Synchrotron X-Ray Microdiffraction Investigation of Scaling Effects on Reliability for Through-Silicon Vias for 3-D Integration

Synchrotron x-ray microdiffraction has been applied to TSV characterization in various studies for nondestructive inspection with submicron resolution due to its high beam intensity and penetration depth. In this paper, the application of this technique to TSV investigations is examined and the correlation of the plastic deformation to the microstructure and extrusion behavior along with the effect of TSV dimensional scaling is examined. It is shown that the variability of the copper microstructure and resulting TSV behavior requires a larger number of samples in order to report statistically significant observations. The role of the microstructure in creating statistical scatter is demonstrated through microdiffraction measurements of grain orientation correlated with the observed peak widening, which shows that degraded TSV reliability is largely due to the high elastic anisotropy of copper. After taking the statistical variations into account, the scaling effect was clearly observed, with larger plastic deformation in 2μm diameter TSVs than in 5μm diameter TSVs consistent with microstructure variations. This is confirmed by TSV extrusion measurements, which show that the magnitude and statistical spread of the via extrusion for the 2μm diameter TSVs is higher than that of the 5μm diameter TSVs. These results, validated by thermomechanical simulation, demonstrate first that large sample sizes are required in copper TSV investigations due to high variability, which is not improved with scaling

On the exponential transform of lemniscates

It is known that the exponential transform of a quadrature domain is a rational function for which the denominator has a certain separable form. In the present paper we show that the exponential transform of lemniscate domains in general are not rational functions, of any form. Several examples are given to illustrate the general picture. The main tool used is that of polynomial and meromorphic resultants.Comment: 19 pages, to appear in the Julius Borcea Memorial Volume, (eds. Petter Branden, Mikael Passare and Mihai Putinar), Trends in Mathematics, Birkhauser Verla

Human preferences for sexually dimorphic faces may be evolutionarily novel

This article has been made available through the Brunel Open Access Publishing Fund.A large literature proposes that preferences for exaggerated sex typicality in human faces (masculinity/femininity) reflect a long evolutionary history of sexual and social selection. This proposal implies that dimorphism was important to judgments of attractiveness and personality in ancestral environments. It is difficult to evaluate, however, because most available data come from largescale, industrialized, urban populations. Here, we report the results for 12 populations with very diverse levels of economic development. Surprisingly, preferences for exaggerated sex-specific traits are only found in the novel, highly developed environments. Similarly, perceptions that masculine males look aggressive increase strongly with development, specifically, urbanization. These data challenge the hypothesis that facial dimorphism was an important ancestral signal of heritable mate value. One possibility is that highly developed environments provide novel opportunities to discern relationships between facial traits and behavior by exposing individuals to large numbers of unfamiliar faces, revealing patterns too subtle to detect with smaller samples

Web platform vs in-person genetic counselor for return of carrier results from exome sequencing a randomized clinical trial

© 2018 American Medical Association. All rights reserved. IMPORTANCE A critical bottleneck in clinical genomics is the mismatch between large volumes of results and the availability of knowledgeable professionals to return them. OBJECTIVE To test whether a web-based platform is noninferior to a genetic counselor for educating patients about their carrier results from exome sequencing. DESIGN, SETTING, AND PARTICIPANTS A randomized noninferiority trial conducted in a longitudinal sequencing cohort at the National Institutes of Health from February 5, 2014, to December 16, 2016, was used to compare the web-based platform with a genetic counselor. Among the 571 eligible participants, 1 to 7 heterozygous variants were identified in genes that cause a phenotype that is recessively inherited. Surveys were administered after cohort enrollment, immediately following trial education, and 1 month and 6 months later to primarily healthy postreproductive participants who expressed interest in learning their carrier results. Both intention-to-treat and per-protocol analyses were applied. INTERVENTIONS A web-based platform that integrated education on carrier results with personal test results was designed to directly parallel disclosure education by a genetic counselor. The sessions took a mean (SD) time of 21 (10.6), and 27 (9.3) minutes, respectively. MAIN OUTCOMES AND MEASURES The primary outcomes and noninferiority margins (dNI) were knowledge (0 to 8, dNI = -1), test-specific distress (0 to 30, dNI = +1), and decisional conflict (15 to 75, dNI = +6). RESULTS After 462 participants (80.9%) provided consent and were randomized, all but 3 participants (n = 459) completed surveys following education and counseling; 398 (86.1%) completed 1-month surveys and 392 (84.8%) completed 6-month surveys. Participants were predominantly well-educated, non-Hispanic white, married parents; mean (SD) age was 63 (63.1) years and 246 (53.6%) were men. The web platform was noninferior to the genetic counselor on outcomes assessed at 1 and 6 months: knowledge (mean group difference, -0.18; lower limit of 97.5% CI, -0.63; dNI = -1), test-specific distress (median group difference, 0; upper limit of 97.5% CI, 0; dNI = +1), and decisional conflict about choosing to learn results (mean group difference, 1.18; upper limit of 97.5% CI, 2.66; dNI = +6). There were no significant differences between the genetic counselors and web-based platform detected between modes of education delivery in disclosure rates to spouses (151 vs 159; relative risk [RR], 1.04; 95% CI, 0.64-1.69; P > .99), children (103 vs 117; RR, 1.07; 95% CI, 0.85-1.36; P = .59), or siblings (91 vs 78; RR, 1.17; 95% CI, 0.94-1.46; P = .18). CONCLUSIONS AND RELEVANCE This trial demonstrates noninferiority of web-based return of carrier results among postreproductive, mostly healthy adults. Replication studies among younger and more diverse populations are needed to establish generalizability. Yet return of results via a web-based platform may be sufficient for subsets of test results, reserving genetic counselors for return of results with a greater health threat

Recombination rate and selection strength in HIV intra-patient evolution

The evolutionary dynamics of HIV during the chronic phase of infection is driven by the host immune response and by selective pressures exerted through drug treatment. To understand and model the evolution of HIV quantitatively, the parameters governing genetic diversification and the strength of selection need to be known. While mutation rates can be measured in single replication cycles, the relevant effective recombination rate depends on the probability of coinfection of a cell with more than one virus and can only be inferred from population data. However, most population genetic estimators for recombination rates assume absence of selection and are hence of limited applicability to HIV, since positive and purifying selection are important in HIV evolution. Here, we estimate the rate of recombination and the distribution of selection coefficients from time-resolved sequence data tracking the evolution of HIV within single patients. By examining temporal changes in the genetic composition of the population, we estimate the effective recombination to be r=1.4e-5 recombinations per site and generation. Furthermore, we provide evidence that selection coefficients of at least 15% of the observed non-synonymous polymorphisms exceed 0.8% per generation. These results provide a basis for a more detailed understanding of the evolution of HIV. A particularly interesting case is evolution in response to drug treatment, where recombination can facilitate the rapid acquisition of multiple resistance mutations. With the methods developed here, more precise and more detailed studies will be possible, as soon as data with higher time resolution and greater sample sizes is available.Comment: to appear in PLoS Computational Biolog

Differences in wild-type– and R338L-tenase complex formation are at the root of R338L-factor IX assay discrepancies

Adeno-associated virus (AAV) gene therapy has the potential to functionally cure hemophilia B by restoring factor (F)IX concentrations into the normal range. Next-generation AAV therapies express a naturally occurring gain-of-function FIX variant, FIX-Padua (R338L-FIX), that increases FIX activity (FIX:C) by approximately eightfold compared with wild-type FIX (FIX-WT). Previous studies have shown that R338L-FIX activity varies dramatically across different clinical FIX:C assays, which complicates the monitoring and management of patients. To better understand mechanisms that contribute to R338L-FIX assay discrepancies, we characterized the performance of R338L-FIX in 13 1-stage clotting assays (OSAs) and 2 chromogenic substrate assays (CSAs) in a global field study. This study produced the largest R338L-FIX assay dataset to date and confirmed that clinical FIX:C assay results vary over threefold. Both phospholipid and activating reagents play a role in OSA discrepancies. CSA generated the most divergent FIX:C results. Manipulation of FIX:C CSA kits demonstrated that specific activity gains for R338L-FIX were most profound at lower FIX:C concentrations and that these effects were enhanced during the early phases of FXa generation. Supplementing FX into CSA had the effect of dampening FIX-WT activity relative to R338L-FIX activity, suggesting that FX impairs WT tenase formation to a greater extent than R338L-FIX tenase. Our data describe the scale of R338L-FIX assay discrepancies and provide insights into the causative mechanisms that will help establish best practices for the measurement of R338LFIX activity in patients after gene therapy

Hardness characterisation of grey cast iron and its tribological performance in a contact lubricated with soybean oil

The effect of hardness of grey cast iron flat specimen on its wear and friction on the contact were characterised with the presence of vegetable oil as biolubricant. Prior to the tribological test, the as - received grey cast iron flat specimen hardness was characterised. Friction and wear tests were then conducted using a ball - on - flat reciprocating sliding contact. The one - way analysis of variance (ANOVA) was used to determine the significance of friction and wear data with a 95% significance level. The wear scars after the test were then characterised by surface roughness and wear mechanism. The microstructure and elemental analysis we re also reported. The average value of hardness was 210 HV with a large difference between minimum (185 HV) and maximum (250 HV) values. The friction and wear performance of grey cast iron specimens with soybean oil varied with its hardness. The specimens with higher hardness gave lower friction coefficient and greater wear resistance than the lower hardness specimens. The difference in coefficient of friction produced between high hardness specimens (COF = 0.122) and low hardness specimens (COF = 0.140) wa s 17%. In terms of mass loss, the low hardness 2 specimens (mass loss = 50.38 mg) and the high hardness specimens (mass loss = 12.90 mg) produced a difference of 74%. It is shown that, with soybean oil lubricant, the grey cast iron specimen can produce wide range of tribological data especially on mass loss due to its hardness distribution. The influence of soybean oil lubrication in this work is less in improving the wear resistance (about 7%), but greater for friction reduction (about 24%) compared to an un lubricated grey cast iron surface. The hardness of grey cast iron specimen is an important parameter that needs to be specifically measured and controlled on the contact due to wide hardness distribution of grey cast iron may produce variation in tribologi cal data

Evolution of cooperation driven by zealots

Recent experimental results with humans involved in social dilemma games suggest that cooperation may be a contagious phenomenon and that the selection pressure operating on evolutionary dynamics (i.e., mimicry) is relatively weak. I propose an evolutionary dynamics model that links these experimental findings and evolution of cooperation. By assuming a small fraction of (imperfect) zealous cooperators, I show that a large fraction of cooperation emerges in evolutionary dynamics of social dilemma games. Even if defection is more lucrative than cooperation for most individuals, they often mimic cooperation of fellows unless the selection pressure is very strong. Then, zealous cooperators can transform the population to be even fully cooperative under standard evolutionary dynamics.Comment: 5 figure