An Arabidopsis mutant disrupted in valine catabolism is also compromised in peroxisomal fatty acid β-oxidation

AbstractCharacterisation of the Arabidopsis dbr5 mutant, which was isolated on the basis of 2,4-dichlorophenoxybutyric acid (2,4-DB) resistance, revealed that it is disrupted in the CHY1 gene. CHY1 encodes a peroxisomal protein that is 43% identical to the mammalian β-hydroxyisobutryl-CoA hydrolase of valine catabolism. We show that 2,4-DB resistance and the associated sucrose dependent seedling growth are due to a large activity decrease of 3-ketoacyl-CoA thiolase, which is involved in peroxisomal fatty acid β-oxidation. 14C-feeding studies demonstrate that dbr5 and chy1 seedlings are reduced in valine catabolism. These data support the hypothesis that CHY1 plays a key role in peroxisomal valine catabolism and that disruption of this enzyme results in accumulation of a toxic intermediate, methacrylyl-CoA, that inhibits 3-ketoacyl-CoA thiolase activity and thus blocks peroxisomal β-oxidation. We also show that CHY1 is repressed in seedlings grown on sugars, which suggests that branched chain amino acid catabolism is transcriptionally regulated by nutritional status

Expression of the Myxoma Virus Tumor Necrosis Factor Receptor Homologue and M11L Genes Is Required to Prevent Virus-Induced Apoptosis in Infected Rabbit T Lymphocytes

AbstractMyxoma virus is a leporipoxvirus that causes a highly lethal virulent disease known as myxomatosis in the European rabbit. An important aspect of myxoma virus pathogenesis is the ability of the virus to productively infect lymphocytes and spread to secondary sites via lymphatic channels. We investigated the infection of the CD4+T lymphoma cell line RL-5 with myxoma virus and Shope fibroma virus, a related but benign leporipoxvirus, and observed that myxoma virus, but not Shope fibroma virus, was able to productively infect RL-5 cells. We also discovered that infection of RL-5 cells with Shope fibroma virus or attenuated myxoma virus mutants containing disruptions in either the T2 or the M11L gene resulted in the rapid induction of DNA fragmentation, followed by morphological changes and loss in cell integrity characteristic of cell death by apoptosis. Purified exogenous T2 protein was unable to prevent apoptosis, suggesting that T2 functions intracellularly. Thus, myxoma virus T2, originally described as a secreted homologue of the tumor necrosis factor receptor, and M11L, a novel transmembrane species with no known cellular homologue, function to extend virus host range for replication in rabbit T lymphocytes through the inhibition of apoptosis in infected T lymphocytes

The effect of whole grain wheat sourdough bread consumption on serum lipids in healthy normoglycemic/normoinsulinemic and hyperglycemic/hyperinsulinemic adults depends on presence of the APOE E3/E3 genotype: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies associate consumption of whole grain foods, including breads, with reduced cardiovascular disease (CVD) risk; however, few studies have compared wheat whole grains with wheat refined grains.</p> <p>Methods</p> <p>This study investigated effects of 6-week consumption of whole grain wheat sourdough bread in comparison to white bread on fasting serum lipids in normoglycemic/normoinsulinemic (NGI; n = 14) and hyperglycemic/hyperinsulinemic (HGI; n = 14) adults. The influence of single-nucleotide polymorphisms, 3 within the <it>APOE </it>gene (E2, E3, E4) and 2 within the hepatic lipase gene promoter (<it>LIPC </it>-514C>T, LIPC -250G>A) were considered.</p> <p>Results</p> <p>At baseline, HGI participants had significantly higher body weight, waist circumference, body fat, and fasted glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), glucagon, triacylglycerols (TAG) and TAG:HDL-cholesterol, compared to NGI participants; however, none of these in addition to none of the other serum lipids, differed between bread treatments, within either participant group. For participants with the <it>APOE </it>E3/E3 genotype, LDL-cholesterol (<it>P </it>= 0.02) increased in the NGI group (n = 7), and TAG (<it>P </it>= 0.03) and TAG:HDL-cholesterol (<it>P </it>= 0.04) increased in the HGI group (n = 10), following consumption of whole grain wheat sourdough compared to white bread.</p> <p>Conclusions</p> <p>In summary, 6-week consumption of whole grain wheat sourdough bread did not significantly modulate serum lipids in NGI or HGI adults; however, it significantly increased LDL-cholesterol, TAG and TAG:HDL-cholesterol in participants with the <it>APOE </it>E3/E3 genotype. These data add to limited literature comparing wheat whole grains to wheat refined grains on CVD risk and highlight the need to consider genetic variation in relation to lipoprotein lipid content and CVD risk.</p

The relationship between types of childhood victimisation and young adulthood criminality

BackgroundPrevious research suggests that some types of childhood abuse and neglect are related to an increased likelihood of perpetrating criminal behaviour in adulthood. Little research, however, has examined associations between multiple different types of childhood victimisation and adult criminal behaviour.AimsWe sought to examine the contribution of multiple and diverse childhood victimisations on adult criminal behaviour. Our central hypothesis was that, after controlling for gender, substance use and psychopathy, each type of childhood victimisation â specifically experience of property offences, physical violence, verbal abuse, sexual abuse, neglect and witnessed violence â would be positively and independently related to criminal behaviour in young adults.MethodsWe examined data from a large, nationally representative sample of 2244 young Swedish adults who reported at least one form of victimisation, using hierarchical regression analysis to also account for gender, substance use and psychopathy.ResultsExperiences of physical assaults, neglect and witnessing violence as a child were significantly associated with adult criminal behaviour, but not experiences of property, verbal or sexual victimizations.ConclusionsOur findings help to identify those forms of harm to children that are most likely to be associated with later criminality. Even after accounting for gender, substance misuse and psychopathology, childhood experience of violence â directly or as a witness â carries risk for adulthood criminal behaviour, so such children need targeted support and treatment. Copyright © 2016 John Wiley & Sons, Ltd.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138903/1/cbm2002.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138903/2/cbm2002_am.pd

Filling in the gaps:A grounded theory of the experiences and needs of healthcare staff following a colleague death by suicide in the UK

Health-workers are more likely to die by suicide than their counterparts in other occupational groups. The suicide of a staff member can be widely felt by colleagues, leading to complex emotional and cognitive responses. Exposure to suicide heightens the risk of dying by suicide. We investigated the impact of a colleague suicide on National Health Service (NHS) staff. Twenty-nine staff were interviewed; all participants were white British, and so not representative of the ethnic make-up of the NHS. Data were analyzed using grounded theory methods. A theory, “filling in the gaps” was developed. Staff experiences gave rise to needs that were not always met. Staff endeavoured to “fill in the gaps” in support; however, sometimes fell through those gaps. Organizational and professional contexts shaped their experiences and responses. Recommendations include skilled and targeted support and compassion for affected staff. Cultural change is needed to challenge suicide stigma and unhelpful narratives

Understanding drivers of antibiotic resistance genes in High Arctic soil ecosystems

This work is licensed under a Creative Commons Attribution 4.0 International License.Soils in tropical and temperate locations are known to be a sink for the genetic potential of anthropogenic-driven acquired antibiotic resistance (AR). In contrast, accumulation of acquired AR is less probable in most Polar soils, providing a platform for characterizing background resistance and establishing a benchmark for assessing AR spread. Here, high-throughput qPCR and geochemistry were used to quantify the abundance and diversity of both antibiotic resistance genes (ARGs) and selected mobile genetic elements (MGEs) across eight soil clusters in the Kongsfjorden region of Svalbard in the High Arctic. Relative ARG levels ranged by over two orders of magnitude (10−6 to 10−4 copies/16S rRNA gene copy), and showed a gradient of potential human and wildlife impacts across clusters as evidenced by altered geochemical conditions and increased “foreign” ARG abundances (i.e., allochthonous), including blaNDM-1. Impacted clusters exhibited 100× higher total ARGs and MGEs in tandem with elevated secondary nutrients, especially available P that is typically low and limiting in Arctic soils. In contrast, ARGs in less-impacted clusters correlated strongly to local soil lithology. The most plausible source of exogenous P and allochthonous ARGs in this region is bird and other wildlife guano, disseminated either by local human wastes or via direct carriage and deposition. Regardless of pathway, accumulation of apparent allochthonous ARGs and MGEs in High Arctic soils is concerning, highlighting the importance of characterizing Arctic sites now to establish benchmarks for tracking AR spread around the world

Lentiviral-mediated gene transfer to the sheep brain: Implications for gene therapy in batten disease

The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are inherited neurodegenerative lysosomal storage diseases with common clinical features of blindness and seizures culminating in premature death. Gene-therapy strategies for these diseases depend on whether the missing activity is a secreted lysosomal protein taken up by neighboring cells, or an intramembrane protein that requires careful targeting. Therapies are best developed in animal models with large complex human-like brains. Lentiviral-mediated gene delivery to neural cell cultures from normal sheep and sheep affected with an NCL resulted in green fluorescent protein (GFP) expression in neurons and neuroblasts, more efficiently than in astrocytes. Similar transgene expression was obtained from two constitutive promoters, the viral MND promoter and the human EF1α promoter. In vivo studies showed stable and persistent GFP expression throughout the cell bodies, axons, and dendrites from intracortical injections and indicated ependymal and subependymal transduction. The sheep showed no ill effects from the injections. These data support continuing gene-therapy trials in the sheep models of Batten disease

A qualitative study of design stakeholders' views of developing and implementing a registry-based learning health system.

BACKGROUND:New opportunities to record, collate, and analyze routine patient data have prompted optimism about the potential of learning health systems. However, real-life examples of such systems remain rare and few have been exposed to study. We aimed to examine the views of design stakeholders on designing and implementing a US-based registry-enabled care and learning system for cystic fibrosis (RCLS-CF). METHODS:We conducted a two-phase qualitative study with stakeholders involved in designing, implementing, and using the RCLS-CF. First, we conducted semi-structured interviews with 19 program personnels involved in design and delivery of the program. We then undertook 11 follow-up interviews. Analysis of interviews was based on the constant comparative method, supported by NVivo software. RESULTS:The organizing principle for the RCLS-CF was a shift to more partnership-based relationships between patients and clinicians, founded in values of co-production, and facilitated by technology-enabled data sharing. Participants proposed that, for the system to be successful, the data it collects must be both clinically useful and meaningful to patients and clinicians. They suggested that the prerequisites included a technological infrastructure capable of supporting data entry and joint decision-making in an accessible way, and a set of social conditions, including willingness from patients and clinicians alike to work together in new ways that build on the expertise of both parties. Follow-up interviews highlighted some of the obstacles, including technical challenges and practical constraints on refiguring relationships between clinicians and patients. CONCLUSIONS:The values and vision underlying the RCLS-CF were shared and clearly and consistently articulated by design stakeholders. The challenges to realization were often not at the level of principle, but were both practical and social in character. Lessons from this study may be useful to other systems looking to harness the power of "big data" registries, including patient-reported data, for care, research, and quality improvement

Working conditions, psychological distress and suicidal ideation: cross-sectional survey study of UK junior doctors

Background Evidence attests a link between junior doctors' working conditions and psychological distress. Despite increasing concerns around suicidality among junior doctors, little is known about its relationship to their working conditions. Aims To (a) establish the prevalence of suicidal ideation among junior doctors in the National Health Service; (b) examine the relationships between perceived working conditions and suicidal ideation; and (c) explore whether psychological distress (e.g. symptoms of depression and anxiety) mediates these relationships. Method Junior doctors were recruited between March 2020 and January 2021, for a cross-sectional online survey. We used the Health and Safety Executive's Management Standards Tool; Depression, Anxiety and Stress Scale 21; and Paykel Suicidality Scale to assess working conditions, psychological distress and suicidality, respectively. Results Of the 424 participants, 50.2% reported suicidal ideation, including 6.1% who had made an attempt on their own life. Participants who identified as LGBTQ+ (odds ratio 2.18, 95% CI 1.15-4.12) or reported depression symptoms (odds ratio 1.10, 95% CI 1.07-1.14) were more likely to report suicidal ideation. No direct relationships were reported between working conditions (i.e. control, support, role clarity, strained relationships, demand and change) and suicidal ideation. However, depression symptoms mediated all six relationships. Conclusions This sample of junior doctors reported alarming levels of suicidal ideation. There may be an indirect relationship between working conditions and suicidal ideation via depressive symptoms. Clearer research exploring the experience of suicidality in junior doctors is needed, including those who identify as LGBTQ+. Systematic interventions addressing working environment are needed to support junior doctors' mental health