Biology subjects

Meek, T.

Publications and source records attributed to Meek, T..

3 recordsLinked to original sources

bioRxiv2024

Reciprocal regulation of m6A modification and miRNA production machineries via phase separation-dependent and -independent mechanisms

Methyltransferase complex (MTC) deposits N6-adenosine (m6A) onto RNA, whereas microprocessor produces miRNA. Whether and how these two distinct complexes cross-regulate each other has been poorly studied. Here we report that the MTC subunit B (MTB) tends to form insoluble condensates with poor activity, with its level monitored by 20S proteasome. Conversely, the microprocessor component SERRATE (SE) forms liquid-like condensates, which in turn promotes solubility and stability of MTB, leading to increased MTC activity. Consistently, the hypomorphic lines expressing SE variants, defective in MTC interaction or liquid-like phase behavior, exhibit reduced m6A level. Reciprocally, MTC can recruit microprocessor to MIRNA loci, prompting co-transcriptional cleavage of primary miRNA (pri-miRNAs) substrates. Additionally, pri-miRNAs carrying m6A modifications at their single-stranded basal regions are enriched by m6A readers, which retain microprocessor in the nucleoplasm for continuing processing. This reveals an unappreciated mechanism of phase separation in RNA modification and processing through MTC and microprocessor coordination.

plant biology↗

bioRxiv2020

Potent in vitro anti-SARS-CoV-2 activity by gallinamide A and analogues via inhibition of cathepsin L

The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic, has led to substantial mortality, together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L activity with IC50 values in the picomolar range. Lead molecules possessed selectivity over cathepsin B and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro and PLpro. We demonstrate that gallinamide A and two lead analogues potently inhibit SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range, thus further highlighting the potential of cathepsin L as a COVID-19 antiviral drug target.

biochemistry↗

bioRxiv2019

Physiotherapist confidence level in mobilising stroke patients after decompressive hemicraniectomy: are helmets useful?

IntroductionDecompressive hemicraniectomy is a lifesaving measure in malignant middle cerebral artery infarction; however, this leaves patients with a skull defect. There is variability of helmet use in this patient group across Britain. We aimed to examine whether (1) specialist physiotherapist were more confident mobilising a patient with hemiparesis and skull defect than a non-specialist physiotherapist (2) non-specialist and specialist physiotherapists would be more comfortable mobilising this patient with a helmet as opposed to without a helmet.\n\nMethodsWe carried out a cross-sectional online survey of specialist physiotherapists and non-specialist physiotherapists in Britain. Recruitment was through mailing lists. Physiotherapists were asked to rank their confidence level on a 5-point Likert scale of mobilising an example patient with and without a helmet. They were also asked about the number of additional therapists needed to safely mobilise the patient.\n\nFindings96 physiotherapists completed the survey; 44 were specialists and 52 were non-specialists. Specialist physiotherapists felt more comfortable mobilising patients (mean difference = 0.68, p < 0.001). Non-specialist physiotherapists felt significantly more comfortable mobilising patients with a helmet (mean difference = 0.96, p value < 0.001), as did specialist physiotherapists (mean difference = 0.68, p value < 0.001). There was no difference in confidence level arising from helmet use between the two groups (p = 0.72).\n\nConclusionsUse of helmets may allow specialist and non-specialist physiotherapists to feel more comfortable when mobilising stroke patients post-decompressive hemicraniectomy. Consideration should be made by hospitals and health systems for the provision of helmets this patient group, to maximise functional gains.

neuroscience↗