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Exploitation of the Mediator complex by viruses
Full text linkJust as biophysicists were identifying the component proteins of functional RNA polymerase II (RNAPII) complexes, virologists were identifying viral proteins that control it with peculiar efficiency [1]. Purified transcription components phosphorylate the RNAPII carboxyl-terminal domain (CTD) to initiate transcription, and this is enhanced by viral transactivators. In this way, viral proteins with their potent transcription activation domains (TADs) served as powerful tools for the characterization of DNA binding domains and TAD structures, e.g., the “acidic activator” (an acidic amphipathic alpha helix) and in the identification of host proteins that control transcription. The herpes simplex virus (HSV) transactivator, virion protein 16 (VP16, α-TIF, and Vmw65), was particularly valuable in transcription assays [1–3].
In the early 90s, prior to discovery of Mediator, a cyclin of unknown function, cyclin C, identified in screens for the rescue of yeast deficient in CLN genes (G1 cyclins) [4–6], was found to activate cyclin-dependent kinase 8 (CDK8) to phosphorylate the RNAPII CTD, placing it firmly at transcription control, not cell cycle [7–9]. At the same time, virologists discovered that VP16 and the adenovirus E1A proteins were associated with a large complex with cyclin C/CDK8 kinase activity [10].
This same period saw the sequence of an acutely transforming oncogenic retrovirus, walleye dermal sarcoma virus (WDSV) [11]. The WDSV genome encodes a retroviral cyclin (RV-cyclin) with only distant homology to any eukaryotic cyclin. The RV-cyclin rescued CLN-deficient yeast and induced hyperplastic lesions in mice carrying its transgene [12,13].
At this point, many components of Mediator had been identified as parts of a large, thyroid-hormone receptor complex (TRAP, THRAP, activator-recruited cofactor (ARC), and cofactor required for Sp1 activation (CRSP)) [14,15], and in 2002, the whole ARC/CRSP complex (Mediator) was purified by its VP16 affinity and its structure visualized by cryo-EM [16]. We showed that the RV-cyclin colocalized with transcription and splicing complexes in nuclei of mammalian cells and, in 2002, demonstrated its specific binding to and activation of human CDK8 (walleye and human CDK8 proteins are 98% identical) [17,18]. This was the first association of CDK8 with oncogenesis. In 2008, CDK8 was identified as an oncogene in a majority of human colon carcinomas and has since been implicated in a variety of human metastatic cancers [19,20]
Geminivirus C4 proteins inhibit GA signaling via prevention of NbGAI degradation, to promote viral infection and symptom development in N. benthamiana
Full text linkThe phytohormone gibberellin (GA) is a vital plant signaling molecule that regulates plant growth and defense against abiotic and biotic stresses. To date, the molecular mechanism of the plant responses to viral infection mediated by GA is still undetermined. DELLA is a repressor of GA signaling and is recognized by the F-box protein, a component of the SCFSLY1/GID2 complex. The recognized DELLA is degraded by the ubiquitin-26S proteasome, leading to the activation of GA signaling. Here, we report that ageratum leaf curl Sichuan virus (ALCScV)-infected N. benthamiana plants showed dwarfing symptoms and abnormal flower development. The infection by ALCScV significantly altered the expression of GA pathway-related genes and decreased the content of endogenous GA in N. benthamiana. Furthermore, ALCScV-encoded C4 protein interacts with the DELLA protein NbGAI and interferes with the interaction between NbGAI and NbGID2 to prevent the degradation of NbGAI, leading to inhibition of the GA signaling pathway. Silencing of NbGAI or exogenous GA3 treatment significantly reduces viral accumulation and disease symptoms in N. benthamiana plants. The same results were obtained from experiments with the C4 protein encoded by tobacco curly shoot virus (TbCSV). Therefore, we propose a novel mechanism by which geminivirus C4 proteins control viral infection and disease symptom development by interfering with the GA signaling pathway
The ABC Model of Happiness—Neurobiological Aspects of Motivation and Positive Mood, and Their Dynamic Changes through Practice, the Course of Life
Full text linkBackground: Happiness is a feeling, an immediate experience, not a cognitive construct. It is based on activity in the brain’s neurobiological reward and motivation systems, which have been retained in evolution. This conceptual review provides an overview of the basic neurobiological principles behind happiness phenomena and proposes a framework for further classification. Results: Three neurobiologically distinct types of happiness exist: (A) wanting, (B) avoiding, and (C) non-wanting. Behind these types lies a dynamic gradation, ranging from the more youthful anticipation, pleasure and ecstasy (A), to stress processing, escape and relief (B) as we find them accentuated in the middle-aged, to deep satisfaction, quiescence and inner joy (C), which is particularly attributed to older people. As a result, the development of happiness and satisfaction over the course of life typically takes the form of a U-curve. Discussion: The outlined triad and dynamic of happiness leads to the paradoxical finding that the elderly seem to be the happiest—a phenomenon that is termed “satisfaction paradox”. This assumed change in happiness and contentment over the life span, which includes an increasing “emancipation” from the idea of good health as a mandatory prerequisite for happiness and contentment, can itself be changed—it is trainable. Conclusions: Programs for mindfulness, contemplation, or stress reduction, including positive psychology and mind–body/behavioral medicine training, seem to be capable of influencing the course happiness over time: Happiness can be shaped through practice
Most common reasons for primary care visits in low- and middle-income countries: A systematic review
Full text linkWith the Covid-19 pandemic and the introduction of the WHO’s Essential Diagnostics List (EDL), increasing global attention is focused on the crucial role of diagnostics in achieving universal health coverage. To create national EDLs and to aid health system planning, it is vital to understand the most common conditions with which people present at primary care health facilities. We undertook a systematic review of the most common reasons for primary care visits in low- and middle-income countries. Six databases were searched for articles published between January 2009 and December 2019, with the search updated on MEDLINE to January 2021. Data on the most common patient reasons for encounter (RFEs) and provider diagnoses were collected. 17 of 22,279 screened articles were included. Most studies used unvalidated diagnostic classification systems or presented provider diagnosis data grouped by organ system, rather than presenting specific diagnoses. No studies included data from low-income countries. Only four studies (from Brazil, India, Nigeria and South Africa) using the ICPC-2 classification system contained RFE and provider diagnosis data and could be pooled. The top five RFEs from the four studies were headache, fever, back or low back symptom, cough and pain general/multiple sites. The top five diagnoses were uncomplicated hypertension, upper respiratory tract infection, type 2 diabetes, malaria and health maintenance/prevention. No psychological symptoms were among the top 10 pooled RFEs. There was more variation in top diagnoses between studies than top RFEs, showing the importance of creating location-specific lists of essential diagnostics for primary care. Future studies should aim to sample primary care facilities from across their country of study and use ICPC-3 to report both patient RFEs and provider diagnoses
Effect of Astragalus membranaceus Root on the Serum Metabolome of Preweaning Dairy Calves
Full text linkThe effect of the Astragalus membranaceus root (AMR) on the serum metabolic profiles of preweaning calf were investigated in this study. Sixteen preweaning Holstein calves were randomly allocated into two groups with eight calves per group, and offered a control basal diet (CON group) or supplemented with 20 g superfine powder of AMR (AMR group) for 14 day. Serum samples were collected from calves on day 0, 7 and 14. Serum albumin, globulin, total protein, glucose, reduced glutathione and superoxide dismutase were evaluated. Serum metabolic profiling was analyzed using ultra-high-performance liquid chromatography–time-of-flight mass spectrometry. The results demonstrated that there were no significantly difference of total protein, glucose, reduced glutathione and superoxide dismutase between the CON group and AMR group (p > 0.05), while within the CON group and AMR group, serum glucose showed a continuous upward trend from 0 day to 14 day (p < 0.001). Untargeted metabolomics analysis found the metabolism of preweaning calf was considerably changed during growth, mainly including amino acid metabolism and carbohydrate metabolism and showed an increasing in protein synthesis and gluconeogenesis. 19 differential metabolites have been screened after supplementing AMR for 14 day, nine of which were up-regulated, including ornithine, L-pyroglutamic acid, L-proline and D-proline, and 10 down-regulated, containing L-kynurenine, 5-hydroxyindoleacetate, linoleic acid and 4-pyridoxic acid. Pathway analysis found these metabolites mainly participated in three primary pathways: arginine and proline metabolism, tryptophan metabolism and glutathione metabolism (p < 0.05), while linoleic acid metabolism and vitamin B6 metabolism were also enriched (0.1 < p < 0.05). Such metabolic changes reflected the enhancement of the antioxidant and anti-inflammatory capacity of preweaning calves
The Impact of the Renovation of Grassland on the Development of Segetal Weeds in Organic Farming
Full text linkThe intensive use or discontinuation of the use of swards can compromise biodiversity, yields, and feed quality; thus, leading to the degradation of permanent grasslands. Various methods of renovation are employed to restore the usability of degraded swards. In the years 2013–2016, a monofactorial field experiment was carried out on the Experimental Farm in Grabów (province of Mazowieckie, Poland). The experiment involved swards being reseeded after ploughing (P) and after disking with a compact harrow (H), with a non-renovated sward as the control treatment. The plots under renovation were reseeded with a lucerne–grass mixture. Both seedbed preparation methods for the renewed sward, ploughing (P) or shallow disking to a depth of 5 cm (H), were found to be effective for increasing sward yields, restricting weed growth, and reducing the number of weeds in the sward. The ploughing-based renovation method (P) had a strongly restrictive effect on biodiversity, as expressed by the H’ function value vis-à-vis the harrow method (H) and the non-renewed control (NR). Dicotyledonous species accounted for 92.3% of the weed population in the studied treatments. Of these, Taraxacum officinale, Achillea milefolium, Capsella bursa-pastoris, and Plantago maior occurred in the highest numbers
The Pricing Strategy of the Agricultural Product Supply Chain with Farmer Cooperatives as the Core Enterprise
Full text linkThe pricing strategy of agricultural products not only affects the product demand and purchasing behavior of consumers, but also the income distribution of node enterprises and the overall profit of the agricultural supply chain. This paper studies the pricing strategy of the agricultural product supply chain with farmer cooperatives as the core enterprise. Considering the heterogeneous demand of consumers, this paper introduces the degree of agricultural product characteristics and establishes a dynamic pricing model for agricultural products under decentralized decision-making and centralized decision-making and designs a revenue sharing coordination contract. The results indicate that the overall profit of the supply chain obtained by pricing agricultural products through a decentralized decision-making model is lower than that created under centralized decision-making. Improving the degree of agricultural product’s characteristics and adopting the revenue sharing contract is conducive to the Pareto improvement of supply members. The relevant recommendations provide a reference for the product pricing strategy of this type of agricultural product supply chai
Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status
Full text linkHER2-low breast cancers were reported to have distinct clinicopathological characteristics from HER2-zero; however, the difference in their genetic features remains unclear. This study investigated the clinical and molecular features of breast tumors according to HER2 status.
Methods
We analyzed the clinicopathological and genomic data of 523 Chinese women with breast cancer. Genomic data was generated by targeted next-generation sequencing (NGS) of breast tumor samples using a commercial 520 gene panel. The cohort was stratified according to HER2 status as HER2-zero (n = 90), HER2-low (n = 231), and HER2-positive (n = 202) according to their immunohistochemistry and fluorescence in situ hybridization results.
Results
HER2-low breast tumors were enriched with hormone receptor-positive tumors, and who had lower Ki67 expression levels. Genes were differentially mutated across HER2 subgroups. HER2-low tumors had significantly more mutations involved in PI3K-Akt signaling than HER2-positive (p < 0.001) and HER2-zero breast tumors (p < 0.01). HER2-zero tumors had more mutations in checkpoint factors (p < 0.01), Fanconi anemia (p < 0.05), and p53 signaling and cell cycle pathway (p < 0.05) compared to HER2-low breast tumors. Compared with HER2-zero tumors, HER2-low tumors had significantly lower pathological complete response rates after neoadjuvant therapy (15.9% vs. 37.5%, p = 0.042) and proportion of relapsed/progressed patients across follow-up time points (p = 0.031), but had comparable disease-free survival (p = 0.271).
Conclusion
Our results demonstrate the distinct clinical and molecular features and clinical outcomes of HER2-low breast tumors
Autism spectrum disorders as a risk factor for adolescent self-harm: a retrospective cohort study of 113,286 young people in the UK
Full text linkIndividuals with autism spectrum disorder (ASD) are at particularly high risk of suicide and suicide attempts. Presentation to a hospital with self-harm is one of the strongest risk factors for later suicide. We describe the use of a novel data linkage between routinely collected education data and child and adolescent mental health data to examine whether adolescents with ASD are at higher risk than the general population of presenting to emergency care with self-harm.
Methods
A retrospective cohort study was conducted on the population aged 11–17 resident in four South London boroughs between January 2009 and March 2013, attending state secondary schools, identified in the National Pupil Database (NPD). Exposure data on ASD status were derived from the NPD. We used Cox regression to model time to first self-harm presentation to the Emergency Department (ED).
Results
One thousand twenty adolescents presented to the ED with self-harm, and 763 matched to the NPD. The sample for analysis included 113,286 adolescents (2.2% with ASD). For boys only, there was an increased risk of self-harm associated with ASD (adjusted hazard ratio 2·79, 95% CI 1·40–5·57, P<0·01). Several other factors including school absence, exclusion from school and having been in foster care were also associated with a higher risk of self-harm
Pulmonary haemorrhage as the earliest sign of severe leptospirosis in hamster model challenged with Leptospira interrogans strain HP358
Full text linkSevere leptospirosis is challenging as it could evolve rapidly and potentially fatal if appropriate management is not performed. An understanding of the progression and pathophysiology of Leptospira infection is important to determine the early changes that could be potentially used to predict the severe occurrence of leptospirosis. This study aimed to understand the kinetics pathogenesis of Leptospira interrogans strain HP358 in the hamster model and identify the early parameters that could be used as biomarkers to predict severe leptospirosis.
Methodology/Principal findings
Male Syrian hamsters were infected with Leptospira interrogans strain HP358 and euthanized after 24 hours, 3, 4, 5, 6 and 7 days post-infection. Blood, lungs, liver and kidneys were collected for leptospiral detection, haematology, serum biochemistry and differential expression of pro- and anti-inflammatory markers. Macroscopic and microscopic organ damages were investigated. Leptospira interrogans strain HP358 was highly pathogenic and killed hamsters within 6–7 days post-infection. Pulmonary haemorrhage and blood vessel congestion in organs were noticed as the earliest pathological changes. The damages in organs and changes in biochemistry value were preceded by changes in haematology and immune gene expression.
Conclusion/Significance
This study deciphered haemorrhage as the earliest manifestation of severe leptospirosis and high levels of IL-1β, CXCL10/IP-10, CCL3/MIP-α, neutrophils and low levels of lymphocytes and platelets serve as a cumulative panel of biomarkers in severe leptospirosis.
Author summary
As the severe form of leptospirosis could progress rapidly and be potentially fatal if not treated earlier, deciphering the pathophysiology kinetics of infection is crucial to determine the parameters of disease severity. To understand this, we challenged hamsters with the highly virulent Leptospira interrogans strain HP358. Pulmonary haemorrhage was observed as the earliest pathological change followed by liver and kidneys damages. The increased expression of IL-1β, CXCL10/IP-10, CCL3/MIP-α, high neutrophils and low lymphocytes and platelets production observed in the present study indicate that these parameters could serve as a cumulative panel of biomarkers in severe leptospirosis