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Objective The objectives of this study were: (1) to describe burden of rheumatoid arthritis (RA) and trends from 1990 to 2019 using the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) data, (2) to describe age and sex differences in RA and (3) to compare Canada’s RA burden to that of other countries.Methods Disease burden indicators included prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs) and disability-adjusted life-years (DALYs). GBD estimated fatal and non-fatal outcomes using published literature, survey data and health insurance claims. Data were analysed by Bayesian meta-regression, cause of death ensemble model and other statistical methods. DALYs for Canada were compared with DALYs of countries with similarly high Socio-Demographic Index values.Results In Canada, the RA prevalence rate increased by 27% between 1990 and 2019, mortality rate decreased by 27%, YLL rate decreased by 30%, YLD increased by 27% and DALY rate increased by 13%, all age standardised. The decline in RA mortality and YLL rates was especially pronounced after 2002. The disease burden was higher in females for all indicators, and DALY rates were higher among older age groups, peaking at age 75–79 years. Prevalence and DALYs were higher in Canada compared with global rates.Conclusion Trends in RA burden indicators over time and differences by age and sex have important implications for Canadian policy-makers, researchers and care providers. Early identification and management of RA in women may help reduce the overall burden of RA in Canada.

Key Clinical Message We report a case of fatal disseminated aspergillosis in the setting of administration of zanubrutinib, a second‐generation Bruton's tyrosine kinase inhibitor thought to have a lower rate of immunosuppression‐related side effects.

Argonaute 2 (AGO2) binds RAS and is required for cellular transformation. Here, the authors establish a KRAS-driven mouse model of pancreatic cancer with conditional loss of AGO2 and show that the early phase of neoplastic lesion initiation is dependent on EGFR/RAS but not AGO2, while AGO2 is required for pancreatic ductal adenocarcinoma progression and metastasis.

Lung cancer is the deadliest malignancy in the United States. Non-small cell lung cancer (NSCLC) accounts for 85% of cases and is frequently driven by activating mutations in the gene encoding the KRAS GTPase (e.g., KRASG12D). Our previous work demonstrated that Argonaute 2 (AGO2)--a component of the RNA-induced silencing complex (RISC)--physically interacts with RAS and promotes its downstream signaling. We therefore hypothesized that AGO2 could promote KRASG12D-dependent NSCLC in vivo. To test the hypothesis, we evaluated the impact of Ago2 knockout in the KPC (LSL-Kras G12D/+;p53f/f;Cre) mouse model of NSCLC. In KPC mice, intratracheal delivery of adenoviral Cre drives lung-specific expression of a stopfloxed KRASG12D allele and biallelic ablation of p53. Simultaneous biallelic ablation of floxed Ago2 inhibited KPC lung nodule growth while reducing proliferative index and improving pathological grade. We next applied the KPHetC model, in which the Clara cell-specific CCSP-driven Cre activates KRASG12D and ablates a single p53 allele. In these mice, Ago2 ablation also reduced tumor size and grade. In both models, Ago2 knockout inhibited ERK phosphorylation (pERK) in tumor cells, indicating impaired KRAS signaling. RNA sequencing (RNA-seq) of KPC nodules and nodule-derived organoids demonstrated impaired canonical KRAS signaling with Ago2 ablation. Strikingly, accumulation of pERK in KPC organoids depended on physical interaction of AGO2 and KRAS. Taken together, our data demonstrate a pathogenic role for AGO2 in KRAS-dependent NSCLC. Given the prevalence of this malignancy and current difficulties in therapeutically targeting KRAS signaling, our work may have future translational relevance. [ABSTRACT FROM AUTHOR]

The analysis of essential genes in pathogens can be used to discover potential antimicrobial targets. Here, the authors use a machine learning model and chemogenomic analyses to generate genome-wide gene essentiality predictions for the fungal pathogen Candida albicans, define the function of three uncharacterized essential genes, and identify the target of a new antifungal compound.

ABSTRACT Fungal infections contribute to over 1.5 million deaths annually, with Candida albicans representing one of the most concerning human fungal pathogens. While normally commensal in nature, compromise of host immunity can result in C. albicans disseminating into the human bloodstream, causing infections with mortality rates of up to 40%. A contributing factor to this high mortality rate is the limited arsenal of antifungals approved to treat systemic infections. The most widely used antifungal class, the azoles, inhibits ergosterol biosynthesis by targeting Erg11. The rise of drug resistance among C. albicans clinical isolates, particularly against the azoles, has escalated the need to explore novel antifungal strategies. To address this challenge, we screened a 9,600-compound subset of the University of Tokyo Core Chemical Library to identify molecules with novel antifungal activity against C. albicans. The most potent hit molecule was CpdLC-6888, a 2,5-disubstituted pyridine compound, which inhibited growth of C. albicans and closely-related species. Chemical-genetic, biochemical, and modeling analyses suggest that CpdLC-6888 inhibits Erg11 in a manner similar to the azoles despite lacking the canonical five-membered nitrogen-containing azole ring. This work characterizes the antifungal activity of a 2,5-disubstituted pyridine against C. albicans, supporting the mining of existing chemical collections to identify compounds with novel antifungal activity. IMPORTANCE Pathogenic fungi represent a serious but underacknowledged threat to human health. The treatment and management of these infections relies heavily on the use of azole antifungals, a class of molecules that contain a five-membered nitrogen-containing ring and inhibit the biosynthesis of the key membrane sterol ergosterol. By employing a high-throughput chemical screen, we identified a 2,5-disubstituted pyridine, termed CpdLC-6888, as possessing antifungal activity against the prominent human fungal pathogen Candida albicans. Upon further investigation, we determined this molecule exhibits azole-like activity despite being structurally divergent. Specifically, transcriptional repression of the azole target gene ERG11 resulted in hypersensitivity to CpdLC-6888, and treatment of C. albicans with this molecule blocked the production of the key membrane sterol ergosterol. Therefore, this work describes a chemical scaffold with novel antifungal activity against a prevalent and threatening fungal pathogen affecting human health, expanding the repertoire of compounds that can inhibit this useful antifungal drug target.

The purpose of this paper is to propose a new kind of P systems on simplicial complexes. We present the basic discrete Morse structure, membrane structures on complexes, and communication rules. A new grid-based clustering technique is described based on this kind of new P systems. Examples are given to show the effect of the algorithm. The new P systems provide an alternative for traditional membrane computing.

This study explores the emergence and productivity of word order usage in Mandarin-speaking typically-developing (TD) children and children with autism spectrum disorder (ASD), and examines how this emergence relates to frequency of use in caregiver input. Forty-two caregiver-child dyads participated in video-recorded 30-min semi-structured play sessions. Eleven children with ASD were matched with 10 20-month-old TD children and another 11 children with ASD were matched with 10 26-month-old TD children, on expressive language. We report four major findings: (1) Preschool Mandarin-speaking children with ASD produced word order structures with pervasive ellipsis at similar rates to language-matched TD children, but also displayed differences from TD children in their usage of SVt and VtO frames; (2) Grammatical productivity was observed in both TD children and children with ASD; moreover, children with ASD with higher expressive language produced less stereotyped language; (3) Both TD children and children with ASD heard a range of word orders in their caregivers’ input, with TD children’s input greater in amount and complexity; however, caregivers of both groups also showed no age/language-related changes in word order usage; (4) Few word-order-specific correlations emerged between caregivers and their children; however, strong correlations were observed for mean length of utterances (MLU) for both groups: Caregivers who produced longer/more complex utterances had children who did the same. Taken together, it seems that despite their pragmatic deficits, the early grammatical knowledge of word order in Mandarin-exposed children with ASD is well preserved and in general follows the typical developmental pattern. Moreover, caregiver input is broadly rather than finely tuned to the linguistic development of TD children and children with ASD, and plays a more important role in children’s general syntactic development than in specific word order acquisition. Thus, early word order usage in preschool Mandarin-speaking TD children and children with ASD may be influenced by both caregiver input and child abilities.