Mechanistic differences between in vitro assays for hydrazone-based small molecule inhibitors of anthrax lethal factor

A systematically generated series of hydrazones were analyzed as potential inhibitors of anthrax lethal factor. The hydrazones were screened using one UV-based and two fluorescence-based in vitro assays. The study identified several inhibitors with IC50 values in the micromolar range, and importantly, significant differences in the types of inhibition were observed with the different assays.     

Robust spatial extent inference with a semiparametric bootstrap joint inference procedure

Spatial extent inference (SEI) is widely used across neuroimaging modalities to adjust for multiple comparisons when studying brain‐phenotype associations that inform our understanding of disease. Recent studies have shown that Gaussian random field (GRF)‐based tools can have inflated family‐wise error rates (FWERs). This has led to substantial controversy as to which processing choices are necessary to control the FWER using GRF‐based SEI. The failure of GRF‐based methods is due to unrealistic assumptions about the spatial covariance function of the imaging data. A permutation procedure is the most robust SEI tool because it estimates the spatial covariance function from the imaging data. However, the permutation procedure can fail because its assumption of exchangeability is violated in many imaging modalities. Here, we propose the (semi‐) parametric bootstrap joint (PBJ; sPBJ) testing procedures that are designed for SEI of multilevel imaging data. The sPBJ procedure uses a robust estimate of the spatial covariance function, which yields consistent estimates of standard errors, even if the covariance model is misspecified. We use the methods to study the association between performance and executive functioning in a working memory functional magnetic resonance imaging study. The sPBJ has similar or greater power to the PBJ and permutation procedures while maintaining the nominal type 1 error rate in reasonable sample sizes. We provide an R package to perform inference using the PBJ and sPBJ procedures.     

Translational optical coherence elastography for assessment of systemic sclerosis

Systemic sclerosis (SSc‐scleroderma) is an autoimmune disorder with high mortality rate that results in excessive accumulation of collagen in the skin and internal organs. Currently, the modified Rodnan Skin Score (mRSS) is the gold standard for evaluating the dermal thickening due to SSc. However, mRSS has noticeable inter‐ and intra‐observer variabilities as quantified by the interclass correlation coefficient (ICC: 0.6‐0.75). In this work, optical coherence elastography (OCE) combined with structural optical coherence tomography (OCT) image analysis was used to assess skin thickness in 12 SSc patients and healthy volunteers. Inter‐ (ICC: 0.62‐0.99) and intra‐observer (ICC > 0.90) assessment of OCT/OCE showed excellent reliability. Clinical assessments, including histologically assessed dermal thickness (DT), mRSS, and site‐specific mRSS (SMRSS) were also performed for further validation. The OCE and OCT results from the forearm demonstrated the highest correlation (OCE: 0.78, OCT: 0.65) with SMRSS. Importantly, OCE and OCT had stronger correlations with the histological DT (OCT: r = .78 and OCE: r = .74) than SMRSS (r = .57), indicating the OCT/OCE could outperform semi‐quantitative clinical assessments such as SMRSS. Overall, these results demonstrate that OCT/OCE could be useful for rapid, noninvasive and objective assessments of SSc onset and monitoring skin disease progression and treatment response.     

Ion channels as therapeutic antibody targets

It is now well established that antibodies have numerous potential benefits when developed as therapeutics. Here, we evaluate the technical challenges of raising antibodies to membrane-spanning proteins together with enabling technologies that may facilitate the discovery of antibody therapeutics to ion channels. Additionally, we discuss the potential targeting opportunities in the anti-ion channel antibody landscape, along with a number of case studies where functional antibodies that target ion channels have been reported. Antibodies currently in development and progressing towards the clinic are highlighted.     

Pragmatic assessment of exercise in routine care using an MDHAQ: associations with changes in RAPID3 and other clinical variables

BackgroundExercise is associated with major benefits in patients with rheumatic diseases for both cardiovascular and rheumatic status. However, information about exercise generally is not collected systematically in routine rheumatology care. A multidimensional health assessment questionnaire (MDHAQ), which was designed for busy clinical settings, includes a query about exercise status. We analyzed possible associations between change in MDHAQ exercise scores and other MDHAQ measures in patients with various rheumatic diseases over one year.MethodsIn one rheumatology clinical setting, all patients, regardless of diagnosis, complete an MDHAQ before seeing a rheumatologist. The MDHAQ includes scores for physical function, pain, and patient global estimate, compiled into an index, routine assessment of patient index data (RAPID3), as well as a self-report joint count and a query about exercise. Patients were classified into four groups according to their exercise status at baseline and one year later as: EXER-Yes (regular exercise), EXER-Yes; EXER-No (no regular exercise), EXER-Yes; EXER-Yes, EXER-No; and EXER-No, EXER-No. These groups were compared using the chi square and Kruskal-Wallis tests and analysis of variance (ANOVA).ResultsPatients who reported regular exercise at baseline were younger, had higher formal education, and better clinical status than other patients. The EXER-No, EXER-Yes group had greater improvement in other MDHAQ variables than patients in the other three groups. By contrast, the EXER-Yes, EXER-No group was the only group with poorer status one year later.ConclusionsThe MDHAQ exercise query indicates that regular exercise is associated with better clinical status. Patients in the EXER-No, EXER-Yes group reported the best clinical improvement, although it is not known whether exercise preceded or followed the improved clinical status.     

The phylogenetic position of Ovavesicula popilliae (Microsporidia) and its relationship to Antonospora and Paranosema based on small subunit rDNA analysis

Comparative small subunit rDNA sequence analyses, indicate that Ovavesicula popilliae, a microsporidian parasite of the Japanese beetle, Popillia japonica, represents a distant sister group to Paranosema and Antonospora. These three genera represent a second major group (the Nosema/Vairimorpha clade representing the first) of Microsopridia which infect terrestrial insects, suggesting independent origins for both groups. Phylogenetic analyses of Ovavesicula and other Microsporidia having a multi-sporous sporogony reveal that this condition is found in several unrelated taxa implying either that multi-sporous sporogony is the ancestral condition for Microsporidia or that it has multiple origins.