Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, reduced fertility, and randomization of the left/right body axis. It is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious axonemal defect for pathogenic variants using whole exome capture, next generation sequencing, and bioinformatic analysis assuming an autosomal recessive trait. We identified one subject with an apparently homozygous nonsense variant [(c.1762C\u3eT), p.(Arg588*)] in the uncharacterized CFAP57 gene. Interestingly, the variant results in the skipping of exon 11 (58 amino acids), which may be due to disruption of an exonic splicing enhancer. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Nasal cells from the PCD patient express a shorter, mutant version of CFAP57 and the protein is not incorporated into the axoneme. The missing 58 amino acids include portions of WD repeats that may be important for loading onto the intraflagellar transport (IFT) complexes for transport or docking onto the axoneme. A reduced beat frequency and an alteration in ciliary waveform was observed. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is highly conserved in organisms that assemble motile cilia. CFAP57 is allelic with the BOP2/IDA8/FAP57 gene identified previously in Chlamydomonas reinhardtii. Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass tag (TMT) mass spectroscopy shows that FAP57 is missing, and the g inner dyneins (DHC7 and DHC3) and the d inner dynein (DHC2) are reduced, but the FAP57 paralog FBB7 is increased. Together, our data identify a homozygous variant in CFAP57 that causes PCD that is likely due to a defect in the inner dynein arm assembly process

The atmospheric boundary layer and the "gray zone" of turbulence: a critical review

Recent increases in computing power mean that atmospheric models for numerical weather prediction are now able to operate at grid spacings of the order of a few hundred meters, comparable to the dominant turbulence length scales in the atmospheric boundary layer. As a result, models are starting to partially resolve the coherent overturning structures in the boundary layer. In this resolution regime, the so‐called boundary‐layer "gray zone", neither the techniques of high‐resolution atmospheric modeling (a few tens of meters resolution) nor those of traditional meteorological models (a few kilometers resolution) are appropriate because fundamental assumptions behind the parameterizations are violated. Nonetheless, model simulations in this regime may remain highly useful. In this paper, a newly‐formed gray‐zone boundary‐layer community lays the basis for parameterizing gray‐zone turbulence, identifies the challenges in high‐resolution atmospheric modeling and presents different gray‐zone boundary‐layer models. We discuss both the successful applications and the limitations of current parameterization approaches, and consider various issues in extending promising research approaches into use for numerical weather prediction. The ultimate goal of the research is the development of unified boundary‐layer parameterizations valid across all scales

A prospective, double-blind, randomized, controlled clinical trial comparing standard wound care with adjunctive hyperbaric oxygen therapy (HBOT) to standard wound care only for the treatment of chronic, non-healing ulcers of the lower limb in patients with diabetes mellitus: a study protocol

<p>Abstract</p> <p>Background</p> <p>It has been suggested that the use of adjunctive hyperbaric oxygen therapy improves the healing of diabetic foot ulcers, and decreases the risk of lower extremity amputations. A limited number of studies have used a double blind approach to evaluate the efficacy of hyperbaric oxygen therapy in the treatment of diabetic ulcers. The primary aim of this study is to assess the efficacy of hyperbaric oxygen therapy plus standard wound care compared with standard wound care alone in preventing the need for major amputation in patients with diabetes mellitus and chronic ulcers of the lower limb.</p> <p>Methods/Design</p> <p>One hundred and eighteen (59 patients per arm) patients with non-healing diabetic ulcers of the lower limb, referred to the Judy Dan Research and Treatment Centre are being recruited if they are at least 18 years of age, have either Type 1 or 2 diabetes with a Wagner grading of foot lesions 2, 3 or 4 on lower limb not healing for at least 4 weeks. Patients receive hyperbaric oxygen therapy every day for 6 weeks during the treatment phase and are provided ongoing wound care and weekly assessments. Patients are required to return to the study centre every week for an additional 6 weeks of follow-up for wound evaluation and management. The primary outcome is freedom from having, or meeting the criteria for, a major amputation (below knee amputation, or metatarsal level) up to 12 weeks after randomization. The decision to amputate is made by a vascular surgeon. Other outcomes include wound healing, effectiveness, safety, healthcare resource utilization, quality of life, and cost-effectiveness. The study will run for a total of about 3 years.</p> <p>Discussion</p> <p>The results of this study will provide detailed information on the efficacy of hyperbaric oxygen therapy for the treatment of non-healing ulcers of the lower limb. This will be the first double-blind randomized controlled trial for this health technology which evaluates the efficacy of hyperbaric oxygen therapy in prevention of amputations in diabetic patients.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00621608">NCT00621608</a></p

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Biodetection of a specific odor signature in mallard feces associated with infection by low pathogenic avian influenza A virus.

Outbreaks of avian influenza virus (AIV) infection included the spread of highly pathogenic AIV in commercial poultry and backyard flocks in the spring of 2015. This resulted in estimated losses of more than $8.5 million from federal government expenditures,$1.6 billion from direct losses to produces arising from destroyed turkey and chicken egg production, and economy-wide indirect costs of $3.3 billion from impacts on retailers and the food service industries. Additionally, these outbreaks resulted in the death or depopulation of nearly 50 million domestic birds. Domesticated male ferrets (Mustela putorius furo) were trained to display a specific conditioned behavior (i.e. active scratch alert) in response to feces from AIV-infected mallards in comparison to feces from healthy ducks. In order to establish that ferrets were identifying samples based on odors associated with infection, additional experiments controlled for potentially confounding effects, such as: individual duck identity, housing and feed, inoculation concentration, and day of sample collection (post-infection). A final experiment revealed that trained ferrets could detect AIV infection status even in the presence of samples from mallards inoculated with Newcastle disease virus or infectious laryngotracheitis virus. These results indicate that mammalian biodetectors are capable of discriminating the specific odors emitted from the feces of non-infected versus AIV infected mallards, suggesting that the health status of waterfowl can be evaluated non-invasively for AIV infection via monitoring of volatile fecal metabolites. Furthermore, in situ monitoring using trained biodetectors may be an effective tool for assessing population health