The cellular protein MCM3AP is required for inhibition of cellular DNA synthesis by the IE86 protein of human cytomegalovirus.

Like all DNA viruses, human cytomegalovirus (HCMV) infection is known to result in profound effects on host cell cycle. Infection of fibroblasts with HCMV is known to induce an advance in cell cycle through the G(0)-G(1) phase and then a subsequent arrest of cell cycle in early S-phase, presumably resulting in a cellular environment optimum for high levels of viral DNA replication whilst precluding replication of cellular DNA. Although the exact mechanisms used to arrest cell cycle by HCMV are unclear, they likely involve a number of viral gene products and evidence points to the ability of the virus to prevent licensing of cellular DNA synthesis. One viral protein known to profoundly alter cell cycle is the viral immediate early 86 (IE86) protein--an established function of which is to initially drive cells into early S phase but then inhibit cellular DNA synthesis. Here we show that, although IE86 interacts with the cellular licensing factor Cdt1, it does not inhibit licensing of cellular origins. Instead, IE86-mediated inhibition of cellular DNA synthesis requires mini-chromosome-maintenance 3 (MCM3) associated protein (MCM3AP), which can cause subsequent inhibition of initiation of cellular DNA synthesis in a licensing-independent manner

Is there evidence of selection in the dopamine receptor D4 gene in Australian invasive starling populations?

 Although population genetic theory is largely based on the premise that loci under study are selectively neutral, it has been acknowledged that the study of DNA sequence data under the influence of selection can be useful. In some circumstances, these loci show increased population differentiation and gene diversity. Highly polymorphic loci may be especially useful when studying populations having low levels of diversity overall, such as is often the case with threatened or newly established invasive populations. Using common starlings Sturnus vulgaris sampled from invasive Australian populations, we investigated sequence data of the dopamine receptor D4 gene (DRD4), a locus suspected to be under selection for novelty-seeking behaviour in a range of taxa including humans and passerine birds. We hypothesised that such behaviour may be advantageous when species encounter novel environments, such as during invasion. In addition to analyses to detect the presence of selection, we also estimated population differentiation and gene diversity using DRD4 data and compared these estimates to those from microsatellite and mitochondrial DNA sequence data, using the same individuals. We found little evidence for selection on DRD4 in starlings. However, we did find elevated levels of within-population gene diversity when compared to microsatellites and mitochondrial DNA sequence, as well as a greater degree of population differentiation. We suggest that sequence data from putatively nonneutral loci are a useful addition to studies of invasive populations, where low genetic variability is expected

Test Procedure for Conducted Energy Weapons

Several studies have discussed the need for reliable uniform testing of Conducted Energy Weapons (CEWs) independent of the manufacturer. We propose a test proceedure that will enable organizations across Canada to test CEWs in a reliable, repeatable manner. This proceedure includes, but goes beyond, the one proposed by the manufacturer. Test results so obtained will also enable: acceptance and regular validation of function of weapons in inventories of police service; post incedent testing to determine whether the weapon was functioning normally; collection of weapons data across Canada to allow research on trends with age of weapon or other factors related to performance. The authors represent a group of subject matter experts who have been involved in research on or testing of CEWs

Outcome after steroid withdrawal in pediatric renal transplant patients receiving tacrolimus-based immunosuppression

Background. Corticosteroids have always been an integral part of immunosuppressive regimens in renal transplantation. The primary goal of this analysis was to assess the safety of steroid withdrawal in our pediatric renal transplant recipients receiving tacrolimus-based immunosuppression. Methods. Between December 1989 and December 1996, 82 renal transplantations were performed in pediatric patients receiving tacrolimus-based immunosuppression. Two of these patients lost their grafts within 3 weeks of transplantation (and were still on steroids at the time of graft loss), and were excluded from further analysis. Seventy-four patients (92.5%) were taken off prednisone a median of 5.7 months after transplantation. Of these 74, 56 (70%) remained off prednisone (OFF), and 18 (22.5%) were restarted on prednisone a median of 14.8 months after discontinuing steroids (OFF → ON). 6(7.5%) were never taken off prednisone (ON). The mean follow-up was 59±23 months. Results. The 1-, 3-, and 5-year actuarial patient survival rates in the OFF group were 100%, 98%, and 96%, respectively; in the OFF → ON group, they were 100%, 100%, and 100%, and in the ON group, they were 100%, 83%, and 83%. The 1-, 3-, and 5- year actuarial graft survival rates in the OFF group were 100%, 95%, and 82%, respectively; in the OFF → ON group, they were 100%, 89%, and 83%; and in the ON group, they were 100%, 50%, and 33%. Two of the six graft losses in the OFF group, three out of four in the OFF → ON Group, and two out of five in the ON group, were to chronic rejection. A time-dependent Cox regression analysis showed that the hazard for graft failure for those who came and stayed off prednisone was 0.178 relative to those who were never withdrawn from prednisone (P=0.005). Patients who were 10 years of age or younger were withdrawn from prednisone earlier (median: 5 months) than those older than 10 years (median: 7.3 months, P=0.02). In addition, patients who never had acute rejection were withdrawn from steroids earlier (median: 5 months) than those who had one or more episodes of acute rejection (median: 7.6 months, P=0.001). There was no effect of donor age, race, sex, recipient race, sex, cadaveric versus living donor, 48-hr graft function, panel reactive antibody, and total HLA mismatches or matches on the likelihood of being weaned off steroids. Serum creatinine at most recent follow-up in the OFF group was 1.2±0.5 mg/dl; in the OFF → ON group, it was 1.8±0.9 mg/dl, and in the ON group it was 2.0 mg/dl (P<0.003). The incidence of rejection in the OFF, OFF → ON, and ON groups was 39%, 77%, and 100%, respectively (P<0.05). Conclusion. These data suggest that steroid withdrawal in pediatric renal transplant patients receiving tacrolimus-based immunosuppression is associated with reasonable short- and medium-term patient and graft survival, and acceptable renal function. Patients who discontinue and then resume steroids had patient and graft survival rates comparable with those in patients who discontinue and stay off steroids, but had a higher serum creatinine and a higher incidence of rejection

Can starling eggs be useful as a biomonitoring tool to study organohalogenated contaminants on a worldwide scale

Large-scale international monitoring studies are important to assess emission patterns and environmental distributions of organohalogenated contaminants (OHCs) on a worldwide scale. In this study, the presence of OHCs was investigated on three continents (Europe, North America and Australasia), using eggs of starlings (Sturnus vulgaris and Sturnus unicolor) to assess their suitability for large-scale monitoring studies. To the best of our knowledge, this is the first study using bird eggs of the same species as a biomonitor for OHCs on an intercontinental scale. We found significant differences in OHC concentrations of the eggs among sampling locations, except for hexachlorocyclohexanes (HCHs). Mean concentrations of sum polychlorinated biphenyls (PCBs) in eggs ranged from 78 ± 26 ng/g lipid weight (lw) in Australia to 2900 ± 1300 ng/g lw in the United States. The PCB profile was dominated by CB 153 and CB 138 in all locations, except for New Zealand, where the contribution of CB 95, CB 101 and CB 149 was also high. The highest mean sum polybrominated diphenyl ether (PBDE) concentrations were found in Canada (4400 ± 830 ng/g lw), while the lowest mean PBDE concentrations were measured in Spain (3.7 ± 0.1 ng/g lw). The PBDE profile in starling eggs was dominated by BDE 47 and BDE 99 in all countries, but in Belgium, the higher brominated PBDEs had a higher contribution compared to other countries. For the organochlorine pesticides (OCPs), dichlorodiphenyltrichloroethanes (DDTs) ranged from 110 ± 16 ng/g lw in France to 17,000 ± 3400 ng/g lw in New Zealand, while HCHs and hexachlorobenzene were generally in low concentrations in all sampling locations. Chlordanes were remarkably high in eggs from the United States (2500 ± 1300 ng/g lw). The OCP profile in all countries was largely dominated by p,p′-DDE. In general, the worldwide trends we observed in starling eggs were in accordance with the literature on human and environmental OHC data, which suggests that there is potential for using starling eggs as a biomonitoring tool on a large geographical scale. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed

Openings and closings in Spanish email conversations

Despite the increasing interest scholarly research has shown in the study of computer-mediated communication, there is still a need to investigate the empirical validity of assumed homogeneity of language usage over the net and focus on the social diversity and variation that characterizes any communication. With this in mind, the present paper is an investigation into the stylistic choices that a particular group of email users made when engaged in a specific activity type. More specifically, it explores the variation in the discourse practices employed to open and close emails in conversation alongside the institutional power of participants and the interactional position of each email contributing to the conversation. To carry out this study a corpus of short email conversations in Peninsular Spanish was collected (n = 240). The analysis focused on the opening and closing sequences of the emails that made up the conversations and considered opening and closing linguistic conventions as discursive practices that members of a community may use strategically. The findings revealed that the discursive practices under scrutiny were subject not only to technological but also to social and interactional constraints and thus highlighted contextual variability. Further, the high degree of sociability in the electronic episodes studied was interpreted as reflecting a ¿people first, business second¿ communicative style

The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD+-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a β-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates β-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of β-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of β−catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in β−catenin-driven malignancies

The pathophysiology of fluid and electrolyte balance in the older adult surgical patient

Background & aims: Age-related physiological changes predispose even the healthy older adult to fluid and electrolyte abnormalities which can cause morbidity and mortality. The aim of this narrative review is to highlight key aspects of age-related pathophysiological changes that affect fluid and electrolyte balance in older adults and underpin their importance in the perioperative period. Methods: The Web of Science, MEDLINE, PubMed and Google Scholar databases were searched using key terms for relevant studies published in English on fluid balance in older adults during the 15 years preceding June 2013. Randomised controlled trials and large cohort studies were sought; other studieswere used when these were not available. The bibliographies of extracted papers were also searched for relevant articles. Results: Older adults are susceptible to dehydration and electrolyte abnormalities, with causes ranging from physical disability restricting access to fluid intake to iatrogenic causes including polypharmacy and unmonitored diuretic usage. Renal senescence, as well as physical and mental decline, increase this susceptibility. Older adults are also predisposed to water retention and related electrolyte abnormalities, exacerbated at times of physiological stress. Positive fluid balance has been shown to be an independent risk factor for morbidity and mortality in critically ill patients with acute kidney injury. Conclusions: Age-related pathophysiological changes in the handling of fluid and electrolytes make older adults undergoing surgery a high-risk group and an understanding of these changes will enable better management of fluid and electrolyte therapy in the older adult