TTF1 control of LncRNA synthesis delineates a tumor suppressor pathway directly regulating the ribosomal RNA genes.

The tumor suppressor p14/19ARF regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). However, the role played by TTF1 in regulating the rRNA genes and in potentially controlling growth has remained unclear. We now show that TTF1 expression regulates cell growth by determining the cellular complement of ribosomes.

Implementation of an audit and feedback module targeting low-value clinical practices in a provincial trauma quality assurance program: a cost-effectiveness study.

Background: Audit and Feedback (A&F) interventions based on quality indicators have been shown to lead to significant improvements in compliance with evidence-based care including de-adoption of low-value practices (LVPs). Our primary aim was to evaluate the cost-effectiveness of adding a hypothetical A&F module targeting LVPs for trauma admissions to an existing quality assurance intervention targeting high-value care and risk-adjusted outcomes. A secondary aim was to assess how certain A&F characteristics might influence its cost-effectiveness.

Transcription factor UBF depletion in mouse cells results in downregulation of both downstream and upstream elements of the rRNA transcription network.

Transcription/processing of the ribosomal RNA (rRNA) precursor, as part of ribosome biosynthesis, is intensively studied and characterized in eukaryotic cells. Here, we constructed shRNA-based mouse cell lines partially silenced for the Upstream Binding Factor UBF, the master regulator of rRNA transcription and organizer of open rDNA chromatin. Full Ubf silencing in vivo is not viable, and these new tools allow further characterization of rRNA transcription and its coordination with cellular signaling.

HMG-boxes, ribosomopathies and neurodegenerative disease.

The UBTF E210K neuroregression syndrome is a predominantly neurological disorder caused by recurrent dominant variants in Upstream Binding Factor, that is, essential for transcription of the ribosomal RNA genes. This unusual form of ribosomopathy is characterized by a slow decline in cognition, behavior, and sensorimotor functioning during the critical period of development. UBTF (or UBF) is a multi-HMGB-box protein that acts both as an epigenetic factor to establish "open" chromatin on the ribosomal genes and as a basal transcription factor in their RNA Polymerase I transcription.

Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs-Lessons from Animal Studies.

In 2020, fentanyl and its analogs contributed to ~65% of drug-attributed fatalities in the USA, with a threatening increasing trend during the last ten years. These synthetic opioids used as potent analgesics in human and veterinary medicine have been diverted to recreational aims, illegally produced and sold. Like all opioids, central nervous system depression resulting from overdose or misuse of fentanyl analogs is characterized clinically by the onset of consciousness impairment, pinpoint miosis and bradypnea.

Transcatheter Patent Foramen Ovale Closure in Patients With Transient Ischemic Attack.

Limited data exist on patients with a transient ischemic attack (TIA) who underwent patent foramen ovale (PFO) closure. The objectives of this study were to determine the clinical and procedural characteristics and long-term outcomes of patients with TIA who underwent transcatheter PFO closure. This was a multicenter study including 1,012 consecutive patients who underwent PFO closure after a cerebrovascular event.

The human RNA polymerase I structure reveals an HMG-like docking domain specific to metazoans.

Transcription of the ribosomal RNA precursor by RNA polymerase (Pol) I is a major determinant of cellular growth, and dysregulation is observed in many cancer types. Here, we present the purification of human Pol I from cells carrying a genomic GFP fusion on the largest subunit allowing the structural and functional analysis of the enzyme across species. In contrast to yeast, human Pol I carries a single-subunit stalk, and in vitro transcription indicates a reduced proofreading activity.

Transcatheter Patent Foramen Ovale Closure in Stroke Patients with Thrombophilia: Current Status and Future Perspectives.

Transcatheter patent foramen ovale (PFO) closure is a safe and effective treatment for secondary prevention after a PFO-associated stroke as demonstrated in multiple large randomized clinical trials. However, these trials excluded a significant proportion of patients who could have benefited from percutaneous PFO closure due to coexisting potential confounders such as additional thromboembolic risk factors, namely thrombophilia. Since scarce and conflicting data existed on such patients, current clinical management guidelines on patients with PFO mainly recommended against PFO closure in patients with thrombophilia and failed to provide any recommendation on the type and duration of antithrombotic treatment after transcatheter PFO closure.

Control of ribosomal RNA synthesis by hematopoietic transcription factors.

Ribosomal RNAs (rRNAs) are the most abundant cellular RNAs, and their synthesis from rDNA repeats by RNA polymerase I accounts for the bulk of all transcription. Despite substantial variation in rRNA transcription rates across cell types, little is known about cell-type-specific factors that bind rDNA and regulate rRNA transcription to meet tissue-specific needs. Using hematopoiesis as a model system, we mapped about 2,200 ChIP-seq datasets for 250 transcription factors (TFs) and chromatin proteins to human and mouse rDNA and identified robust binding of multiple TF families to canonical TF motifs on rDNA.

Liquid-Liquid Phase Separation in Cancer Signaling, Metabolism and Anticancer Therapy.

The cancer state is thought to be maintained by genetic and epigenetic changes that drive a cancer-promoting gene expression program. However, recent results show that cellular states can be also stably maintained by the reorganization of cell structure leading to the formation of biological condensates via the process of liquid-liquid phase separation. Here, we review the data showing cancer-specific biological condensates initiated by mutant oncoproteins, RNA-binding proteins, or lincRNAs that regulate oncogenic gene expression programs and cancer metabolism.

MAP2K2 Delays Recovery in Murine Models of Acute Lung Injury and Associates with Acute Respiratory Distress Syndrome Outcome.

Acute respiratory distress syndrome (ARDS) remains a significant problem in need of new pharmaceutical approaches to improve its resolution. Studies comparing gene expression signatures in rodents and humans with lung injury reveal conserved pathways, including MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-related protein kinase) activation. In preclinical acute lung injury (ALI) models, inhibition of MAP2K1 (MAPK kinase 1)/MAP2K2 (MAPK kinase 2) improves measures of ALI.

Ribosomal DNA promoter recognition is determined in vivo by cooperation between UBTF1 and SL1 and is compromised in the UBTF-E210K neuroregression syndrome.

Transcription of the ~200 mouse and human ribosomal RNA genes (rDNA) by RNA Polymerase I (RPI/PolR1) accounts for 80% of total cellular RNA, around 35% of all nuclear RNA synthesis, and determines the cytoplasmic ribosome complement. It is therefore a major factor controlling cell growth and its misfunction has been implicated in hypertrophic and developmental disorders. Activation of each rDNA repeat requires nucleosome replacement by the architectural multi-HMGbox factor UBTF to create a 15.

Canadian Nationwide Survey on Pediatric Malnutrition Management in Tertiary Hospitals.

Disease-associated malnutrition (DAM) is common in hospitalized children. This survey aimed to assess current in-hospital practices for clinical care of pediatric DAM in Canada. An electronic survey was sent to all 15 tertiary pediatric hospitals in Canada and addressed all pillars of malnutrition care: screening, assessment, treatment, monitoring and follow-up.

Assessing the Potential Impact of Disruptions Due to COVID-19 on HIV Among Key and Lower-Risk Populations in the Largest Cities of Cameroon and Benin.

Background: The COVID-19 pandemic indirectly impacts HIV epidemiology in Central/West Africa. We estimated the potential impact of COVID-19-related disruptions to HIV prevention/treatment services and sexual partnerships on HIV incidence and HIV-related deaths among key populations including female sex workers (FSW), their clients, men who have sex with men, and overall.

Setting: Yaoundé (Cameroon) and Cotonou (Benin).

Similar impact and replacement disease after pneumococcal conjugate vaccine introduction in hospitalised children with invasive pneumococcal disease in Europe and North America.

High incidence of childhood invasive pneumococcal disease (IPD) in the US declined steeply after 7-valent pneumococcal conjugate vaccine (PCV7) introduction, outweighing reductions observed elsewhere. We re-analysed aggregate published data and compared pre- and post-PCV IPD-incidence in different countries to explore PCV impact on hospitalised and outpatient IPD separately. The proportion of hospitalised IPD cases was consistently high (>80%) in England&Wales, Finland, the Netherlands, and Quebec/Canada, but only 32% in the US before PCV introduction, increasing to 69% during the PCV era.

The chemotherapeutic agent CX-5461 irreversibly blocks RNA polymerase I initiation and promoter release to cause nucleolar disruption, DNA damage and cell inviability.

In the search for drugs to effectively treat cancer, the last 10 years have seen a resurgence of interest in targeting ribosome biogenesis. CX-5461 is a potential inhibitor of ribosomal RNA synthesis that is now showing promise in phase I trials as a chemotherapeutic agent for a range of malignancies. Here, we show that CX-5461 irreversibly inhibits ribosomal RNA transcription by arresting RNA polymerase I (RPI/Pol1/PolR1) in a transcription initiation complex.

Clinical efficiency and safety of the oticon medical neuro cochlear implant system: a multicenter prospective longitudinal study.

Objective: This prospective longitudinal cohort study at six tertiary referral centers in Canada and Denmark describes the clinical efficiency and surgical safety of cochlear implantation with the Oticon Medical Neuro cochlear implant system, including the Neuro Zti implant, the EVO electrode array, and the Neuro One sound processor.

Methods: Patients were adult cochlear implant candidates with bilateral sensorineural hearing loss.

Results: The mean HINT scores in quiet pre-operatively and at 3, 6, and 12 months post-activation were 13%, 58%, 67%, and 72%, respectively, and in noise (+10 dB SNR) 13%, 46%, 53%, and 59%, respectively.

Burden of respiratory infections and otitis media in the Inuit population of Nunavik, Quebec, Canada.

Background: Respiratory infections are a major health problem in the Inuit population of Nunavik, province of Quebec, Canada.

Objectives: A study was undertaken to assess the burden of lower (LRTI) and upper respiratory tract infections (URTI) and otitis media (OM) and to explore some of their determinants including the pneumococcal conjugate vaccine (PCV) status.

Methods: The reference population includes children less than 5 years of age born in 1994-2010 and a sample of 825 children was selected for this study.

Hospitalizations for lower respiratory tract infections in children in relation to the sequential use of three pneumococcal vaccines in Quebec.

Objectives: In Quebec, three pneumococcal conjugate vaccines (PCV) were used sequentially starting in December 2004. The objective of the study was to investigate the association between exposure to different PCV regimens and hospitalizations for lower respiratory tract infection (LRTI).

Methods: Records with a main diagnosis of LRTI in children born in 2000-2012 and observed up to their second birthday were extracted from the provincial hospital administrative database.