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A hungry but finicky king wants Wobbly Bob as his new cook, but must pitch in to do everything the cook is afraid to do, from fishing to frying.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are caused by mutation of the proteasome shuttle factor Ubiquilin 2 ( UBQLN2 ), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate that UBQLN2 regulates the domesticated gag-pol retrotransposon ‘paternally expressed gene 10 (PEG10)’ in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated ‘nucleocapsid’ fragment, which uniquely localizes to the nucleus and changes the expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through the regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.

A screen of a genomic library from Mycobacterium tuberculosis (Mtb) identified a small, unannotated open reading frame (MT0196) that encodes a 4.9-kDa, cysteine-rich protein. Despite extensive nucleotide divergence, the amino acid sequence is highly conserved among mycobacteria that are pathogenic in vertebrate hosts. We synthesized the protein and found that it preferentially binds up to six Cu( I ) ions in a solvent-shielded core. Copper, cadmium and compounds that generate nitric oxide or superoxide induced the gene's expression in Mtb up to 1,000-fold above normal expression. The native protein bound copper within Mtb and partially protected Mtb from copper toxicity. We propose that the product of the MT0196 gene be named mycobacterial metallothionein (MymT). To our knowledge, MymT is the first metallothionein of a Gram-positive bacterium with a demonstrated function.

Existing drugs are slow to eradicate Mycobacterium tuberculosis (Mtb) in patients and have failed to control tuberculosis globally. One reason may be that host conditions impair Mtb’s replication, reducing its sensitivity to most antiinfectives. We devised a high-throughput screen for compounds that kill Mtb when its replication has been halted by reactive nitrogen intermediates (RNIs), acid, hypoxia, and a fatty acid carbon source. At concentrations routinely achieved in human blood, oxyphenbutazone (OPB), an inexpensive anti-inflammatory drug, was selectively mycobactericidal to nonreplicating (NR) Mtb. Its cidal activity depended on mild acid and was augmented by RNIs and fatty acid. Acid and RNIs fostered OPB’s 4-hydroxylation. The resultant 4-butyl-4-hydroxy-1-(4-hydroxyphenyl)-2-phenylpyrazolidine-3,5-dione (4-OH-OPB) killed both replicating and NR Mtb, including Mtb resistant to standard drugs. 4-OH-OPB depleted flavins and formed covalent adducts with N -acetyl-cysteine and mycothiol. 4-OH-OPB killed Mtb synergistically with oxidants and several antituberculosis drugs. Thus, conditions that block Mtb’s replication modify OPB and enhance its cidal action. Modified OPB kills both replicating and NR Mtb and sensitizes both to host-derived and medicinal antimycobacterial agents.

\"An amiable Navy veteran loses his comfortable job at a big-box store, enrolls in community college, and seeks to reinvent himself while falling for his apathetic speech professor in this romantic comedy re-teaming Academy Award-winning Charlie Wilson's War co-stars Tom Hanks and Julia Roberts. Larry Crowne (Hanks) has just been downsized. The unfortunate victim of a failing economy, Larry decides that his best option to avoid becoming idle is to take some classes at his local community college. In no time, Larry befriends a colorful group of moped-obsessed outcasts on the road to self-improvement, and begins working to sharpen his communication skills in a public speaking class taught by Mercedes Tainot (Roberts). Disenchanted with her job and bored in her marriage, Mercedes has begun to feel as if she's missing out on life. But whenever she's with Larry, all of her problems seem to disappear. Now, just as Larry and Mercedes are feeling as if their lives have been put on hold, they both discover that fate sometimes has a way of giving us exactly what we need, at precisely the right time\"--Allmovie.com, December 27, 2019.

The COVID-19 pandemic altered the way many people worked. Remote and creative ways were favoured and utilised for consultation activities. In this paper, we draw attention to how we have used creative methods over the teleconferencing platform ‘ZOOM’ to consult with children and their parents when we were unable to consult with them face-to-face. We document a clear timeline of how we have worked together to co-create an animation and information sheet about receiving outpatient parenteral antimicrobial therapy (OPAT). We identify the opportunities and challenges we faced.

Antimycobacterial agents might shorten the course of treatment by reducing the number of phenotypically tolerant bacteria if they could kill M. tuberculosis in diverse metabolic states. Here we report two chemically disparate classes of agents that kill M. tuberculosis both when it is replicating and when it is not. Under replicating conditions, the tricyclic 4-hydroxyquinolines and a barbituric acid analogue deplete intrabacterial magnesium as a mechanism of action, and for both compounds, mutations in CorA, a putative Mg 2+ /Co 2+ transporter, conferred resistance to the compounds when M. tuberculosis was under replicating conditions but not under nonreplicating conditions, illustrating that a given compound can kill M. tuberculosis in different metabolic states by disparate mechanisms. Targeting magnesium metallostasis represents a previously undescribed antimycobacterial mode of action that might cripple M. tuberculosis in a Mg 2+ -deficient intraphagosomal environment of macrophages. A defining characteristic of treating tuberculosis is the need for prolonged administration of multiple drugs. This may be due in part to subpopulations of slowly replicating or nonreplicating Mycobacterium tuberculosis bacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding this problem is the increasing incidence of heritable multidrug-resistant M. tuberculosis . A search for new antimycobacterial chemical scaffolds that can kill phenotypically drug-tolerant mycobacteria uncovered tricyclic 4-hydroxyquinolines and a barbituric acid derivative with mycobactericidal activity against both replicating and nonreplicating M. tuberculosis . Both families of compounds depleted M. tuberculosis of intrabacterial magnesium. Complete or partial resistance to both chemotypes arose from mutations in the putative mycobacterial Mg 2+ /Co 2+ ion channel, CorA. Excess extracellular Mg 2+ , but not other divalent cations, diminished the compounds’ cidality against replicating M. tuberculosis . These findings establish depletion of intrabacterial magnesium as an antimicrobial mechanism of action and show that M. tuberculosis magnesium homeostasis is vulnerable to disruption by structurally diverse, nonchelating, drug-like compounds. IMPORTANCE Antimycobacterial agents might shorten the course of treatment by reducing the number of phenotypically tolerant bacteria if they could kill M. tuberculosis in diverse metabolic states. Here we report two chemically disparate classes of agents that kill M. tuberculosis both when it is replicating and when it is not. Under replicating conditions, the tricyclic 4-hydroxyquinolines and a barbituric acid analogue deplete intrabacterial magnesium as a mechanism of action, and for both compounds, mutations in CorA, a putative Mg 2+ /Co 2+ transporter, conferred resistance to the compounds when M. tuberculosis was under replicating conditions but not under nonreplicating conditions, illustrating that a given compound can kill M. tuberculosis in different metabolic states by disparate mechanisms. Targeting magnesium metallostasis represents a previously undescribed antimycobacterial mode of action that might cripple M. tuberculosis in a Mg 2+ -deficient intraphagosomal environment of macrophages.

Recovery colleges provide personalised educational mental health support for people who self-refer. The research evidence supporting them is growing, with key components and the positive experiences of attendees reported. However, the quantitative outcome evidence and impact on economic outcomes is limited. To evaluate the impact of attending a UK recovery college for students who receive a full educational intervention. This is a pre- and post-intervention study, with predominantly quantitative methods. Participants recruited over an 18-month period (01.2020-07.2021) completed self-reported well-being (Short Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS)) and recovery (Process of Recovery (QPR)) surveys, and provided details and evidence of employment and educational status. Descriptive statistics for baseline data and Shapiro-Wilk, Wilcoxon signed-rank and paired -tests were used to compare pre- and post-intervention scores, with Hedges' -statistic as a measure of effect size. Medical records were reviewed and a brief qualitative assessment of changes reported by students was conducted. Of 101 student research participants, 84 completed the intervention. Well-being (mean SWEMWBS scores 17.3 and 21.9; = 80) and recovery (mean QPR scores 27.2 and 38.8; = 75) improved significantly ( < 0.001; Hedges' of 1.08 and 1.03). The number of economically inactive students reduced from 53 (69%) to 19 (24.4%). No research participants were referred for specialist mental health support while students. 'Within-self' and 'practical' changes were described by students following the intervention. Findings detail the largest self-reported pre-post data-set for students attending a recovery college, and the first data detailing outcomes of remote delivery of a recovery college.