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Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

Staphylococcus aureus is the leading cause of skin and skin structure infection (SSSI), a primary portal of entry for invasive infection. Our prior studies discovered a role for protective innate memory against recurrent methicillin-resistant S. aureus (MRSA) SSSI. In the present study, the dynamics and mechanisms of this response were explored in recurrent SSSI in WT mice. Priming by prior infection reduced skin lesion severity and MRSA burden, and protected against dissemination at day 7 but not day 2. Cytokine and cellular signatures in SSSI differed at day 2 versus 7, and were distinct in skin versus blood or spleen. Cytokines associated with protection in skin included increased IL-17, IL-6, monokine inducible by IFN-γ (MIG), and RANTES, while increased IP-10 correlated with protection from dissemination. Cellular signatures of protection included increased Th17, M1 macrophage, and dendritic cell populations in abscesses, and total macrophages in lymph nodes. Priming potentiated S. aureus-specific phagocytic killing by bone marrow-derived macrophages in vitro, and their adoptive transfer into naïve skin afforded protective efficacy in vivo. Present findings indicate that protective immunity in recurrent S. aureus infection is locally targeted, and involves specific memory conferred by macrophages. These insights provide targets for vaccine and immunotherapeutic development against MRSA.

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.

Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI). The high frequency of recurring SSSI due to S. aureus, including methicillin-resistant S. aureus (MRSA) strains, despite high titers of specific antibodies and circulating T cells, implies that traditional adaptive immunity imparts incomplete protection. We hypothesized that innate immune memory contributes to the protective host defense against recurring MRSA infection. To test this hypothesis, SSSI was induced in wild-type and rag1-/- mice in the BALB/c and C57BL/6 backgrounds. Prior infection (priming) of wild-type and rag1-/- mice of either background afforded protection against repeat infection, as evidenced by reduced abscess severities and decreased CFU densities compared to those in naive controls. Interestingly, protection was greater on the previously infected flank than on the naive flank for wild-type and rag1-/- mice. For wild-type mice, protective efficacy corresponded to increased infiltration of neutrophils (polymorphonuclear leukocytes [PMN]), macrophages (MΦ), Langerin+ dendritic cells (LDC), and natural killer (NK) cells. Protection was associated with the induction of interleukin-17A (IL-17A), IL-22, and gamma interferon (IFN-γ) as well as the antimicrobial peptides CRAMP and mβD-3. Priming also protected rag1-/- mice against recurring SSSI, with increased MΦ and LDC infiltration and induction of IL-22, CRAMP, and mβD-3. These findings suggest that innate immune memory, mediated by specific cellular and molecular programs, likely contributes to the localized host defense in recurrent MRSA SSSI. These insights support the development of targeted immunotherapeutic strategies to address the challenge of MRSA infection.

Introduction: There has been increased interest in using autologous tissues since the Food and Drug Administration banned transvaginal mesh for pelvic organ prolapse in 2019. Our study aims to assess patients' perspective of functional and cosmetic impact on the fascia lata harvest site in patients undergoing fascia lata harvest for the treatment of stress urinary incontinence (SUI). Methods: This is a prospective survey study of a retrospective cohort of patients who underwent a fascia lata pubovaginal sling between 2017 and 2022. Participants completed a survey regarding the functional and cosmetic outcomes of the harvest site. Results: Seventy‐two patients met the inclusion criteria. Twenty‐nine patients completed the survey for a completion rate of 40.3%. For functional symptoms, 24.1% (7/29) of patients reported leg discomfort, 10.3% (3/29) reported leg weakness, 10.3% (3/29) reported a bulge, 17.2% (5/29) reported scar pain, 14.8% (4/27) reported scar numbness, and 17.2% (5/29) reported paresthesia at the scar. For cosmetic outcomes, 72.4% (21/29) reported an excellent or good scar appearance. On the PGI‐I, 75.9% (22/29) reported their condition as very much better (48.3%, 14/29) or much better (27.6%, 8/29). Conclusions: The majority of patients reported being satisfied with the functional and cosmetic outcomes of their harvest site as well as satisfied with the improvement in their SUI. Less than 25% of patients report harvest site symptoms, including leg weakness, scar bulging, scar pain, scar numbness, or paresthesia in the scar. This is important in the context of appropriate preoperative discussion and counseling regarding fascia lata harvest. [ABSTRACT FROM AUTHOR]

BackgroundMutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly.Methods and resultsWhole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F.ConclusionsOur data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.

Context: Professionalism education is essential for the professional development and workplace readiness of allied health care students across the globe, but it presents a pedagogical challenge for educators. Students' understanding of professionalism varies at different educational stages and across different disciplines. Objective: To conceptualize professionalism education, with a particular focus on the sports environment, and to apply pedagogical frameworks to professionalism education in this field. Background: Traditional approaches to teaching professionalism have focused on role models; however, poor role modeling and the ''hidden curriculum'' present a threat to student professional development. Specific challenges to learning professionalism become apparent in the sports environment where students are exposed to cultures and practices that may be discordant with what is taught in the classroom. Synthesis: The idea of threshold concepts provides a useful pedagogical framework for conceptualizing the challenge of learning professionalism for students and can help to uncover the hidden curriculum. The evolving professional curriculum provides a framework for student professional development, focusing on developing students as reflective practitioners, skilled communicators, and collaborative team members. Students need to learn the skill of reflective practice, which can be facilitated through structured reflective models, reflective journal writing, and critical reflective group discussions. Creating opportunities for authentic reflection and discussion can facilitate students linking theory to real-world practice and help to make sense of their experiences. Recommendation(s) and Conclusion(s): Pragmatic recommendations for curriculum planning, teaching, and learning activities; stakeholder engagement; and research are proposed to develop professionalism education in the sports environment and to mitigate some risks presented by the hidden curriculum.