KNAW Research Articles

Combined GIP receptor and GLP1 receptor agonism attenuates NAFLD in male APOE∗3-Leiden.CETP mice.

Combined glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism is superior to single GLP1R agonism with respect to glycemic control and weight loss in obese patients with or without type 2 diabetes. As insulin resistance and obesity are strong risk factors for nonalcoholic fatty liver disease (NAFLD), in the current study we investigated the effects of combined GIPR/GLP1R agonism on NAFLD development. Male APOE∗3-Leiden.CETP mice, a humanized model for diabetic dyslipidemia and NAFLD when fed a high-fat high-cholesterol diet, received subcutaneous injections with either vehicle, a GIPR agonist, a GLP1R agonist, or both agonists combined every other day. GIPR and GLP1R agonism reduced body weight and additively lowered fasting plasma levels of glucose, triglycerides and total cholesterol. Strikingly, we report an additive reduction in hepatic steatosis as evidenced by lower hepatic lipid content and NAFLD scores. Underlying the lipid-lowering effects were a reduced food intake and intestinal lipid absorption and an increased uptake of glucose and triglyceride-derived fatty acids by energy-combusting brown adipose tissue. Combined GIPR/GLP1R agonism also attenuated hepatic inflammation as evidenced by a decreased number of monocyte-derived Kupffer cells and a reduced expression of inflammatory markers. Together, the reduced hepatic steatosis and inflammation coincided with lowered markers of liver injury. We interpretate that GIPR and GLP1R agonism additively attenuate hepatic steatosis, lower hepatic inflammation, ameliorate liver injury, together preventing NAFLD development in humanized APOE∗3-Leiden.CETP mice. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to attenuate NAFLD progression in humans. This work was supported by a grant from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences [CVON-GENIUS-II] to P.C.N.R., a Lilly Research Award Program [LRAP] Award to P.C.N.R. and S.K., a Dutch Heart Foundation [2017T016] grant to S.K., and an NWO-VENI grant [09150161910073] to M.R.B.; J.F.D.B. is supported by the Nutrition and Health initiative of the University of Groningen; Z.Y. is supported by a full-time PhD scholarship from the China Scholarship Council (201806850094 to Z.Y.).

Flecainide is associated with a reduction in arrhythmic events in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the ZonMW Priority Medicines for Rare Diseases and Orphan Drugs (grant 113304045 to Dr Van der Werf) and the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development and the Royal Netherlands Academy of Sciences (PREDICT2 to Dr. Wilde). Background In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), β-blocker may be insufficiently protective. A randomized clinical trial showed that flecainide reduces ventricular arrhythmias (VAs) in CPVT and small retrospective cohort studies suggest that this translates into a reduction of arrhythmic events. Objective To evaluate the efficacy of flecainide when added to β-blockers for the prevention of arrhythmic events (AE) in a large cohort of patients with CPVT using paired analysis. Methods From two international registries, this multicentre retrospective cohort study included patients with a clinical and/or genetic diagnosis of CPVT using flecainide as an adjunct to β-blockers. The study period, which comprised a pre- and on-flecianide period, was defined as the period in which background therapy, i.e. β-blocker type (β1-selective or nonselective), left cardiac sympathetic denervation (LCSD), and implantable cardioverter-defibrillator (ICD) treatment status, remained unchanged within individual patients. The primary endpoint was AEs, defined as SCD, sudden cardiac arrest (SCA), appropriate ICD shock, and arrhythmic syncope. The effect of flecainide on AE rates was assessed using a generalized linear mixed model assuming Poisson distribution and random effects for patients. Results Two-hundred forty-seven patients (median age at start of flecainide 18 years [IQR 14-29], 123 [50%] female, median flecainide dose 2.2 mg/kg/day [IQR 1.7-3.1]) were included. At baseline, 70 (28%) patients had an ICD and 21 (9%) had a LCSD performed. Nonselective β-blockers were used by 133 (54%) patients. During a median pre-flecainide follow-up of 2.1 years (IQR 0.4-7.2), 41 patients experienced 58 AEs. During a median on-flecainide follow-up of 2.9 years (IQR 1.0-6.0), 23 patients experienced 38 AEs. There was a significant reduction in AEs after initiation of flecainide (OR 0.55 [0.38-0.83]; p=0.007). Among patients who were symptomatic before diagnosis or before the initiation of flecainide (n=167), flecainide was associated with a significant reduction in AEs (OR 0.49 [0.31-0.77]; p=0.002). Among patients with ≥1 AE on β-blocker therapy (n=41), adding flecainide was associated with a significant reduction in AEs (OR 0.25 [0.14-0.45]; p<0.001). Conclusion Flecainide was associated with a reduction in AEs when added to β-blockers in patients with CPVT in the overall cohort, symptomatic patients, and particularly in patients with breakthrough AEs on β-blocker therapy.

En/En. Tegen ideologische begrenzing van academische vrijheid

In 2021 the Royal Netherlands Academy of Sciences (Koninklijke Nederlandse Academie van Wetenschappen, KNAW) published the report “Academic Freedom in the Netherlands”. That report explicitly creates room for ideological limitations on academic freedom. I argue that this is at odds with the critical nature of science. Ideological limitations at the academy can foster a culture of (self)censorship. Not just among individual researchers, but also at a more systemic level. The core of my argument is that ideology and science can coexist (and/and), but that ideological limitation ought not to exist (and/or).

Computational modeling identifies the cellular electromechanical effects of disrupted intracellular calcium handling in arrhythmogenic cardiomyopathy patients

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NWO - ZonMw (VIDI grant 016.176.340 to JL) Dutch Heart Foundation (ERA-CVD JTC2018 grant 2018T094; Dr. Dekker Program grant 2015T082 to JL) The Netherlands Cardio Vascular Research Initiative (CVON): the Dutch Heart Foundation, Dutch Federation of University Medical Center, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences (CVON-eDETECT 2015-12 and CVON-PREDICT2 2018-30 to TvV). Background Patients with arrhythmogenic cardiomyopathy (ACM), an inherited progressive cardiac disease, mostly remain asymptomatic until the occurrence of life-threatening arrhythmias. Previous research identified disturbed calcium handling as a potential disease-initiating mechanism [1], but how this translates to arrhythmogenesis and cardiac mechanical dysfunction remains unknown. Purpose To characterize disturbed molecular regulators of intracellular calcium (Ca2+) handling in patients with ACM and predict their effects on action potential (AP), calcium transient (CaT) and tension development in both left and right ventricles (LV, RV) using a computer model of cellular electromechanics. Methods We performed gene expression (qPCR) and protein level (Western blot) analysis using LV and RV tissue samples obtained from 5 ACM patients who underwent heart transplant and 5 controls with no history of cardiac disease. Changes in protein levels were implemented in our recent human electromechanical cardiomyocyte computer model [2]. CaT, AP and tension traces were simulated and compared to control. Clinical data (age, sex, genetics, ECG, echocardiography) were related to the simulation outcome. Results Measured protein levels varied significantly between the 5 patients and between individual LV and RV samples. Exemplary results for one ACM patient are shown in the figure below. In the LV, AP duration was shorter than control (221ms vs. 255ms), CaT peak was increased (0.52µM vs. 0.39µM) but CaT amplitude was reduced due to increased diastolic Ca2+ (0.26µM vs. 0.060µM). Relaxation was also impaired, as shown by a longer CaT and tension duration (965ms vs. 640ms), and an increased diastolic tension (10mN vs. 4.8mN). In the RV, AP duration was shortened, and CaT and tension peak were lower than in the LV (0.37µM and 13.6mN). Diastolic levels were elevated compared to control, and CaT and tension development were prolonged. This can be related to the measured Ca2+ changes: in the LV, a lower activity of the sodium-calcium exchanger (NCX) (22% of control) and SERCA pump (52%) combined with an increased ryanodine receptor (RyR) activity (96%) may impair the extrusion of Ca2+, leading to accumulation of Ca2+ and increased diastolic Ca2+ levels. In the RV, milder changes in NCX (48% of control) and RyR (11%) may explain the larger Ca2+ extrusion, leading to lower CaT peak and diastolic levels. The patient showed a normal LV size, a severely dilated RV, as well as a poor LV fractional shortening suggesting increased ventricular stiffness, in line with the potential impaired relaxation shown by the simulations. Conclusion By integrating protein level data from ACM patients into a computational model of cellular electromechanics, we quantified the electromechanical effects of patient-specific Ca2+ handling changes. Future whole-heart extensions of this work have the potential to identify and understand proarrhythmic mechanisms in ACM patients.

Editorial introductions

Editorial introductions

Should germline genome editing be allowed? The effect of treatment characteristics on public acceptability.

To what extent do characteristics of germline genome editing (GGE) determine whether the general public supports permitting the clinical use of GGE? The risk that GGE would cause congenital abnormalities had the largest effect on support for allowing GGE, followed by effectiveness of GGE, while costs, the type of application (disease or enhancement) and the effect on child well-being had moderate effects. Scientific progress on GGE has increased the urgency of resolving whether and when clinical application of GGE may be ethically acceptable. Various expert bodies have suggested that the treatment characteristics will be key in determining whether GGE is acceptable. For example, GGE with substantial risks (e.g. 15% chance of a major congenital abnormality) may be acceptable to prevent a severe disease but not to enhance non-medical characteristics or traits of an otherwise healthy embryo (e.g. eye colour or perhaps in the future more complex traits, such as intelligence). While experts have called for public engagement, it is unclear whether and how much the public acceptability of GGE is affected by the treatment characteristics proposed by experts. The vignette-based survey was disseminated in 2018 among 1857 members of the Dutch general public. An online research panel was used to recruit a sample representing the adult Dutch general public. A literature review identified the key treatment characteristics of GGE: the effect on the well-being of the future child, use for disease or enhancement, risks for the future child, effectiveness (here defined as the chance of a live birth, assuming that if the GGE was not successful, the embryo would not be transferred), cost and availability of alternative treatments/procedures to prevent the genetic disease or provide enhancement (i.e. preimplantation genetic testing (PGT)), respectively. For each treatment characteristic, 2-3 levels were defined to realistically represent GGE and its current alternatives, donor gametes and ICSI with PGT. Twelve vignettes were created by fractional factorial design. A multinominal logit model assessed how much each treatment characteristic affected participants' choices. The 1136 respondents (response rate 61%) were representative of the Dutch adult population in several demographics. Respondents were between 18 and 89 years of age. When no alternative treatment/procedure is available, the risk that GGE would cause (other) congenital abnormalities had the largest effect on whether the Dutch public supported allowing GGE (coefficient = -3.07), followed by effectiveness (coefficient = 2.03). Costs (covered by national insurance, coefficient = -1.14), the type of application (disease or enhancement; coefficient = -1.07), and the effect on child well-being (coefficient = 0.97) had similar effects on whether GGE should be allowed. If an alternative treatment/procedure (e.g. PGT) was available, participants were not categorically opposed to GGE, however, they were strongly opposed to using GGE for enhancement (coefficient = -3.37). The general acceptability of GGE was higher than participants' willingness to personally use it (P < 0.001). When participants considered whether they would personally use GGE, the type of application (disease or enhancement) was more important, whereas effectiveness and costs (covered by national insurance) were less important than when they considered whether GGE should be allowed. Participants who were male, younger and had lower incomes were more likely to allow GGE when no alternative treatment/procedure is available. Some (e.g. ethnic, religious) minorities were not well represented. To limit complexity, not all characteristics of GGE could be included (e.g. out-of-pocket costs), therefore, the views gathered from the vignettes reflect only the choices presented to the respondents. The non-included characteristics could be connected to and alter the importance of the studied characteristics. This would affect how closely the reported coefficients reflect 'real-life' importance. This study is the first to quantify the substantial impact of GGE's effectiveness, costs (covered by national insurance), and effect on child well-being on whether the public considered GGE acceptable. In general, the participants were strikingly risk-averse, in that they weighed the risks of GGE more heavily than its benefits. Furthermore, although only a single study in one country, the results suggests that-if sufficiently safe and effective-the public may approve of using GGE (presumably combined with PGT) instead of solely PGT to prevent passing on a disease. The reported public views can serve as input for future consideration of the ethics and governance of GGE. Young Academy of the Royal Dutch Academy of Sciences (UPS/RB/745), Alliance Grant of the Amsterdam Reproduction and Development Research Institute (2017-170116) and National Institutes of Health Intramural Research Programme. No competing interests. N/A.

European first responder systems and differences in return of spontaneous circulation and survival after out-of-hospital cardiac arrest: A study of registry cohorts.

BackgroundIn Europe, survival-rates after out-of-hospital cardiac arrest (OHCA) vary widely between regions. Whether a system dispatching First Responders (FRs; main FR-types: firefighters, police officers, citizen-responders) is present or not may be associated with survival-rates. This study aimed to assess the association between having a dispatched FR-system and rates of return of spontaneous circulation (ROSC) and survival across Europe.MethodsResults of an inventory of dispatched FR-systems for OHCA in Europe were combined with aggregate ROSC and survival data from the EuReCa-TWO study and additionally collected data. Regression analysis (weighted on number of patients included per region) was performed to study the association between having a dispatched FR-system and ROSC and survival-rates to hospital discharge in the total population and in patients with shockable initial rhythm, witnessed OHCA and bystander cardiopulmonary resuscitation (CPR; Utstein comparator group). For regions without a dispatched FR-system, the theoretical survival-rate if a dispatched FR-system would have existed was estimated.FindingsWe included 27 European regions. There were 15,859 OHCAs in the total group and 2,326 OHCAs in the Utstein comparator group. Aggregate ROSC and survival-rates were significantly higher in regions with an FR-system compared to regions without (ROSC: 36% [95%CI 35%-37%] vs. 24% [95%CI 23%–25%]; P<0.001; survival in total population [N=15.859]: 13% [95%CI 12%–15%] vs. 5% [95%CI 4%–6%]; P<0.001; survival in Utstein comparator group [N=2326]: 33% [95%CI 30%–36%] vs. 18% [95%CI 16%–20%]; P<0.001), and in regions with more than one FR-type compared to regions with only one FR-type. All main FR-types were associated with higher survival-rates (all P<0.050).InterpretationEuropean regions with dispatched FRs showed higher ROSC and survival-rates than regions without.FundingThis project/work has received funding from the European Union's Horizon 2020 research and innovation programme under acronym ESCAPE-NET, registered under grant agreement No 733381 (IO, HLT and MTB) and the European Union's COST programme under acronym PARQ, registered under grant agreement No CA19137 (IO, DC, HLT, MTB). HLT and MTB were supported by a grant from the Netherlands CardioVascular Research Initiative, Dutch Heart Foundation, Dutch Federation of University Medical Centres, Netherlands Organization for Health Research and Development, Royal Netherlands Academy of Sciences - CVON2017-15 RESCUED (HLT), and CVON2018-30 Predict2 (HLT and MTB).

Editorial introductions

Editorial introductions

Evidence for the decays of and * * Supported in part by National Key Basic Research Program of China (2015CB856700); National Natural Science Foundation of China (NSFC)(11235011, 11275266, 11335008, 11425524, 11625523, 11635010); the Chinese Academy of Sciences (CAS) Large-Scale Scientific Facility Program; the CAS Center for Excellence in Particle Physics (CCEPP); Joint Large-Scale Scientific Facility Funds of the NSFC and

We study the hadronic decays of to the final states and , using an annihilation data sample of 567 pb-1 taken at a center-of-mass energy of 4.6 GeV with the BESIII detector at the BEPCII collider. We find evidence for the decays and with statistical significance of and , respectively. Normalizing to the reference decays and , we obtain the ratios of the branching fractions and to be and , respectively. The upper limits at the 90% confidence level are set to be and . Using BESIII measurements of the branching fractions of the reference decays, we determine % (<0.68%) and % (<1.9%). Here, the first uncertainties are statistical and the second systematic. The obtained branching fraction of is consistent with the previous measurement, and the branching fraction of is measured for the first time.

Editorial introductions

Editorial introductions

Editorial introduction

One year ago, in July 2017, 173 statisticians from all around the world gathered in Groningen, (The Netherlands) for a whole week to celebrate the 32nd International Workshop on Statistical Modelling (IWSM) 2017. The scientific program of IWSM 2017 comprised a one-day short course on Statistical Models for Social Network Dynamics, five invited keynote talks, 57 contributed talks, and 51 poster contributions. As usual for the IWSM workshop series, nearly all topical fields of Statistical Modelling were covered, and the peer-reviewed contributions were of high scientific quality. Fortunately, Marijtje van Duijn from the editorial board of Statistica Neerlandica had a great idea and suggested to launch a Statistica Neerlandica special issue on Statistical Modelling, featuring selected IWSM 2017 contributions. In my role as chair of the IWSM, I liked this idea to bundle some of the most interesting contributions in a special issue, and fortunately, the whole editorial board of Statistica Neerlandica supported Marijtje's idea as well. During last year's IWSM workshop, we selected the most appropriate contributions and invited the presenters to submit scientific papers on their works. To ensure the highest scientific quality, all submitted papers underwent a strict peer review process, and only the finally accepted papers have been published in this special issue. This is the special issue that so many statistical modellers have been waiting for: It consists of 11 articles with an average length of exactly 20 pages (standard deviation: 6.47), and I am convinced that the papers are representative of typical IWSM contributions. Moreover, I hope that the reader will enjoy reading the 11 articles as much as I enjoyed editing them. I thank the Statistical Modelling Society (Amsterdam) for giving me the opportunity to host the IWSM in Groningen in 2017. My thanks also go to the editorial board of Statistica Neerlandica for supporting the idea to launch a special issue on Statistical Modelling and for making me the responsible guest editor of this special issue. I also would like to thank all the members of the scientific committee and the local organizing committee for the support before and at the IWSM 2017. Special thanks go to the sponsors of IWSM 2017, especially to the “Koninklijke Nederlandse Akademie van Wetenschappen” (KNAW), the “Netherlands Organisation for Scientific Research” (NWO), the Dutch “Stochastics - Theoretical and Applied Research” (STAR) cluster, R studio, the province and city of Groningen, C. R. Rao Stichting, and the Toyota Motor Corporation. Finally yet importantly, I would like to thank all the authors who contributed to this special issue. On a personal note, I would like to add that I am very happy that the contributing authors, the editorial board of Statistica Neerlandica, and the editors of Wiley worked so hard and efficiently, so that I can keep my promise, namely that the special issue will have been published in July 2018. This paper is in pleasant anticipation of the IWSM 2018, which will shortly take place in Bristol, England (15–20 July 2018).

Measurement of the integrated Luminosities of cross-section scan data samples around the (3770) mass region**Supported by National Key Basic Research Program of China (2015CB856700), National Natural Science Foundation of China (NSFC) (11235011, 11335008, 11425524, 11625523, 11635010), the Chinese Academy of Sciences (CAS) Large-Scale Scientific Facility Program, the CAS Center for Excellence in Particle Physics (CCEPP), Joint Large-Scale Scientific Facility Funds

To investigate the nature of the (3770) resonance and to measure the cross section for , a cross-section scan data sample, distributed among 41 center-of-mass energy points from 3.73 to 3.89 GeV, was taken with the BESIII detector operated at the BEPCII collider in the year 2010. By analyzing the large angle Bhabha scattering events, we measure the integrated luminosity of the data sample at each center-of-mass energy point. The total integrated luminosity of the data sample is , where the first uncertainty is statistical and the second systematic.

Editorial introductions

Editorial introductions

Determination of the number of ψ(3686) events at BESIII**Supported by the Ministry of Science and Technology of China (2009CB825200), National Natural Science Foundation of China (NSFC) (11235011, 11322544, 11335008, 11425524, 11475207), the Chinese Academy of Sciences (CAS) Large-Scale Scientific Facility Program, the Collaborative Innovation Center for Particles and Interactions (CICPI), Joint Large-Scale Scientific Facility Funds of the NSFC and CAS

The numbers of ψ(3686) events accumulated by the BESIII detector for the data taken during 2009 and 2012 are determined to be and , respectively, by counting inclusive hadronic events, where the uncertainties are systematic and the statistical uncertainties are negligible. The number of events for the sample taken in 2009 is consistent with that of the previous measurement. The total number of ψ(3686) events for the two data taking periods is .

Measurement of integrated luminosity and center-of-mass energy of data taken by BESIII at **Supported in part by National Key Basic Research Program of China (2015CB856700), National Natural Science Foundation of China (NSFC) (11235011, 11322544, 11335008, 11425524, 11635010, 11675184, 11735014), the Chinese Academy of Sciences (CAS) Large-Scale Scientific Facility Program; the CAS Center for Excellence in Particle Physics (CCEPP); the Collaborative

To study the nature of the state Y (2175), a dedicated data set of e+e− collision data was collected at the center-of-mass energy of 2.125 GeV with the BESIII detector at the BEPCII collider. By analyzing large-angle Bhabha scattering events, the integrated luminosity of this data set is determined to be 108.49±0.02±0.85 pb−1, where the first uncertainty is statistical and the second one is systematic. In addition, the center-of-mass energy of the data set is determined with radiative dimuon events to be 2126.55±0.03±0.85 MeV, where the first uncertainty is statistical and the second one is systematic.

Measurement of the absolute branching fraction for Λc+→Λμ+νμ

We report the first measurement of the absolute branching fraction for $\Lambda^+_{c}\rightarrow \Lambda \mu^+\nu_{\mu}$. This measurement is based on a sample of $e^+e^-$ annihilation data at a center-of-mass energy of $\sqrt{s}=4.6$ GeV collected with the BESIII detector at the BEPCII storage rings. The sample corresponds to an integrated luminosity of 567 pb$^{-1}$. The branching fraction is determined to be $\mathcal B({\Lambda^+_c\rightarrow \Lambda \mu^+\nu_{\mu}})=(3.49\pm0.46({\rm stat})\pm0.27({\rm syst}))\%$. In addition, we calculate the ratio $\mathcal{B}(\Lambda^+_c\rightarrow \Lambda \mu^+\nu_{\mu})/\mathcal{B}(\Lambda^+_c\rightarrow \Lambda e^+\nu_{e})$ to be $0.96\pm0.16({\rm stat})\pm0.04({\rm syst})$.

Exosomal MicroRNA Clusters Are Important for the Therapeutic Effect of Cardiac Progenitor Cells

Although current evidence indicates that cardiac progenitor cells (CPCs) may improve cardiac repair after ischemic injury, the exact mechanism for this cardioprotective effect to date remains undefined. In this issue of Circulation Research , Gray et al1 report on the use of systems biology to link the change in exosomal microRNAs (miRNA) to the beneficial effects of CPCs during ischemic injury in mice. Expression analysis showed that exosomes from hypoxic CPCs contain a higher level of a subset of miRNAs than exosomes coming from normoxic CPCs. To connect the relevance of the change in miRNA levels to the biological effect of exosomes, the authors performed a principle component analysis of the miRNA expression profiles in exosomes, which identified 4 unique miRNA clusters, which after further mathematical modeling seemed to correlate to a biological effect related to the therapeutic benefit. Instead of studying the biological function of a single miRNA, computational modeling can be applied to integrate multiple variants to gain more insight into the overall relationship and interaction between the different datasets. Gray et al1 show that especially for miRNA biology, where a miRNA can target up to hundreds of genes in a parallel, systems biology could turn out to be a suitable approach for predicting a biological outcome or therapeutic benefit. Article, see p 255 Cells communicate with each other via direct cell–cell contact and secretion of soluble factors. Soluble factors that are gaining an increasing amount of attention are extracellular membrane vesicles. The ability of vesicles to transport different molecules, such as proteins, peptides, mRNA, and microRNAs, from one cell to the other and their general body-wide distribution make them attractive candidates for horizontal information transfer between cells.2 Although the release of vesicles to influence other cells seems to be straightforward, multiple mechanisms, size distributions, …

Vestibular Role of KCNQ4 and KCNQ5 K+ Channels Revealed by Mouse Models

The function of sensory hair cells of the cochlea and vestibular organs depends on an influx of K(+) through apical mechanosensitive ion channels and its subsequent removal over their basolateral membrane. The KCNQ4 (Kv7.4) K(+) channel, which is mutated in DFNA2 human hearing loss, is expressed in the basal membrane of cochlear outer hair cells where it may mediate K(+) efflux. Like the related K(+) channel KCNQ5 (Kv7.5), KCNQ4 is also found at calyx terminals ensheathing type I vestibular hair cells where it may be localized pre- or postsynaptically. Making use of Kcnq4(-/-) mice lacking KCNQ4, as well as Kcnq4(dn/dn) and Kcnq5(dn/dn) mice expressing dominant negative channel mutants, we now show unambiguously that in adult mice both channels reside in postsynaptic calyx-forming neurons, but cannot be detected in the innervated hair cells. Accordingly, whole cell currents of vestibular hair cells did not differ between genotypes. Neither Kcnq4(-/-), Kcnq5(dn/dn) nor Kcnq4(-/-)/Kcnq5(dn/dn) double mutant mice displayed circling behavior found with severe vestibular impairment. However, a milder form of vestibular dysfunction was apparent from altered vestibulo-ocular reflexes in Kcnq4(-/-)/Kcnq5(dn/dn) and Kcnq4(-/-) mice. The larger impact of KCNQ4 may result from its preferential expression in central zones of maculae and cristae, which are innervated by phasic neurons that are more sensitive than the tonic neurons present predominantly in the surrounding peripheral zones where KCNQ5 is found. The impact of postsynaptic KCNQ4 on vestibular function may be related to K(+) removal and modulation of synaptic transmission.

Albert Van Helden;, Sven Dupré;, Rob van Gent;, Huib Zuidervaart (Editors). The Origins of the Telescope. (Based on papers presented at the conference “The Invention of the Dutch Telescope: Its Origins and Impact on Science, Culture, and Society, 1550–1650,” Royal Netherlands Academy of Arts and Sciences, September 2008, Middelburg.) (History of Science and Scholarship in the Netherlands, 12.) 368 pp.,

Previous articleNext article No AccessBook ReviewsAlbert Van Helden;, Sven Dupré;, Rob van Gent;, Huib Zuidervaart (Editors). The Origins of the Telescope. (Based on papers presented at the conference “The Invention of the Dutch Telescope: Its Origins and Impact on Science, Culture, and Society, 1550–1650,” Royal Netherlands Academy of Arts and Sciences, September 2008, Middelburg.) (History of Science and Scholarship in the Netherlands, 12.) 368 pp., illus., figs., bibl., index. Amsterdam: Koninklijke Nederlandse Akademie van Wetenschappen, 2010. €49 (cloth).Jim BennettJim Bennett Search for more articles by this author PDFPDF PLUSFull Text Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmail SectionsMoreDetailsFiguresReferencesCited by Isis Volume 103, Number 2June 2012 Publication of the History of Science Society Article DOIhttps://doi.org/10.1086/667497 Views: 41Total views on this site © 2012 by The History of Science Society. All rights reserved.PDF download Crossref reports no articles citing this article.

New finds of rodents and insectivores from the Upper Miocene at Plakias (Crete, Greece)

This paper provides new information on the Late Miocene small mammal assemblage from Plakias, which includes a re-evaluation of the rodents described in De Bruijn and Meulenkamp (Proceedings Koninklijke Nederlandse Akademie van Wetenschappen, Series B, 75(1), 54–60, 1972) and a description of the rodents and insectivores collected in 2011. Combined, they show a quite diverse fauna, dominated by the eomyid Eomyops cf. catalaunicus. The new collection yielded a hitherto unknown genus of murid (Cricetinae gen. et sp. indet), which brings, combined with Eumyarion leemanni and Cricetulodon cretensis, the number of murids on three. The previous identifications of the scuirids and glirids have been revised. Insectivores, not know from the original collection, are represented by Erinaceinae gen. et sp. indet, Lantanotheriumsanmigueli and Paenelimnoecus sp. The assemblage is tentatively correlated to the lower part of MN 9, with an estimated age of ~9.9 Ma.