Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides

The therapeutic and research potentials of oligonucleotides (ONs) have been hampered in part by their inability to effectively escape endosomal compartments to reach their cytosolic and nuclear targets. Splice-switching ONs (SSOs) can be used with endosomolytic small molecule compounds to increase functional delivery. So far, development of these compounds has been hindered by a lack of high-resolution methods that can correlate SSO trafficking with SSO activity. Here we present in-depth characterization of two novel endosomolytic compounds by using a combination of microscopic and functional assays with high spatiotemporal resolution. This system allows the visualization of SSO trafficking, evaluation of endosomal membrane rupture, and quantitates SSO functional activity on a protein level in the presence of endosomolytic compounds. We confirm that the leakage of SSO into the cytosol occurs in parallel with the physical engorgement of LAMP1-positive late endosomes and lysosomes. We conclude that the new compounds interfere with SSO trafficking to the LAMP1-positive endosomal compartments while inducing endosomal membrane rupture and concurrent ON escape into the cytosol. The efficacy of these compounds advocates their use as novel, potent, and quick-acting transfection reagents for antisense ONs

Orthologue chemical space and its influence on target prediction

Motivation In silico approaches often fail to utilize bioactivity data available for orthologous targets due to insufficient evidence highlighting the benefit for such an approach. Deeper investigation into orthologue chemical space and its influence toward expanding compound and target coverage is necessary to improve the confidence in this practice. Results Here we present analysis of the orthologue chemical space in ChEMBL and PubChem and its impact on target prediction. We highlight the number of conflicting bioactivities between human and orthologues is low and annotations are overall compatible. Chemical space analysis shows orthologues are chemically dissimilar to human with high intra-group similarity, suggesting they could effectively extend the chemical space modelled. Based on these observations, we show the benefit of orthologue inclusion in terms of novel target coverage. We also benchmarked predictive models using a time-series split and also using bioactivities from Chemistry Connect and HTS data available at AstraZeneca, showing that orthologue bioactivity inclusion statistically improved performance

Vaughan-Jackson-like syndrome as an unusual presentation of Kienböck's disease: a case report

<p>Abstract</p> <p>Introduction</p> <p>Kienböck's disease is a condition of osteonecrosis of the lunate bone in the hand, and most patients present with a painful and sometimes swollen wrist with a limited range of motion in the affected wrist. Vaughan-Jackson syndrome is characterized by the disruption of the digital extensor tendons, beginning on the ulnar side with the extensor digiti minimi and extensor digitorum communis tendon of the small finger. It is most commonly associated with rheumatoid arthritis. We describe a case of a patient with an unusual presentation of Kienböck's disease with symptoms similar to those of Vaughan-Jackson syndrome.</p> <p>Case presentation</p> <p>A 40-year-old man of Indian ethnic origin with no known history of trauma presented to our clinic with a ten-day history of an inability to extend his right little and ring fingers with associated pain in his right wrist. He was being treated with long-term steroids but had no other significant medical history. His examination revealed an inability to extend the metacarpal and phalangeal joints of the right ring and little fingers with localized tenderness over the lunate bone. Spontaneous disruption of the extensor tendons was diagnosed clinically and, after radiological investigation, was confirmed to be secondary to dorsal extrusion of the fragmented lunate bone. The patient underwent surgical repair of the tendons and had a full recovery afterward.</p> <p>Conclusion</p> <p>Kienböck's disease, though rare, is an important cause of spontaneous extensor tendon rupture. The original description of Vaughan-Jackson syndrome was of rupture of the extensor tendons of the little and ring fingers caused by attrition at an arthritic inferior radioulnar joint. We describe a case of a patient with Kienböck's disease that first appeared to be a Vaughan-Jackson-like syndrome.</p

A Systematic Review of Longitudinal Trajectories of Mental Health Problems in Children with Neurodevelopmental Disabilities

YesTo review the longitudinal trajectories – and the factors influencing their development – of mental health problems in children with neurodevelopmental disabilities. Systematic review methods were employed. Searches of six databases used keywords and MeSH terms related to children with neurodevelopmental disabilities, mental health problems, and longitudinal research. After the removal of duplicates, reviewers independently screened records for inclusion, extracted data (outcomes and influencing factors), and evaluated the risk of bias. Findings were tabulated and synthesized using graphs and a narrative. Searches identified 94,662 unique records, from which 49 publications were included. The median publication year was 2015. Children with attention deficit hyperactivity disorder were the most commonly included population in retrieved studies. In almost 50% of studies, trajectories of mental health problems changed by Swedish Research Council (2018-05824_VR

From Big Data to Artificial Intelligence: Chemoinformatics meets new challenges.

Abstract: The increasing volume of biomedical data in chemistry and life sciences requires development of new methods and approaches for their analysis. Artificial Intelligence and machine learning, especially neural networks, are increasingly used in the chemical industry, in particular with respect to Big Data. This editorial highlights the main results presented during the special session of the International Conference on Neural Networks organized by “Big Data in Chemistry” project and draws perspectives on the future progress of the field. Graphical Abstract: [Figure not available: see fulltext.]