Search

Abstract Cytidine deaminase (CDA) converts cytidine and deoxycytidine into uridine and deoxyuridine as part of the pyrimidine salvage pathway. Elevated levels of CDA are found in pancreatic tumors and associated with chemoresistance. Recent evidence suggests that CDA has additional functions in cancer cell biology. In this work, we uncover a novel role of CDA in pancreatic cancer cell metabolism. CDA silencing impairs mitochondrial metabolite production, respiration, and ATP production in pancreatic cancer cells, leading to a so-called Pasteur effect metabolic shift towards glycolysis. Conversely, we find that CDA expression promotes mitochondrial biogenesis and oxidative phosphorylation, independently of CDA deaminase activity. Furthermore, we observe that patient primary cells overexpressing CDA are more sensitive to mitochondria-targeting drugs. Collectively, this work shows that CDA plays a non-canonical role in pancreatic cancer biology by promoting mitochondrial function, which could be translated into novel therapeutic vulnerabilities.

Abstract Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/BCR::ABL1, a distinct entity within the group of AML with defining genetic abnormalities, belong to the adverse-risk group of the 2022 ELN classification. However, there is little data on outcome since the era of tyrosine kinase inhibitors. Among 5819 AML cases included in the DATAML registry, 20 patients with de novo BCR::ABL1 +AML (0.3%) were identified. Eighteen patients treated with standard induction chemotherapy were analyzed in this study. Imatinib was added to chemotherapy in 16 patients. The female-to-male ratio was 1.25 and median age was 54 years. The t(9;22) translocation was the sole chromosomal abnormality in 12 patients. Main gene mutations detected by NGS were ASXL1, RUNX1 and NPM1. Compared with patients with myeloid blast phase of chronic myeloid leukemia (CML-BP), de novo BCR::ABL1 +AML had higher WBC, fewer additional chromosomal abnormalities, lower CD36 or CD7 expression and no ABL1 mutations. Seventeen patients (94.4%) achieved complete remission (CR) or CR with incomplete hematologic recovery. Twelve patients were allografted in first remission. With a median follow-up of 6.3 years, the median OS was not reached and 2-year OS was 77% (95% CI: 50–91). Four out of five patients who were not transplanted did not relapse. Comparison of BCR::ABL1 +AML, CML-BP, 2017 ELN intermediate (n = 643) and adverse-risk patients (n = 863) showed that patients with BCR::ABL1 +AML had a significant better outcome than intermediate and adverse-risk patients. BCR::ABL1 +AML patients treated with imatinib and intensive chemotherapy should not be included in the adverse-risk group of current AML classifications.

Foot and mouth disease (FMD) is a highly contagious viral disease affecting cloven-hoofed animals. This disease is one of the most important in animal health due to its significant socio-economic impact, especially in case of an outbreak. One important challenge associated with this disease is the ability of the FMD virus (FMDV) to persist in its hosts through still unresolved underlying mechanisms. The absence of relevant in vitro models is one factor preventing advancement in our understanding of FMDV persistence. While a primary bovine cell model has been established using cells from FMDV primary and persistence site in cattle, it appeared interesting to develop a similar model based on ovine anatomical sites of interest to compare host-pathogen interactions. Thus, epithelial cells derived from the palatine tonsils and the dorsal soft palate were isolated and cultured. Their epithelial nature was confirmed using immunofluorescence. Following monolayer infection with FMDV O/FRA/1/2001 Clone 2.2, the FMDV-sensitivity of these cells was evaluated. Dorsal soft palate (DSP) cells were also expanded in multilayers at the air-liquid interface to mimic a stratified epithelium sensitive to FMDV infection. Our investigation revealed the presence of infectious virus, as well as viral antigens and viral RNA, up to 35 days after infection of the cell multilayers. Further experiment with DSP cells from different individuals needs to be reproduced to confirm the robustness of the new model of persistence in multilayer DSP. The establishment of such primary cells creates new opportunities for FMDV research and analysis in sheep cells.

Generation Z, also known as the centennials, has been widely discussed in various studies. Gen Z's behavior in consuming news and information is shown in the way they access information, choose news topics and media platforms, and determine which media they will frequently go to specifically. The purpose of this study is to explore Gen Z's consumption of news on mainstream media and the factors that influence it, and to delve into their perceptions of the function of mainstream media in exercising social control and being a trusted source of information. The method used in the research is qualitative with a case study approach. The results show that Gen Z's exploration of information is influenced by interest, locality, proximity, selfsatisfaction, and incidental matters. These five factors are closely related to the specific characteristics of Gen Z and can be input for local and national mainstream media to follow the direction of development that is now held by the young generation. Mainstream media also remains Gen Z's reference for truth verification; even though they do not have a tendency to be loyal to one media and deliberately access the web pages of mainstream media directly

Abstract Background Recessive deleterious variants are known to segregate in livestock populations, as in humans, and some may be lethal in the homozygous state. Results We used phased 50 k single nucleotide polymorphism (SNP) genotypes and pedigree data to scan the genome of 6845 Manech Tête Rousse dairy sheep to search for deficiency in homozygous haplotypes (DHH). Five Manech Tête Rousse deficient homozygous haplotypes (MTRDHH1 to 5) were identified, with a homozygous deficiency ranging from 84 to 100%. These haplotypes are located on Ovis aries chromosome (OAR)1 (MTRDHH2 and 3), OAR10 (MTRDHH4), OAR13 (MTRDHH5), and OAR20 (MTRDHH1), and have carrier frequencies ranging from 7.8 to 16.6%. When comparing at-risk matings between DHH carriers to safe matings between non-carriers, two DHH (MTRDHH1 and 2) were linked with decreased insemination success and/or increased stillbirth incidence. We investigated the MTRDHH1 haplotype, which substantially increased stillbirth rate, and identified a single nucleotide variant (SNV) inducing a premature stop codon (p.Gln409*) in the methylmalonyl-CoA mutase (MMUT) gene by using a whole-genome sequencing approach. We generated homozygous lambs for the MMUT mutation by at-risk mating between heterozygous carriers, and most of them died within the first 24 h after birth without any obvious clinical symptoms. Reverse transcriptase-qPCR and western blotting on post-mortem liver and kidney biological samples showed a decreased expression of MMUT mRNA in the liver and absence of a full-length MMUT protein in the mutant homozygous lambs. Conclusions We identified five homozygous deficient haplotypes that are likely to harbor five independent deleterious recessive variants in sheep. One of these was detected in the MMUT gene, which is associated with lamb lethality in the homozygous state. A specific management of these haplotypes/variants in the MTR dairy sheep selection program would help enhance the overall fertility and lamb survival.

Teachers' beliefs about emotions can provide an overview of how teachers support the development of emotional competence in early childhood. This study aimed to investigate preschool teachers’ beliefs about emotional competence and emotion socialization. A sample of 194 preschool teachers from 22 Kindergartens completed the Teachers' Emotion Beliefs Scale (TEBS) and open questionnaires. The data were analyzed using descriptive statistical techniques and thematic analysis. The research results showed that 67% of teachers had developmentally appropriate beliefs, while 33% of teachers had beliefs that were not appropriate to children's emotional development. The developmentally appropriate belief explains the importance of the teacher's role in facilitating children's emotional competence. On the other hand, unappropriateness is explained by teachers' beliefs regarding children's expressions of negative emotions (such as sadness and anger), which according to teachers, young children do not need to express these emotions for certain reasons. Furthermore, the results of the open-ended questionnaire showed several teacher limitations regarding conceptual understanding of children's emotional competence, as well as in using appropriate strategies for emotional socialization (especially in helping children manage negative emotions). The way teachers socialize emotions is based on their beliefs regarding children's emotional competence.

Abstract Background Acute myeloid leukemia (AML) with myelodysplasia‐related characteristics is a heterogeneous subset of AML that has been challenged throughout the history of myeloid malignancies classifications, considered to have similar outcomes as intermediate‐ or adverse‐risk AML depending on the subgroup. However, little is known about the fate of these patients in refractory or relapsed situation (R/R) after first line therapy. Methods A large series of R/R AML patients, recorded in the French DATAML registry, have received either intensive chemotherapy (ICT), azacitidine (AZA) as single agent, or best supportive care (BSC). A cohort of 183 patients (median age 63‐year‐old) with what was called at the time AML‐MRC has been explored, and data are reported here. Results Patient status was refractory for 93, while 90 had relapsed. Respectively, 88, 34, and 61 were included in the three treatment arms. The median OS of the whole cohort was 4.2 months (95%CI: 3.1–5.6) with a mean 1‐year overall survival of 24% ± 3.2%. There was no significant survival difference between refractory and relapsed patients. The BSC group had overall a significantly worse outcome (p = 0.0001), and this remained true in both refractory (p = 0.01) and relapsed (p = 0.002) patients. Similar survivals were observed in both groups comparing ICT and AZA. Conclusions These data, reporting about an ill‐explored population, indicate the poor prognosis of this condition where both ICT and AZA can be proposed. The latter, which was demonstrated here to be a feasible option, should be added to new targeted therapies.

Abstract Relapse remains a major challenge in the clinical management of acute myeloid leukemia (AML) and is driven by rare therapy‐resistant leukemia stem cells (LSCs) that reside in specific bone marrow niches. Hypoxia signaling maintains cells in a quiescent and metabolically relaxed state, desensitizing them to chemotherapy. This suggests the hypothesis that hypoxia contributes to the chemoresistance of AML‐LSCs and may represent a therapeutic target to sensitize AML‐LSCs to chemotherapy. Here, we identify HIFhigh and HIFlow specific AML subgroups (inv(16)/t(8;21) and MLLr, respectively) and provide a comprehensive single‐cell expression atlas of 119,000 AML cells and AML‐LSCs in paired diagnostic‐relapse samples from these molecular subgroups. The HIF/hypoxia pathway signature is attenuated in AML‐LSCs compared with more differentiated AML cells but is more expressed than in healthy hematopoietic cells. Importantly, chemical inhibition of HIF cooperates with standard‐of‐care chemotherapy to impair AML growth and to substantially eliminate AML‐LSCs in vitro and in vivo. These findings support the HIF pathway in the stem cell‐driven drug resistance of AML and unravel avenues for combinatorial targeted and chemotherapy‐based approaches to specifically eliminate AML‐LSCs.

Abstract The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and suboptimal responses to JAK inhibitors such as ruxolitinib. A better understanding of cellular changes induced by ruxolitinib is required to develop new combinatory therapies to improve treatment efficacy. Here, we demonstrate that ruxolitinib induced autophagy in JAK2V617F cell lines and primary MPN patient cells through the activation of protein phosphatase 2A (PP2A). Inhibition of autophagy or PP2A activity along with ruxolitinib treatment reduced proliferation and increased the death of JAK2V617F cells. Accordingly, proliferation and clonogenic potential of JAK2V617F-driven primary MPN patient cells, but not of normal hematopoietic cells, were markedly impaired by ruxolitinib treatment with autophagy or PP2A inhibitor. Finally, preventing ruxolitinib-induced autophagy with a novel potent autophagy inhibitor Lys05 improved leukemia burden reduction and significantly prolonged the mice’s overall survival compared with ruxolitinib alone. This study demonstrates that PP2A-dependent autophagy mediated by JAK2 activity inhibition contributes to resistance to ruxolitinib. Altogether, our data support that targeting autophagy or its identified regulator PP2A could enhance sensitivity to ruxolitinib of JAK2V617F MPN cells and improve MPN patient care.

Abstract Face masks are often recommended in community settings to prevent the airborne transmission of respiratory viruses or bacteria. Our first objective was to develop an experimental bench to assess the viral filtration efficiency (VFE) of a mask with a methodology similar to the normative measurement of bacterial filtration efficiency (BFE) used to determine the filtration performance of medical masks. Then, using three categories of masks of increasing filtration quality (two types of community masks and one type of medical mask), filtration performances measured ranged from 61.4 to 98.8% of BFE and from 65.5 to 99.2% of VFE. A strong correlation (r = 0.983) between bacterial and viral filtration efficiency was observed for all types of masks and for the same droplets size in the 2–3 µm range. This result confirms the relevance of the EN14189:2019 standard using bacterial bioaerosols to evaluate mask filtration, to also extrapolate mask performances whatever their filtration quality against viral bioaerosols. Indeed, it appears that the filtration efficiency of masks (for micrometer droplet sizes and low bioaerosol exposure times) depends mainly on the size of the airborne droplet, rather than on the size of the infectious agent contained in that droplet.

Abstract Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte–monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.

Foot-and-mouth disease (FMD) is a highly contagious viral disease of cloven-hoofed animals that has a significant socio-economic impact. One concern associated with this disease is the ability of its etiological agent, the FMD virus (FMDV), to persist in its hosts through underlying mechanisms that remain to be elucidated. While persistence has been described in cattle and small ruminants, it is unlikely to occur in pigs. One of the factors limiting the progress in understanding FMDV persistence and, in particular, differential persistence is the lack of suitable in vitro models. A primary bovine cell model derived from the dorsal soft palate, which is the primary site of replication and persistence of FMDV in cattle, has been developed, and it seemed relevant to develop a similar porcine model. Cells from two sites of FMDV replication in pigs, namely, the dorsal soft palate and the oropharyngeal tonsils, were isolated and cultured. The epithelial character of the cells from the dorsal soft palate was then assessed by immunofluorescence. The FMDV-sensitivity of these cells was assessed after monolayer infection with FMDV O/FRA/1/2001 Clone 2.2. These cells were also grown in multilayers at the air-liquid interface to mimic a stratified epithelium susceptible to FMDV infection. Consistent with what has been shown in vivo in pigs, our study showed no evidence of persistence of FMDV in either the monolayer or multilayer model, with no infectious virus detected 28 days after infection. The development of such a model opens up new possibilities for the study and diagnosis of FMDV in porcine cells.

Incidents of child abuse increase every year, including cases in West Sumatra. Violence experienced by children can cause physical disorders, impairment in cognitive, emotional, and social development, and discrimination in the social environment. The government has set rules regarding the protection of children against violence. Still, not all people know the forms of child abuse, their impact on children, and how to report child abuse cases. Therefore, we held a webinar, "Knowing more about child abuse," to educate people. One hundred three participants from various backgrounds attended this activity, but only 90 completed the pre-test and post-test questionnaires. Based on paired T-test, there was a significant increase in the mean score of participants' knowledge about emotional violence, sexual violence, and neglect/abandonment after the webinar (p

Abstract Can medical face masks be replaced by reusable community face masks with similar performance? The influence of the number of wash cycles, the wash temperature and the use of detergent was evaluated on the performance of one medical face masks (MFM) and ten community face masks (CFM). The performance of the new and washed masks was characterized from the bacterial filtration efficiency (BFE) and the differential pressure (DP). The tests on the new masks showed that the MFM had always better BFE than CFMs. Although two of the CFMs showed a BFE value exceeding 95%, only one can be classified as type I MFM based on both BFE and DP requirements. The influence of the washing parameters was investigated on the MFM and these two CMFs with excellent BFE properties. The parameters had no effect on the BFE of CFMs whilst the MFM exhibited a loss in efficiency when washed with detergent. The DP of masks were not impacted by the washing. The results clearly show that even though a compromise has to be made between the BFE and breathability, it seems possible to manufacture CFMs with performances similar to a type I MFM, without achieving type II requirements.

Survivors of Covid-19 can still experience symptoms such as being still infected with a virus known as Long Covid-19. Covid-19 survivors with long Covid-19 experience physical and psychological disorders. Psychological disorders include cognitive disorders, memory loss, anxiety, sleep disorders, quality of life disorders, and work problems. This problem will undoubtedly impact individual productivity, so it is necessary to carry out a "Long Covid-19 Hotline". This activity aims to provide health services to Covid-19 survivors to overcome their Post-Covid conditions. The Psychologist Team of Psychology Study Program and Respiration and Pulmonology Medical Faculty Universitas Andalas conducted this activity by telephone in September and October 2021. Activities were carried out by providing psychological consultation or further recommendations for participants' psychological complaints. The results of the psychological condition of participants using Generalized Anxiety Disorder (GAD) 7 screening tools showed that the highest complaints were anxiety at 46%, insomnia at 24%, difficulty concentrating at 13%, and depression at 9% and stress at 8%. As for the follow-up results after the consultation, 90% of participants' psychological complaints were reduced, 89% of participants had made follow-up recommendations, and 100% of participants felt this activity was beneficial. Based on a survey of Covid-19 survivors, their psychological condition improved after conducting a Long Covid-19 Hotline.

Abstract The family of hexokinases (HKs) catalyzes the first step of glycolysis, the ATP-dependent phosphorylation of glucose to glucose-6-phosphate. While HK1 and HK2 are ubiquitously expressed, the less well-studied HK3 is primarily expressed in hematopoietic cells and tissues and is highly upregulated during terminal differentiation of some acute myeloid leukemia (AML) cell line models. Here we show that expression of HK3 is predominantly originating from myeloid cells and that the upregulation of this glycolytic enzyme is not restricted to differentiation of leukemic cells but also occurs during ex vivo myeloid differentiation of healthy CD34+ hematopoietic stem and progenitor cells. Within the hematopoietic system, we show that HK3 is predominantly expressed in cells of myeloid origin. CRISPR/Cas9 mediated gene disruption revealed that loss of HK3 has no effect on glycolytic activity in AML cell lines while knocking out HK2 significantly reduced basal glycolysis and glycolytic capacity. Instead, loss of HK3 but not HK2 led to increased sensitivity to ATRA-induced cell death in AML cell lines. We found that HK3 knockout (HK3-null) AML cells showed an accumulation of reactive oxygen species (ROS) as well as DNA damage during ATRA-induced differentiation. RNA sequencing analysis confirmed pathway enrichment for programmed cell death, oxidative stress, and DNA damage response in HK3-null AML cells. These signatures were confirmed in ATAC sequencing, showing that loss of HK3 leads to changes in chromatin configuration and increases the accessibility of genes involved in apoptosis and stress response. Through isoform-specific pulldowns, we furthermore identified a direct interaction between HK3 and the proapoptotic BCL-2 family member BIM, which has previously been shown to shorten myeloid life span. Our findings provide evidence that HK3 is dispensable for glycolytic activity in AML cells while promoting cell survival, possibly through direct interaction with the BH3-only protein BIM during ATRA-induced neutrophil differentiation.

How should we deliberate with citizens who entertain post-truth beliefs in democratic societies? This is a central question for those interested in wielding the epistemic potential of democratic deliberation against post-truth. Yet, the strength of proposed deliberative solutions depends on the accuracy with which post-truth is diagnosed. Taking seriously the connection between epistemic diagnosis and deliberative remedy, this paper looks at the motivations provided by non-vaccinating parents for their beliefs and argues for an understanding of post-truth as misplaced distrust in testimony, as against a standard view of post-truth as indifference to fact. Second, the paper argues this new diagnosis of post-truth renders ineffective deliberative strategies aiming to harness the power of impersonal reason and accuracy, of the kind recently defended by Simone Chambers. Instead, combating post-truth as the paper defines it is effectively accomplished through employing bridging rhetoric. [ABSTRACT FROM AUTHOR]

Juveniles are also involved in behaviors that violate the law, such as in cases of sexual violence. This study aims to describe the experiences of mothers whose children are perpetrators of sexual violence. The study used a qualitative phenomenological method. Five mothers of a sexual offender charged by the juvenile court participated in this study. They were interviewed about their parenting experiences using in-depth interviews. The data were analyzed using interpretative phenomenological analysis (IPA). Thirteen subordinate themes were found and grouped into three superordinate themes, including (1) feeling like a mother, (2) role of mothers, (3) maternal sense of competence. The mothers of juvenile sexual offenders perceived that they had failed as parents and that parenting competence was lacking. They considered peer influence and uninvolved partners in parenting practice as the source of difficulties in managing their child’s problematic behavior.

Abstract Objective Causal mutations for major genes that underlie a broad range of morphological traits are often located within exons of genes that then affect protein functions. Non-model organism genetic studies are not easy to perform due to the lack of genome-wide molecular tools such as SNP genotyping array. Genotyping-By-Sequencing (GBS) methods offer an alternative. Consequently, we used this approach that is focused on the exome to target and identify major genes in rabbit populations. Data description We used a heterologous enrichment method before sequencing, allowing us to capture the rabbit exome using the marketed human panel since mammal protein coding genes are well conserved across the phylogenic tree of species. This targeted strategy was performed on 52 French rabbits from 5 different French strains (Californian, New-Zealand, Castor, Chinchilla and Laghmere). We generated 3.4 billion sequencing reads and approximately 29–140 million of reads per DNA sample. The expected exome coverage per sample ranged between 118 and 566X. The present dataset could be useful for the scientific community working on rabbit species in order to (i) improve the annotation of the rabbit reference genome Oryctolagus cuniculus (OryCun2.0), (ii) enrich the characterization of polymorphisms segregating in rabbits and (iii) evaluate the genetic biodiversity in different rabbit strains. Raw sequences were deposited in the European Nucleotide Archive (ENA) at the European Molecular Biology Laboratory- European Bioinformatics Institute (EMBL-EBI) data portal under bioproject accession number PRJEB37917.