Sf3b4 regulates chromatin remodeler splicing and Hox expression.

SF3B proteins form a heptameric complex in the U2 small nuclear ribonucleoprotein, essential for pre-mRNA splicing. Heterozygous pathogenic variants in human SF3B4 are associated with head, face, limb, and vertebrae defects. Using the CRISPR/Cas9 system, we generated mice with constitutive heterozygous deletion of Sf3b4 and showed that mutant embryos have abnormal vertebral development. Vertebrae abnormalities were accompanied by changes in levels and expression pattern of Hox genes in the somites. RNA sequencing analysis of whole embryos and somites of Sf3b4 mutant and control litter mates revealed increased expression of other Sf3b4 genes. However, the mutants exhibited few differentially expressed genes and a large number of transcripts with differential splicing events (DSE), predominantly increased exon skipping and intron retention. Transcripts with increased DSE included several genes involved in chromatin remodeling that are known to regulate Hox expression. Our study confirms that Sf3b4 is required for normal vertebrae development and shows, for the first time, that like Sf3b1, Sf3b4 also regulates Hox expression. We propose that abnormal splicing of chromatin remodelers is primarily responsible for vertebral defects found in Sf3b4 heterozygous mutant embryos.

The Impact of Consumer Wearable Devices on Physical Activity and Adherence to Physical Activity in Patients with Cardiovascular Disease: A Systematic Review of Systematic Reviews and Meta-Analyses.

Objective: Consumer wearable devices allow physical activity to be measured objectively, which can be useful in remote cardiovascular disease management. This review aimed to summarize the effects of using wearable devices to monitor physical activity/adherence to physical activity in adults with cardiovascular disease. Methods: The review used The Cochrane Overview of Reviews Methodology. The databases searched were PubMed, EMBASE, CINAHL, Web of Science, and the Cochrane Database of Systematic Reviews, the date of the last search was October 12, 2021. Risk of bias was assessed using the AMSTAR-2® tool. Results: Of the 767 records, we identified 6 systematic reviews (SRs) and meta-analyses (MA) that met our inclusion criteria. The individual SRs did not consistently favor the use of wearables, but the MA syntheses each found significant effects, favoring wearable devices in measures, including mean steps per day and mean time spent completing moderate-to-vigorous physical activity. The MA on adherence to cardiac rehabilitation (CR) found greater adherence to CR with the use of a mobile app than with no app support. Summary: Within this review, there were SRs demonstrating no difference and reviews indicating a positive impact with the use of wearables for physical activity/adherence measures in individuals with cardiovascular conditions, with no studies demonstrating a negative impact. The six SR/MAs included had methodological flaws, which introduced potential biases. Additionally, the MAs included a small number of studies, which limits their generalizability. The protocol for this review was registered on PROSPERO, the international prospective register of systematic reviews (#CRD42021286699).

Snrpb is required in murine neural crest cells for proper splicing and craniofacial morphogenesis.

Heterozygous mutations in SNRPB, an essential core component of the five small ribonucleoprotein particles of the spliceosome, are responsible for cerebrocostomandibular syndrome (CCMS). We show that Snrpb heterozygous mouse embryos arrest shortly after implantation. Additionally, heterozygous deletion of Snrpb in the developing brain and neural crest cells models craniofacial malformations found in CCMS, and results in death shortly after birth. RNAseq analysis of mutant heads prior to morphological defects revealed increased exon skipping and intron retention in association with increased 5' splice site strength. We found increased exon skipping in negative regulators of the P53 pathway, along with increased levels of nuclear P53 and P53 target genes. However, removing Trp53 in Snrpb heterozygous mutant neural crest cells did not completely rescue craniofacial development. We also found a small but significant increase in exon skipping of several transcripts required for head and midface development, including Smad2 and Rere. Furthermore, mutant embryos exhibited ectopic or missing expression of Fgf8 and Shh, which are required to coordinate face and brain development. Thus, we propose that mis-splicing of transcripts that regulate P53 activity and craniofacial-specific genes contributes to craniofacial malformations. This article has an associated First Person interview with the first author of the paper.

Spliceosomopathies and neurocristopathies: Two sides of the same coin?

Mutations in core components of the spliceosome are responsible for a group of syndromes collectively known as spliceosomopathies. Patients exhibit microcephaly, micrognathia, malar hypoplasia, external ear anomalies, eye anomalies, psychomotor delay, intellectual disability, limb, and heart defects. Craniofacial malformations in these patients are predominantly found in neural crest cells-derived structures of the face and head. Mutations in eight genes SNRPB, RNU4ATAC, SF3B4, PUF60, EFTUD2, TXNL4, EIF4A3, and CWC27 are associated with craniofacial spliceosomopathies. In this review, we provide a brief description of the normal development of the head and the face and an overview of mutations identified in genes associated with craniofacial spliceosomopathies. We also describe a model to explain how and when these mutations are most likely to impact neural crest cells. We speculate that mutations in a subset of core splicing factors lead to disrupted splicing in neural crest cells because these cells have increased sensitivity to inefficient splicing. Hence, disruption in splicing likely activates a cellular stress response that includes increased skipping of regulatory exons in genes such as MDM2 and MDM4, key regulators of P53. This would result in P53-associated death of neural crest cells and consequently craniofacial malformations associated with spliceosomopathies.

Highly Sustained Release of Bactericides from Complex Coacervates.

Materials for preventing harmful bacterial contamination attract widespread interest in areas that include healthcare, home/personal care products, and crop protection. One approach to achieving this functionality is through the sustained release of antibacterial compounds. To this end, we show how putty-like complex coacervates, formed through the association of poly(allylamine hydrochloride) (PAH) with pentavalent tripolyphosphate (TPP) ions, can provide a sustained antibacterial effect by slowly releasing bactericides. Using triclosan (TC) as a model bactericide, we demonstrate that, through their dispersion in the parent PAH solution with nonionic surfactants, hydrophobic biocides can be efficiently and predictably encapsulated within PAH/TPP coacervates. Once encapsulated, the bactericide can be released over multiple months, and the release rates can be readily tuned by varying the bactericide and surfactant compositions used during encapsulation. Through this release, the PAH/TPP coacervates provide sustained bactericidal activity against model Gram-positive and Gram-negative bacteria (Staphylococcus aureus and Escherichia coli) grown under a nutrient-rich condition over at least two weeks. Thereafter, though some partial activity persists after one month, the release slows down and the bactericide-eluting coacervates lose their efficacy. Overall, we show that bactericide release from easy-to-prepare complex coacervates can provide a pathway to sustained disinfection.

Snap29 mutant mice recapitulate neurological and ophthalmological abnormalities associated with 22q11 and CEDNIK syndrome.

Synaptosomal-associated protein 29 (SNAP29) encodes a member of the SNARE family of proteins implicated in numerous intracellular protein trafficking pathways. SNAP29 maps to the 22q11.2 region and is deleted in 90% of patients with 22q11.2 deletion syndrome (22q11.2DS). Moreover, bi-allelic SNAP29 mutations in patients are responsible for CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome. A mouse model that recapitulates abnormalities found in these syndromes is essential for uncovering the cellular basis of these disorders. In this study, we report that mice with a loss of function mutation of Snap29 on a mixed CD1;FvB genetic background recapitulate skin abnormalities associated with CEDNIK, and also phenocopy neurological and ophthalmological abnormalities found in CEDNIK and a subset of 22q11.2DS patients. Our work also reveals an unanticipated requirement for Snap29 in male fertility and supports contribution of hemizygosity for SNAP29 to the phenotypic spectrum of abnormalities found in 22q11.2DS patients.

Neonatal endosurgical congenital diaphragmatic hernia repair: a systematic review and meta-analysis.

OBJECTIVE: To compare outcomes of open and endosurgical neonatal congenital diaphragmatic hernia (CDH) repairs. BACKGROUND: Historically a surgical emergency, neonatal CDH repair is now deferred pending stabilization of characteristically labile cardiopulmonary physiology. Usually accomplished via laparotomy, surgical repair may acutely worsen lung function; conversely, by reducing the visceral hernia, surgery might improve it. Theoretically, endosurgical repair could minimize deleterious effects of surgery while garnering benefits from decompressing the CDH lung. As endosurgical repair gains popularity, it is important to investigate whether or not minimally-invasive neonatal CDH repair has benefits. METHODS: We searched Medline, Embase, and Cochrane Trials databases for studies comparing open with endosurgical CDH repair. Non-neonatal series and reports without comparison groups were excluded. References from papers and conference proceedings were also hand searched. Meta-analysis used a fixed effects model and was reported in accordance with PRISMA. RESULTS: We included 3 studies (1 unpublished; none randomized); all compared thoracoscopic and open CDH repair and together described 143 patients. All studies had limitations, including use of historical controls. Demographics, CDH sidedness, APGAR and associated anomaly prevalence were similar between groups. For endosurgical repair, recurrence was higher (RR: 3.2 [1.1, 9.3], P = 0.03) and operative time longer (WMD 50 minutes [32, 69], P < 0.00001). Survival and patch usage were not different between open and endosurgical groups. CONCLUSIONS: Neonatal thoracoscopic CDH repair has greater recurrence rates and operative times but similar survival and patch usage compared with open surgery. A prospective registry for all such cases would guide development of trials (Stage 2b; IDEAL recommendations).