Off-the-record target zones:theory with an application to Hong Kong’s Currency Board

This paper provides a modelling framework for evaluating the exchange rate dynamics of a target zone regime with undisclosed bands. We generalize the literature to allow for asymmetric one-sided regimes. Market participants' beliefs concerning an undisclosed band change as they learn more about central bank intervention policy. We apply the model to Hong Kong's one-sided currency board mechanism. In autumn 2003, the Hong Kong dollar appreciated from close to 7.80 per US dollar to 7.70, as investors feared that the currency board would be abandoned. In the wake of this appreciation, the monetary authorities finally revamped the regime as a symmetric two-sided system with a narrow exchange rate band

TMEM16A and TMEM16B modulate pheromone-evoked action potential firing in mouse vomeronasal sensory neurons

The mouse vomeronasal system controls several social behaviors. Pheromones and other social cues are detected by sensory neurons in the vomeronasal organ (VNO). Stimuli activate a transduction cascade that leads to membrane potential depolarization, increase in cytosolic Ca2+ level, and increased firing. The Ca2+-activated chloride channels TMEM16A and TMEM16B are co-expressed within microvilli of vomeronasal neurons, but their physiological role remains elusive. Here, we investigate the contribution of each of these channels to vomeronasal neuron firing activity by comparing wild-type (WT) and knock-out (KO) mice. Performing loosepatch recordings from neurons in acute VNO slices, we show that spontaneous activity is modified by Tmem16a KO, indicating that TMEM16A, but not TMEM16B, is active under basal conditions. Upon exposure to diluted urine, a rich source of mouse pheromones, we observe significant changes in activity. Vomeronasal sensory neurons (VSNs) from Tmem16a cKO and Tmem16b KO mice show shorter interspike intervals (ISIs) compared with WT mice, indicating that both TMEM16A and TMEM16B modulate the firing pattern of pheromone-evoked activity in VSNs

The signalling channel of Central Bank interventions:modelling the Yen/US dollar exchange rate

This paper presents a theoretical framework analysing the signalling channel of exchange rate interventions as an informational trigger. We develop an implicit target zone framework with learning in order to model the signalling channel. The theoretical premise of the model is that interventions convey signals that communicate information about the exchange rate objectives of the central bank. The model is used to analyse the impact of Japanese FX interventions during the period 1999--2011 on the yen/US dollar dynamics

An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis "ph-like" BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.This work was supported by the Israel Science Foundation (# 1178/12 to S.I.), Children with Cancer (UK) (S.I. and T.E.), Swiss Bridge Foundation (S.I.), WLBH Foundation (S.I.), Waxman Cancer Research Foundation (S.I.), US–Israel Binational Science Foundation, Israeli health ministry ERA-NET program (#CANCER11-FP-127 to S.I.), Hans Neufeld Stiftung, the International Collaboration Grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, a partnership of the Israel Cancer Research Fund and City of Hope (S.I. grants # 00161), the Nevzlin Genomic Center for Precision Medicine in Schneider Children’s Medical Center of Israel, The European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813091 (S.I.) and the Israel Childhood Cancer Foundation (S.I.). I.G. was partially supported by Israeli ministry of Immigrant Absorption.info:eu-repo/semantics/publishedVersio

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Modulation of pheromone responses in vomeronasal sensory neurons

Chemosensation allows individuals to perceive chemical stimuli from the surrounding environment leading the survival of all the species. The vomeronasal organ (VNO) is a peripheral sensory organ present in many mammals that is involved in the detection of pheromones. Pheromones are substances released by animals which trigger behavior and physiological changes of other individuals of the same species. The binding of pheromones is transduced into electrical signals by specialized neurons that transfer to the central nervous system the information carried by social cues. Ligand binding to vomeronasal receptors on microvilli of the dendritic knobs of vomeronasal sensory neurons (VSNs) triggers a biochemical cascade that activates a PLC-dependent second messenger transduction that ultimately results in the TRPC2 channel gating allowing the inward flow of sodium and calcium. The increase in cytosolic calcium concentration plays several roles in signal transduction, involving the activation of other ion channels. Previous studies showed that calcium activated chloride currents are activated by cytosolic calcium increase in mouse VSNs, and that both TMEM16A and TMEM16B, two proteins forming calcium-activated chloride channels, are co-expressed in microvilli of VSNs, but their physiological role is still uncertain. With the help of two mouse models, TMEM16A cKO and TMEM16B KO mice, we provide evidence of the role of both channels in spontaneous firing and evoked activity in VSNs. Extracellular recordings in loose-patch configuration showed that firing pattern of spontaneous activity was affected in VSNs from TMEM16A cKO mice, showing less activity with respect to WT neurons, while VSNs from TMEM16B KO mice showed spontaneous firing comparable to WT. During urine-evoked activity both channels are involved in modulation of firing. Inter spike interval (ISI) distribution of evoked activity showed that VSNs from TMEM16A cKO and TMEM16B KO fire with shorter intervals than WT neurons. We conclude that calcium-activated chloride current modulates the firing of VSNs varying the effect with an activity-dependent mode. Adaptation is an additional mechanism of response modulation common in sensory systems. To evaluate the molecular players involved in sensory adaptation in VNO during early pheromone processing, we used whole-cell recordings in the current-clamp mode to measure the action potential firing of VSNs stimulated by diluted urine. We performed a paired pulse protocol with different inter-pulse intervals (IPIs), ranging from 5 to 60 seconds. We found that VSNs reduced their firing rate depending on the duration of preceding stimulation and on IPIs. Surprisingly, similar results were obtained also upon stimulation with direct injection of current, which does not activate neither the receptors nor the signaling cascade, suggesting that the adaptation would be, at least partially, independent from the initial sensory transduction cascade. We reveal that sodium currents in VSNs undergo to a slow recovery from inactivation that last several seconds mirroring the time scale of paired pulse experiments. Our results provide a foundation for future work investigating the precise molecular mechanisms of modulation of pheromones signaling at peripheral level during early stages of firing in VSNs