Evolution of pathogenicity and sexual reproduction in eight Candida genomes

Candida species are the most common cause of opportunistic fungal infection worldwide. Here we report the genome sequences of six Candida species and compare these and related pathogens and non-pathogens. There are significant expansions of cell wall, secreted and transporter gene families in pathogenic species, suggesting adaptations associated with virulence. Large genomic tracts are homozygous in three diploid species, possibly resulting from recent recombination events. Surprisingly, key components of the mating and meiosis pathways are missing from several species. These include major differences at the mating-type loci (MTL); Lodderomyces elongisporus lacks MTL, and components of the a1/2 cell identity determinant were lost in other species, raising questions about how mating and cell types are controlled. Analysis of the CUG leucine-to-serine genetic-code change reveals that 99% of ancestral CUG codons were erased and new ones arose elsewhere. Lastly, we revise the Candida albicans gene catalogue, identifying many new genes.publishe

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Glial ankyrins facilitate paranodal axoglial junction assembly

Neuron-glia interactions establish functional membrane domains along myelinated axons. These include nodes of Ranvier, paranodal axoglial junctions, and juxtaparanodes. Paranodal junctions are the largest vertebrate junctional adhesion complex, are essential for rapid saltatory conduction, and contribute to assembly and maintenance of nodes. However, the molecular mechanisms underlying paranodal junction assembly are poorly understood. Ankyrins are cytoskeletal scaffolds traditionally associated with Na+ channel clustering in neurons and important for membrane domain establishment and maintenance in many cell types. Here, we show that ankyrinB, expressed by Schwann cells, and ankyrinG, expressed by oligodendrocytes, are highly enriched at the glial side of paranodal junctions where they interact with the essential glial junctional component neurofascin 155. Conditional knockout of ankyrins in oligodendrocytes disrupts paranodal junction assembly and delays nerve conduction during early development in mice. Thus, glial ankyrins function as major scaffolds that facilitate early and efficient paranodal junction assembly in the developing central nervous system

Feline mycobacterial disease in northern California: Epidemiology, clinical features, and antimicrobial susceptibility.

BackgroundMycobacterial infections in cats are challenging to treat and incompletely described.Hypothesis/objectivesTo describe the features of mycobacterial infections in cats from northern California.AnimalsNineteen cats, all with nontuberculous mycobacterial (NTM) infections; 4 with Mycobacterium avium infection, 15 with rapid-growing mycobacterial (RGM) infection.MethodsRetrospective study. Cases with positive mycobacterial culture, species identification, and susceptibility testing were included. Descriptive statistics were used. Fisher's exact test and Mann-Whitney U test were used for comparisons between M avium and RGM infections (P ≤ .05).ResultsRapid-growing mycobacterial cases included Mycobacterium smegmatis (9), Mycobacterium fortuitum (4), Mycobacterium abscessus (1), and Mycobacterium thermoresistibile (1). Mycobacterium avium infections were more likely than RGM infections to be disseminated (3/4 vs 0/15; P = .004). Disease of the skin/subcutis (15/15 vs 0/4; P < .001) and outdoor access (14/15 vs 0/4; P = .001) were primary features of RGM infections. Resistance to fluoroquinolones and aminoglycosides was common among M avium isolates. A high prevalence of resistance to third- and fourth-generation cephalosporins was noted in RGM species. Death/euthanasia was noted only in M avium cases (3/4). Twelve of 15 cats with RGM infection had available follow-up; 4 of these cats achieved remission.Conclusions and clinical importanceThe most prevalent RGM species isolated from cats from northern California are M smegmatis and M fortuitum. Susceptibility to prescribed antimicrobials does not appear to guarantee treatment success. Combination drug treatment is recommended. Repeat culture and susceptibility testing should be performed when disease is persistent/relapsing

Efficacy of a micronized, nanocrystal fenofibrate formulation in treatment of hyperlipidemia in dogs.

BackgroundSafe, effective, and readily available drug therapies are required for the management of hyperlipidemia and its associated complications in dogs.ObjectivesTo investigate the efficacy of a micronized, nanocrystal formulation of fenofibrate (Tricor) in the treatment of hyperlipidemia in dogs.AnimalsTen client-owned dogs with primary (n = 7) and secondary (n = 3) hyperlipidemia. All dogs had hypertriglyceridemia at baseline; 3 dogs also had hypercholesterolemia.MethodsProspective dose-escalation study. Dogs were treated with fenofibrate orally once daily in up to 3 cycles of 21 days each. Fenofibrate dose was increased at the end of each cycle if hypertriglyceridemia persisted and adverse effects were not documented. Complete blood count, biochemistry, and urine protein:creatinine ratio were collected serially. Baseline (T0) parameters were compared to time of maximal reduction in serum triglyceride concentrations (T1) and reported as median (range).ResultsTriglycerides normalized in all dogs (T0 = 662 mg/dL [189-2391]; T1 = 113 mg/dL [81-132]; P = .002). Fenofibrate dose at T1 = 6.4 mg/kg PO q24h (range, 2.2-13.5). T1 was achieved at 3 (n = 4), 6 (n = 4), and 9 (n = 2) weeks. Serum cholesterol concentrations decreased in 9 of 10 dogs. Quiet demeanor and firm stools in 1 dog were the only reported adverse reactions. Fenofibrate administration resulted in a significant reduction in median alkaline phosphatase activity (P = .049).Conclusions and clinical importanceOver 21 to 63 days, TriCor was effective in the management of primary and secondary hyperlipidemia in dogs