Fosfowash: Early proof of concept study investigating intravesical fosfomycin for recurrent urinary tract infections

NA, research letter

Ten simple rules for creating a brand-new virtual academic meeting (even amid a pandemic)

The increased democratization of the creation, implementation, and attendance of academic conferences has been a serendipitous benefit of the movement toward virtual meetings. The Coronavirus Disease 2019 (COVID-19) pandemic has accelerated the transition to online conferences and, in parallel, their democratization, by necessity. This manifests not just in the mitigation of barriers to attending traditional physical conferences but also in the presentation of new, and more importantly attainable, opportunities for young scientists to carve out a niche in the landscape of academic meetings. Here, we describe an early “proof of principle” of this democratizing power via our experience organizing the Canadian Computational Neuroscience Spotlight (CCNS; crowdcast.io/e/CCNS), a free 2-day virtual meeting that was built entirely amid the pandemic using only virtual tools. While our experience was unique considering the obstacles faced in creating a conference during a pandemic, this was not the only factor differentiating both our experience and the resulting meeting from other contemporary online conferences. Specifically, CCNS was crafted entirely by early career researchers (ECRs) without any sponsors or partners, advertised primarily using social media and “word of mouth,” and designed specifically to highlight and engage trainees. From this experience, we have distilled “10 simple rules” as a blueprint for the design of new virtual academic meetings, especially in the absence of institutional support or partnerships, in this unprecedented environment. By highlighting the lessons learned in implementing our meeting under these arduous circumstances, we hope to encourage other young scientists to embrace this challenge, which would serve as a critical next step in further democratizing academic meetings.

Initial Development of Mechanical Arm Support for Spinal Muscular Atrophy Patient

Spinal Muscular Atrophy or SMA disorder is generally thought to have affected as many as 1 in 40 in country like USA. SMA type 2 and 3 are commonly found in Indonesia. Children who suffer from SMA disease cannot move their hands with flexion - extension and abduction - adduction orientation maximally, because the muscles in the patient cannot support the movements of the hand. In this project, an initial joint effort was conducted by SGU and Bioteknik Design, to develop an active mechanical arm support with muscular feedback. Hence, the hand movements of the patient can be supported externally through detecting the muscle tension produced by moving the patient's hand. The tension is detected using Carbon Nanotube (CNT)-coated thread Mechanomyography (MMG) sensor. The sensor signal is then fed into Arduino microcontroller, to give appropriate control signal to the universal power window motor. As an early proof of concept, wood was used as the main structural material for the arm support. The project, however, did not go as expected due to the lack of torque from the motor and missed feedback connection from the sensor. A counter balance mechanism like spring may be attached for future improvement.

An Exon-Specific Small Nuclear U1 RNA (ExSpeU1) Improves Hepatic OTC Expression in a Splicing-Defective spf/ash Mouse Model of Ornithine Transcarbamylase Deficiency

OTC splicing mutations are generally associated with the severest and early disease onset of ornithine transcarbamylase deficiency (OTCD), the most common urea cycle disorder. Noticeably, splicing defects can be rescued by spliceosomal U1snRNA variants, which showed their efficacy in cellular and animal models. Here, we challenged an U1snRNA variant in the OTCD mouse model (spf/ash) carrying the mutation c.386G > A (p.R129H), also reported in OTCD patients. It is known that the R129H change does not impair protein function but affects pre-mRNA splicing since it is located within the 5′ splice site. Through in vitro studies, we identified an Exon Specific U1snRNA (ExSpeU1O3) that targets an intronic region downstream of the defective exon 4 and rescues exon inclusion. The adeno-associated virus (AAV8)-mediated delivery of the ExSpeU1O3 to mouse hepatocytes, although in the presence of a modest transduction efficiency, led to increased levels of correct OTC transcripts (from 6.1 ± 1.4% to 17.2 ± 4.5%, p = 0.0033). Consistently, this resulted in increased liver expression of OTC protein, as demonstrated by Western blotting (~3 fold increase) and immunostaining. Altogether data provide the early proof-of-principle of the efficacy of ExSpeU1 in the spf/ash mouse model and encourage further studies to assess the potential of RNA therapeutics for OTCD caused by aberrant splicing.

Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease (CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different—yet largely unknown—mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population.

Out of COVID, a conference: lessons from creating a new, free, and entirely virtual academic meeting amidst a pandemic

One potentially positive result of the movement towards virtual academic meetings, accelerated by the COVID-19 pandemic, is increased democratization of the creation, implementation, and attendance of academic conferences. Here we describe an early ``proof of principle" of this democratizing power via our experience organizing the Canadian Computational Neuroscience Spotlight (CCNS), a free two-day virtual meeting that was built entirely amidst the pandemic using only virtual tools. This meeting was unique not just in the challenges faced by creating a conference during a pandemic: it was crafted entirely by early-career researchers and without any sponsors or partners, advertised primarily using social media and ``word of mouth", and designed specifically to highlight and engage trainees. It is our hope that this success will encourage other young scientists to embrace the challenge of organizing their own unique conferences facilitated by the benefits of the digital space, further democratizing the landscape of academic meetings.

Topical RNAi for Sustainable Animal Health

Animal health measures mainly rely on vaccination or chemical control for major pests and pathogens, causing issues of residue, toxicity and development of resistance. For example, control of Sheep flystrike and lice-infestation affecting the Australia’s sheep/wool industry (>3.5 B) have developed resistance to nearly all control chemicals used in the past. Topicals RNAi provides an innovative clean-green, non-toxic, environmentally sustainable biological control solution. Biodegradable clay particles as carriers can be used to deliver double stranded RNA (dsRNA), the key trigger molecule of RNA interference pathway. As an early proof of concept, we investigated the stability dsRNA loaded on two types of Clay particles: Clay 1 (releases dsRNA under acidic conditions) and Clay 2 (releases dsRNA under alkaline conditions) on cattle hide. Cattle skin was treated with Cy3 labelled dsRNA alone and Cy3 labelled dsRNA loaded on Clay1 or Clay2. The skin samples treated with the Cy3 formulations were imaged using confocal microscopy. Once imaged, the skin samples were washed and stored at room temperature for 5 days, later the samples were re-imaged to detect the fluorescent signal (Figure 1). The dsRNA loaded on clay particles was stable unlike naked Cy3-dsRNA which degraded and was not visible after washing. This increased inherent stability of the dsRNA molecules, combined with the environmental stability afforded by the Clay particles, offers promise to provide a sustainable solution for animal health. Topical RNAi can reduce reliance on trade withholding periods of meat/wool without chemical residues, enhance animal welfare and increase production of premium quality meat/wool, improve export potential, competitiveness and long-term profitability of livestock industry.

0142 TAK-925, an Orexin 2 Receptor-Selective Agonist, Enhanced Cortical Arousal in a Narcolepsy Mouse Model Different from Effects of Modafinil

Introduction Patients with narcolepsy type 1 (NT1) suffer from distressing symptoms such as excessive daytime sleepiness (EDS) and cataplexy. Modafinil is widely used as a therapy for NT1; however, it has limited efficacy for EDS and no efficacy for cataplexy. TAK-925 is an orexin 2 receptor (OX2R)-selective agonist which improves multiple symptoms of narcolepsy such as fragmentation of wakefulness and cataplexy-like episodes, and also reduces weight gain, in orexin/ataxin-3 mice, a narcolepsy mouse model. An early proof of concept study showed TAK-925 increased wakefulness compared to placebo in individuals with NT1; however, a head-to-head comparison between TAK-925 and modafinil in NT1 has not been performed to date. In this study, we carefully compared the wake-promoting effects of TAK-925 and modafinil in orexin/ataxin-3 mice. Methods TAK-925 or modafinil was administered to orexin/ataxin-3 mice at zeitgeber time 12, and the sleep/wakefulness states were evaluated based on electroencephalogram (EEG) and electromyogram measurements. EEG spectral analysis was performed by fast Fourier transform during wakefulness. EEG frequency band was divided into five frequency bands: delta, theta, alpha, beta, and gamma. Results Both TAK-925 and modafinil significantly increased wakefulness time, and ameliorated fragmentation of wakefulness, in orexin/ataxin-3 mice during active phase. In contrast, TAK-925, but not modafinil, significantly decreased delta power, and increased alpha and gamma power during wakefulness in orexin/ataxin-3 mice, suggesting a shift in EEG power density toward higher frequencies. Conclusion TAK-925, but not modafinil, enhanced cortical arousal and suppressed signs of somnolence and drowsiness. In a phase 1 study in individuals with NT1, TAK-925 was found to have pronounced effects on the maintenance of wakefulness test, reaching a total duration of 40 minutes wake time at some doses tested. Spectral analysis will be evaluated in future studies in NT1 patients. Support This work was conducted by Takeda Pharmaceutical Company Limited.

Caraglio and Rosso Fiorentino between Pen and Press

The John Rylands Library’s recently rediscovered Spencer Album 8050 contains a proof state of the Battle of the Romans and the Sabines, an engraving pivotal in the short-lived but ambitious collaboration between Jacopo Caraglio (1500–65) and Rosso Fiorentino (1495–1540) in Rome. This proof impression was first printed in black ink, and then densely covered with hand-drawn ink. A comparison between the new proof state and previously identified states of the engraving using a novel technical approach involving long-wave infrared light to isolate the printed lines optically indicates that the Spencer proof state precedes any other known state of the engraving. The use of penwork and printing on this early proof and subsequent proof states demonstrates how Caraglio and Rosso saw drawing and printing as intimately connected, iterative steps in the print’s production.