WISP genes are members of the connective tissue growth factor family that are up-regulated in Wnt-1-transformed cells and aberrantly expressed in human colon tumors

Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40-fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis

Genetic Interactions between Doublecortin and Doublecortin-like Kinase in Neuronal Migration and Axon Outgrowth

SummaryAlthough mutations in the human doublecortin gene (DCX) cause profound defects in cortical neuronal migration, a genetic deletion of Dcx in mice produces a milder defect. A second locus, doublecortin-like kinase (Dclk), encodes a protein with similar “doublecortin domains” and microtubule stabilization properties that may compensate for Dcx. Here, we generate a mouse with a Dclk mutation that causes no obvious migrational abnormalities but show that mice mutant for both Dcx and Dclk demonstrate perinatal lethality, disorganized neocortical layering, and profound hippocampal cytoarchitectural disorganization. Surprisingly, Dcx−/y;Dclk−/− mutants have widespread axonal defects, affecting the corpus callosum, anterior commissure, subcortical fiber tracts, and internal capsule. Dcx/Dclk-deficient dissociated neurons show abnormal axon outgrowth and dendritic structure, with defects in axonal transport of synaptic vesicle proteins. Dcx and Dclk may directly or indirectly regulate microtubule-based vesicle transport, a process critical to both neuronal migration and axon outgrowth

An Investigation of Racing Performance and Whip Use by Jockeys in Thoroughbred Races

Concerns have been expressed concerning animal-welfare issues associated with whip use during Thoroughbred races. However, there have been no studies of relationships between performance and use of whips in Thoroughbred racing. Our aim was to describe whip use and the horses' performance during races, and to investigate associations between whip use and racing performance. Under the Australian Racing Board (ARB) rules, only horses that are in contention can be whipped, so we expected that whippings would be associated with superior performance, and those superior performances would be explained by an effect of whipping on horse velocities in the final 400 m of the race. We were also interested to determine whether performance in the latter sections of a race was associated with performance in the earlier sections of a race. Measurements of whip strikes and sectional times during each of the final three 200 metre (m) sections of five races were analysed. Jockeys in more advanced placings at the final 400 and 200 m positions in the races whipped their horses more frequently. Horses, on average, achieved highest speeds in the 600 to 400 m section when there was no whip use, and the increased whip use was most frequent in the final two 200 m sections when horses were fatigued. This increased whip use was not associated with significant variation in velocity as a predictor of superior placing at the finish

Flogging tired horses: who wants whipping and who would walk away if whipping horses were withheld?

Recent studies have cast doubt on the effectiveness of whipping horses during races and this has led to questions concerning its continuing justification. Furthermore, it has been argued that whipping tired horses in racing is the most televised form of violence to animals. The present study used de-identified data from a recent independent Australian poll (n = 1,533) to characterise the 26% of respondents (113 females and 271 males) who support the whipping of racehorses and the 10% of racing enthusiasts in the sample (44 females and 63 males) who would stop watching races and betting on them if whipping were banned. Logistic regression models examining associations between age, gender, and income level of respondents demonstrated that those who support racehorse whipping are significantly more likely to be male. Among racing enthusiasts who would stop watching races and betting on them if whipping were banned, those in the lowest income bracket were over-represented. The more frequently respondents attended races or gambled on them, the more likely they were to agree that horses should be hit with a whip during the normal course of a race. These findings align with previous studies of violence among men and women but may also be attributed to male support of traditional gambling practices. Globally, racing organisations may consider the findings of the present study helpful in their deliberations on the merits of continuing the practice of whipping tired horses in the name of sport. The study might also provide important data for stakeholders who demand that it continues

Associations of moderate to vigorous physical activity and sedentary behavior with depressive and anxiety symptoms in self-isolating people during the COVID-19 pandemic:A cross-sectional survey in Brazil

This is a cross-sectional study evaluating the associations of self-reported moderate to vigorous physical activity, and sedentary behavior with depressive, anxiety, and co-occurring depressive and anxiety symptoms (D&A) in self-isolating Brazilians during the COVID-19 pandemic. Depressive and anxiety symptoms were collected using the Beck Depression and Anxiety Inventories (BDI and BAI). Among the 937 participants (females=72.3%), those performing ≥30 min/day of moderate to vigorous or ≥15 min/day of vigorous physical activity had lower odds of prevalent depressive, anxiety, and co-occurring D&A symptoms. Those spending ≥10 h/day sedentary were more likely to have depressive symptoms.status: publishe

Platelet factor-4 and its p17-70 peptide inhibit myeloma proliferation and angiogenesis in vivo

<p>Abstract</p> <p>Background</p> <p>Angiogenesis plays an important role in the development of multiple myeloma (MM). The interaction between MM cells and the bone marrow microenvironment stimulates the proliferation and migration of endothelial progenitor cells (EPCs). Vascular endothelial growth factor (VEGF) contributes to the formation of new blood vessels by actively recruiting circulating EPCs. The production of proangiogenic and antiangiogenic factors is also dysregulated in MM. Platelet factor 4 (PF4) is a potent angiostatic cytokine that inhibits angiogenesis and tumor growth in several animal models.</p> <p>Methods</p> <p>In this study, we stably transfected human myeloma cell lines with the PF4 gene or the sequence encoding its more potent p17-70 peptide and investigated the effects of PF4 and p17-70 on angiogenesis and tumor growth <it>in vitro </it>and in a SCID-rab myeloma model.</p> <p>Results</p> <p>PF4 and p17-70 significantly attenuated VEGF production, both <it>in vitro </it>and <it>in vivo</it>. In a migration study using a Transwell system, PF4 or p17-70 markedly suppressed the migration of co-cultured human endothelial progenitor cells. PF4 or p17-70 also caused a significant reduction in microvessel densities in myeloma xenografts and markedly reduced the tumor volume in the SCID mice. Kaplan-Meier analysis demonstrated that PF4 and p17-70 significantly extended the overall survival of SCID mice bearing human myeloma xenografts.</p> <p>Conclusions</p> <p>Our findings indicate that PF4 or p17-70 could be valuable in combating multiple myeloma by disrupting tumor angiogenesis.</p

Fluphenazine-induced acute and tardive dyskinesias in monkeys

Five Cebus apella monkeys were treated with biweekly injections of fluphenazine enanthate (0.1–3.2 mg/kg IM). Three of these completed 1 full year of treatment, one injured its leg after 6 months of treatment and was killed, and another died of unknown causes after 9 months of treatment. All monkeys displayed abnormal movements corresponding to the early appearing extrapyramidal symptoms of neuroleptic-treated patients. These consisted initially of slowing or absence of volitional movement, trembling of the hands, trembling of the entire body, and general drowsy behavior. As treatment progessed, a variety of abnormal postures and movements appeared after each injection that were not exacerbated by drug withdrawal and, as tested at the end of the year, could be abolished or prevented with benztropine mesylate (0.2–0.5 mg/kg IM). The three monkeys that completed 1 year of treatment with fluphenazine were then withdrawn from the drug. After withdrawal, all three developed movements similar in appearance to those of patients with tardive dyskinesia (TD). Reinstitution of fluphenazine treatment, as tested in one monkey, abolished all movements resembling TD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46432/1/213_2004_Article_BF00555204.pd

Deep sequencing-based expression analysis shows major advances in robustness, resolution and inter-lab portability over five microarray platforms

The hippocampal expression profiles of wild-type mice and mice transgenic for δC-doublecortin-like kinase were compared with Solexa/Illumina deep sequencing technology and five different microarray platforms. With Illumina's digital gene expression assay, we obtained ∼2.4 million sequence tags per sample, their abundance spanning four orders of magnitude. Results were highly reproducible, even across laboratories. With a dedicated Bayesian model, we found differential expression of 3179 transcripts with an estimated false-discovery rate of 8.5%. This is a much higher figure than found for microarrays. The overlap in differentially expressed transcripts found with deep sequencing and microarrays was most significant for Affymetrix. The changes in expression observed by deep sequencing were larger than observed by microarrays or quantitative PCR. Relevant processes such as calmodulin-dependent protein kinase activity and vesicle transport along microtubules were found affected by deep sequencing but not by microarrays. While undetectable by microarrays, antisense transcription was found for 51% of all genes and alternative polyadenylation for 47%. We conclude that deep sequencing provides a major advance in robustness, comparability and richness of expression profiling data and is expected to boost collaborative, comparative and integrative genomics studies

DNA repair, genome stability and cancer: a historical perspective

The multistep process of cancer progresses over many years. The prevention of mutations by DNA repair pathways led to an early appreciation of a role for repair in cancer avoidance. However, the broader role of the DNA damage response (DDR) emerged more slowly. In this Timeline article, we reflect on how our understanding of the steps leading to cancer developed, focusing on the role of the DDR. We also consider how our current knowledge can be exploited for cancer therapy

Normal radial migration and lamination are maintained in dyslexia-susceptibility candidate gene homolog Kiaa0319 knockout mice

AbstractDevelopmental dyslexia is a common disorder with a strong genetic component, but the underlying molecular mechanisms are still unknown. Several candidate dyslexia-susceptibility genes, including KIAA0319, DYX1C1, and DCDC2, have been identified in humans. RNA interference experiments targeting these genes in rat embryos have shown impairments in neuronal migration, suggesting that defects in radial cortical migration could be involved in the disease mechanism of dyslexia. Here we present the first characterisation of a Kiaa0319 knockout mouse line. Animals lacking KIAA0319 protein do not show anatomical abnormalities in any of the layered structures of the brain. Neurogenesis and radial migration of cortical projection neurons are not altered, and the intrinsic electrophysiological properties of Kiaa0319-deficient neurons do not differ from those of wild-type neurons. Kiaa0319 overexpression in cortex delays radial migration, but does not affect final neuronal position. However, knockout animals show subtle differences suggesting possible alterations in anxiety-related behaviour and in sensorimotor gating. Our results do not reveal a migration disorder in the mouse model, adding to the body of evidence available for Dcdc2 and Dyx1c1 that, unlike in the rat in utero knockdown models, the dyslexia-susceptibility candidate mouse homolog genes do not play an evident role in neuronal migration. However, KIAA0319 protein expression seems to be restricted to the brain, not only in early developmental stages but also in adult mice, indicative of a role of this protein in brain function. The constitutive and conditional knockout lines reported here will be useful tools for further functional analyses of Kiaa0319