Synthesis of chelating bidentate and tridentate cyano ligands and their complexes with Group VII metal carbonyls

Two new bidentate cyano ligands, DiCN-3 (2) and DEN-4 (3) (a,w-bis(2-cyanophenoxy)propane and -butane, respectively), have been prepared. These ligands and the ethane analogue DEN-2 (1) react with Mn(C0)5Br to afford complexes of the composition Mr~(cO)~(DicN-n)Br (n= 2, 9; n = 3, 10; n = 4, 11). Complexes 9 and 10 appear to be mononuclear and contain 13- and 14-membered chelate rings, respectively. Ligand 3 in 11 might be either chelated or bridged. IR studies of the reaction between 1-3 and Mn2(C0)6(CH&N)2(p-Br)2 show that, under identical conditions, more nitrile groups of 1 than of 2 and 3 are bound to the Mn(C0)3Br unit; this results suggests that DiCN-2 is a better chelating ligand than DiCN-3 or DiCN-4. A novel tricyano ligand, TriCN (1,3,5-tris(2-cyanophenyl)benzene (8)) has been synthesized from 2methylacetophenone. TriCN functions either as a bidentate ligand, as in M(CO)3(TriCN)Br (M = Mn, 12; M = Re, 14), or as a tridentate ligand, as in [M(CO),(TriCN)]PF6 (M = Mn, 13; M = Re, IS). Complexes 13 and 15 of TriCN are the first examples in which a tridentate cyano ligand chelates to a single metal center through its nitrogen lone pairs

HIV-infected sex workers with beneficial HLA-variants are potential hubs for selection of HIV-1 recombinants that may affect disease progression

Cytotoxic T lymphocyte (CTL) responses against the HIV Gag protein are associated with lowering viremia; however, immune control is undermined by viral escape mutations. The rapid viral mutation rate is a key factor, but recombination may also contribute. We hypothesized that CTL responses drive the outgrowth of unique intra-patient HIV-recombinants (URFs) and examined gag sequences from a Kenyan sex worker cohort. We determined whether patients with HLA variants associated with effective CTL responses (beneficial HLA variants) were more likely to carry URFs and, if so, examined whether they progressed more rapidly than patients with beneficial HLA-variants who did not carry URFs. Women with beneficial HLA-variants (12/52) were more likely to carry URFs than those without beneficial HLA variants (3/61) (p < 0.0055; odds ratio = 5.7). Beneficial HLA variants were primarily found in slow/standard progressors in the URF group, whereas they predominated in long-term non-progressors/survivors in the remaining cohort (p = 0.0377). The URFs may sometimes spread and become circulating recombinant forms (CRFs) of HIV and local CRF fragments were over-represented in the URF sequences (p < 0.0001). Collectively, our results suggest that CTL-responses associated with beneficial HLA variants likely drive the outgrowth of URFs that might reduce the positive effect of these CTL responses on disease progression

The need to promote behaviour change at the cultural level: one factor explaining the limited impact of the MEMA kwa Vijana adolescent sexual health intervention in rural Tanzania. A process evaluation

Background - Few of the many behavioral sexual health interventions in Africa have been rigorously evaluated. Where biological outcomes have been measured, improvements have rarely been found. One of the most rigorous trials was of the multi-component MEMA kwa Vijana adolescent sexual health programme, which showed improvements in knowledge and reported attitudes and behaviour, but none in biological outcomes. This paper attempts to explain these outcomes by reviewing the process evaluation findings, particularly in terms of contextual factors. Methods - A large-scale, primarily qualitative process evaluation based mainly on participant observation identified the principal contextual barriers and facilitators of behavioural change. Results - The contextual barriers involved four interrelated socio-structural factors: culture (i.e. shared practices and systems of belief), economic circumstances, social status, and gender. At an individual level they appeared to operate through the constructs of the theories underlying MEMA kwa Vijana - Social Cognitive Theory and the Theory of Reasoned Action – but the intervention was unable to substantially modify these individual-level constructs, apart from knowledge. Conclusion - The process evaluation suggests that one important reason for this failure is that the intervention did not operate sufficiently at a structural level, particularly in regard to culture. Recently most structural interventions have focused on gender or/and economics. Complementing these with a cultural approach could address the belief systems that justify and perpetuate gender and economic inequalities, as well as other barriers to behaviour change

Beyond the Hype: A Real-World Evaluation of the Impact and Cost of Machine Learning-Based Malware Detection

There is a lack of scientific testing of commercially available malware detectors, especially those that boast accurate classification of never-before-seen (i.e., zero-day) files using machine learning (ML). The result is that the efficacy and gaps among the available approaches are opaque, inhibiting end users from making informed network security decisions and researchers from targeting gaps in current detectors. In this paper, we present a scientific evaluation of four market-leading malware detection tools to assist an organization with two primary questions: (Q1) To what extent do ML-based tools accurately classify never-before-seen files without sacrificing detection ability on known files? (Q2) Is it worth purchasing a network-level malware detector to complement host-based detection? We tested each tool against 3,536 total files (2,554 or 72% malicious, 982 or 28% benign) including over 400 zero-day malware, and tested with a variety of file types and protocols for delivery. We present statistical results on detection time and accuracy, consider complementary analysis (using multiple tools together), and provide two novel applications of a recent cost-benefit evaluation procedure by Iannaconne & Bridges that incorporates all the above metrics into a single quantifiable cost. While the ML-based tools are more effective at detecting zero-day files and executables, the signature-based tool may still be an overall better option. Both network-based tools provide substantial (simulated) savings when paired with either host tool, yet both show poor detection rates on protocols other than HTTP or SMTP. Our results show that all four tools have near-perfect precision but alarmingly low recall, especially on file types other than executables and office files -- 37% of malware tested, including all polyglot files, were undetected.Comment: Includes Actionable Takeaways for SOC

Covariation in urban birds providing cultural services or disservices and people

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.1. The spatial distributions of biodiversity and people vary across landscapes, and are critical to the delivery of ecosystem services and disservices. The high densities of people, and often of birds, in urban areas lead to frequent human-avian interactions, which can be positive or negative for people’s well-being. The identities of the bird species providing these services or disservices tend to be quite different, however it is unclear how their abundance and richness covary with human population density, and hence with potential recipients of these services and disservices. 2. We surveyed bird populations in 106 tiles (500x500 m) across the 174 km2 of an extended urban area in southern England. From the literature, we identified two groups of species: those associated with positive interactions for human well-being, and those that display behaviours that are negative for human well-being. We estimated the abundance (adjusted for detection probability) and richness of each group, and modelled how they covary with human population density. 3. Aggregation of population estimates for the 35 service and nine disservice species observed revealed 593,128 (95% confidence interval: 541,817-657,046) and 225,491 (200,134-235,066) birds, respectively. Across the surveyed tiles there were 1.09 service, and 0.42 disservice birds per person. 4. There was a peaking quadratic relationship between service abundance and human population density, but a negative linear relationship between richness and human density. Conversely, there were positive linear relationships for both abundance and richness of disservice species with human density. The ratio of service to disservice birds shifted from 3.5 to 1 at intermediate human densities to 1 to 1 in more densely populated areas. 5. Synthesis and applications. Differences in the distributions of service and disservice species, and the extremely low ratios of birds to people particularly in socioeconomically deprived areas, mean that people there have few opportunities for contact with birds, and the contact that they do have is equally likely to be negative as positive for human well-being. We recommend spatial targeting of improvements in green infrastructure, combined with the targeted provisioning of food and nesting places for service species, to promote positive interactions between birds and people.We thank M. Evans and M. Gregory for their fieldwork, and J. Harris and R. Corstanje for their advice and logistical support. All authors were supported by the Fragments, Functions, Flows and Urban Ecosystem Services project, NERC grant NE/J015237/1, funded under the NERC Biodiversity and Ecosystem Service Sustainability programme. The authors declare no conflict of interest

Deweyan tools for inquiry and the epistemological context of critical pedagogy

This article develops the notion of resistance as articulated in the literature of critical pedagogy as being both culturally sponsored and cognitively manifested. To do so, the authors draw upon John Dewey\u27s conception of tools for inquiry. Dewey provides a way to conceptualize student resistance not as a form of willful disputation, but instead as a function of socialization into cultural models of thought that actively truncate inquiry. In other words, resistance can be construed as the cognitive and emotive dimensions of the ongoing failure of institutions to provide ideas that help individuals both recognize social problems and imagine possible solutions. Focusing on Dewey\u27s epistemological framework, specifically tools for inquiry, provides a way to grasp this problem. It also affords some innovative solutions; for instance, it helps conceive of possible links between the regular curriculum and the study of specific social justice issues, a relationship that is often under-examined. The aims of critical pedagogy depend upon students developing dexterity with the conceptual tools they use to make meaning of the evidence they confront; these are background skills that the regular curriculum can be made to serve even outside social justice-focused curricula. Furthermore, the article concludes that because such inquiry involves the exploration and potential revision of students\u27 world-ordering beliefs, developing flexibility in how one thinks may be better achieved within academic subjects and topics that are not so intimately connected to students\u27 current social lives, especially where students may be directly implicated

Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: Two randomised, double-blind, phase 3, non-inferiority trials

none27siBackground Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations. Tenofovir alafenamide is a novel tenofovir prodrug with a 90% reduction in plasma tenofovir concentrations. Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens. Methods In these two controlled, double-blind phase 3 studies, we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries. Patients were randomly assigned (1:1) to receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/tenofovir alafenamide) or 300 mg tenofovir disoproxil fumarate (E/C/F/tenofovir disoproxil fumarate) with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size 4) and was stratified by HIV-1 RNA, CD4 count, and region (USA or ex-USA). Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses. The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration (FDA) snapshot algorithm (pre-specified non-inferiority margin of 12%) and pre-specified renal and bone endpoints at 48 weeks. These studies are registered with ClinicalTrials.gov, numbers NCT01780506 and NCT01797445. Findings We recruited patients from Jan 22, 2013, to Nov 4, 2013 (2175 screened and 1744 randomly assigned), and gave treatment to 1733 patients (866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate). E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate, with 800 (92%) of 866 patients in the tenofovir alafenamide group and 784 (90%) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL (adjusted difference 2·0%, 95% CI -0·7 to 4·7). Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate (0·08 vs 0·12 mg/dL; p<0·0001), significantly less proteinuria (median % change -3 vs 20; p<0·0001), and a significantly smaller decrease in bone mineral density at spine (mean % change -1·30 vs -2·86; p<0·0001) and hip (-0·66 vs -2·95; p<0·0001) at 48 weeks. Interpretation Through 48 weeks, more than 90% of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success. Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide. Although these studies do not have the power to assess clinical safety events such as renal failure and fractures, our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile. Funding Gilead Sciences.openSax, Paul E; Wohl, David; Yin, Michael T.; Post, Frank; Dejesus, Edwin; Saag, Michael; Pozniak, Anton; Thompson, Melanie; Podzamczer, Daniel; Molina, Jean Michel; Oka, Shinichi; Koenig, Ellen; Trottier, Benoit; Andrade-Villanueva, Jaime; Crofoot, Gordon; Custodio, Joseph M.; Plummer, Andrew; Zhong, Lijie; Cao, Huyen; Martin, Hal; Callebaut, Christian; Cheng, Andrew K.; Fordyce, Marshall W.; Mccallister, Scott; for the GS-US-292-0104/0111 Study Team [...; Pierluigi Viale; ...]Sax, Paul E; Wohl, David; Yin, Michael T.; Post, Frank; Dejesus, Edwin; Saag, Michael; Pozniak, Anton; Thompson, Melanie; Podzamczer, Daniel; Molina, Jean Michel; Oka, Shinichi; Koenig, Ellen; Trottier, Benoit; Andrade-Villanueva, Jaime; Crofoot, Gordon; Custodio, Joseph M.; Plummer, Andrew; Zhong, Lijie; Cao, Huyen; Martin, Hal; Callebaut, Christian; Cheng, Andrew K.; Fordyce, Marshall W.; Mccallister, Scott; for the GS-US-292-0104/0111 Study Team [..; Pierluigi Viale; ..

Response of Merkel cell polyomavirus-positive Merkel cell carcinoma xenografts to a survivin inhibitor

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer associated with high mortality. Merkel cell polyomavirus (MCV), discovered in 2008, is associated with ∼80% of MCC. The MCV large tumor (LT) oncoprotein upregulates the cellular oncoprotein survivin through its conserved retinoblastoma protein-binding motif. We confirm here that YM155, a survivin suppressor, is cytotoxic to MCV-positive MCC cells in vitro at nanomolar levels. Mouse survival was significantly improved for NOD-Scid-Gamma mice treated with YM155 in a dose and duration dependent manner for 3 of 4 MCV-positive MCC xenografts. One MCV-positive MCC xenograft (MS-1) failed to significantly respond to YM155, which corresponds with in vitro dose-response activity. Combination treatment of YM155 with other chemotherapeutics resulted in additive but not synergistic cell killing of MCC cell lines in vitro. These results suggest that survivin targeting is a promising therapeutic approach for most but not all MCV-positive MCCs. © 2013 Dresang et al

Inverse Association between Methylation of Human Papillomavirus Type 16 DNA and Risk of Cervical Intraepithelial Neoplasia Grades 2 or 3

The clinical relevance of human papillomavirus type 16 (HPV16) DNA methylation has not been well documented, although its role in modulation of viral transcription is recognized.Study subjects were 211 women attending Planned Parenthood clinics in Western Washington for routine Papanicolaou screening who were HPV16 positive at the screening and/or subsequent colposcopy visit. Methylation of 11 CpG dinucleotides in the 3' end of the long control region of the HPV16 genome was examined by sequencing the cloned polymerase chain reaction products. The association between risk of CIN2/3 and degree of CpG methylation was estimated using a logistic regression model.CIN2/3 was histologically confirmed in 94 (44.5%) of 211 HPV16 positive women. The likelihood of being diagnosed as CIN2/3 increased significantly with decreasing numbers of methylated CpGs (meCpGs) in the 3' end of the long control region (P(for trend) = 0.003). After adjusting for HPV16 variants, number of HPV16-positive visits, current smoking status and lifetime number of male sex partners, the odds ratio for the association of CIN2/3 with ≥4 meCpGs was 0.31 (95% confidence interval, 0.12-0.79). The proportion of ≥4 meCpGs decreased appreciably as the severity of the cervical lesion increased (P(for trend) = 0.001). The inverse association remained similar when CIN3 was used as the clinical endpoint. Although not statistically significant, the ≥4 meCpGs-related risk reduction was more substantial among current, as compared to noncurrent, smokers.Results suggest that degree of the viral genome methylation is related to the outcome of an HPV16 cervical infection