A Practical Application of Data Mining Methods to Build Predictive Models for Autism Spectrum Disorder Based on Biosensor Data From Janssen Autism Knowledge Engine (JAKE®)

Abstract

The Janssen Autism Knowledge Engine (JAKE^®) collects a large number of features from five biosensors across a range of tasks. The application of data mining methods to these data may be a useful approach to enable objective discrimination between autism spectrum disorder (ASD) and typically developing (TD) participants. Following a prospective observational study using JAKE, ASD participants classified as “moderate” or “severe” based on total scores on the Social Responsiveness Scale, and TD participants were used to build models, using repeated cross-validation, to identify biosensor features contributing to diagnosis. Four different models (partial least squares, random forest, elastic net, and C5.0) were chosen to build diagnostic classifiers using the training set, and the fitted models were evaluated on the test set. Model performance on the training set, based on receiver operating characteristics (ROC), was moderate (area under ROC curve = 0.61–0.72), and model performance on the test set based on kappa statistic was between 0.40 and 0.46 across the four models. Data mining methods applied to biosensor data can lead to models that discriminate ASD from TD. This method may prove useful in creating new diagnostic tests for ASD.     

The Enterovirus 3C Protease Inhibitor SG85 Efficiently Blocks Rhinovirus Replication and Is Not Cross-Resistant with Rupintrivir

The novel enterovirus protease inhibitor (PI) SG85 effectively inhibits the in vitro replication of 14 rhinoviruses representative of species A and B (median 50% effective concentration, 0.04 μM). A low-level SG85-resistant variant was selected that carried amino acid substitutions S127G and T143A in the 3C protease. Both substitutions are required for low-level resistance to SG85, as demonstrated by reverse genetics. Interestingly, there is no cross-resistance to SG85 and rupintrivir (another PI); a structural explanation is provided for this observation.     

Gentian violet 1% solution in the treatment of wounds in the geriatric patient: a retrospective study

To review the use of gentian violet 1% (GV) in a long-term care facility for the treatment of small, open wounds and extremity eschars of all sizes and thickness. The records of all the patients receiving topical GV therapy over a period of 1 year, from May 19, 2007 - May 19, 2008 were reviewed. The total sample was 70 patients (38 male, 32 female), average age 65.9 y.o., with 111 wounds (41 patients had >1 wound). The types of wounds were divided into 3 categories: 1) Split-thickness scabs (N = 37) limited to the epithelium, 2) full-thickness eschars and wounds with no depth <1 cm (N = 50), and 3) full-thickness eschars >1 cm located on the lower extremity (average 3.3 cm in diameter [N = 24]). All the wounds had been treated the same: topical application of GV to the wounds daily. None of the patients had any documented adverse events to the GV. Out of the 111 wounds, 103 healed completely. All wounds remained negative for cellulitis. 1) GV is a viable alternative topical agent for healing small, superficial wounds, ineffective scabs, and both small and large pressure ulcer eschars on lower extremities of geriatric patients, 2) there was very little evidence of scarring with the use of GV.     

COVID-19, Mental Health and Its Relationship with Workplace Accidents

The general objective of this article is to show the relationship that exists in the COVID-19 pandemic, the mental health of people and the propensity for work-related accidents in companies. Various results are shown that detail how COVID-19 has generated and is generating mental alterations in people such as post-traumatic stress disorder, PTSD for its acronym in English. Likewise, data are presented that report the influence of mental health as a precursor to workplace accidents in different industries, with which it can be concluded that COVID-19 needs a comprehensive approach in companies to prevent it from negatively impacting workers and they end up accident during their daily work. Some concrete actions are proposed to promote and avoid in companies so that workers can be better managed in times of a COVID-19 pandemic.     

Novel Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) Gene in Indian Cases of Rett Syndrome

Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Both the classic and atypical forms of Rett syndrome are primarily due to mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with atypical Rett syndrome, X-linked infantile spasms sharing common features of generally early-onset seizures and mental retardation. CDKL5 is known as serine/threonine protein kinase 9 (STK9) and is mapped to the Xp22 region. It has a conserved serine/threonine kinase domain within its amino terminus and a large C-terminal region. Disease-causing mutations are distributed in both the amino terminal domain and in the large C-terminal domain. We have screened the CDKL5 gene in 44 patients with atypical Rett syndrome who had tested negative for MECP2 gene mutations and have identified 6 sequence variants, out of which three were novel and three known mutations. Two of these novel mutations p.V966I and p.A1011V were missense and p.H589H a silent mutation. Other known mutations identified were p.V999M, p.Q791P and p.T734A. Sequence homology for all the mutations revealed that the two mutations (p.Q791P and p.T734A) were conserved across species. This indicated the importance of these residues in structure and function of the protein. The damaging effects of these mutations were analysed in silico using PolyPhen-2 online software. The PolyPhen-2 scores of p.Q791P and p.T734A were 0.998 and 0.48, revealing that these mutations could be deleterious and might have potential functional effect. All other mutations had a low score suggesting that they might not alter the activity of CDKL5. We have also analysed the position of the mutations in the CDKL5 protein and found that all the mutations were present in the C-terminal domain of the protein. The C-terminal domain is required for cellular localization through protein–protein interaction; any mutations in this domain might alter this function of the protein. This is the first report from India showing the mutation in CDKL5 gene in Indian cases of Rett syndrome. Our study emphasizes the role of CDKL5 mutation screening in cases of atypical Rett syndrome with congenital seizure variant.     

Allelic loss of chromosomes 8 and 19 in MENX‐associated rat pheochromocytoma

Pheochromocytomas are neoplasias of neural crest origin that arise from the chromaffin cells of the adrenal medulla. Pheochromocytomas arise with complete penetrance in rats homozygous for a germ‐line frameshift mutation of Cdkn1b, encoding the cell cycle inhibitor p27KIP1 (MENX syndrome). We performed a genome‐wide scan for allelic imbalance comparing 20 rat pheochromocytoma DNAs with normal rat DNA to better understand the pathobiology of the tumors and to correlate the findings with human pheochromocytoma. We identified allelic imbalance (AI) at candidate regions on rat chromosomes 8 and 19. Interestingly, the regions often lost in rat tumors are syntenic to regions involved in human pheochromocytomas. Fluorescence in situ hybridization analysis further validated the AI data. Sdhd and Rassf1a were analyzed in detail as they map to regions of AI on chromosome 8 and their homologues are implicated in human pheochromocytoma: we found no genetic mutations nor decreased expression. We also analyzed additional candidate genes, that is, rat homologues of genes predisposing to human pheochromocytoma and known tumor‐suppressor genes, but we found no AI. In contrast, we observed frequent overexpression of Cdkn2a and Cdkn2c, encoding the cell cycle inhibitors p16INK4a and p18INK4c, respectively. The relative small number of allelic changes we found in rat pheochromocytoma might be related to their nonmalignant status and losses at chromosomes 8 and 19 are events that precede malignancy. Because of the high concordance of affected loci between rat and human tumors, studies of the MENX‐associated pheochromocytomas should facilitate the identification of novel candidate genes implicated in their human counterpart.     

Future directions for community engagement as a public health approach to palliative care in Australia

The origins of contemporary public health approaches to palliative and end-of-life care can be traced to Victoria, Australia. The work of Allan Kellehear and the palliative care unit at La Trobe University proved seminal, and this continues to grow. But while the growth of compassionate communities continues internationally, both challenges and opportunities remain for communities in Australia. In this context, we discuss future directions for community engagement as a public health approach to palliative care.

Drawing from examples of community activities and from the literature, we highlight the use of arts and social media as an emerging strength from which to build. Through the lens of positive education, we propose a positive paradigm for death education in schools to promote positive dying. The relevance and potential contribution of appreciative inquiry is then explored as an asset-based public health approach to support sustainable community development. Collective action towards these future directions will contribute to the continued flourishing of public health approaches to palliative care in Australia.     

Peptide aldehyde inhibitors challenge the substrate specificity of the SARS-coronavirus main protease

SARS coronavirus main protease (SARS-CoV M^pro) is essential for the replication of the virus and regarded as a major antiviral drug target. The enzyme is a cysteine protease, with a catalytic dyad (Cys-145/His-41) in the active site. Aldehyde inhibitors can bind reversibly to the active-site sulfhydryl of SARS-CoV M^pro. Previous studies using peptidic substrates and inhibitors showed that the substrate specificity of SARS-CoV M^pro requires glutamine in the P1 position and a large hydrophobic residue in the P2 position. We determined four crystal structures of SARS-CoV M^pro in complex with pentapeptide aldehydes (Ac-ESTLQ-H, Ac-NSFSQ-H, Ac-DSFDQ-H, and Ac-NSTSQ-H). Kinetic data showed that all of these aldehydes exhibit inhibitory activity towards SARS-CoV M^pro, with K_i values in the μM range. Surprisingly, the X-ray structures revealed that the hydrophobic S2 pocket of the enzyme can accommodate serine and even aspartic-acid side-chains in the P2 positions of the inhibitors. Consequently, we reassessed the substrate specificity of the enzyme by testing the cleavage of 20 different tetradecapeptide substrates with varying amino-acid residues in the P2 position. The cleavage efficiency for the substrate with serine in the P2 position was 160-times lower than that for the original substrate (P2 = Leu); furthermore, the substrate with aspartic acid in the P2 position was not cleaved at all. We also determined a crystal structure of SARS-CoV M^pro in complex with aldehyde Cm-FF-H, which has its P1-phenylalanine residue bound to the relatively hydrophilic S1 pocket of the enzyme and yet exhibits a high inhibitory activity against SARS-CoV M^pro, with K_i = 2.24 ± 0.58 μM. These results show that the stringent substrate specificity of the SARS-CoV M^pro with respect to the P1 and P2 positions can be overruled by the highly electrophilic character of the aldehyde warhead, thereby constituting a deviation from the dogma that peptidic inhibitors need to correspond to the observed cleavage specificity of the target protease.