistically significant parameter for H (P = .001) and for BW1 (P = .03). Age was not a statistically significant parameter for bone width (BW1: P = .37; BW2: P = .31; BW3: P = .51) or for the height of the alveolar process (P = .41) in the posterior mandible. Overall, 73 (57.5%) edentulous sites were evaluated to be without visible lingual undercuts; 13 (10.2%) sites exhibited lingual undercuts classified as influential for implant placement. Precise evaluation of the alveolar crest by cross-sectional imaging is of great value to analyze vertical and buccolingual bone dimensions in different locations in the posterior mandible. In addition, CBCTs are valuable to diagnosing the presence of and potential problems caused by lingual undercuts prior to implant placement.

Comparative theoretical analysis of continuous wave laser cutting of metals at 1 and 10 um wavelength

We present a derivation and, based on it, an extension of a model originally proposed by V.G. Niziev to describe continuous wave laser cutting of metals. Starting from a local energy balance and by incorporating heat removal through heat conduction to the bulk material, we find a differential equation for the cutting profile. This equation is solved numerically and yields, besides the cutting profiles, the maximum cutting speed, the absorptivity profiles, and other relevant quantities. Our main goal is to demonstrate the model’s capability to explain some of the experimentally observed differences between laser cutting at around 1 and 10 μm wavelengths. To compare our numerical results to experimental observations, we perform simulations for exactly the same material and laser beam parameters as those used in a recent comparative experimental study. Generally, we find good agreement between theoretical and experimental results and show that the main differences between laser cutting with 1- and 10-μm beams arise from the different absorptivity profiles and absorbed intensities. Especially the latter suggests that the energy transfer, and thus the laser cutting process, is more efficient in the case of laser cutting with 1-μm beams.

Transcriptional analysis of left-sided colitis, pancolitis, and ulcerative colitis-associated dysplasia.

BACKGROUND It is unknown why patients with extensive ulcerative colitis (UC) have a higher risk of colorectal cancer compared with patients with left-sided UC. This study characterizes the inflammatory processes in left-sided UC, pancolitis, and UC-associated dysplasia at the transcriptional level to identify potential biomarkers and transcripts of importance for the carcinogenic behavior of chronic inflammation. METHODS The Affymetrix GeneChip Human Genome U133 Plus 2.0 was applied on colonic biopsies from UC patients with left-sided UC, pancolitis, dysplasia, and controls. Reverse transcription polymerase chain reaction and immunohistochemistry were performed for validating selected transcripts in the initial cohort and in 2 independent cohorts of patients with UC. Microarray data were analyzed by principal component analysis, and reverse transcription polymerase chain reaction and immunohistochemistry data by the Wilcoxon's rank-sum test. RESULTS The principal component analysis results revealed separate clusters for left-sided UC, pancolitis, dysplasia, and controls. Close clustering of dysplastic and pancolitic samples indicated similarities in gene expression. Indeed, 101 and 656 parallel upregulated and downregulated transcripts, respectively, were identified in specimens from dysplasia and pancolitis. Validation of selected transcripts hereof identified insulin receptor alpha (INSRA) and MAP kinase interacting serine/threonine kinase 2 (MKNK2) with an enhanced expression in dysplasia compared with left-sided UC and controls, whereas laminin γ2 (LAMC2) was found with a lower expression in dysplasia compared with the remaining 3 groups. CONCLUSIONS This study demonstrates pancolitis and left-sided UC as distinct inflammatory processes at the transcriptional level, and identifies INSRA, MKNK2, and LAMC2 as potential critical transcripts in the inflammation-driven preneoplastic process of UC.

Genetic analysis of white facial and leg markings in the Swiss Franches-Montagnes Horse Breed

White markings and spotting patterns in animal species are thought to be a result of the domestication process. They often serve for the identification of individuals but sometimes are accompanied by complex pathological syndromes. In the Swiss Franches-Montagnes horse population, white markings increased vastly in size and occurrence during the past 30 years, although the breeding goal demands a horse with as little depigmented areas as possible. In order to improve selection and avoid more excessive depigmentation on the population level, we estimated population parameters and breeding values for white head and anterior and posterior leg markings. Heritabilities and genetic correlations for the traits were high (h(2) > 0.5). A strong positive correlation was found between the chestnut allele at the melanocortin-1-receptor gene locus and the extent of white markings. Segregation analysis revealed that our data fit best to a model including a polygenic effect and a biallelic locus with a dominant-recessive mode of inheritance. The recessive allele was found to be the white trait-increasing allele. Multilocus linkage disequilibrium analysis allowed the mapping of the putative major locus to a chromosomal region on ECA3q harboring the KIT gene.