Differential silencing of STAT3 isoforms leads to changes in STAT3 activation.

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in multiple fundamental biological processes and a key player in cancer development and progression. STAT3 is activated upon tyrosine phosphorylation and is constitutively active in various malignancies; therefore, the expression of pSTAT3 has been recognized as a predictor of poor survival. STAT3 encodes two alternatively-spliced STAT3 isoforms: the full-length STAT3α isoform and the truncated STAT3ß isoform. These isoforms have been suggested as the reason for the occasionally observed opposing roles of STAT3 in cancer: an oncogene, on one hand, and a tumor suppressor on the other. To investigate their roles in aggressive breast cancer, we separately silenced each isoform and found that they affect each other's activation, impacting cell viability, cytokine expression, and migration. Silencing specific isoforms can lead to a more favorable balance of activated STAT3 proteins in the cell. Distinguishing between the two isoforms and their active forms is crucial for STAT3-related cancer diagnosis and therapy.

Functional near-infrared spectroscopy imaging of the prefrontal cortex during a naturalistic comedy movie.

Naturalistic stimulation (i.e., movies and auditory narratives of some minutes' length) has been a powerful approach to bringing more real-life experiences into laboratory experiments. Data-driven, intersubject correlation (ISC) analysis permits examining to what extent activity in a specific brain region correlates across participants during exposure to a naturalistic stimulus, as well as testing whether neural activity correlates with behavioral measures. Notably, most of the previous research with naturalistic stimuli was conducted using functional fMRI (fMRI). Here, we tested whether a naturalistic approach and the ISC are feasible using functional near-infrared spectroscopy (fNIRS) - the imaging method particularly suited for populations of patients and children. Fifty-three healthy adult participants watched twice a 3-min segment of a Charlie Chaplin movie while we recorded the brain activity on the surface of their prefrontal cortex using fNIRS. In addition, an independent group of 18 participants used a continuous scoring procedure to rate the extent to which they felt that different parts of the movie fragment were funny. Our two findings were as follows. First, we found higher-than-zero ISC in fNIRS signals in the prefrontal cortex lobes, a result that was particularly high in the oxygenated channels during the first repetition of the movie. Second, we found a significant negative correlation between oxygenated brain signals and ratings of the movie's humorousness. In a series of control analyses we demonstrated that this latter correlation could not be explained by various non-humor-related movie sensory properties (e.g., auditory volume and image brightness). The key overall outcome of the present study is that fNIRS in combination with the naturalistic paradigms and the ISC might be a sensitive and powerful research method to explore cognitive processing. Our results also suggest a potential role of the prefrontal cortex in humor appreciation.

miR-155: A Potential Biomarker for Predicting Mortality in COVID-19 Patients.

COVID-19, a pandemic of severe acute respiratory syndrome caused by Coronavirus 2 (SARS-CoV-2), continues to pose diagnostic and therapeutic challenges due to its unpredictable clinical course. Prognostic biomarkers may improve care by enabling quick identification of patients who can be safely discharged home versus those who may need careful respiratory monitoring and support. MicroRNAs (miRNAs) have risen to prominence as biomarkers for many disease states and as tools to assist in medical decisions. In the present study, we aimed to examine circulating miRNAs in hospitalized COVID-19 patients and to explore their potential as biomarkers for disease severity. We studied, by quantitative PCR, the expressions of miR-21, miR-146a, miR-146b, miR-155, and miR-499 in peripheral blood. We found that mild COVID-19 patients had 2.5-fold less circulating miR-155 than healthy people, and patients with a severe COVID-19 disease had 5-fold less circulating miR-155 than healthy people. In addition, we found that miR-155 is a good predictor of COVID-19 mortality. We suggest that examining miR-155 levels in patients' blood, upon admission to hospital, will ameliorate the care given to COVID-19 patients.

MiRNA-124a: a Potential Biomarker for Neurological Deficits Following Cardiac Surgery in Pediatric Patients.

Brain injury is a major source of patient morbidity after cardiac surgery in children. New early accurate biomarkers are needed for the diagnosis of patients at risk for cerebral postoperative damage. Specific circulating miRNAs have been found as suitable biomarkers for many diseases. We tested whether miRNA-124a reflects neurological injury in pediatric patients following heart surgery. Serum samples were obtained from 34 patients before and six hours after heart surgery. MiRNAs-124a was quantified by RQ-PCR. MiRNA-124a levels six hours after heart surgery correlated with the neurological outcome of the patients. In children with neurological deficits, miRNA-124a levels increased while in those with no neurological deficits the levels decreased. MiRNA-124a was able, at six hours after the operation, to identify patients who are at risk for the appearance of neurological deficits. Circulating miRNA-124a is a potential biomarker for the appearance of neurological deficits in pediatric patients following heart surgery. Graphical Abstract.

STAT3 isoforms differentially affect ACE2 expression: A potential target for COVID-19 therapy.

The SARS-coronavirus 2 is the aetiologic agent COVID-19. ACE2 has been identified as a cell entry receptor for the virus. Therefore, trying to understand how the gene is controlled has become a major goal. We silenced the expression of STAT3α and STAT3ß, and found that while silencing STAT3α causes an increase in ACE2 expression, silencing STAT3ß causes the opposite effect. Studying the role of STAT3 in ACE2 expression will shed light on the molecular events that contribute to the progression of the disease and that the different roles of STAT3α and STAT3ß in that context must be taken in consideration. Our results place STAT3 in line with additional potential therapeutic targets for treating COVID-19 patients.

Preoperative miRNA-208a as a Predictor of Postoperative Complications in Children with Congenital Heart Disease Undergoing Heart Surgery.

Major perioperative cardiovascular events are important causes of morbidity in pediatric patients with congenital heart disease who undergo reparative surgery. Current preoperative clinical risk assessment strategies have poor accuracy for identifying patients who will sustain adverse events following heart surgery. There is an ongoing need to integrate clinical variables with novel technology and biomarkers to accurately predict outcome following pediatric heart surgery. We tested whether preoperative levels of miRNAs-208a can serve as such a biomarker. Serum samples were obtained from pediatric patients immediately before heart surgery. MiRNA-208a was quantified by RQ-PCR. Correlations between the patient's clinical variables and miRNA levels were tested. Lower levels of preoperative miRNA-208a correlated with and could predict the appearance of postoperative cardiac and inflammatory complications. MiRNA-208a may serve as a biomarker for the prediction of patients who are at risk to develop complications following surgery for the repair of congenital heart defects.

Patterns of psychiatric hospitalizations among migrant workers and asylum-seekers in Israel: a single hospital archive study, 2005-2011.

Aim: Migrants have increased risk for psychiatric hospitalizations. Over the last decades Israel has become a destination for migration of migrant workers and asylum-seekers.Methods: The current retrospective study retrieved socio-demographic, clinical and migration-related chart data for 117 migrants admitted to a major Israeli psychiatric hospital between 2005-2011, to delineate characteristics and risk-factors for psychiatric hospitalizations. Multivariate logistic regression analyses were performed to predict re-hospitalization.Results: Of the study sample, 61% were single men, 20% had been exposed to trauma, 15% had prior psychiatric hospitalizations and 24% had attempted suicide. Approximately, 76% were involuntarily hospitalized and diagnosed with psychosis. None were diagnosed with PTSD. Approximately, 20% were re-hospitalized. Factors significantly associated with re-hospitalization were male gender (OR = 15.2, 95%, CI 1.8-126.9, p = 0.012), prior psychiatric hospitalization (OR = 15.4, 95% CI 2.1-111.9, p < 0.01), being single (OR = 5.96, 95% CI1.14-31.07, p = 0.03) and traumatic exposure (OR = 4.75, 95% CI: 1.17-19.36, p= 0.03). Shorter duration in Israel, unemployment, asylum-seekers, no temporary-visa and use of restraints were more prevalent among those re-hospitalized.Conclusion: Identification of migrants at risk and trauma-informed, culturally relevant services can reduce hospitalizations.

Circulating MicroRNAs: a Potential Biomarker for Cardiac Damage, Inflammatory Response, and Left Ventricular Function Recovery in Pediatric Viral Myocarditis.

Viral myocarditis (VM) can be a life-threatening event resulting in cardiac failure, chronic cardiomyopathy, and death. VM typically includes three phases, i.e., acute, subacute, and resolution/chronic. We prospectively investigated cardiac- and inflammatory-associated plasma-circulating miRNA levels in eight pediatric patients with VM during the three stages of the disease. The level of cardiac-associated miR-208a was significantly elevated during the acute phase compared with the subacute and resolution/chronic phases. The level of cardiac- and inflammatory-associated miR-21 was significantly elevated during the acute phase compared to the resolution/chronic phase. Moreover, cardiac-associated miR-208b levels during the subacute phase correlated with systolic left ventricular function recovery as measured during the resolution/chronic phase. The findings of our study demonstrate an association between cardiac damage and the inflammatory response and the expression of miR-208a and miR-21 during the pathological progression of myocarditis. We also found that miR-208b levels exhibit a prognostic significance for left ventricular functional recovery.

MiRNA-208a as a Sensitive Early Biomarker for the Postoperative Course Following Congenital Heart Defect Surgery.

Current clinical risk assessment strategies have poor accuracy for identifying patients who will suffer adverse perioperative events. There is an ongoing need to integrate clinical variables with novel technology and biomarkers to accurately predict outcome after pediatric heart surgery. We tested the hypothesis that miRNAs-208a, -208b, and -499 can serve as noninvasive biomarkers for the extent of myocardial damage and the postoperative clinical course of pediatric patients with congenital heart defects (CHDs) at an early time point following surgery. Serum samples were obtained from 79 pediatric patients before and 6, 12, and 24 h after surgery. MiRNAs-208a, -208b, and -499 were quantified by RQ-PCR. Correlations between the patient's clinical variables and miRNA levels were tested. Our results show that the levels of the three miRNAs were elevated at 6 h after surgery, remained high at 12 h and declined at 24 h after the operation. The amount of all three miRNAs at 6 h after surgery correlated with surgical and laboratory parameters. Their amount at 12 h after surgery correlated with the length of stay at the hospital. Expression levels of miRNA-208a at 6 h were related to the appearance of cardiac complications, and could predict whether a patient will sustain complications or will be ventilated for more than 48 h after surgery. Circulating miRNA-208a is a predictor for the risk of developing cardiac complications during the postoperative course as early as 6 h after heart surgery for CHD in pediatric patients.

Culture as a Double-Edged Sword: The Posttraumatic Experience of Indigenous Ethnic Minority Veterans.

The applicability of Western concepts regarding the treatment of trauma in soldiers from indigenous ethnic minority backgrounds has scarcely been researched. This study explored the subjective meaning of living with chronic posttraumatic stress disorder (PTSD) among indigenous Bedouin veterans of the Israel Defense Forces (IDF), who are of Arab ethnicity and Muslim faith. In-depth, semistructured qualitative interviews were conducted with 10 Bedouin veterans suffering from PTSD and three Bedouin mental health clinicians working with this population. Two themes emerged: "I wanted to be like everyone else," referring to participants' experiences during their military service, and "Fluctuating between belonging and abandonment," referring to veterans' experiences of living with mental health problems in a traditional minority community. These findings highlight the importance of conducting a comprehensive inquiry into the complex cultural and social backgrounds of indigenous minority veterans suffering from PTSD, and the interplay between the conflicted identities and multiple "realities" they experience.

New Role for Interleukin-13 Receptor α1 in Myocardial Homeostasis and Heart Failure.

BACKGROUND: The immune system plays a pivotal role in myocardial homeostasis and response to injury. Interleukins-4 and -13 are anti-inflammatory type-2 cytokines, signaling via the common interleukin-13 receptor α1 chain and the type-2 interleukin-4 receptor. The role of interleukin-13 receptor α1 in the heart is unknown. METHODS AND RESULTS: We analyzed myocardial samples from human donors (n=136) and patients with end-stage heart failure (n=177). We found that the interleukin-13 receptor α1 is present in the myocardium and, together with the complementary type-2 interleukin-4 receptor chain Il4ra, is significantly downregulated in the hearts of patients with heart failure. Next, we showed that Il13ra1-deficient mice develop severe myocardial dysfunction and dyssynchrony compared to wild-type mice (left ventricular ejection fraction 29.7±9.9 versus 45.0±8.0; P=0.004, left ventricular end-diastolic diameter 4.2±0.2 versus 3.92±0.3; P=0.03). A bioinformatic analysis of mouse hearts indicated that interleukin-13 receptor α1 regulates critical pathways in the heart other than the immune system, such as extracellular matrix (normalized enrichment score=1.90; false discovery rate q=0.005) and glucose metabolism (normalized enrichment score=-2.36; false discovery rate q=0). Deficiency of Il13ra1 was associated with reduced collagen deposition under normal and pressure-overload conditions. CONCLUSIONS: The results of our studies in humans and mice indicate, for the first time, a role of interleukin-13 receptor α1 in myocardial homeostasis and heart failure and suggests a new therapeutic target to treat heart disease.

Alternative Splicing of STAT3 Is Affected by RNA Editing.

A-to-I RNA editing, carried out by adenosine deaminase acting on RNA (ADAR) enzymes, is an epigenetic phenomenon of posttranscriptional modifications on pre-mRNA. RNA editing in intronic sequences may influence alternative splicing of flanking exons. We have previously shown that conditions that induce editing result in elevated expression of signal transducer and activator of transcription 3 (STAT3), preferentially the alternatively-spliced STAT3ß isoform. Mechanisms regulating alternative splicing of STAT3 have not been elucidated. STAT3 undergoes A-to-I RNA editing in an intron residing in proximity to the alternatively spliced exon. We hypothesized that RNA editing plays a role in regulating alternative splicing toward STAT3ß. In this study we extend our observation connecting RNA editing to the preferential induction of STAT3ß expression. We study the involvement of ADAR1 in STAT3 editing and reveal the connection between editing and alternative splicing of STAT3. Deferoaxamine treatment caused the induction in STAT3 RNA editing and STAT3ß expression. Silencing ADAR1 caused a decrease in STAT3 editing and expression with a preferential decrease in STAT3ß. Cells transfected with a mutated minigene showed preferential splicing toward the STAT3ß transcript. Editing in the STAT3 intron is performed by ADAR1 and affects STAT3 alternative splicing. These results suggest that RNA editing is one of the molecular mechanisms regulating the expression of STAT3ß.

Micro-RNA-208a, -208b, and -499 as Biomarkers for Myocardial Damage After Cardiac Surgery in Children.

OBJECTIVES: To test the hypothesis that cardiac-enriched micro-RNAs can serve as accurate biomarkers that reflect myocardial injury and to predict the postoperative course following pediatric cardiac surgery. Micro-RNAs have emerged as plasma biomarkers for many pathologic states. We aimed to quantify preoperative and postoperative plasma levels of cardiac-enriched micro-RNA-208a, -208b, and -499 in children undergoing cardiac surgery and to evaluate correlations between their levels, the extent of myocardial damage, and the postoperative clinical course. DESIGN: PICU. PATIENTS: Thirty pediatric patients that underwent open heart surgery for the correction of congenital heart defects between January 2012 to July 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At 12 hours post surgery, the plasma levels of the micro-RNAs increased by 300- to 4,000-fold. At 24 hours, their levels decreased but remained significantly higher than before surgery. Micro-RNA levels were associated with troponin levels, longer cardiopulmonary bypass and aortic crossclamp times, maximal postoperative aspartate aminotransferase levels, and delayed hospital discharge. CONCLUSIONS: Circulating micro-RNA-208a, -208b, and -499 are detectable in the plasma of children undergoing cardiac surgery and may serve as novel biomarkers for monitoring and forecasting postoperative myocardial injury and recovery.

Cultural Perspectives on the Aftereffects of Combat Trauma: Review of a Community Study of Bedouin IDF Servicemen and Their Families.

Combat trauma may affect servicemen from indigenous, traditional communities in ways that warrant special attention. The Bedouins, who enlist in the Israel Defense Forces (IDF) voluntarily, represent a unique, closed, collectivist cultural minority, potentially in a predicament in light of ongoing sociopolitical events. This paper summarizes findings and lessons learned from a community study of Bedouin IDF servicemen and their families residing in Israel's Western Galilee. This is the only research endeavor to have addressed trauma exposure and posttraumatic reactions in this community. The sampling strategies and interview schedule were designed in consideration of participation barriers typical of hard-to-reach populations. Data collection followed an extended phase of liaising with key informants and building trust. Study limitations are discussed in terms of the challenges presented by this type of research. Interviews conducted with 317 men, 129 wives, and 67 mothers revealed high levels of trauma exposure and posttraumatic stress disorder (PTSD) in the men, and related distress in wives and mothers, but not in the children. The role of aggression in mediating the impact of PTSD and concepts such as shame, the loss of personal resources, and beliefs about retribution are highlighted as key issues for a culturally relevant understanding of traumatized indigenous communities.

F11R expression upon hypoxia is regulated by RNA editing.

F11R is a cell adhesion molecule found on the surface of human platelets. It plays a role in platelet aggregation, cell migration and cell proliferation. F11R is subjected to RNA editing, a post-transcriptional modification which affects RNA structure, stability, localization, translation and splicing. RNA editing in the 3'UTR of F11R and RNA levels are increased upon hypoxia. We therefore set to examine if RNA editing plays a role in the increase of F11R RNA seen upon hypoxic conditions. We show that ADAR1, but not ADAR2, takes part in the editing of F11R however editing alone is not sufficient for obtaining an elevation in RNA levels. In addition we show that hyper-edited mature mRNAs are retained in the nucleus and are associated with p54(nrb). We therefore conclude that hypoxia-induced edited RNAs of F11R are preferentially stabilized and accumulate in the nucleus preventing their export to the cytoplasm for translation. This mechanism may be used by additional proteins in the cell as part of the cell's effort to reduce metabolism upon hypoxic stress.

In the aftermath of trauma: a community study of Bedouin IDF servicemen and their families.

BACKGROUND: Data are scarce on the effects of trauma and post-traumatic stress disorder (PtSD) on minority servicemen from non-western communities and the indirect impact on their spouses and other family members. METHOD: Interviews were completed with Bedouin servicemen in the Israel Defense Forces (N=317) and co-resident wives (N=129) and mothers (N=67). RESULTS: Servicemen had high levels of trauma exposure and PtSD. Aggression displayed by married servicemen fully mediated the strong and positive relationship between their PtSD and wives' post-traumatic, depressive, and somatic symptoms. Mothers' more severe emotional distress was unrelated to sons' diagnostic status, but positively associated with sons' aggression. LIMITATIONS: these include sampling method, cross-sectional design, retrospective reports, and absence of data on onset of symptoms. CONCLUSIONS: Profound cultural barriers to care require a proactive approach towards non-western servicemen, including (1) identification and initial treatment of trauma-related symptoms before discharge, (2) community education, and (3) training primary care physicians to address PtSD and related problems among servicemen and their families.

Increased RNA editing in children with cyanotic congenital heart disease.

PURPOSE: To test the hypothesis that RNA editing is altered in pediatric patients with cyanotic congenital heart disease (CHD) and to determine whether A-to-I RNA editing is associated with the postoperative course following cardiac surgery. Cyanotic CHD is associated with a unique pathophysiology caused by chronic hypoxia. The perioperative course of cyanotic infants is partly dictated by the degree of expression of inflammatory and cardiac genes, some of which undergo A-to-I RNA editing. METHODS: RNA was extracted pre- and postoperatively from blood samples of cyanotic and acyanotic patients. Each sample was analyzed for A-to-I RNA editing using automatic DNA sequencing of an intronic segment of the MED13 gene. RNA expression levels of adenosine deaminase acting on RNA (ADAR) enzymes responsible for RNA editing were examined by quantitative reverse-transcriptase polymerase chain reaction. RESULTS: A-to-I RNA editing in MED13 was significantly higher among cyanotic patients (n = 19) than acyanotic ones (n = 18) both pre- and postoperatively, as manifested by average editing at seven highly edited sites (27.4 ± 8.5% versus 20.8 ± 10.2%; P = 0.038) and editing at specific sites, e.g., position 14 (20.2 ± 5.1% versus 14.5 ± 5.2%; P = 0.002). Cyanotic patients exhibited a more complicated postoperative course than acyanotic patients. ADAR2 RNA levels were significantly lower among cyanotic patients. CONCLUSIONS: Cyanotic children manifest significantly higher rates of A-to-I RNA editing than acyanotic children as well as a more complicated surgical course. Posttranscriptional RNA changes may affect cellular and metabolic pathways and influence the perioperative course following hypoxia.

Resource loss and posttraumatic responses in Bedouin members of the Israeli Defense Forces.

This study examined the impact of exposure to traumatizing events in an ethnic minority group of Bedouin members of the Israel Defense Forces (N = 317). Guided by the conservation of resources (COR) theory (Hobfoll, 1988), the authors hypothesized that loss of resources would mediate the relationship between trauma and posttraumatic responses. We found that loss of personal resources (e.g., self-esteem, self-mastery) was the best predictor of psychological distress among traumatized Bedouin servicemen. Our findings suggest the significance of personal resources within collectivist communities in coping with trauma and maintaining resilience. This study contributes to the understanding of the ethnocultural aspects of trauma and the potential interventions that may be tailored for minority groups.

A-to-I RNA editing is induced upon hypoxia.

Regulating gene expression is part of a cell's response to hypoxia. A-to-I RNA editing is an epigenetic phenomenon that can contribute to RNA and protein levels and to isoform diversity. In this study, we identified alterations in the levels of RNA editing following hypoxic stress in three genes: MED13, STAT3, and F11R. Changes in editing levels were associated with changes in RNA levels. These results suggest that A-to-I RNA editing may be one of the mechanisms used by cells to regulate changes in gene expression after hypoxia. These findings could lead to a novel therapeutic approach and better health care for children with hypoxemia.