Universal Vectorial and Ultrasensitive Nanomechanical Force Field Sensor

Miniaturization of force probes into nanomechanical oscillators enables ultrasensitive investigations of forces on dimensions smaller than their characteristic length scale. Meanwhile it also unravels the force field vectorial character and how its topology impacts the measurement. Here we expose an ultrasensitive method to image 2D vectorial force fields by optomechanically following the bidimensional Brownian motion of a singly clamped nanowire. This novel approach relies on angular and spectral tomography of its quasi frequency-degenerated transverse mechanical polarizations: immersing the nanoresonator in a vectorial force field does not only shift its eigenfrequencies but also rotate eigenmodes orientation as a nano-compass. This universal method is employed to map a tunable electrostatic force field whose spatial gradients can even take precedence over the intrinsic nanowire properties. Enabling vectorial force fields imaging with demonstrated sensitivities of attonewton variations over the nanoprobe Brownian trajectory will have strong impact on scientific exploration at the nanoscale

A description of the origins, design and performance of the TRAITS-SGP Atlantic salmon Salmo salar L. cDNA microarray

The origins, design, fabrication and performance of an Atlantic salmon microarray are described. The microarray comprises 16 950 Atlantic salmon-derived cDNA features, printed in duplicate and mostly sourced from pre-existing expressed sequence tag (EST) collections [SALGENE and salmon genome project (SGP)] but also supplemented with cDNAs from suppression subtractive hybridization libraries and candidate genes involved in immune response, protein catabolism, lipid metabolism and the parr–smolt transformation. A preliminary analysis of a dietary lipid experiment identified a number of genes known to be involved in lipid metabolism. Significant fold change differences (as low as 1.2x) were apparent from the microarray analysis and were confirmed by quantitative real-time polymerase chain reaction analysis. The study also highlighted the potential for obtaining artefactual expression patterns as a result of cross-hybridization of similar transcripts. Examination of the robustness and sensitivity of the experimental design employed demonstrated the greater importance of biological replication over technical (dye flip) replication for identification of a limited number of key genes in the studied system. The TRAITS (TRanscriptome Analysis of Important Traits of Salmon)–salmon genome project microarray has been proven, in a number of studies, to be a powerful tool for the study of key traits of Atlantic salmon biology. It is now available for use by researchers in the wider scientific community

Protein crystals in adenovirus type 5-infected cells: requirements for intranuclear crystallogenesis, structural and functional analysis

Intranuclear crystalline inclusions have been observed in the nucleus of epithelial cells infected with Adenovirus serotype 5 (Ad5) at late steps of the virus life cycle. Using immuno-electron microscopy and confocal microscopy of cells infected with various Ad5 recombinants modified in their penton base or fiber domains, we found that these inclusions represented crystals of penton capsomers, the heteromeric capsid protein formed of penton base and fiber subunits. The occurrence of protein crystals within the nucleus of infected cells required the integrity of the fiber knob and part of the shaft domain. In the knob domain, the region overlapping residues 489–492 in the FG loop was found to be essential for crystal formation. In the shaft, a large deletion of repeats 4 to 16 had no detrimental effect on crystal inclusions, whereas deletion of repeats 8 to 21 abolished crystal formation without altering the level of fiber protein expression. This suggested a crucial role of the five penultimate repeats in the crystallisation process. Chimeric pentons made of Ad5 penton base and fiber domains from different serotypes were analyzed with respect to crystal formation. No crystal was found when fiber consisted of shaft (S) from Ad5 and knob (K) from Ad3 (heterotypic S5-K3 fiber), but occurred with homotypic S3K3 fiber. However, less regular crystals were observed with homotypic S35-K35 fiber. TB5, a monoclonal antibody directed against the Ad5 fiber knob was found by immunofluorescence microscopy to react with high efficiency with the intranuclear protein crystals in situ. Data obtained with Ad fiber mutants indicated that the absence of crystalline inclusions correlated with a lower infectivity and/or lower yields of virus progeny, suggesting that the protein crystals might be involved in virion assembly. Thus, we propose that TB5 staining of Ad-infected 293 cells can be used as a prognostic assay for the viability and productivity of fiber-modified Ad5 vectors

Identifying molecular mediators of the relationship between body mass index and endometrial cancer risk:a Mendelian randomization analysis

Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR. Methods Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10−8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR

International Coercion, Emulation and Policy Diffusion: Market-Oriented Infrastructure Reforms, 1977-1999

Why do some countries adopt market-oriented reforms such as deregulation, privatization and liberalization of competition in their infrastructure industries while others do not? Why did the pace of adoption accelerate in the 1990s? Building on neo-institutional theory in sociology, we argue that the domestic adoption of market-oriented reforms is strongly influenced by international pressures of coercion and emulation. We find robust support for these arguments with an event-history analysis of the determinants of reform in the telecommunications and electricity sectors of as many as 205 countries and territories between 1977 and 1999. Our results also suggest that the coercive effect of multilateral lending from the IMF, the World Bank or Regional Development Banks is increasing over time, a finding that is consistent with anecdotal evidence that multilateral organizations have broadened the scope of the “conditionality” terms specifying market-oriented reforms imposed on borrowing countries. We discuss the possibility that, by pressuring countries into policy reform, cross-national coercion and emulation may not produce ideal outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/40099/3/wp713.pd

Observational study of lenalidomide in patients with mantle cell lymphoma who relapsed/progressed after or were refractory/intolerant to ibrutinib (MCL-004).

BACKGROUND: The observational MCL-004 study evaluated outcomes in patients with relapsed/refractory mantle cell lymphoma who received lenalidomide-based therapy after ibrutinib failure or intolerance. METHODS: The primary endpoint was investigator-assessed overall response rate based on the 2007 International Working Group criteria. RESULTS: Of 58 enrolled patients (median age, 71 years; range, 50-89), 13 received lenalidomide monotherapy, 11 lenalidomide plus rituximab, and 34 lenalidomide plus other treatment. Most patients (88%) had received ≥ 3 prior therapies (median 4; range, 1-13). Median time from last dose of ibrutinib to the start of lenalidomide was 1.3 weeks (range, 0.1-21.7); 45% of patients had partial responses or better to prior ibrutinib. Primary reasons for ibrutinib discontinuation were lack of efficacy (88%) and ibrutinib toxicity (9%). After a median of two cycles (range, 0-11) of lenalidomide-based treatment, 17 patients responded (8 complete responses, 9 partial responses), for a 29% overall response rate (95% confidence interval, 18-43%) and a median duration of response of 20 weeks (95% confidence interval, 2.9 to not available). Overall response rate to lenalidomide-based therapy was similar for patients with relapsed/progressive disease after previous response to ibrutinib (i.e., ≥PR) versus ibrutinib-refractory (i.e., ≤SD) patients (30 versus 32%, respectively). The most common all-grade treatment-emergent adverse events after lenalidomide-containing therapy (n = 58) were fatigue (38%) and cough, dizziness, dyspnea, nausea, and peripheral edema (19% each). At data cutoff, 28 patients have died, primarily due to mantle cell lymphoma. CONCLUSION: Lenalidomide-based treatment showed clinical activity, with no unexpected toxicities, in patients with relapsed/refractory mantle cell lymphoma who previously failed ibrutinib therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02341781 . Date of registration: January 14, 2015

Drivers of patient global assessment in patients with rheumatoid arthritis who are close to remission:an analysis of 1588 patients

Objectives: ACR/EULAR Boolean remission in RA is frequently not obtained solely due to a patient global assessment (PGA) >1/10 (a condition often designated as near-remission). This study aimed to assess which domains of impact could explain an elevated PGA in near-remission patients. Methods: We performed an ancillary analysis of data from three cross-sectional studies in patients with established RA. Three disease activity states were defined: remission (tender and swollen joint counts, CRP and PGA all ⩽1), near-remission (tender and swollen joint counts, and CRP are all ≤1 but PGA >1) and non-remission. Physical and psychological domains were assessed using the RA Impact of Disease 0-10 (numeric rating scale) as explanatory factors of PGA. Univariable and multivariable linear regression analyses were performed to explain PGA. Results: A total of 1588 patients (79.1% females) were analysed. The mean disease duration was 13.0 years (s.d. 9.8) and the 28-joint DAS with four variables was 3.2 (s.d. 1.4). Near-remission [mean PGA 3.6 (s.d. 1.9)] was more frequent (19.1%) than remission (12.3%). Scores of RA Impact of Disease domains were similar in near-remission and non-remission patients. In near-remission, PGA was explained (R2adjusted = 0.55) by pain (β = 0.29), function (β = 0.23), physical well-being (β = 0.19) and fatigue (β = 0.15). Conclusion: Near-remission was more frequent than remission. These patients, despite having no signs of significant inflammation, report an impact of disease similar to the non-remission patients. PGA in near-remission seems to be driven by physical rather than psychological domains. Selecting the best therapy for these patients requires a better understanding of the meaning of PGA, both globally and in individual patients

Specific niche requirements underpin multidecadal range edge stability, but may introduce barriers for climate change adaptation

Aim: To investigate some of the environmental variables underpinning the past and present distribution of an ecosystem engineer near its poleward range edge. Location: >500 locations spanning >7,400 km around Ireland. Methods: We collated past and present distribution records on a known climate change indicator, the reef-forming worm Sabellaria alveolata (Linnaeus, 1767) in a biogeographic boundary region over 182 years (1836–2018). This included repeat sampling of 60 locations in the cooler 1950s and again in the warmer 2000s and 2010s. Using species distribution modelling, we identified some of the environmental drivers that likely underpin S. alveolata distribution towards the leading edge of its biogeographical range in Ireland. Results: Through plotting 981 records of presence and absence, we revealed a discontinuous distribution with discretely bounded sub-populations, and edges that coincide with the locations of tidal fronts. Repeat surveys of 60 locations across three time periods showed evidence of population increases, declines, local extirpation and recolonization events within the range, but no evidence of extensions beyond the previously identified distribution limits, despite decades of warming. At a regional scale, populations were relatively stable through time, but local populations in the cold Irish Sea appear highly dynamic and vulnerable to local extirpation risk. Contemporary distribution data (2013–2018) computed with modelled environmental data identified specific niche requirements which can explain the many distribution gaps, namely wave height, tidal amplitude, stratification index, then substrate type. Main conclusions: In the face of climate warming, such specific niche requirements can create environmental barriers that may prevent species from extending beyond their leading edges. These boundaries may limit a species’ capacity to redistribute in response to global environmental change

Protein expression, survival and docetaxel benefit in node-positive breast cancer treated with adjuvant chemotherapy in the FNCLCC - PACS 01 randomized trial

International audienceABSTRACT: INTRODUCTION: The PACS01 trial has demonstrated that docetaxel addition to adjuvant anthracycline-based chemotherapy improves disease-free survival (DFS) and overall survival of node-positive early breast cancer (EBC). We searched for prognostic and predictive markers for docetaxel benefit. METHODS: Tumor samples from 1.099 recruited women were analyzed for the expression of 34 selected proteins using immunohistochemistry. The prognostic and predictive values of each marker and four molecular subtypes (luminal A, luminal B, HER2-overexpressing, and triple-negative) were tested. RESULTS: Progesterone receptor-negativity (HR=0.66; 95%CI 0.47-0.92, P=0.013), and Ki67-positivity (HR=1.53; 95%CI 1.12-2.08, P=0.007) were independent adverse prognostic factors. Out of the 34 proteins, only Ki67-positivity was associated with DFS improvement with docetaxel addition (adjusted HR=0.51, 95%CI 0.33-0.79 for Ki67-positive versus HR=1.10, 95%CI 0.75-1.61 for Ki67-negative tumors, P for interaction=0.012). Molecular subtyping predicted the docetaxel benefit, but without providing additional information to Ki67 status. The luminal A subtype did not benefit from docetaxel (HR=1.16, 95%CI 0.73-1.84); the reduction in the relapse risk was 53% (HR=0.47, 95%CI 0.22-1.01), 34% (HR=0.66, 95%CI 0.37-1.19), and 12% (HR=0.88, 95%CI 0.49-1.57) in the luminal B, HER2-overexpressing, and triple-negative subtypes, respectively. CONCLUSIONS: In patients with node-positive EBC receiving adjuvant anthracycline-based chemotherapy, the most powerful predictor of docetaxel benefit is Ki67-positivity