RAD21 mutations cause a human cohesinopathy.

The evolutionarily conserved cohesin complex was originally described for its role in regulating sister-chromatid cohesion during mitosis and meiosis. Cohesin and its regulatory proteins have been implicated in several human developmental disorders, including Cornelia de Lange (CdLS) and Roberts syndromes. Here we show that human mutations in the integral cohesin structural protein RAD21 result in a congenital phenotype consistent with a "cohesinopathy." Children with RAD21 mutations display growth retardation, minor skeletal anomalies, and facial features that overlap findings in individuals with CdLS. Notably, unlike children with mutations in NIPBL, SMC1A, or SMC3, these individuals have much milder cognitive impairment than those with classical CdLS. Mechanistically, these mutations act at the RAD21 interface with the other cohesin proteins STAG2 and SMC1A, impair cellular DNA damage response, and disrupt transcription in a zebrafish model. Our data suggest that, compared to loss-of-function mutations, dominant missense mutations result in more severe functional defects and cause worse structural and cognitive clinical findings. These results underscore the essential role of RAD21 in eukaryotes and emphasize the need for further understanding of the role of cohesin in human development.

Positive regulation of c-Myc by cohesin is direct, and evolutionarily conserved.

Contact between sister chromatids from S phase to anaphase depends on cohesin, a large multi-subunit protein complex. Mutations in sister chromatid cohesion proteins underlie the human developmental condition, Cornelia de Lange syndrome. Roles for cohesin in regulating gene expression, sometimes in combination with CCCTC-binding factor (CTCF), have emerged. We analyzed zebrafish embryos null for cohesin subunit rad21 using microarrays to determine global effects of cohesin on gene expression during embryogenesis. This identified Rad21-associated gene networks that included myca (zebrafish c-myc), p53 and mdm2. In zebrafish, cohesin binds to the transcription start sites of p53 and mdm2, and depletion of either Rad21 or CTCF increased their transcription. In contrast, myca expression was strongly downregulated upon loss of Rad21 while depletion of CTCF had little effect. Depletion of Rad21 or the cohesin-loading factor Nipped-B in Drosophila cells also reduced expression of myc and Myc target genes. Cohesin bound the transcription start site plus an upstream predicted CTCF binding site at zebrafish myca. Binding and positive regulation of the c-Myc gene by cohesin is conserved through evolution, indicating that this regulation is likely to be direct. The exact mechanism of regulation is unknown, but local changes in histone modification associated with transcription repression at the myca gene were observed in rad21 mutants.

Early policy actions and emergency response to the COVID-19 pandemic in Mongolia: experiences and challenges.

Country-led control measures to contain the spread of the novel coronavirus, COVID-19, have been diverse. Originating in Wuhan, China, in December, 2019, the COVID-19 outbreak was declared a pandemic by WHO on March 11, 2020. In recognition of the severity of the outbreak, and having the longest shared border with China, the Government of Mongolia activated the State Emergency Committee in January, 2020, on the basis of the 2017 Disaster Protection Law. As a result, various public health measures have been taken that led to delaying the first confirmed case of COVID-19 until March 10, 2020, and with no intensive care admissions or deaths until July 6, 2020. These measures included promoting universal personal protection and preventions, such as the use of face masks and handwashing, restricting international travel, suspending all training and educational activities from kindergartens to universities, and banning major public gatherings such as the celebration of the national New Year holiday. These measures have been accompanied by active infection surveillance and self-isolation recommendations. The Mongolian case shows that with robust preventive systems, an effective response to a pandemic can be mounted in a low-income or middle-income country. We hereby examine the emergency preparedness experience, effectiveness, and challenges of the early outbreak policies on COVID-19 prevention in Mongolia, as well as any unintended consequences.

Expression of cohesin and condensin genes during zebrafish development supports a non-proliferative role for cohesin.

Cohesin and condensin are similar, but distinct multi-subunit protein complexes that have well-described roles in sister chromatid cohesion and chromosome condensation, respectively. Recently it has emerged that cohesin, and proteins that regulate cohesin function have additional developmental roles. To further understand the role of cohesin in development, we analyzed the expression of genes encoding cohesin and condensin subunits in developing zebrafish embryos and juvenile brain. We found that cohesin subunits are expressed in a pattern that is similar (but not quite identical) to the expression of condensin subunits. Cohesin genes smc1a, rad21, pds5b and smc3 were expressed in the forebrain ventricular zone, the tectum, the mid-hindbrain boundary, the fourth ventricle, branchial arches, the otic vesicle, the eye and faintly in the developing pectoral fins. Condensin genes smc2 and smc4 were expressed in the forebrain ventricular zone, the tectum, the mid-hindbrain boundary, the fourth ventricle, branchial arches, eye and pectoral fins. Condensin genes were additionally expressed in the hindbrain proliferative zone, an area in which cohesin genes were not detected. A comparison with pcna expression and BrdU incorporation revealed that the expression of cohesins and condensins closely overlap with zones of proliferation. Interestingly, cohesin genes were expressed in non-proliferating cells flanking rhombomere boundaries in the developing brain. In mature brain and eye, cohesin was expressed in both proliferating cells and in broad zones of post-mitotic cells. The distribution of cohesin and condensin mRNAs supports existing evidence for a non-cell cycle role for cohesin in the developing brain.

Physiotherapy practice and delegation policies in oxygen administration: a survey of ontario hospitals.

PURPOSE: As of 2008, the Regulated Health Professions Act in Ontario stipulates that administration of oxygen is a controlled act, which physiotherapists are not authorized to perform but which may be delegated to physiotherapists by another health professional authorized to perform this act. The aims of this study were (1) to survey physiotherapy practice of oxygen administration in Ontario hospitals and (2) to determine the proportion and characteristics of hospitals with delegation policies for physiotherapists to administer oxygen. METHOD: Postal surveys were sent to 208 hospitals. Data were collected on hospital characteristics; the presence of delegation policies; and the practice and training of physiotherapists, physiotherapy assistants, and students in oxygen administration. Data were described by summative statistics. Fisher's exact test and Cramer's V statistic were used to examine associations. Potential prognostic factors were analyzed using logistic regression. RESULTS: Response rate was 82.7%. Physiotherapists administered oxygen in 39% of hospitals, and 28% of hospitals had delegation policies. Larger, urban, or teaching hospitals and those with a matrix structure were most likely to have delegation policies and physiotherapists who administered oxygen. Rehabilitation hospitals were also likely to have such policies. CONCLUSION: Physiotherapists administer oxygen in less than half of Ontario hospitals, very few of which have delegation policies.