Template-dependent DNA ligation for the synthesis of modified oligonucleotides.

Chemical modification of DNA is a common strategy to improve the properties of oligonucleotides, particularly for therapeutics and nanotechnology. Existing synthetic methods essentially rely on phosphoramidite chemistry or the polymerization of nucleoside triphosphates but are limited in terms of size, scalability, and sustainability. Herein, we report a robust alternative method for the de novo synthesis of modified oligonucleotides using template-dependent DNA ligation of shortmer fragments.

ICON 2023: International Scientific Tendinopathy Symposium Consensus - the core outcome set for Achilles tendinopathy (COS-AT) using a systematic review and a Delphi study of professional participants and patients.

To develop a core outcome set for Achilles tendinopathy (COS-AT) for use in clinical trials we performed a five-step process including (1) a systematic review of available outcome measurement instruments, (2) an online survey on truth and feasibility of the available measurement instruments, (3) an assessment of the methodological quality of the selected outcome measurement instruments, (4) an online survey on the outcome measurement instruments as COS and (5) a consensus in-person meeting. Both surveys were completed by healthcare professionals and patients. The Outcome Measures in Rheumatology guidelines with a 70% threshold for consensus were followed.

Youth Athletes With Sever's Disease Exhibit Altered Achilles Tendon Ultrasound Characteristics: A Retrospective Case-Control Study.

Objectives: Calcaneal apophysitis (Sever's disease) is an overuse condition caused by repetitive traction stress to the calcaneal apophysis. Whether Achilles tendon morphology is altered in this young patient population remains unknown. Therefore, we aimed to identify differences in Achilles tendon morphology between youth athletes diagnosed with calcaneal apophysitis and healthy controls.

Effective engineering of a ketoreductase for the biocatalytic synthesis of an ipatasertib precursor.

Semi-rational enzyme engineering is a powerful method to develop industrial biocatalysts. Profiting from advances in molecular biology and bioinformatics, semi-rational approaches can effectively accelerate enzyme engineering campaigns. Here, we present the optimization of a ketoreductase from Sporidiobolus salmonicolor for the chemo-enzymatic synthesis of ipatasertib, a potent protein kinase B inhibitor.

Enhancing dermatology nursing education in Scotland and Ireland: a multifaceted approach.

The purpose of the National Dermatology Improvement Project was to identify the educational requirements of dermatology nurses and understand factors impacting the uptake of education for nurses. An educational needs analysis was performed to evaluate the strengths and weaknesses of current and future educational provision for all levels of nursing staff. Data were collected from department managers using questionnaires and interviews, and focus groups were held with nursing staff in bands 2-7.

Maximal daily stepping cadence partially explains functional capacity of individuals with end-stage knee osteoarthritis.

Background: Individuals with end-stage knee osteoarthritis (OA) walk at a lower intensity (ie, slower step cadence) contributing to worse physical function. Previous literature reports daily step counts and sedentary time, with little information regarding stepping bouts or cadence. Determining relationships between daily higher stepping cadence duration and clinical outcomes can move the field toward optimal daily stepping prescription.

Walking Exercise Sustainability Through Telehealth for Veterans With Lower-Limb Amputation: A Study Protocol.

Objective: This randomized controlled superiority trial will determine if an 18-month telehealth walking exercise self-management program produces clinically meaningful changes in walking exercise sustainability compared to attention-control education for veterans living with lower-limb amputation.

Methods: Seventy-eight participants with lower-limb amputation (traumatic or nontraumatic) aged 50 to 89 years will be enrolled. Two groups will complete 6 one-on-one intervention sessions, and 6 group sessions over an 18-month intervention period.

Effect of Symptom Duration on Injury Severity and Recovery in Patients With Achilles Tendinopathy.

Background: Achilles tendinopathy is a common overuse condition. Distinguishing between early- and late-stage tendinopathy may have implications on treatment decisions and recovery expectations.

Purpose: To compare the effects of time and baseline measures of tendon health on outcomes among patients with varying symptom durations after 16 weeks of comprehensive exercise treatment.

Towards the controlled enzymatic synthesis of LNA containing oligonucleotides.

Enzymatic, XNA synthesis represents an alternative method for the production of long oligonucleotides containing chemical modifications at distinct locations. While such an approach is currently developed for DNA, controlled enzymatic synthesis of XNA remains at a relative state of infancy. In order to protect the masking groups of 3'--modified LNA and DNA nucleotides against removal caused by phosphatase and esterase activities of polymerases, we report the synthesis and biochemical characterization of nucleotides equipped with ether and robust ester moieties.

B chromosomes reveal a female meiotic drive suppression system in Drosophila melanogaster.

Selfish genetic elements use a myriad of mechanisms to drive their inheritance and ensure their survival into the next generation, often at a fitness cost to its host. Although the catalog of selfish genetic elements is rapidly growing, our understanding of host drive suppression systems that counteract self-seeking behavior is lacking. Here, we demonstrate that the biased transmission of the non-essential, non-driving B chromosomes in Drosophila melanogaster can be achieved in a specific genetic background.

The Association Between COVID-19 and Febrile Seizure: A Retrospective Case-Control Study.

Background/objective: Throughout the pandemic, febrile seizures have resulted from infection secondary to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The objective of this study is to determine if there is an increased association between COVID-19 and febrile seizures as compared with other causes of febrile seizures.

Methods: This was a retrospective case control study.

Mass Balance of the Indoleamine 2,3-Dioxygenase Inhibitor Navoximod (GDC-0919) in Rats and Dogs: Unexpected Cyanide Release from Imidazo[5,1-]isoindole and Species Differences in Glucuronidation.

Navoximod (GDC-0919) is a small molecule inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1) developed to reduce T cell immunosuppression associated with cancer. This study describes the absorption, metabolism, and excretion (AME) of navoximod in rats and dogs after a single oral dose of [C]-navoximod. An unexpected thiocyanate metabolite M1 and a chiral inversion metabolite M51 were captured as the major circulating metabolites in rats, accounting for 30% and 18% of 0-24 hours exposure, respectively.

Evaluation of 3'-phosphate as a transient protecting group for controlled enzymatic synthesis of DNA and XNA oligonucleotides.

Chemically modified oligonucleotides have advanced as important therapeutic tools as reflected by the recent advent of mRNA vaccines and the FDA-approval of various siRNA and antisense oligonucleotides. These sequences are typically accessed by solid-phase synthesis which despite numerous advantages is restricted to short sequences and displays a limited tolerance to functional groups. Controlled enzymatic synthesis is an emerging alternative synthetic methodology that circumvents the limitations of traditional solid-phase synthesis.

Differences in Recovery of Tendon Health Explained by Midportion Achilles Tendinopathy Subgroups: A 6-Month Follow-up.

To (1) evaluate whether the defining characteristics of previously reported Achilles tendinopathy subgroups were reproducible in a cohort with midportion Achilles tendinopathy and (2) compare recovery trajectories and outcomes. Prospective single cohort study. Participants (n = 114; 57 women; age [mean ± standard deviation]: 47 ± 12 years) received the Silbernagel protocol and were evaluated at baseline, and at 8, 16, and 24 weeks.

Case Studies for Overcoming Challenges in Using Big Data in Cancer.

The analysis of big healthcare data has enormous potential as a tool for advancing oncology drug development and patient treatment, particularly in the context of precision medicine. However, there are challenges in organizing, sharing, integrating, and making these data readily accessible to the research community. This review presents five case studies illustrating various successful approaches to addressing such challenges.

Challenges to Using Big Data in Cancer.

Big data in healthcare can enable unprecedented understanding of diseases and their treatment, particularly in oncology. These data may include electronic health records, medical imaging, genomic sequencing, payor records, and data from pharmaceutical research, wearables, and medical devices. The ability to combine datasets and use data across many analyses is critical to the successful use of big data and is a concern for those who generate and use the data.

Determining the feasibility of exercise therapy and activity modification for treating adolescents with heel pain: a study protocol.

Calcaneal apophysitis and Achilles tendinopathy are common overuse injuries characterised by insidious posterior heel pain with activity. Calcaneal apophysitis is commonly diagnosed in adolescents, although Achilles tendinopathy is understudied in the adolescent population and is therefore rarely considered until adulthood. Exercise therapy and activity modification have the highest level of evidence for treating Achilles tendinopathy, while calcaneal apophysitis is treated with anecdotal and passive treatment or complete rest.

Screening methods for enzyme-mediated alcohol oxidation.

Alcohol oxidation for the generation of carbonyl groups, is an essential reaction for the preparation of fine chemicals. Although a number of chemical procedures have been reported, biocatalysis is a promising alternative for more sustainable and selective processes. To speed up the discovery of novel (bio)catalysts for industrial applications, efficient screening approaches need to be established.

ICON 2020-International Scientific Tendinopathy Symposium Consensus: A Systematic Review of Outcome Measures Reported in Clinical Trials of Achilles Tendinopathy.

Background: Nine core domains for tendinopathy have been identified. For Achilles tendinopathy there is large variation in outcome measures used, and how these fit into the core domains has not been investigated.

Objective: To identify all available outcome measures outcome measures used to assess the clinical phenotype of Achilles tendinopathy in prospective studies and to map the outcomes measures into predefined health-related core domains.

Towards the enzymatic synthesis of phosphorothioate containing LNA oligonucleotides.

Therapeutic oligonucleotides require the addition of multiple chemical modifications to the nucleosidic scaffold in order to improve their drug delivery efficiency, cell penetration capacity, biological stability, and pharmacokinetic properties. This chemical modification pattern is often accompanied by a synthetic burden and by limitations in sequence length. Here, we have synthesized a nucleoside triphosphate analog bearing two simultaneous modifications at the level of the sugar (LNA) and the backbone (thiophosphate) and have tested its compatibility with enzymatic DNA synthesis which could abrogate some of these synthetic limitations.

Beyond the Diagnosis: Using Patient Characteristics and Domains of Tendon Health to Identify Latent Subgroups of Achilles Tendinopathy.

Objective: To identify latent subgroups among patients with Achilles tendinopathy, describe patient characteristics and clinical attributes that defined each subgroup, and develop a clinical classification model for subgroup membership.

Design: Cross-sectional study.

Methods: One hundred forty-five participants (men, n = 73; mean ± SD age, 51 ± 14 years) with clinically diagnosed Achilles tendinopathy completed a baseline evaluation, including demographics and medical history, patient-reported outcome measures, a clinical exam, tendon structure measures via ultrasound imaging and continuous shear-wave elastography, and a functional test battery.

Multi-Scale Organization of the Genome.

Interphase chromatin, despite its appearance, is a highly organized framework of loops and bends. Chromosomes are folded into topologically associating domains, or TADs, and each chromosome and its homolog occupy a distinct territory within the nucleus. In , genome organization is exceptional because homologous chromosome pairing is in both germline and somatic tissues, which promote interhomolog interactions such as transvection that can affect gene expression in .