Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML

Impaired CK1 Delta Activity Attenuates SV40-Induced Cellular Transformation In Vitro and Mouse Mammary Carcinogenesis In Vivo

Simian virus 40 (SV40) is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1δ mutants exhibited a reduced kinase activity compared to wtCK1δ in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1δ activity. When stably over-expressed in maximal transformed SV-52 cells, CK1δ mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1δ. To characterize the effects of CK1δ on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1δ under the control of the whey acidic protein (WAP) gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T) mice. Both WAP-T mice as well as WAP-mutCK1δ/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1δ/WAP-T bi-transgenic animals. The reduced CK1δ activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1δ activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1δ/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA repair. Our data show that inactivating mutations in CK1δ impair SV40-induced cellular transformation in vitro and mouse mammary carcinogenesis in vivo

More Than Smell—COVID-19 Is Associated With Severe Impairment of Smell, Taste, and Chemesthesis

Correction: Chemical Senses, Volume 46, 2021, bjab050, https://doi.org/10.1093/chemse/bjab050 Published: 08 December 2021Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change +/- 100) revealed a mean reduction of smell (-79.7 +/- 28.7, mean +/- standard deviation), taste (-69.0 +/- 32.6), and chemesthetic (-37.3 +/- 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis.The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.Peer reviewe

Recent smell loss is the best predictor of COVID-19 among individuals with recent respiratory symptoms

In a preregistered, cross-sectional study we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC=0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4<10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable

Meta-analysis of QTL reveals the genetic control of yield-related traits and seed protein content in pea

National audiencePea is one of the most important grain legume crops in temperate regions worldwide. Improving pea yield is a critical breeding target. Nine inter-connected pea recombinant inbred line populations were evaluated in nine environments at INRAE Dijon, France and genotyped using the GenoPea 13.2 K SNP array. Each population has been evaluated in two to four environments. A multi-population Quantitative Trait Loci (QTL) analysis for seed weight per plant (SW), seed number per plant (SN), thousand seed weight (TSW) and seed protein content (SPC) was done. QTL were then projected on the multi-population consensus map and a meta-analysis of QTL was performed. This analysis identified 17 QTL for SW, 16 QTL for SN, 35 QTL for TSW and 21 QTL for SPC, shedding light on trait relationships. These QTL were resolved into 27 metaQTL. Some of them showed small confidence intervals of less than 2 cM encompassing less than one hundred underlying candidate genes. The precision of metaQTL and the potential candidate genes reported in this study enable their use for marker-assisted selection and provide a foundation towards map-based identification of causal polymorphisms

Potential endocrine disrupting properties of toys for babies and infants.

Plastic toys mouthed by children may be a source of exposure to endocrine active substances. The purpose of this study was to measure hormonal activity of substances leaching from toys and to identify potential endocrine disruptors causing that activity. For this purpose, migration experiments of toys were conducted in saliva simulants. The CALUX® assays were used to detect (anti-) estrogenic and (anti-) androgenic activity of 18 toys. Chemical trace analysis-namely, GC-MS and HPLC-MS- was used to identify which compounds may be responsible for endocrine activity in the sample migrates. Nine out of 18 tested toys showed significant estrogenic activity. For two samples, the detected estrogenic activity could be well explained by detecting the known endocrine active substance bisphenol A (BPA). For all identified substances, including BPA, a risk assessment for human health was performed by comparing the exposure dose, calculated based on the determined substance concentration, to toxicological reference values. Using worst-case scenarios, the exposure to BPA by mouthing of the two estrogen active, BPA-containing toys could be above the temporary TDI that EFSA has calculated. This demonstrates that some toys could significantly contribute to the total exposure to BPA of babies and infants. For seven out of nine estrogen active samples, the source of the estrogen activity could not be explained by analysis for 41 known or suspected endocrine active substances in plastic, indicating that the estrogen activities were caused by currently unknown endocrine active substances, or by endocrine active substances that would currently not be suspected in toys

Implementation and Initial Analysis of a Laboratory-Based Weekly Biosurveillance System, Provence-Alpes-Côte d’Azur, France

We describe the implementation of an automated infectious disease surveillance system that uses data collected from 210 microbiologic laboratories throughout the Provence-Alpes-Côte d’Azur region in France. Each week, these facilities report bacterial species that have been isolated from patients in their area. An alarm is triggered whenever the case count for a bacterial species infection exceeds 2 SDs of the historical mean for that species at the participating laboratory. At its inception in July 2013, the system monitored 611 bacterial species. During July 1, 2013–March 20, 2016, weekly analyses of incoming surveillance data generated 34 alarms signaling possible infectious disease outbreaks; after investigation, 14 (41%) of these alarms resulted in health alerts declared by the regional health authority. We are currently improving the system by developing an Internet-based surveillance platform and extending our surveillance to include more laboratories in the region