ERC Grant Agreement Research Articles

One-Way Functions and (Im)perfect Obfuscation

A program obfuscator takes a program and outputs a “scrambled” version of it, where the goal is that the obfuscated program will not reveal much about its structure beyond what is apparent from executing it. There are several ways of formalizing this goal. Specifically, in indistinguishability obfuscation, first defined by Barak et al. (CRYPTO 2001), the requirement is that the results of obfuscating any two functionally equivalent programs (circuits) will be computationally indistinguishable. Recently, a fascinating candidate construction for indistinguishability obfuscation was proposed by Garg et al. (FOCS 2013). This has led to a flurry of discovery of intriguing constructions of primitives and protocols whose existence was not previously known (for instance, fully deniable encryption by Sahai and Waters, STOC 2014). Most of them explicitly rely on additional hardness assumptions, such as one-way functions. Our goal is to get rid of this extra assumption. We cannot argue that indistinguishability obfuscation of all polynomial-time circuits implies the existence of one-way functions, since if P = NP, then program obfuscation (under the indistinguishability notion) is possible. Instead, the ultimate goal is to argue that if P 6= NP and program obfuscation is possible, then one-way functions exist. Our main result is that if NP 6⊆ io-BPP and there is an efficient (even imperfect) indistinguishability obfuscator, then there are one-way functions. In addition, we show that the existence of an indistinguishability obfuscator implies (unconditionally) the existence of SZKarguments for NP. This, in turn, provides an alternative version of our main result, based on the assumption of hard-on-the average NP problems. To get some of our results we need obfuscators for simple programs such as 3CNF formulas. ∗This paper incorporates the manuscript of Moran and Rosen [MR13]. †Weizmann Institute of Science. Email: {ilan.komargodski,moni.naor,eylon.yogev}@weizmann.ac.il. Supported in part by a grant from the I-CORE Program of the Planning and Budgeting Committee, the Israel Science Foundation, BSF, IMOS and the Citi Foundation. Moni Naor is the incumbent of the Judith Kleeman Professorial Chair. ‡IDC Herzliya. Email: talm@idc.ac.il. Supported by ISF grant no. 1790/13 and by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 293843 §Cornell University. Email: rafael@cs.cornell.edu. Supported in part by a Alfred P. Sloan Fellowship, Microsoft New Faculty Fellowship, NSF Award CNS1217821, NSF CAREER Award CCF-0746990, NSF Award CCF-1214844, AFOSR YIP Award FA9550-10-1-0093, and DARPA and AFRL under contract FA8750-11-20211. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the Defense Advanced Research Projects Agency or the US Government. ¶IDC Herzliya. Email: alon.rosen@idc.ac.il. Supported by ISF grant no. 1255/12 and by the ERC under the EU’s Seventh Framework Programme (FP/2007-2013) ERC Grant Agreement n. 307952.

107P Ultra-sensitive monitoring mutations in cancer patients using superRCA mutation detection assays

107P Ultra-sensitive monitoring mutations in cancer patients using superRCA mutation detection assays

In vivo whole brain microvascular imaging in mice using transcranial 3D Ultrasound Localization Microscopy

SummaryBackgroundNon-invasive high-resolution imaging of the cerebral vascular anatomy and function is key for the study of intracranial aneurysms, stenosis, arteriovenous malformations, and stroke, but also neurological pathologies, such as degenerative diseases. Direct visualization of the microvascular networks in the whole brain remains however challenging in vivo.MethodsIn this work, we performed 3D ultrafast ultrasound localization microscopy (ULM) using a 2D ultrasound matrix array and mapped the whole-brain microvasculature and flow at microscopic resolution in C57Bl6 mice in vivo.FindingsWe demonstrated that the mouse brain vasculature can be imaged directly through the intact skull at a spatial resolution of 20 µm and over the whole brain depth and at high temporal resolution (750 volumes.s−1). Individual microbubbles were tracked to estimate the flow velocities that ranged from 2 mm.s−1 in arterioles and venules up to 100 mm.s−1 in large vessels. The vascular maps were registered automatically with the Allen atlas in order to extract quantitative vascular parameters such as local flow rates and velocities in regions of interest.InterpretationWe show the potential of 3D ULM to provide new insights into whole-brain vascular flow in mice models at unprecedented vascular scale for an in vivo technique. This technology is highly translational and has the potential to become a major tool for the clinical investigation of the cerebral microcirculation.FundingThis study was supported by the European Research Council under the European Union's Seventh Framework Program (FP/2007-2013) / ERC Grant Agreement n° 311025 and by the Fondation Bettencourt-Schueller under the program “Physics for Medicine”. We acknowledge the ART (Technological Research Accelerator) biomedical ultrasound program of INSERM.

THE POSSIBILITY OF AN OUTSIDE: THEORETICAL PREAMBLE

History and TheoryVolume 60, Issue 4 p. 3-19 Article THE POSSIBILITY OF AN OUTSIDE: THEORETICAL PREAMBLE ULRICH TIMME KRAGH, ULRICH TIMME KRAGH Adam Mickiewicz University in Poznań, PolandI wish to dedicate this theme issue of History and Theory to my dear friend and erudite guru Frank R. Ankersmit, a genuine intellectual. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC Grant Agreement no. 615574, “Narrative Modes of Historical Discourse in Asia” (NAMO) hosted by Adam Mickiewicz University in Poznań, Poland.Search for more papers by this author ULRICH TIMME KRAGH, ULRICH TIMME KRAGH Adam Mickiewicz University in Poznań, PolandI wish to dedicate this theme issue of History and Theory to my dear friend and erudite guru Frank R. Ankersmit, a genuine intellectual. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC Grant Agreement no. 615574, “Narrative Modes of Historical Discourse in Asia” (NAMO) hosted by Adam Mickiewicz University in Poznań, Poland.Search for more papers by this author First published: 15 December 2021 https://doi.org/10.1111/hith.12233 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume60, Issue4December 2021Pages 3-19 RelatedInformation

New Caledonian crows' planning behaviour: a reply to de Mahy et al .

New Caledonian crows' planning behaviour: a reply to de Mahy <i>et al</i> .

Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts.

STUDY QUESTIONIs cord blood DNA methylation associated with having been conceived by medically assisted reproduction?SUMMARY ANSWERThis study does not provide strong evidence of an association of conception by medically assisted reproduction with variation in infant blood cell DNA methylation.WHAT IS KNOWN ALREADYMedically assisted reproduction consists of procedures used to help infertile/subfertile couples conceive, including ART. Due to its importance in gene regulation during early development programming, DNA methylation and its perturbations associated with medically assisted reproduction could reveal new insights into the biological effects of assisted reproductive technologies and potential adverse offspring outcomes.STUDY DESIGN, SIZE, DURATIONWe investigated the association of DNA methylation and medically assisted reproduction using a case–control study design (N = 205 medically assisted reproduction cases and N = 2439 naturally conceived controls in discovery cohorts; N = 149 ART cases and N = 58 non-ART controls in replication cohort).PARTICIPANTS/MATERIALS, SETTINGS, METHODSWe assessed the association between medically assisted reproduction and DNA methylation at birth in cord blood (205 medically assisted conceptions and 2439 naturally conceived controls) at >450 000 CpG sites across the genome in two sub-samples of the UK Avon Longitudinal Study of Parents and Children (ALSPAC) and two sub-samples of the Norwegian Mother, Father and Child Cohort Study (MoBa) by meta-analysis. We explored replication of findings in the Australian Clinical review of the Health of adults conceived following Assisted Reproductive Technologies (CHART) study (N = 149 ART conceptions and N = 58 controls).MAIN RESULTS AND THE ROLE OF CHANCEThe ALSPAC and MoBa meta-analysis revealed evidence of association between conception by medically assisted reproduction and DNA methylation (false-discovery-rate-corrected P-value < 0.05) at five CpG sites which are annotated to two genes (percentage difference in methylation per CpG, cg24051276: Beta = 0.23 (95% CI 0.15,0.31); cg00012522: Beta = 0.47 (95% CI 0.31, 0.63); cg17855264: Beta = 0.31 (95% CI 0.20, 0.43); cg17132421: Beta = 0.30 (95% CI 0.18, 0.42); cg18529845: Beta = 0.41 (95% CI 0.25, 0.57)). Methylation at three of these sites has been previously linked to cancer, aging, HIV infection and neurological diseases. None of these associations replicated in the CHART cohort. There was evidence of a functional role of medically assisted reproduction-induced hypermethylation at CpG sites located within regulatory regions as shown by putative transcription factor binding and chromatin remodelling.LIMITATIONS, REASONS FOR CAUTIONSWhile insufficient power is likely, heterogeneity in types of medically assisted reproduction procedures and between populations may also contribute. Larger studies might identify replicable variation in DNA methylation at birth due to medically assisted reproduction.WIDER IMPLICATIONS OF THE FINDINGSNewborns conceived with medically assisted procedures present with divergent DNA methylation in cord blood white cells. If these associations are true and causal, they might have long-term consequences for offspring health.STUDY FUNDING/COMPETING INTERESTS(S)This study has been supported by the US National Institute of Health (R01 DK10324), the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 669545, European Union’s Horizon 2020 research and innovation programme under Grant agreement no. 733206 (LifeCycle) and the NIHR Biomedical Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Methylation data in the ALSPAC cohort were generated as part of the UK BBSRC funded (BB/I025751/1 and BB/I025263/1) Accessible Resource for Integrated Epigenomic Studies (ARIES, http://www.ariesepigenomics.org.uk). D.C., J.J., C.L.R. D.A.L and H.R.E. work in a Unit that is supported by the University of Bristol and the UK Medical Research Council (Grant nos. MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/6). B.N. is supported by an NHMRC (Australia) Investigator Grant (1173314). ALSPAC GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (Contract no. N01-ES-75558), NIH/NINDS (Grant nos. (i) UO1 NS 047537-01 and (ii) UO1 NS 047537-06A1). For this work, MoBa 1 and 2 were supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and the Norwegian Research Council/BIOBANK (Grant no. 221097). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, Project no. 262700.D.A.L. has received support from national and international government and charity funders, as well as from Roche Diagnostics and Medtronic for research unrelated to this study. The other authors declare no conflicts of interest.TRIAL REGISTRATION NUMBERN/A.

(Invited) Resonator and SERS Sensing in the Field of Drug Delivery

Introduction Our research center of excellence IDUN combines research in nanosensors/centrifugal microfluidics and microfabricated devices for oral drug delivery. This allows us to explore the synergy between sensor development and search for new pharmaceutical delivery tools and materials. Our developed nanosensors get access to unique polymers and biomolecules and are able to characterize, among others, small volumes of materials and molecules, which are today not possible to analyze by any standard technologies. We will show examples of recent findings and results within drug/polymer characterization (1) and process monitoring (2) using nanomechanical sensors. Also, new applications within therapeutic drug monitoring using Surface Enhanced Raman Scattering (SERS) will be presented as well as sensor integration with centrifugal microfluidics platforms. Resonators By monitoring the resonance frequency shift of micrometer sized strings or cantilevers coated with thin layers of polymers, it is possible to monitor phase transitions using only ng of material. We have been able to observe beta relaxation of polymers (3) and drugs (2), see figure 1. These systems also allowed us to monitor degradation of biomaterials used in the fabrication of the microcontainers (4). Also, strings are inherently sensitive to temperature changes (5). The resonant frequency detunes as a function of temperature and temperature changes down to 10-5 °C can be detected. The effect has been used to perform photothermal IR spectra on samples deposited on resonating strings and resonating filters. This has been used to for example study the amorphous and crystalline forms of indomethacin (1). As an alternative to cleanroom fabricated resonators we have used single drug and collagen particles as micro mechanical resonators, thereby eliminating the need for cleanroom processing. This method additionally makes it possible to study the behavior of single crystals, which would otherwise be extremely difficult/impossible. This method has, among others, allowed us to study new phenomena in the hydration/dehydration of drugs (6). Centrifugal microfluidics The optics and mechanics from a DVD player can be used to realize compact and sensitive sensor systems. By rotating a polymer disc with integrated microfluidic channels it is possible to manipulate liquid samples such as blood – performing crucial operations like separation, valving and mixing. We integrate sensor elements such as cantilevers, nanoparticles, resonating strings and SERS substrates with centrifugal microfluidics (7). The sensors are read out by a DVD pick-up head, which can perform transmission/absorption measurements and can detect nm deflections. Also, electrodes and spectrometers are integrated on a disc platform, facilitating electrochemical/Raman measurements. Our nanopillar SERS substrate can be used for sample filtration and separation. Here the nanopillars function similarly to a filter paper in chromatography and can be used to distinguish e.g. different components in a urine sample as well as drug residuals. A SERS chip is placed in a centrifugal microfluidics platform, whereby the sample can be initially centrifuged. Subsequently half the SERS chip is exposed to the centrifuged liquid. Hereby, liquid can travel up the chip by the so-called wicking effect, and depending on affinity of molecules to the surface, different molecules will travel different lengths. Hereby, a separation is secured and the different molecules are read-out as bands on the SERS chip. Acknowledgements This research has received funding from the ERC grant agreement n° 320535 and from the Center of Excellence ’IDUN’ granted by Danish National Research Foundation, DNRF122/the Velux Foundations.

(Invited) Resonator and SERS Sensing in the Field of Drug Delivery

Introduction Our research center of excellence IDUN combines research in nanosensors/centrifugal microfluidics and microfabricated devices for oral drug delivery. This allows us to explore the synergy between sensor development and search for new pharmaceutical delivery tools and materials. Our developed nanosensors get access to unique polymers and biomolecules and are able to characterize, among others, small volumes of materials and molecules, which are today not possible to analyze by any standard technologies. We will show examples of recent findings and results within drug/polymer characterization (1) and process monitoring (2) using nanomechanical sensors. Also, new applications within therapeutic drug monitoring using Surface Enhanced Raman Scattering will be presented as well as sensor integration with centrifugal microfluidics platforms. Resonators By monitoring the resonance frequency shift of micrometer sized strings or cantilevers coated with thin layers of polymers, it is possible to monitor phase transitions using only ng of material. We have been able to observe beta relaxation of polymers (3) and drugs (2), see figure 1. These systems also allowed us to monitor degradation of biomaterials used in the fabrication of the microcontainers (4). Also, strings are inherently sensitive to temperature changes (5). The resonant frequency detunes as a function of temperature and temperature changes down to 10-5 °C can be detected. The effect has been used to perform photothermal IR spectra on samples deposited on resonating strings and resonating filters. This has been used to for example study the amorphous and crystalline forms of indomethacin (1). Centrifugal microfluidics The optics and mechanics from a DVD player can be used to realize compact and sensitive sensor systems. By rotating a polymer disc with integrated microfluidic channels it is possible to manipulate liquid samples such as blood – performing crucial operations like separation, valving and mixing. We integrate sensor elements such as cantilevers, nanoparticles, resonating strings and surface enhanced Raman scattering (SERS) substrates with centrifugal microfluidics (6). The sensors are read out by a DVD pick-up head, which can perform transmission/absorption measurements and can detect nm deflections. Also, electrodes and spectrometers are integrated on a disc platform, facilitating electrochemical/Raman measurements. Acknowledgements This research has received funding from the ERC grant agreement n° 320535 and from the Center of Excellence ’IDUN’ granted by Danish National Research Foundation, DNRF122/the Velux Foundations.

Multi-Period Regional Survey Data from Vidarbha, Maharashtra, India

Presented here are the data collected during regional surveys of Vidarbha, India, which were collected to reconstruct the societal and cultural changes that took place in this region during the mid-first millennium CE. Following an overview of the data and their research context, we describe the methods that were used to collect, process and analyse them. This is accompanied by a critical assessment of the factors that constrained the survey and our results. The dataset is then described in detail, with a thorough account of each data group and how they are arranged, presented and archived. Finally, we discuss how these data can be reused in the continued archaeological study of this region, and comparative studies of site distributions. Funding statement: Fieldwork and research were part of the Asia Beyond Boundaries project, an ERC Synergy project funded by the European Research Council under the European Union’s 7th Framework Programme (FP7/2007-2013)/ERC grant agreement no. 609823, awarded to Dr Michael Willis.

419 Revisiting cardiac Doppler index with single heart beat 4D ultrafast echocardiography

Abstract Funding Acknowledgements European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement n° 311025 and the ANR-10-IDEX-00 Background 4D echocardiography has the strong potential to improve cardiac index quantification by providing reproducible and user independent measurements. Quantification of left ventricle volume and ejection fraction, for instance, have been shown to be more reliable using 4D echocardiography. However, Doppler index evaluation has not yet benefited from it, due to limited volume rates and single location estimation when assessing spectral Doppler. Purpose In this study, we propose to demonstrate the feasibility of performing semi-automatic evaluation of cardiac Doppler indices within a single heartbeat on three human hearts by performing 4D ultrafast echocardiography, a new technique allowing a drastic volume rate increase. Methods A 4D ultrafast echocardiography scanner prototype connected to a matrix probe was developed to image the human heart. The probe was positioned on the apical 4-chamber view of N = 3 volunteers. High volume rate (5200 volume/s) acquisitions were performed three times by two different trained cardiologists. 4D color flow and tissue Doppler imaging were computed from the each single heartbeat acquisition. Spectral Doppler were derived at each voxel of the volumes. Region of interest such as LV outflow tract, mitral inflow or basal inferoseptal locations were automatically detected. Doppler index were derived from Doppler spectra and tissue velocity curves at these locations, and were compared against indices obtained using a clinical procedure based on 2D echocardiography. Results For each acquisition and the three volunteers, major Doppler indices: E, A, E/A, S, e’, a’, e’/a’, s’, E/e’, cardiac output were successfully assessed during a single heartbeat. A high degree of similarity between the indices assessed by 4D ultrafast echocardiography and clinical 2D measurements were found.(p &amp;gt; 0.05 for each index). Conclusions 4D ultrafast echocardiography can quantify the major cardiac Doppler indices in a single heart beat acquisition. It promises to improve patient care by accelerating examination time and to improve results reproducibility by removing most of the operator dependency. It also offers a unique feature by enabling E/e’ index assessment in the same heart beat which could be of a great interest for atrial fibrillation patients. Abstract 419 Figure.

Start of Antiplatelet Therapy Increases the Prevalence of Intraplaque Hemorrhage in Patients With Advanced Carotid Artery Lesions: A Longitudinal MR Imaging Study

Introduction: Intraplaque hemorrhage (IPH) is an important feature of plaque vulnerability. Patients with a history of transient ischemic attack or stroke are treated with platelet aggregation inhibitors to prevent secondary myocardial infarction or ischemic stroke. Although antiplatelet medication is effective in reduction of clot formation, it also has adverse effects. It has therefore been hypothesized that platelet aggregation inhibitors could also initiate the onset or progression of IPH. A histopathological study on 154 carotid endarterectomy plaques found that preoperative antiplatelet therapy was associated with an increase in the prevalence of repeated IPH in symptomatic carotid plaques. This longitudinal study investigates the effect of antiplatelet agents on the prevalence of IPH. Methods: 63 symptomatic patients underwent carotid MRI at baseline and after two years of follow-up. Presence of IPH in both carotid arteries was scored. Medication prescription before and after the index event and after follow-up was collected.The presence of IPH was determined using MP-RAGE images and analysed blinded for the clinical data using dedicated vessel wall analysis software (VesselMass). IPH was considered present when a hyperintense signal, compared to the sternocleidomastoid muscle, was visible in the bulk of the plaque. Results: A significant higher prevalence of any IPH was found two years after the index event (42.9% vs. 55.6%; p = 0.008) (Figure 1) Patients already using antiplatelet agents before the index event (n=19) did not show significantly more IPH (52.6% vs. 63.2%, p = 0.50) at follow-up. Patients who did not use platelet aggregation inhibitors before the index event (n=44) and were prescribed medication after the event, showed a significantly higher prevalence of IPH (38.6% vs. 52.3%, p=0.031) at follow-up (Figure 2) Conclusion: Patients who started antiplatelet therapy after the index event show a significant increase in bilateral IPH two years after inclusion, while no significant changes in IPH status were found in the patients that already use antiplatelet therapy before the index event. Future studies are warranted to investigate causal relationships. Disclosure: JE Wildberger reports institutional grants from AGFA, Bard, Bayer, GE, Optimed, Philips, Siemens outside the submitted work; and speakers Bureau: Bayer, Siemens outside the submitted work. This research was performed within the framework of the Center for Translational Molecular Medicine (www.ctmm.nl), project PARISk (grant 01C-202), and supported by the Dutch Heart Foundation. This project has received funding from the European Union Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 722609. ME Kooi and JE Wildberger are supported by Stichting de Weijerhorst. ME Kooi is supported by an Aspasia Grant 2018/SGw/00460457 from NWO. J Hendrikse has received funding from the European Research Council under the European Union's Horizon 2020 Programme (H2020) / ERC grant agreement n°637024. FHBM Schreuder is supported by the Dutch Heart Foundation (2012T077).

From laboratory to field: yield stability and shade avoidance genes are massively differentially expressed in the field.

To unravel molecular mechanisms with the ultimate goal to achieve improved stress resilience or increased yield, plants are often studied under highly controlled conditions in which stresses are applied and in which growth‐ or architecture‐related traits are meticulously recorded. Over the past decades, this has led to a boost in our understanding of key molecular players and in strategies to improve yield stability. However, many single‐gene traits fail to translate into applications (Nuccio et al., 2018).

Gestural Cosuppositions within the Transparency Theory

Gestural Cosuppositions within the Transparency Theory

Correction to: The Art Experience

In the published article the following information should have been included: Acknowledgment TSP was financially supported by Durham University’s Addison Wheeler bequest and by the European Research Council, under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement no. 609819 (Somics project).

Dynamics of fitness distributions in the presence of a phenotypic optimum: an integro-differential approach**This work has been carried out in the framework of Archimède Labex of Aix-Marseille University. The project leading to this publication has received funding from Excellence Initiative of Aix-Marseille University—A*MIDEX, a French ‘Investissements d’Avenir’ programme, from the European Research Council under the European Union’s Seventh Framework Programme

We propose an integro-differential description of the dynamics of the fitness distribution in an asexual population under mutation and selection, in the presence of a phenotype optimum. Due to the presence of this optimum, the distribution of mutation effects on fitness depends on the parent’s fitness, leading to a non-standard equation with ‘context-dependent’ mutation kernels.Under general assumptions on the mutation kernels, which encompass the standard n − dimensional Gaussian Fisher’s geometrical model (FGM), we prove that the equation admits a unique time-global solution. Furthermore, we derive a nonlocal nonlinear transport equation satisfied by the cumulant generating function of the fitness distribution. As this equation is the same as the equation derived by Martin and Roques (2016) while studying stochastic Wright–Fisher-type models, this shows that the solution of the main integro-differential equation can be interpreted as the expected distribution of fitness corresponding to this type of microscopic models, in a deterministic limit. Additionally, we give simple sufficient conditions for the existence/non-existence of a concentration phenomenon at the optimal fitness value, i.e. of a Dirac mass at the optimum in the stationary fitness distribution. We show how it determines a phase transition, as mutation rates increase, in the value of the equilibrium mean fitness at mutation-selection balance. In the particular case of the FGM, consistently with previous studies based on other formalisms (Waxman and Peck, 1998, 2006), the condition for the existence of the concentration phenomenon simply requires that the dimension n of the phenotype space be larger than or equal to 3 and the mutation rate U be smaller than some explicit threshold.The accuracy of these deterministic approximations are further checked by stochastic individual-based simulations.

Vascular Calcification-Induced Cognitive Impairment in Pseudoxanthoma Elasticum

Background: With no approved effective therapies for cognitive impairment, the need for new targetable phenotypes is high. We hypothesize that medial arterial calcification of the intracranial arteries, which is a modifiable process, results in increased arterial pulsatility, brain damage, and cognitive decline. Pseudoxanthoma elasticum (PXE) is a monogenetic disorder which results in non-atherosclerotic medial arterial calcification and was therefore used to investigate the effect of medial calcification of the carotid siphon on arterial pulsatility, brain volumes, small vessel disease and cognition. Methods: Magnetic resonance imaging and neurocognitive testing in 50 PXE patients and 42 age-matched controls were performed to compare arterial pulsatility, brain volumes, small vessel disease burden and cognition. Also, in the PXE patients we tested the association of carotid siphon calcification, measured by computed tomography, with arterial pulsatility and its association with brain volumes, small vessel disease and cognition. Results: PXE patients had a significantly higher pulsatility index (1.05(0.94-1.20) vs. 0.94(0.82-1.04), p=0.01), lower grey matter volumes (598±53 vs. 632±53ml, p=0.004), more white matter lesions (WML) (2.6(0.5-7.6) vs. 1.1(0.5-2.4)ml, p=0.04) and more lacunar infarctions (total 64 vs. 8, p=0.04) than controls. Patients scored lower on concentration and processing speed, but higher on memory. Carotid siphon calcification was associated with higher pulsatility indexes (β:0.09, 95%CI: 0.01;0.18), more WMLs (β:5.7, 95%CI: 0.9;10.5) and infarctions (RR:2.8, 95%CI: 1.1;7.0). Higher pulsatility was associated with lower grey matter volumes (β:-54.1, 95%CI: -107.8;-0.5), more WMLs (β:15.5, 95%CI: 7.7;23.3) and lower concentration and processing speed (β:-0.9, 95%CI: -1.8;-0.1). Conclusions: In PXE patients, medial calcification of the carotid siphon, was associated with higher pulsatility index which might contribute to grey matter damage, small vessel disease and cognitive impairment, particularly involving concentration and processing speed. Since arterial calcification is a modifiable process, we identified a potential novel target for the treatment of cognitive impairment. Funding: Dr. Zwanenburg is supported by the European Reasearch Council under the European Union’s Seventh Framework Programme (FP7/2007-2013), grant agreement no. 337333. The research of Prof. Dr. Hendrikse has received funding from the European Research Council under the European Union's Horizon 2020 Programme (H2020)/ERC grant agreement n° 637024 (HEARTOFSTROKE) and H2020 grant agreement No 666881, SVDs@target. Declaration of Interest: J. Bartstra has nothing to disclose Dr. Spiering has nothing to disclose Dr. Kranenburg has nothing to disclose Dr. Geurts has nothing to disclose Dr. den Harder has nothing to disclose Dr. Witkamp has nothing to disclose Dr. Wolterink has nothing to disclose Dr. Zwanenburg reports grants from European research council, from null, during the conduct of the study. Dr. van Valen has nothing to disclose Dr. Koek has nothing to disclose Prof. dr. Mali has nothing to disclose Prof. dr. de Jong has nothing to disclose Prof. Dr. Hendrikse reports grants from European research council, from null, during the conduct of the study. Ethical Approval: The study was approved by the institutional review board of the UMCU (number 16-622/M-X) and written informed consent was obtained from all participants.

A new MEIOB mutation is a recurrent cause for azoospermia and testicular meiotic arrest.

Are there genetic variants that can be used for the clinical evaluation of azoospermic men? A novel homozygous frame-shift mutation in the MEIOB gene was identified in three azoospermic patients from two different families. Up to 1% of all men have complete absence of sperm in the semen, a condition known as azoospermia. There are very few tools for determining the etiology of azoospermia and the likelihood of sperm cells in the testis. The MEIOB gene codes for a single-strand DNA binding protein required for DNA double-strand breaks repair during meiosis. MEIOB appears to be exclusively expressed in human and mouse testis, and MeioB knockout mice are azoospermic due to meiotic arrest. Two brothers with non-obstructive azoospermia (NOA) underwent whole-exome sequencing followed by comprehensive bioinformatics analyses. Candidate variations were further screened in infertile and fertile men, as well as in public and local reference databases. This study included 159 infertile and 77 fertile men. The exomes of two Arab men were completely sequenced. In addition, 213 other men of the same Arab ethnicity (136 infertile and 77 fertile men) underwent restriction fragment length polymorphism (RFLP) screening, as did 21 NOA men, of other ethnicities, with testicular impairment of spermatocyte arrest. All of the infertile men underwent Y-chromosome microdeletion and CFTR gene mutation assessments. Comprehensive bioinformatics analyses were designed to uncover candidate mutations associated with azoospermia. A novel homozygous frame-shift mutation in the MEIOB gene was identified in two brothers of Arab ethnicity. This frame-shift is predicted to result in a truncated MEIOB protein, which lacks the conserved C-terminal DNA binding domain. RFLP screening of the mutation in 157 infertile men, including 112 NOA patients of Arab ethnicity, identified an additional unrelated NOA patient with the same homozygous mutation and a similar testicular impairment. This mutation was not found in available public databases (n > 160 000), nor in the 77 proven fertile men, nor in our database of local Israeli population variations derived from exome and genome sequencing data (n = 500). We have thus far screened for only two specific MEIOB probable pathogenic mutations in a relatively small local cohort. Therefore, the relative incidence of MEIOB mutations in azoospermia should be further assessed in larger and diverse cohorts in order to determine the efficiency of MEIOB sequence screening for clinical evaluations. The relatively high incidence of likely NOA-causing mutations in MEIOB that was found in our cohort supports the idea that a complete screening of this gene might be beneficial for clinical evaluation of NOA patients. This research was supported in part by a grant to EA from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC grant agreement (616088). There are no competing interests. N/A.

Erratum

Population and Development ReviewVolume 44, Issue 4 p. 869-869 ERRATUMFree Access Erratum First published: 19 December 2018 https://doi.org/10.1111/padr.12224AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat This article corrects: The Global Evolution of Travel Visa Regimes. Volume 44, Issue 3, 589–622, article first published online 23 August 2018 In the article by Mathias Czaika, Hein de Haas, and María Villares-Varela, the acknowledgment was missed. The correct acknowledgment should read as follows: Acknowledgment The compilation of the DEMIG VISA database and other research leading to these results is part of the Determinants of Migration (DEMIG) project and has received funding from the European Research Council under the European Community's Seventh Framework Programme (FP7/2007–2013) / ERC Grant Agreement 240940. Additional funding for data compilation has been received from the Oxford Martin School. Part of the analysis and writing has benefited from additional funding received from ERC for the Migration as Development (MADE) project under the European Community's Horizon 2020 Programme (H2020/2015–2020) / ERC Grant Agreement 648496. We apologize for this error. Reference Czaika, Mathias, Hein de Haas, and María Villares-Varela. 2018. The Global Evolution of Travel Visa Regimes. Population and Development Review 44: 589– 622. https://doi.org/10.1111/padr.12166. Wiley Online LibraryPubMedWeb of Science®Google Scholar Volume44, Issue4December 2018Pages 869-869 ReferencesRelatedInformation

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