A disease-linked lncRNA mutation in RNase MRP inhibits ribosome synthesis.

RMRP encodes a non-coding RNA forming the core of the RNase MRP ribonucleoprotein complex. Mutations cause Cartilage Hair Hypoplasia (CHH), characterized by skeletal abnormalities and impaired T cell activation. Yeast RNase MRP cleaves a specific site in the pre-ribosomal RNA (pre-rRNA) during ribosome synthesis. CRISPR-mediated disruption of RMRP in human cells lines caused growth arrest, with pre-rRNA accumulation. Here, we analyzed disease-relevant primary cells, showing that mutations in RMRP impair mouse T cell activation and delay pre-rRNA processing. Patient-derived human fibroblasts with CHH-linked mutations showed similar pre-rRNA processing delay. Human cells engineered with the most common CHH mutation (70AG in RMRP) show specifically impaired pre-rRNA processing, resulting in reduced mature rRNA and a reduced ratio of cytosolic to mitochondrial ribosomes. Moreover, the 70AG mutation caused a reduction in intact RNase MRP complexes. Together, these results indicate that CHH is a ribosomopathy.

Congenital Lung Agenesis: Incidence and Outcome in the North of England.

BACKGROUND: Unilateral lung agenesis is an uncommon congenital abnormality, with a lack of reported accurate incidence estimates. Prognosis is also uncertain, with older literature reporting poor outcomes. METHODS: The North of England register of congenital anomalies (Northern Congenital Abnormality Survey) records cases of congenital anomalies to mothers' resident in the region. We used the register to identify all patients with congenital lung agenesis born between 2004 and 2013 to calculate an accurate incidence estimate and report clinical outcomes with contemporary management. RESULTS: Four patients with congenital lung agenesis were born during the study period, giving an estimated incidence in the North of England of 1.22 per 100,000 live births (95% confidence interval, 0.33-3.11). Two patients had associated congenital heart disease requiring corrective surgery, and one had musculoskeletal anomalies. All four patients are alive and well without a regular oxygen requirement. CONCLUSION: Contrary to previous reports, the medium term outcomes in our patients have been good, even when lung agenesis is associated with other congenital anomalies. Long-term prognosis with modern management remains unknown, and the potential for the development of pulmonary hypertension remains a concern. Birth Defects Research 109:857-859, 2017. © 2017 Wiley Periodicals, Inc.

Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.

Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12Rß1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12Rß1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.

Improving patient safety: lessons from rock climbing.

BACKGROUND: How to improve patient safety remains an intractable problem, despite large investment and some successes. CONTEXT: Academics have argued that the root of the problem is a lack of a comprehensive 'safety culture' in hospitals. Other safety-critical industries such as commercial aviation invest heavily in staff training to develop such a culture, but comparable programmes are almost entirely absent from the health care sector. INNOVATION: In rock climbing and many other dangerous activities, the 'buddy system' is used to ensure that safety systems are adhered to despite adverse circumstances. This system involves two or more people using simple checks and clear communication to prevent problems causing harm. Using this system as an example could provide a simple, original and entertaining way of introducing medical students to the idea that human factors are central to ensuring patient safety. IMPLICATIONS: Teaching the buddy system may improve understanding and acceptance of other patient safety initiatives, and could also be used by junior doctors as a tool to improve the safety of their practice.