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Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor GATA-1 that result in exclusive production of its shorter isoform (GATA-1 S ). Given the common hallmark of altered miRNA expression profiles in haematological malignancies and the pro-leukaemic role of GATA-1 S , we aimed to search for miRNAs potentially able to modulate the expression of GATA-1 isoforms. Starting from an in silico prediction of miRNA binding sites in the GATA-1 transcript, miR-1202 came into our sight as potential regulator of GATA-1 expression. Expression studies in K562 cells revealed that miR-1202 directly targets GATA-1, negatively regulates its expression, impairs GATA-1 S production, reduces cell proliferation, and increases apoptosis sensitivity. Furthermore, data from TAM and myeloid leukaemia patients provided substantial support to our study by showing that miR-1202 down-modulation is accompanied by increased GATA-1 levels, with more marked effects on GATA-1 S . These findings indicate that miR-1202 acts as an anti-oncomiR in myeloid cells and may impact leukaemogenesis at least in part by down-modulating GATA-1 S levels.

The erythroid transcriptional factor Krüppel-like factor 1 (KLF1) is a master regulator of erythropoiesis. Mutations that cause KLF1 haploinsufficiency have been linked to increased fetal hemoglobin (HbF) and hemoglobin A 2 (HbA 2 ) levels with ameliorative effects on the severity of β-thalassemia. With the aim of determining if KLF1 gene variations might play a role in the modulation of β-thalassemia, in this study we screened 17 subjects showing a β-thalassemia-like phenotype with a slight or marked increase in HbA 2 and HbF levels. Overall, seven KLF1 gene variants were identified, of which two were novel. Functional studies were performed in K562 cells to clarify the pathogenic significance of these mutations. Our study confirmed the ameliorative effect on the thalassemia phenotype for some of these variants but also raised the notion that certain mutations may have deteriorating effects by increasing KLF1 expression levels or enhancing its transcriptional activity. Our results indicate that functional studies are required to evaluate the possible effects of KLF1 mutations, particularly in the case of the co-existence of two or more mutations that could differently contribute to KLF1 expression or transcriptional activity and consequently to the thalassemia phenotype.

Do financial resources relate to how important meaning is for one's happiness? Across three large-scale data sets spanning more than 500,000 individuals across 123 countries, we examined the relationship between meaning and happiness for individuals who vary in financial resources. Whether based on actual income level (Studies 1 and 2) or subjective assessments of socioeconomic status (Study 3), the results reveal that meaning is a weaker predictor of happiness for individuals with greater (vs. lesser) financial resources. Collectively, these studies suggest that having greater financial resources weakens the link between meaning and happiness. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Ferroptosis is a recently recognized form of regulated cell death involving lipid peroxidation. Glutathione peroxidase 4 (GPX4) plays a central role in the regulation of ferroptosis through the suppression of lipid peroxidation generation. Connections have been reported between ferroptosis, lipid metabolism, cancer onset, and drug resistance. Recently, interest has grown in ferroptosis induction as a potential strategy to overcome drug resistance in hematological malignancies. GATA-1 is a key transcriptional factor controlling hematopoiesis-related gene expression. Two GATA-1 isoforms, the full-length protein (GATA-1 FL ) and a shorter isoform (GATA-1 S ), are described. A balanced GATA-1 FL /GATA-1 S ratio helps to control hematopoiesis, with GATA-1 S overexpression being associated with hematological malignancies by promoting proliferation and survival pathways in hematopoietic precursors. Recently, optical techniques allowed us to highlight different lipid profiles associated with the expression of GATA-1 isoforms, thus raising the hypothesis that ferroptosis-regulated processes could be involved. Lipidomic and functional analysis were conducted to elucidate these mechanisms. Studies on lipid peroxidation production, cell viability, cell death, and gene expression were used to evaluate the impact of GPX4 inhibition. Here, we provide the first evidence that over-expressed GATA-1 S prevents K562 myeloid leukemia cells from lipid peroxidation-induced ferroptosis. Targeting ferroptosis is a promising strategy to overcome chemoresistance. Therefore, our results could provide novel potential therapeutic approaches and targets to overcome drug resistance in hematological malignancies.

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease, whose presentation and clinical course are highly variable. Identification of novel prognostic factors may contribute to improving the CLL classification and providing indications for treatment options. The zinc finger protein ZNF224 plays a key role in cell transformation, through the control of apoptotic and survival pathways. In this study, we evaluated the potential application of ZNF224 as a novel marker of CLL progression and therapy responsiveness. To this aim, we analyzed ZNF224 expression levels in B lymphocytes from CLL patients at different stages of the disease and in patients showing different treatment outcomes. The expression of ZNF224 was significantly increased in disease progression and dramatically decreased in patients in complete remission after chemotherapy. Gene expression correlation analysis performed on datasets of CLL patients revealed that ZNF224 expression was well correlated with that of some prognostic and predictive markers. Moreover, bioinformatic analysis coupled ZNF224 to NF-κB pathway, and experimental data demonstrated that RNA interference of ZNF224 reduced the activity of the NF-κB survival pathway in CLL cells. Consistently with a pro-survival role, ZNF224 knockdown raised spontaneous and drug-induced apoptosis and inhibited the proliferation of peripheral blood mononuclear cells from CLL patients. Our findings provide evidence for the involvement of ZNF224 in the survival of CLL cells via NF-κB pathway modulation, and also suggest ZNF224 as a prognostic and predictive molecular marker of CLL disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Catapano, Sepe, Toscano, Paolella, Chiurazzi, Barbato, Bruzzese, Arianna, Grosso, Romano, Romano, Costanzo and Cesaro.)

We herein report an innovative antisense approach based on Peptide Nucleic Acids (PNAs) to down-modulate CD5 expression levels in chronic lymphocytic leukemia (CLL). Using bioinformatics tools, we selected a 12-mer tract of the CD5 mRNA as the molecular target and synthesized the complementary and control PNA strands bearing a serine phosphate dipeptide tail to enhance their water solubility and bioavailability. The specific recognition of the 12-mer DNA strand, corresponding to the target mRNA sequence by the complementary PNA strand, was confirmed by non-denaturing polyacrylamide gel electrophoresis, thermal difference spectroscopy, circular dichroism (CD), and CD melting studies. Cytofluorimetric assays and real-time PCR analysis demonstrated the downregulation of CD5 expression due to incubation with the anti-CD5 PNA at RNA and protein levels in Jurkat cell line and peripheral blood mononuclear cells from B-CLL patients. Interestingly, we also observed that transfection with the anti-CD5 PNA increases apoptotic response induced by fludarabine in B-CLL cells. The herein reported results suggest that PNAs could represent a potential candidate for the development of antisense therapeutic agents in CLL., Competing Interests: The authors have declared that no competing interests exist.

GATA-1 is a key regulator of hematopoiesis. A balanced ratio of its two isoforms, GATA-1 FL and GATA-1 S , contributes to normal hematopoiesis, whereas aberrant expression of GATA-1 S alters the differentiation/proliferation potential of hematopoietic precursors and represents a poor prognostic factor in myeloid leukemia. We previously reported that GATA-1 S over-expression correlates with high levels of the succinate dehydrogenase subunit C (SDHC). Alternative splicing variants of the SDHC transcript are over-expressed in several tumors and act as potent dominant negative inhibitors of SDH activity. With this in mind, we investigated the levels of SDHC variants and the oxidative mitochondrial metabolism in myeloid leukemia K562 cells over-expressing GATA-1 isoforms. Over-expression of SDHC variants accompanied by decreased SDH complex II activity and oxidative phosphorylation (OXPHOS) efficiency was found associated only with GATA-1 S . Given the tumor suppressor role of SDH and the effects of OXPHOS limitations in leukemogenesis, identification of a link between GATA-1 S and impaired complex II activity unveils novel pro-leukemic mechanisms triggered by GATA-1 S . Abnormal levels of GATA-1 S and SDHC variants were also found in an acute myeloid leukemia patient, thus supporting in vitro results. A better understanding of these mechanisms can contribute to identify novel promising therapeutic targets in myeloid leukemia.

The rise of social media has led to unprecedented opportunities for individuals to share, or express, their attitudes on social and political issues. What factors affect whether individuals choose to share? This research identifies a novel determinant of attitude sharing-support-oppose framing, defined as whether individuals think of their own attitude in terms of what they support or what they oppose. Support-oppose framing is distinct from attitude valence, as the same attitude can be framed in terms of support (e.g., I support that this policy is bad) or opposition (e.g., I oppose that this policy is good). Seven experiments, two correlational studies, and one field study provide evidence for a support-oppose framing effect, whereby individuals are more likely to share attitudes framed in terms of positions they support rather than positions they oppose. This effect occurs via two pathways. In the first, support-framed attitudes are viewed as more value expressive, which facilitates greater attitude sharing. In the second, support-framed attitudes are believed to promote more positive impressions, which also leads to greater sharing. This effect is attenuated when individuals' typical impression-management goals are relaxed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

HarryOW and Peeb are Mycobacterium smegmatis mc 2 155 Siphoviridae temperate phages with 52,935 and 41,876 base pairs in genome length, respectively. HarryOW belongs to the A1 subcluster and Peeb to the G1 subcluster. They were isolated and annotated by students from the SUNY Old Westbury Science and Technology Entry Program., (Copyright © 2021 Nieto-Fernandez et al.)

Myeloid leukemic cells are intrinsically under oxidative stress due to impaired reactive oxygen species (ROS) homeostasis, a common signature of several hematological malignancies. The present review focuses on the molecular mechanisms of aberrant ROS production in myeloid leukemia cells as well as on the redox-dependent signaling pathways involved in the leukemogenic process. Finally, the relevance of new chemotherapy options that specifically exert their pharmacological activity by altering the cellular redox imbalance will be discussed as an effective strategy to eradicate chemoresistant cells.

People seek to spend time in positive experiences, enjoying and savoring. Yet there is no escaping negative experiences, from the mundane (e.g. arguing) to the massive (e.g. death of a child). Might negative experiences confer a hidden benefit to well-being? We propose that they do, in the form of enhanced meaning in life. Research suggests that negative experiences can serve to boost meaning because they stimulate comprehension (understanding how the event fits into a broader narrative of the self, relationships, and the world), a known pillar of meaning in life. Findings on counterfactual thinking, reflecting on events' implications, and encompassing experiences into broad-based accounts of one's identity support the role of comprehension in contributing to life's meaning from unwanted, unwelcome experiences., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Counterattitudinal-argument generation is a powerful tool for opening people up to alternative views. On the basis of decades of research, it should be especially effective when people adopt the perspective of individuals who hold alternative views. In the current research, however, we found the opposite: In three preregistered experiments (total N = 2,734), we found that taking the perspective of someone who endorses a counterattitudinal view lowers receptiveness to that view and reduces attitude change following a counterattitudinal-argument-generation task. This ironic effect can be understood through value congruence: Individuals who take the opposition's perspective generate arguments that are incongruent with their own values, which diminishes receptiveness and attitude change. Thus, trying to "put yourself in their shoes" can ultimately undermine self-persuasion. Consistent with a value-congruence account, this backfire effect is attenuated when people take the perspective of someone who holds the counterattitudinal view yet has similar overall values.

The aim of this study was the quality of service evaluation of two different organizational ways in delivering infant vaccination according to a Regional Vaccination Plan. Eleven vaccination centres were selected in two Local Health Units (ASLs) belonging to the Regional Health Service of the Lazio Region, Italy. The services offering paediatric vaccinations for children under three years of age, delivered without an appointment (VACP) or with the need for an appointment (VACL), were investigated. The quality aspects under evaluation were communicational efficiency, organisational efficiency and comfort. Subjective data were collected from different stakeholders and involve the elicitation of best and worst feasible performance conditions for the ASLs when delivering VACP/VACL services. Objective data consists in the observation of current performances of the selected vaccination centres. Quality scorecards were obtained from the combination of all data. Benchmarking between VACP and VACL, i.e., two different organisational ways in delivering infant vaccination, can be performed as a result of the probabilistic meaning of the evaluated scores. An expert of vaccination services, i.e., a virtual combination of patients, doctors and nurses, claims the quality of service delivery of the ASLs under investigation with probability 78.03% and 69.67% for VACP and VACL, respectively. In other words, for short, the quality scores of the ASLs were 78.03% for VACP and 69.67% for VACL. Furthermore our results show how to practically improve the current service delivery. The QuaVaTAR approach can result in improvements of the quality of the ASLs for the two different ways of delivering paediatric vaccinations in a simple and intuitive way.

Recent work in judgment and decision-making has shown that a good's price can have irrational effects on people's preferences. People tend to prefer goods that cost more money and assume that such expensive goods will be more effective, even in cases where the price of the good is itself arbitrary. Although much work has documented the existence of these pricing effects, unfortunately little work has addressed where these price effects come from in the first place. Here we use a comparative approach to distinguish between different accounts of this bias and to explore the origins of these effects. Specifically, we test whether brown capuchin monkeys (Cebus apella) are also susceptible to pricing effects within the context of an experimentally trained token economy. Using a capuchin population previously trained in a token market, we explored whether monkeys used price as an indicator of value across four experiments. Although monkeys demonstrated an understanding of which goods had which prices (consistently shifting preferences to cheaper goods when prices were increased), we observed no evidence that such price information affected their valuation of different kinds of goods. These results suggest that human pricing effects may involve more sophisticated human-unique cognitive capacities, such as an understanding of market forces and signaling.

Limbic encephalitis (LE) is a neurological syndrome usually presenting in a paraneoplastic form. Recently many cases were reported with no concurring neoplasia, presenting with specific antibodies for voltage-gated potassium channel or for neuronal membrane antigens. Anti-glutamic acid decarboxylase (GAD) antibodies act against GABAergic receptors of the central nervous system. These antibodies were found in coeliac disease serum and in neurologic patients. We are reporting a case of a 21-year-old coeliac woman manifesting complex multiple-daily partial drug-resistant seizures for 7 years. The diagnosis was of a non paraneoplastic limbic encephalitis, unresponsive to high dose cortisone and IGIV infusion. The use of therapeutic plasma exchange (TPE) has resulted in an improvement in symptoms with quite a long disease-free period of time. When the frequency of the procedures was decreased, seizures appeared again and, after suspension of TPE, the clinical status worsened. The role of TPE in the treatment of LE still has to be defined.

Mice carrying a truncated form of cAMP-responsive element binding protein (CREB)-binding protein (CBP) show several developmental abnormalities similar to patients with Rubinstein-Taybi syndrome (RTS). RTS patients suffer from mental retardation, whereas long-term memory formation is defective in mutant CBP mice. A critical role for cAMP signaling during CREB-dependent long-term memory formation appears to be evolutionarily conserved. From this observation, we reasoned that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect(s) of CBP+/- mice. To this end, we designed a cell-based drug screen and discovered inhibitors of phosphodiesterase 4 (PDE4) to be particularly effective enhancers of CREB function. We extend previous behavioral observations by showing that CBP+/- mutants have impaired long-term memory but normal learning and short-term memory in an object recognition task. We demonstrate that the prototypical PDE4 inhibitor, rolipram, and a novel one (HT0712) abolish the long-term memory defect of CBP+/- mice. Importantly, the genetic lesion in CBP acts specifically to shift the dose sensitivity for HT0712 to enhance memory formation, which conveys molecular specificity on the drug's mechanism of action. Our results suggest that PDE4 inhibitors may be used to treat the cognitive dysfunction of RTS patients.

The hospitalization rate and the mean days of hospitalization of notified viral hepatitis cases in Italy were estimated by a specific surveillance system for acute viral hepatitis over the period 1987-1992. The hospitalization rate was very high, ranging from 88.8% for hepatitis A to 90.9% for non-A, non-B hepatitis. No changes were observed over time. For each type of hepatitis the highest figure was observed in the 15-24 year age group. The mean days of hospitalization of hepatitis B (24.2) and non-A, non-B (20.5) hepatitis was significantly higher (p < 0.05) than that of hepatitis A (16.5). The highest mean days of hospitalization of hepatitis A and B occurred in the 0-14 year age group, while for non-A, non-B hepatitis it was observed in subjects over 24 years of age. These findings indicate a nearly similar rate of hospitalization of all types of hepatitis. Hepatitis B and non-A, non-B hepatitis show a more prolonged course than hepatitis A.

The incidence of hepatitis Delta virus in the general Italian population was estimated by a specific surveillance system for acute viral hepatitis over the period 1987-1992. The hepatitis Delta virus incidence rate declined from 3.1/1,000,000 inhabitants in 1987 to 1.2/1,000,000 in 1992. Males predominated (83.8% of cases); the sex ratio was 5.2. Only 2.5% of cases occurred in subjects younger than 15 years. There were 119 (49.4%) coinfections of Delta and B hepatitis and 122 (50.6%) Delta superinfections in chronic HBsAg carriers. Jaundice was present in 83.6% of cases. The hospitalization rate was 97.5%; median stay in hospital was 25 days (range 1-98 days). The results of multivariate analysis showed that a history of intravenous drug abuse (odds ratio 34.9; confidence interval 95% = 16.8-72.5), household contact with an HBsAg+ carrier (odds ratio 10.7; confidence interval 95% = 4.36-23.30) and a history of two or more sexual partners within the previous 6 months (odds ratio 2.44; confidence interval 95% = 1.34-4.43) were independent risk factors associated with Delta hepatitis. No association was found with the other risk factors considered, such as blood transfusion, surgical intervention, hospitalization, other percutaneous exposures, dental therapy, contact with an icteric case, and household contact with an i.v. drug abuser. These findings indicate that, in Italy, Delta hepatitis currently has a minor impact. In addition to intravenous drug abuse and household contact with an HBsAg+ carrier, heterosexual activity appears to be an efficient route of HDV transmission.

A highly differentiated thyroid cell line (FR-RL) was compared with a less differentiated (FR-T Cl1) and an undifferentiated (1-5G) cell line. FR-TL is modulated in vivo and in vitro by thyrotropin and has the lowest adenylate cyclase and guanylate cyclase and the highest phosphodiesterase activities. In contrast, 1-5G tumor cells do not respond to thyrotropin and have the highest adenylate cyclase guanylate cyclase and lowest hydrolyzing enzyme activities. Intermediate enzyme activities were found in FR-T Cl1 cells. The differences between the two normal rat thyroid cell lines are not due to differences in the composition of the growth medium.