Mapping spot blotch resistance genes in four barley populations

Bipolaris sorokiniana (teleomorph: Cochliobolus sativus) is the fungal pathogen responsible for spot blotch in barley (Hordeum vulgare L.) and occurs worldwide in warmer, humid growing conditions. Current Australian barley varieties are largely susceptible to this disease and attempts are being made to introduce sources of resistance from North America. In this study we have compared chromosomal locations of spot blotch resistance reactions in four North American two-rowed barley lines; the North Dakota lines ND11231-12 and ND11231-11 and the Canadian lines TR251 and WPG8412-9-2-1. Diversity Arrays Technology (DArT)-based PCR, expressed sequence tag (EST) and SSR markers have been mapped across four populations derived from crosses between susceptible parental lines and these four resistant parents to determine the location of resistance loci. Quantitative trait loci (QTL) conferring resistance to spot blotch in adult plants (APR) were detected on chromosomes 3HS and 7HS. In contrast, seedling resistance (SLR) was controlled solely by a locus on chromosome 7HS. The phenotypic variance explained by the APR QTL on 3HS was between 16 and 25% and the phenotypic variance explained by the 7HS APR QTL was between 8 and 42% across the four populations. The SLR QTL on 7HS explained between 52 to 64% of the phenotypic variance. An examination of the pedigrees of these resistance sources supports the common identity of resistance in these lines and indicates that only a limited number of major resistance loci are available in current two-rowed germplasm

Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations.

Oxygen, haemoglobin and cardiac output are integrated components of oxygen transport: each gram of haemoglobin transports 1.34 mls of oxygen in the blood. Low arterial partial pressure of oxygen (PaO2), and haemoglobin saturation (SaO2), are the indices used in clinical assessments, and usually result from low inspired oxygen concentrations, or alveolar/airways disease. Our objective was to examine low blood oxygen/haemoglobin relationships in chronically compensated states without concurrent hypoxic pulmonary vasoreactivity.165 consecutive unselected patients with pulmonary arteriovenous malformations were studied, in 98 cases, pre/post embolisation treatment. 159 (96%) had hereditary haemorrhagic telangiectasia. Arterial oxygen content was calculated by SaO2 x haemoglobin x 1.34/100.There was wide variation in SaO2 on air (78.5-99, median 95)% but due to secondary erythrocytosis and resultant polycythaemia, SaO2 explained only 0.1% of the variance in arterial oxygen content per unit blood volume. Secondary erythrocytosis was achievable with low iron stores, but only if serum iron was high-normal: Low serum iron levels were associated with reduced haemoglobin per erythrocyte, and overall arterial oxygen content was lower in iron deficient patients (median 16.0 [IQR 14.9, 17.4]mls/dL compared to 18.8 [IQR 17.4, 20.1]mls/dL, p<0.0001). Exercise tolerance appeared unrelated to SaO2 but was significantly worse in patients with lower oxygen content (p<0.0001). A pre-defined athletic group had higher Hb:SaO2 and serum iron:ferritin ratios than non-athletes with normal exercise capacity. PAVM embolisation increased SaO2, but arterial oxygen content was precisely restored by a subsequent fall in haemoglobin: 86 (87.8%) patients reported no change in exercise tolerance at post-embolisation follow-up.Haemoglobin and oxygen measurements in isolation do not indicate the more physiologically relevant oxygen content per unit blood volume. This can be maintained for SaO2 ≥78.5%, and resets to the same arterial oxygen content after correction of hypoxaemia. Serum iron concentrations, not ferritin, seem to predict more successful polycythaemic responses

SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis

Dephosphorylation of the inhibitory “S259” site on RAF kinases (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. The MRAS GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase 1 (PP1) to form a heterotrimeric holoenzyme that dephosphorylates this S259 RAF site. MRAS and SHOC2 function as PP1 regulatory subunits providing the complex with striking specificity against RAF. MRAS also functions as a targeting subunit as membrane localization is required for efficient RAF dephosphorylation and ERK pathway regulation in cells. SHOC2’s predicted structure shows remarkable similarities to the A subunit of PP2A, suggesting a case of convergent structural evolution with the PP2A heterotrimer. We have identified multiple regions in SHOC2 involved in complex formation as well as residues in MRAS switch I and the interswitch region that help account for MRAS’s unique effector specificity for SHOC2–PP1. MRAS, SHOC2, and PPP1CB are mutated in Noonan syndrome, and we show that syndromic mutations invariably promote complex formation with each other, but not necessarily with other interactors. Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations is likely driven at the biochemical level by enhanced ternary complex formation and highlights the crucial role of this phosphatase holoenzyme in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human development

Using co-authorship networks to map and analyse global Neglected Tropical Disease research with an affiliation to Germany

Neglected tropical disease research has changed considerably in recent decades, and the German government is committed to addressing its past neglect of NTD research. Our aim was to use an innovative social network analysis of bibliometric data to map neglected tropical disease research networks that are inside of and affiliated with Germany, thereby enabling data-driven health policy decision-making. We created and analysed co-author networks from publications in the SCOPUS database, with a focus on five diseases. We found that Germany's share of global publication output for NTDs is approximately half that of other medical research fields. Furthermore, we identified institutions with prominent NTD research within Germany and strong research collaborations between German institutions and partners abroad, mostly in other high-income countries. This allowed an assessment of strong collaborations for further development, e.g., for research capacity strengthening in low-income-countries, but also for identifying missed opportunities for collaboration within the network. Through co-authorship network analysis of individual researcher networks, we identified strong performers by using classic bibliometric parameters, and we identified academic talent by social network analysis parameters on an individual level

Associations between Polycyclic Aromatic Hydrocarbon–Related Exposures and p53 Mutations in Breast Tumors

Background: Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology. Objectives: We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. Methods: We examined this possibility in a population-based case–control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. Results: We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH–DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation–negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11–2.15] but not p53 mutation–positive (OR = 0.77; 95% CI, 0.43–1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C→A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. Conclusions: These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation

Age-Dependent Targeting of Protein Phosphatase 1 to Ca2+/Calmodulin-Dependent Protein Kinase II by Spinophilin in Mouse Striatum

Mechanisms underlying age-dependent changes of dendritic spines on striatal medium spiny neurons are poorly understood. Spinophilin is an F-actin- and protein phosphatase 1 (PP1)-binding protein that targets PP1 to multiple downstream effectors to modulate dendritic spine morphology and function. We found that calcium/calmodulin-dependent protein kinase II (CaMKII) directly and indirectly associates with N- and C-terminal domains of spinophilin, but F-actin can displace CaMKII from the N-terminal domain. Spinophilin co-localizes PP1 with CaMKII on the F-actin cytoskeleton in heterologous cells, and spinophilin co-localizes with synaptic CaMKII in neuronal cultures. Thr286 autophosphorylation enhances the binding of CaMKII to spinophilin in vitro and in vivo. Although there is no change in total levels of Thr286 autophosphorylation, maturation from postnatal day 21 into adulthood robustly enhances the levels of CaMKII that co-immunoprecipitate with spinophilin from mouse striatal extracts. Moreover, N- and C-terminal domain fragments of spinophilin bind more CaMKII from adult vs. postnatal day 21 striatal lysates. Total levels of other proteins that interact with C-terminal domains of spinophilin decrease during maturation, perhaps reducing competition for CaMKII binding to the C-terminal domain. In contrast, total levels of α-internexin and binding of α-internexin to the spinophilin N-terminal domain increases with maturation, perhaps bridging an indirect interaction with CaMKII. Moreover, there is an increase in the levels of myosin Va, α-internexin, spinophilin, and PP1 in striatal CaMKII immune complexes isolated from adult and aged mice compared to those from postnatal day 21. These changes in spinophilin/CaMKII interactomes may contribute to changes in striatal dendritic spine density, morphology, and function during normal postnatal maturation and aging

Lifetime physical activity and risk of breast cancer in pre-and post-menopausal women

© 2015 Springer Science+Business Media New York To investigate the association between different types of physical activity (PA) and breast cancer. A case–control study of breast cancer was conducted in Western Australia from 2009 to 2011, in which 1205 women with breast cancer and 1789 frequency age-matched breast cancer-free control women were recruited. A self-administered questionnaire was used to collect information about lifetime and age-period recreational, household, occupational and transport physical activities. Detailed questions about demographic characteristics, and relevant reproductive, medical and lifestyle factors were also included. Logistic regression and restrictive cubic spline analyses were applied to investigate the association and dose–response relationship between PA and breast cancer risk. Subgroup analysis was performed regarding menopausal status. We found non-linear dose–response associations between PA and risk of breast cancer. Overall, 95–130 MET-hours/week of total lifetime PA was associated with the lowest breast cancer risk. The effects were stronger among post-menopausal women. We also found that the medium amounts of recreational PA (up to 21 MET-hours/week) were associated with lower breast cancer risk among post-menopausal women. Further analysis on the intensity of recreational PA demonstrated different dose–response associations between moderate- and vigorous-intensity recreational PA and breast cancer risk. We found that PA was associated with a reduced risk of breast cancer among post-menopausal women, but not in a linear fashion. Recreational PA of different intensities may have different dose–response associations with risk of breast cancer

The design and protocol of heat-sensitive moxibustion for knee osteoarthritis: a multicenter randomized controlled trial on the rules of selecting moxibustion location

<p>Abstract</p> <p>Background</p> <p>Knee osteoarthritis is a major cause of pain and functional limitation. Complementary and alternative medical approaches have been employed to relieve symptoms and to avoid the side effects of conventional medication. Moxibustion has been widely used to treat patients with knee osteoarthritis. Our past researches suggested heat-sensitive moxibustion might be superior to the conventional moxibustion. Our objective is to investigate the effectiveness of heat-sensitive moxibustion compared with conventional moxibustion or conventional drug treatment.</p> <p>Methods</p> <p>This study consists of a multi-centre (four centers in China), randomised, controlled trial with three parallel arms (A: heat-sensitive moxibustion; B: conventional moxibustion; C: conventional drug group). The moxibustion locations are different from A and B. Group A selects heat-sensitization acupoint from the region consisting of Yin Lingquan(SP9), Yang Lingquan(GB34), Liang Qiu(ST34), and Xue Hai (SP10). Meanwhile, fixed acupoints are used in group B, that is Xi Yan (EX-LE5) and He Ding (EX-LE2). The conventional drug group treats with intra-articular Sodium Hyaluronate injection. The outcome measures above will be assessed before the treatment, the 30 days of the last moxibustion session and 6 months after the last moxibustion session.</p> <p>Discussion</p> <p>This trial will utilize high quality trial methodologies in accordance with CONSORT guidelines. It will provide evidence for the effectiveness of moxibustion as a treatment for moderate and severe knee osteoarthritis. Moreover, the result will clarify the rules of heat-sensitive moxibustion location to improve the therapeutic effect with suspended moxibustion, and propose a new concept and a new theory of moxibustion to guide clinical practices.</p> <p>Trial Registration</p> <p>The trial is registered at Controlled Clinical Trials: ChiCTR-TRC-00000600.</p

Returning to work after stroke: perspectives of employer stakeholders, a qualitative study.

Purpose: More than 40 % of working age adults with stroke fail to return to work. The work context is a key factor in return to work, but little is known about the experiences of employers in supporting employees with stroke. The aim of this study was to explore return to work after stroke from the employer perspective, to identify key features associated with success and to seek participants’ views regarding the role of healthcare in return to work. Methods: Data was gathered through 18 semi-structured interviews with employer stakeholders and included small business owners, line managers, human resources and occupational health staff. Data was analysed thematically. Results: The main themes identified were: the impact of stroke on the employer, characteristics of the employee, communication, knowledge and information, experience of other stakeholders, integrating healthcare in return to work. Conclusion: Employers face complex emotional and practical issues when helping an employee return to work after stroke, for which many lack knowledge and experience. The range and quality of support networks that they access is variable and advice and support from clinicians is welcomed. Further research is necessary to investigate how such support could be funded and integrated within existing service provision