Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development.

The E2f7 and E2f8 family members are thought to function as transcriptional repressors important for the control of cell proliferation. Here, we have analyzed the consequences of inactivating E2f7 and E2f8 in mice and show that their individual loss had no significant effect on development. Their combined ablation, however, resulted in massive apoptosis and dilation of blood vessels, culminating in lethality by embryonic day E11.5. A deficiency in E2f7 and E2f8 led to an increase in E2f1 and p53, as well as in many stress-related genes. Homo- and heterodimers of E2F7 and E2F8 were found on target promoters, including E2f1. Importantly, loss of either E2f1 or p53 suppressed the massive apoptosis in double-mutant embryos. These results identify E2F7 and E2F8 as a unique repressive arm of the E2F transcriptional network that is critical for embryonic development and control of the E2F1-p53 apoptotic axis.

Belief that addiction is a discrete category is a stronger correlate with stigma than the belief that addiction is biologically based.

BACKGROUND: Drug addiction is stigmatized, and this stigma contributes to poor outcomes for individuals with addiction. Researchers have argued that providing genetic explanations of addiction will reduce stigma, but there has been limited research testing this prediction. METHODS: We presented participants (N = 252) with news articles that either provided genetic or anti-genetic explanations of addiction. RESULTS: There was no effect of article condition on stigma. Participants' biological essentialism correlated with stigma in the context of both opioid and methamphetamine addiction. However, participants' non-biological essentialism was a significantly stronger correlate with stigma. CONCLUSIONS: This suggests that other essentialist beliefs, like belief that categories are discrete, may be more useful than biological essentialism for understanding addiction stigma.

Utility of Cerebral Embolic Protection Devices in Transcatheter Procedures: A Systematic Review and Meta-Analysis.

With the emergence of the largest randomized control trial to date-the Stroke Protection With Sentinel During Transcatheter Aortic Valve Replacement (PROTECTED TAVR) study-we sought to conduct an updated meta-analyses to evaluate the utility of CEP devices on both clinical outcomes and neuroimaging parameters. Electronic databases were queried through November 2022 for clinical trials comparing the utility of Cerebral Embolic Protection (CEP) devices in Transcatheter Aortic Valve Replacement (TAVR) with non-CEP TAVR procedures. Meta-analyses were performed using the generic inverse variance technique, and a random-effects model, and results are presented as weighted mean differences (WMD) for continuous outcomes, and hazard ratios (HR) for dichotomous outcomes. Outcomes of interest included stroke, disabling stroke, nondisabling stroke, bleeding, mortality, vascular complications, new ischemic lesions, acute kidney injury (AKI), and total lesion volume. Thirteen studies (8 RCTs, 5 observational studies) consisting of 128,471 patients were included in the analysis. Results from our meta-analyses showed a significant reduction in stroke (OR: 0.84 [0.74-0.95]; P < 0.01; I2 = 0%), disabling stroke (OR: 0.37 [0.21-0.67]; P < 0.01; I2 = 0%) and bleeding events (OR: 0.91 [0.83-0.99]; P = 0.04; I2 = 0%) through CEP device use in TAVR. The use of CEP devices had no significant impact on nondisabling stroke (OR: 0.94 [0.65-1.37]; P < 0.01; I2 = 0%), mortality (OR: 0.78 [0.53-1.14]; P < 0.01; I2 = 17%), vascular complications (OR: 0.99 [0.63-1.57]; P < 0.01; I2 = 28%), AKI (OR: 0.78 [0.46-1.32]; P < 0.01; I2 = 0%), new ischemic lesions (MD: -1.72 [-4.01, 0.57]; P < 0.001; I2 = 95%) and total lesion volume (MD: -46.11 [-97.38, 5.16]; P < 0.001; I2 = 81%). The results suggest that CEP device use was associated with a lower risk of disabling stroke and bleeding events in patients undergoing TAVR.

Therapeutic Outcomes Following Isolated Transcatheter Tricuspid Valve Repair: A Systematic Review and Meta-analysis.

Tricuspid regurgitation (TR) is traditionally treated surgically, but isolated transcatheter tricuspid valve repair (ITTVR) offers a less invasive option. This study conducts a meta-analysis and systematic review to evaluate ITTVR outcomes in patients with TR. Database searches until March 2023 identified studies assessing ITTVR safety and efficacy in moderate/severe TR patients. Primary outcomes analyzed were severe TR, NYHA functional class improvement, and 6-minute walking distance. Meta-analyses used Risk ratio (RR) or mean difference with a random effects model. The review included 25 studies with 2421 patients. ITTVR improved NYHA functional class (RR: 3.262), reduced TR severity (RR: 0.303), and enhanced 6-minute walking distance (MD: +47.077 m). Echocardiographic parameters improved, including reductions in TR vena contracta, TR EROA, septolateral tricuspid annular diameter, RVEDD, RV FAC, and TAPSE. LVEF and PASP showed no significant changes. ITTVR improves functional outcomes and echocardiographic parameters in TR patients.

Current Practices and Considerations for Transcatheter Mitral Valve Implantation Based on Risk Stratification Among Patients with Mitral Valve Regurgitation.

Mitral Regurgitation (MR) is the most common form of severe valvular disease occurring in developed countries, being caused either primarily on its own or secondary to cardiac disease. Surgical intervention is required for the correction of MR, which could include the replacement or repair of the affected valve. Transcatheter Mitral Valve Replacement (TMVR) in selected patients is of increasing importance, especially after the success of Transcatheter Aortic Valve Replacement. TMVR can be divided into 3 types, that is, valve-in-valve for severe mitral valve disease, valve-in-ring for failed surgical repairs, and valve-in-mitral annular calcifications for mitral valvular disease with severe mitral annular calcifications and poor surgical criteria. The FDA approved Mitral valve-in-valve for patients with a high surgical risk in 2017, while valve-in-ring and valve-in-mitral annular calcifications are still currently under consideration. The SAPIEN M3 valve is relatively new with a trans-septal system, with a success rate of 86%, and no mortality in a 30-day outcome. The Cardiovalve is a bovine pericardium device that has a dual nitinol frame with a custom surgical design to facilitate TMVR. The AHEAD trial will evaluate whether the device is safe to use in a clinical setting and how effective it is for reducing MR in these patients. The trial consists of 30 patients in which the first 5 patients showed 100% technical success and a reduction of MR. This evolution of modern medicine has assisted in many different countries, including Pakistan where there is a higher prevalence of MR and hence, a greater need to apply TMVR in clinical practice.

Frequency of COVID-19 vaccine side effects and its associated factors among the vaccinated population of Pakistan: A cross-sectional study.

Background: Coronavirus disease 2019 (COVID-19) vaccine side effects have an important role in the hesitancy of the general population toward vaccine administration. Therefore, this study was conducted to document the COVID-19 vaccine side effects in our population. Materials and Methods: An online survey-based, cross-sectional study was carried out from September 1, 2021, to October 1, 2021, to document the side effects of the COVID-19 vaccine among the general public. The questionnaire included participants' sociodemographic data, type of vaccine, comorbidities, previous COVID-19 infection, and assessment of side effects reported by them. Results: The majority of the participants were <20 years of age (62.2%), females (74.9%), belonged to the educational sector (58.1%), residents of Sindh (65.7%), and were previously unaffected by COVID-19 infection (73.3%). Sinovac (38.7%) followed by Sinopharm (30.4%) and Moderna (18.4%) were administered more frequently. Commonly reported side effects were injection site pain (82%), myalgia (55%), headache (46%), fatigue/malaise (45%), and fever (41%). Vaccine side effects were more likely to be reported with the first dose as compared to the second dose. On regression analysis, factors associated with occurrence of side effects included younger age (odds ratio [OR]: 6.000 [2.065-17.431], p < 0.001), female gender (OR: 2.373 [1.146-4.914], p = 0.020), marital status (OR: 0.217 [0.085-0.556], p < 0.001), graduate level of education (OR: 0.353 [0.153-0.816], p = 0.015), and occupation being either retired, freelancers, or social workers (OR: 0.310 [0.106-0.909]), p = 0.033). Previous infection with COVID-19 (p = 0.458) and comorbidities were found unrelated (p = 0.707) to the occurrence of side effects. Conclusion: The overall prevalence of local side effects was quite higher than the systemic ones. Further large-scale studies on vaccine safety are required to strengthen public confidence in the vaccination drive.

Distinct Biological Motion Perception in Autism Spectrum Disorder: A Meta-Analysis.

If neurotypical people rely on specialized perceptual mechanisms when perceiving biological motion, then one would not expect an association between task performance and IQ. However, if those with ASD recruit higher order cognitive skills when solving biological motion tasks, performance may be predicted by IQ. In a meta-analysis that included 19 articles, we found an association between biological motion perception and IQ among observers with ASD but no significant relationship among typical observers. If the task required emotion perception, then there was an even stronger association with IQ in the ASD group.

Early Attention to Animacy: Change-Detection in 11-Month-Olds.

Adults are faster and more accurate at detecting changes to animate compared to inanimate stimuli in a change-detection paradigm. We tested whether 11-month-old children detected changes to animate objects in an image more reliably than they detected changes to inanimate objects. During each trial, infants were habituated to an image of a natural scene. Once the infant habituated, the scene was replaced by a scene that was identical except that a target object was removed. Infants dishabituated significantly more often if an animate target had been removed from the scene. Dishabituation results suggested that infants, like adults, preferentially attend to animate rather than to inanimate objects.

Canadian children's concepts of national groups: A comparison with children from the United States.

Understanding the development and structure of people's concepts of national groups can contribute to an understanding of their behavior in the political arena, including perhaps the recent rise in nationalism and anti-immigrant sentiment. Here, we provide a developmental investigation of concepts of national groups in a sample of 5- to 8-year-old Canadian children (N = 79). Using an extensive battery of measures, we assessed the extent to which children conceive of national groups as socially constructed versus as having deeper, perhaps biological, "essences" that shape their members' physical and psychological makeup. At younger ages, Canadian children tended to essentialize national groups, including in a biological sense. At older ages, the biological conception of national groups subsided, but children continued to view these groups as meaningful and informative. A statistical comparison with 5- to 8-year-old American children's responses to the same measures (N = 70; using data from Hussak & Cimpian, 2019) revealed a great degree of overlap, despite substantial differences between the two countries in how national identity is conceived and described. These findings add an important piece to our understanding of the development of concepts of national groups. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Viral MicroRNAs: Interfering the Interferon Signaling.

Interferons are secreted cytokines with potent antiviral, antitumor and immunomodulatory functions. As the first line of defense against viruses, this pathway restricts virus infection and spread. On the contrary, viruses have evolved ingenious strategies to evade host immune responses including the interferon pathway. Multiple families of viruses, in particular, DNA viruses, encode microRNA (miR) that are small, non-protein coding, regulatory RNAs. Virus-derived miRNAs (v-miR) function by targeting host and virus-encoded transcripts and are critical in shaping host-pathogen interaction. The role of v-miRs in viral pathogenesis is emerging as demonstrated by their function in subverting host defense mechanisms and regulating fundamental biological processes such as cell survival, proliferation, modulation of viral life-cycle phase. In this review, we will discuss the role of v-miRs in the suppression of host genes involved in the viral nucleic acid detection, JAK-STAT pathway, and cytokine-mediated antiviral gene activation to favor viral replication and persistence. This information has yielded new insights into our understanding of how v-miRs promote viral evasion of host immunity and likely provide novel antiviral therapeutic targets.

Labelling faces as 'Autistic' reduces the inversion effect.

Does the belief that a face belongs to an individual with autism affect recognition of that face? To address this question, we used the inversion effect as a marker of face recognition. In Experiment 1, participants completed a recognition task involving upright and inverted faces labelled as either 'regular' or 'autistic'. In reality, the faces presented in both conditions were identical. Results revealed a smaller inversion effect for faces labelled as autistic. Thus, simply labelling a face as 'autistic' disrupts recognition. Experiment 2 showed a larger inversion effect after the provision of humanizing versus dehumanizing information about faces labelled as 'autistic'. We suggest changes in the inversion effect could be used as a measure to study stigma within the context of objectification and dehumanization.

Histone deacetylation of RB-responsive promoters: requisite for specific gene repression but dispensable for cell cycle inhibition.

The retinoblastoma tumor suppressor protein (RB) is targeted for inactivation in the majority of human tumors, underscoring its critical role in attenuating cellular proliferation. RB inhibits proliferation by repressing the transcription of genes that are essential for cell cycle progression. To repress transcription, RB assembles multiprotein complexes containing chromatin-modifying enzymes, including histone deacetylases (HDACs). However, the extent to which HDACs participate in transcriptional repression and are required for RB-mediated repression has not been established. Here, we investigated the role of HDACs in RB-dependent cell cycle inhibition and transcriptional repression. We find that active RB mediates histone deacetylation on cyclin A, Cdc2, topoisomerase IIalpha, and thymidylate synthase promoters. We also demonstrate that this deacetylation is HDAC dependent, since the HDAC inhibitor trichostatin A (TSA) prevented histone deacetylation at each promoter. However, TSA treatment blocked RB repression of only a specific subset of genes, thereby demonstrating that the requirement of HDACs for RB-mediated transcriptional repression is promoter specific. The HDAC-independent repression was not associated with DNA methylation or gene silencing but was readily reversible. We show that this form of repression resulted in altered chromatin structure and was dependent on SWI/SNF chromatin remodeling activity. Importantly, we find that cell cycle inhibitory action of RB is not intrinsically dependent on the ability to recruit HDAC activity. Thus, while HDACs do play a major role in RB-mediated repression, they are dispensable for the repression of critical targets leading to cell cycle arrest.

A portable platform to collect and review behavioral data simultaneously with neurophysiological signals.

This paper presents a portable platform to collect and review behavioral data simultaneously with neurophysiological signals. The whole system is comprised of four parts: a sensor data acquisition interface, a socket server for real-time data streaming, a Simulink system for real-time processing and an offline data review and analysis toolbox. A low-cost microcontroller is used to acquire data from external sensors such as accelerometer and hand dynamometer. The micro-controller transfers the data either directly through USB or wirelessly through a bluetooth module to a data server written in C++ for MS Windows OS. The data server also interfaces with the digital glove and captures HD video from webcam. The acquired sensor data are streamed under User Datagram Protocol (UDP) to other applications such as Simulink/Matlab for real-time analysis and recording. Neurophysiological signals such as electroencephalography (EEG), electrocorticography (ECoG) and local field potential (LFP) recordings can be collected simultaneously in Simulink and fused with behavioral data. In addition, we developed a customized Matlab Graphical User Interface (GUI) software to review, annotate and analyze the data offline. The software provides a fast, user-friendly data visualization environment with synchronized video playback feature. The software is also capable of reviewing long-term neural recordings. Other featured functions such as fast preprocessing with multithreaded filters, annotation, montage selection, power-spectral density (PSD) estimate, time-frequency map and spatial spectral map are also implemented.

Upregulation of long noncoding RNA MIAT in aggressive form of chronic lymphocytic leukemias.

Long noncoding RNAs (lncRNAs) are non-proten-coding transcripts of more than 200 nucleotides generated by RNA polymerase II and their expressions are tightly regulated in cell type specific- and/or cellular differential stage specific- manner. MIAT, originally isolated as a candidate gene for myocardial infarction, encodes lncRNA (termed MIAT). Here, we determined the expression level of MIAT in established leukemia/lymphoma cell lines and found its upregulation in lymphoid but not in myeloid cell lineage with mature B cell phenotype. MIAT expression level was further determined in chronic lymphocytic leukemias (CLL), characterized by expansion of leukemic cells with mature B phenotype, to demonstrate relatively high occurrence of MIAT upregulation in aggressive form of CLL carrying either 17p-deletion, 11q-deletion, or Trisomy 12 over indolent form carrying 13p-deletion. Furthermore, we show that MIAT constitutes a regulatory loop with OCT4 in malignant mature B cell, as was previously reported in mouse pulripotent stem cell, and that both molecules are essential for cell survival.

PBX1 is a favorable prognostic biomarker as it modulates 13-cis retinoic acid-mediated differentiation in neuroblastoma.

PURPOSE: Neuroblastoma is an embryonic childhood cancer with high mortality. 13-cis retinoic acid (13-cisRA) improves survival for some patients, but many recur, suggesting clinical resistance. The mechanism of resistance and the normal differentiation pathway are poorly understood. Three-amino-acid loop extension (TALE) family genes are master regulators of differentiation. Because retinoids promote differentiation in neuroblastoma, we evaluated TALE family gene expression in neuroblastoma. EXPERIMENTAL DESIGN: We evaluated expression of TALE family genes in RA-sensitive and -resistant neuroblastoma cell lines, with and without 13-cisRA treatment, identifying genes whose expression correlates with retinoid sensitivity. We evaluated the roles of one gene, PBX1, in neuroblastoma cell lines, including proliferation and differentiation. We evaluated PBX1 expression in primary human neuroblastoma samples by qRT-PCR, and three independent clinical cohort microarray datasets. RESULTS: We confirmed that induction of PBX1 expression, and no other TALE family genes, was associated with 13-cisRA responsiveness in neuroblastoma cell lines. Exogenous PBX1 expression in neuroblastoma cell lines, mimicking induced PBX1 expression, significantly impaired proliferation and anchorage-independent growth, and promoted RA-dependent and -independent differentiation. Reduced PBX1 protein levels produced an aggressive growth phenotype and RA resistance. PBX1 expression correlated with histologic neuroblastoma subtypes, with highest expression in benign ganglioneuromas and lowest in high-risk neuroblastomas. High PBX1 expression is prognostic of survival, including in multivariate analysis, in the three clinical cohorts. CONCLUSIONS: PBX1 is an essential regulator of differentiation in neuroblastoma and potentiates retinoid-induced differentiation. Neuroblastoma cells and tumors with low PBX1 expression have an immature phenotype with poorer prognosis, independent of other risk factors.

Targeted ablation of the WW domain-containing oxidoreductase tumor suppressor leads to impaired steroidogenesis.

The WW domain-containing oxidoreductase (WWOX) gene encodes a 46-kDa tumor suppressor. The Wwox protein contains two N-terminal WW domains that interact with several transcriptional activators containing proline-tyrosine motifs and a central short-chain dehydrogenase/reductase domain that has been suggested to play a role in steroid metabolism. Recently, we have shown that targeted deletion of the Wwox gene in mice leads to postnatal lethality and defects in bone growth. Here, we report that Wwox-deficient mice display impaired steroidogenesis. Mutant homozygous mice are born with gonadal abnormalities, including failure of Leydig cell development in testis and reduced theca cell proliferation in ovary. Furthermore, Wwox(-/-) mice displayed impaired gene expression of key steroidogenesis enzymes. Affymetrix microarray gene analysis revealed differentially expressed related genes in steroidogenesis in knockout mice testis and ovary as compared with control mice. These results demonstrate the essential requirement for the Wwox tumor suppressor in proper steroidogenesis.

SWI/SNF deficiency results in aberrant chromatin organization, mitotic failure, and diminished proliferative capacity.

Switch (SWI)/sucrose nonfermentable (SNF) is an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position to alter transcriptional programs within the cell. It is known that the SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and it has recently been implicated in cancer development. The ATPase action of SWI/SNF is conferred through either the brahma-related gene 1 (Brg1) or brahma (Brm) subunit of the complex, and it is of central importance to the modification of nucleosome position. In this study, the role of the Brg1 and Brm subunits were examined as they relate to chromatin structure and organization. Deletion of the Brg1 ATPase results in dissolution of pericentromeric heterochromatin domains and a redistribution of histone modifications associated with these structures. This effect was highly specific to Brg1 and is not reproduced by the loss of Brm or SNF5/BAF47/INI1. Brg1 deficiency is associated with the appearance of micronuclei and aberrant mitoses that are a by-product of dissociated chromatin structure. Thus, Brg1 plays a critical role in maintaining chromatin structural integrity.

SWI/SNF activity is required for the repression of deoxyribonucleotide triphosphate metabolic enzymes via the recruitment of mSin3B.

The SWI/SNF chromatin remodeling complex plays a critical role in the coordination of gene expression with physiological stimuli. The synthetic enzymes ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase are coordinately regulated to ensure appropriate deoxyribonucleotide triphosphate levels. Particularly, these enzymes are actively repressed as cells exit the cell cycle through the action of E2F transcription factors and the retinoblastoma tumor suppressor/p107/p130 family of pocket proteins. This process is found to be highly dependent on SWI/SNF activity as cells deficient in BRG-1 and Brm subunits fail to repress these genes with activation of pocket proteins, and this deficit in repression can be complemented, via the ectopic expression of BRG-1. The failure to repress transcription does not involve a blockade in the association of E2F or pocket proteins p107 and p130 with promoter elements. Rather, the deficit in repression is due to a failure to mediate histone deacetylation of ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase promoters in the absence of SWI/SNF activity. The basis for this is found to be a failure to recruit mSin3B and histone deacetylase proteins to promoters. Thus, the coordinate repression of deoxyribonucleotide triphosphate metabolic enzymes is dependent on the action of SWI/SNF in facilitating the assembly of repressor complexes at the promoter.