The active site residue V266 of Chlamydial HtrA is critical for substrate binding during both in vitro and in vivo conditions

HtrA is a complex, multimeric chaperone and serine protease important for the virulence and survival of many bacteria. Chlamydia trachomatis is an obligate, intracellular bacterial pathogen that is responsible for severe disease pathology. C. trachomatis HtrA (CtHtrA) has been shown to be highly expressed in laboratory models of disease. In this study, molecular modelling of CtHtrA protein active site structure identified putative S1-S3 subsite residues I242, I265, and V266. These residues were altered by site-directed mutagenesis, and these changes were shown to considerably reduce protease activity on known substrates and resulted in a narrower and distinct range of substrates compared to wild type. Bacterial two-hybrid analysis revealed that CtHtrA is able to interact in vivo with a broad range of protein sequences with high affinity. Notably, however, the interaction was significantly altered in 35 out of 69 clones when residue V266 was mutated, indicating that this residue has an important function during substrate binding

Aqueous Hydricity from Calculations of Reduction Potential and Acidity in Water

Hydricity, or hydride donating ability, is a thermodynamic value that helps define the reactivity of transition metal hydrides. To avoid some of the challenges of experimental hydricity measurements in water, a computational method for the determination of aqueous hydricity values has been developed. With a thermochemical cycle involving deprotonation of the metal hydride (p<i>K</i>_a), 2<i>e</i>^– oxidation of the metal (<i>E</i>°), and 2<i>e</i>^– reduction of the proton, hydricity values are provided along with other valuable thermodynamic information. The impact of empirical corrections (for example, calibrating reduction potentials with 2<i>e</i>^– organic versus 1<i>e</i>^– inorganic potentials) was assessed in the calculation of the reduction potentials, acidities, and hydricities of a series of iridium hydride complexes. Calculated hydricities are consistent with electronic trends and agree well with experimental values

Point‐of‐care detection of fibrosis in liver transplant surgery using near‐infrared spectroscopy and machine learning

Abstract Introduction Visual assessment and imaging of the donor liver are inaccurate in predicting fibrosis and remain surrogates for histopathology. We demonstrate that 3‐s scans using a handheld near‐infrared‐spectroscopy (NIRS) instrument can identify and quantify fibrosis in fresh human liver samples. Methods We undertook NIRS scans on 107 samples from 27 patients, 88 from 23 patients with liver disease, and 19 from four organ donors. Results Liver disease patients had a median immature fibrosis of 40% (interquartile range [IQR] 20–60) and mature fibrosis of 30% (10%–50%) on histopathology. The organ donor livers had a median fibrosis (both mature and immature) of 10% (IQR 5%–15%). Using machine learning, this study detected presence of cirrhosis and METAVIR grade of fibrosis with a classification accuracy of 96.3% and 97.2%, precision of 96.3% and 97.0%, recall of 96.3% and 97.2%, specificity of 95.4% and 98.0% and area under receiver operator curve of 0.977 and 0.999, respectively. Using partial‐least square regression machine learning, this study predicted the percentage of both immature (R2 = 0.842) and mature (R2 = 0.837) with a low margin of error (root mean square of error of 9.76% and 7.96%, respectively). Conclusion This study demonstrates that a point‐of‐care NIRS instrument can accurately detect, quantify and classify liver fibrosis using machine learning

Beyond Happiness and Satisfaction: Toward Well-Being Indices Based on Stated Preference: Dataset.” American Economic Review.

The cornerstone of neoclassical welfare economics is the principle of revealed preference, according to which the ultimate criterion for judging what makes a person better off is what she chooses, in a situation in which she is well informe

Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations

Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases