Bimodal sensing of guidance cues in mechanically distinct microenvironments

Contact guidance due to extracellular matrix architecture is a key regulator of carcinoma invasion and metastasis, yet our understanding of how cells sense guidance cues is limited. Here, using a platform with variable stiffness that facilitates uniaxial or biaxial matrix cues, or competing E-cadherin adhesions, we demonstrate distinct mechanoresponsive behavior. Through disruption of traction forces, we observe a profound phenotypic shift towards a mode of dendritic protrusion and identify bimodal processes that govern guidance sensing. In contractile cells, guidance sensing is strongly dependent on formins and FAK signaling and can be perturbed by disrupting microtubule dynamics, while low traction conditions initiate fluidic-like dendritic protrusions that are dependent on Arp2/3. Concomitant disruption of these bimodal mechanisms completely abrogates the contact guidance response. Thus, guidance sensing in carcinoma cells depends on both environment architecture and mechanical properties and targeting the bimodal responses may provide a rational strategy for disrupting metastatic behavior

Design principles for riboswitch function

Scientific and technological advances that enable the tuning of integrated regulatory components to match network and system requirements are critical to reliably control the function of biological systems. RNA provides a promising building block for the construction of tunable regulatory components based on its rich regulatory capacity and our current understanding of the sequence–function relationship. One prominent example of RNA-based regulatory components is riboswitches, genetic elements that mediate ligand control of gene expression through diverse regulatory mechanisms. While characterization of natural and synthetic riboswitches has revealed that riboswitch function can be modulated through sequence alteration, no quantitative frameworks exist to investigate or guide riboswitch tuning. Here, we combined mathematical modeling and experimental approaches to investigate the relationship between riboswitch function and performance. Model results demonstrated that the competition between reversible and irreversible rate constants dictates performance for different regulatory mechanisms. We also found that practical system restrictions, such as an upper limit on ligand concentration, can significantly alter the requirements for riboswitch performance, necessitating alternative tuning strategies. Previous experimental data for natural and synthetic riboswitches as well as experiments conducted in this work support model predictions. From our results, we developed a set of general design principles for synthetic riboswitches. Our results also provide a foundation from which to investigate how natural riboswitches are tuned to meet systems-level regulatory demands

Risk prediction tools for cancer in primary care.

Numerous risk tools are now available, which predict either current or future risk of a cancer diagnosis. In theory, these tools have the potential to improve patient outcomes through enhancing the consistency and quality of clinical decision-making, facilitating equitable and cost-effective distribution of finite resources such as screening tests or preventive interventions, and encouraging behaviour change. These potential uses have been recognised by the National Cancer Institute as an 'area of extraordinary opportunity' and an increasing number of risk prediction models continue to be developed. The data on predictive utility (discrimination and calibration) of these models suggest that some have potential for clinical application; however, the focus on implementation and impact is much more recent and there remains considerable uncertainty about their clinical utility and how to implement them in order to maximise benefits and minimise harms such as over-medicalisation, anxiety and false reassurance. If the potential benefits of risk prediction models are to be realised in clinical practice, further validation of the underlying risk models and research to assess the acceptability, clinical impact and economic implications of incorporating them in practice are needed.This is the final version of the article. It was first available from NPG via http://dx.doi.org/10.1038/bjc.2015.40

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross-adaptation, and time-dependent sensitization in a complex adaptive system

BACKGROUND: This paper proposes a novel model for homeopathic remedy action on living systems. Research indicates that homeopathic remedies (a) contain measurable source and silica nanoparticles heterogeneously dispersed in colloidal solution; (b) act by modulating biological function of the allostatic stress response network (c) evoke biphasic actions on living systems via organism-dependent adaptive and endogenously amplified effects; (d) improve systemic resilience. DISCUSSION: The proposed active components of homeopathic remedies are nanoparticles of source substance in water-based colloidal solution, not bulk-form drugs. Nanoparticles have unique biological and physico-chemical properties, including increased catalytic reactivity, protein and DNA adsorption, bioavailability, dose-sparing, electromagnetic, and quantum effects different from bulk-form materials. Trituration and/or liquid succussions during classical remedy preparation create “top-down” nanostructures. Plants can biosynthesize remedy-templated silica nanostructures. Nanoparticles stimulate hormesis, a beneficial low-dose adaptive response. Homeopathic remedies prescribed in low doses spaced intermittently over time act as biological signals that stimulate the organism’s allostatic biological stress response network, evoking nonlinear modulatory, self-organizing change. Potential mechanisms include time-dependent sensitization (TDS), a type of adaptive plasticity/metaplasticity involving progressive amplification of host responses, which reverse direction and oscillate at physiological limits. To mobilize hormesis and TDS, the remedy must be appraised as a salient, but low level, novel threat, stressor, or homeostatic disruption for the whole organism. Silica nanoparticles adsorb remedy source and amplify effects. Properly-timed remedy dosing elicits disease-primed compensatory reversal in direction of maladaptive dynamics of the allostatic network, thus promoting resilience and recovery from disease. SUMMARY: Homeopathic remedies are proposed as source nanoparticles that mobilize hormesis and time-dependent sensitization via non-pharmacological effects on specific biological adaptive and amplification mechanisms. The nanoparticle nature of remedies would distinguish them from conventional bulk drugs in structure, morphology, and functional properties. Outcomes would depend upon the ability of the organism to respond to the remedy as a novel stressor or heterotypic biological threat, initiating reversals of cumulative, cross-adapted biological maladaptations underlying disease in the allostatic stress response network. Systemic resilience would improve. This model provides a foundation for theory-driven research on the role of nanomaterials in living systems, mechanisms of homeopathic remedy actions and translational uses in nanomedicine

Effect of different water regimes on nematode reproduction, root galling, plant growth and yield of a lowland and upland Asian rice cultivar grown in two soil types infested by the rice root-knot nematode Meloidogyne graminicola

status: publishe

Evaluation of the host response of lowland and upland rice varieties from Myanmar to the rice root-knot nematode Meloidogyne graminicola

The rice root-knot nematode Meloidogyne graminicola is considered one of the most potentially important nematode pathogens of rice, especially in South and Southeast Asia, in a range of rice production systems. Identification of M. graminicola-resistant or -tolerant rice varieties will enable breeding programmes to develop rice varieties which are able to limit yield losses caused by this nematode species. The host response to M. graminicola infection of 15 lowland rice varieties and 9 upland rice varieties, which are being grown in the summer-irrigated lowland and rainfed upland rice ecosystems in Myanmar, was evaluated in two experiments under screenhouse conditions. The lowland rice experiment was carried out under intermittently flooded conditions in a clay loam soil (i.e. simulating the summer-irrigated lowland rice ecosystem) and the upland rice experiment was carried out at field capacity in a sandy loam soil (i.e. simulating the monsoon rainfed upland rice ecosystem). None of the15 lowland and 9 upland rice varieties were resistant to M. graminicola infection although differences in susceptibility and sensitivity were observed. Six (or 40%) out of the 15 lowland varieties examined were classified as less susceptible (LS) to M. graminicola infection, five (or 33.3%) as moderately susceptible (MS) while four (or 26.7%) as highly susceptible (HS). One (or 11.1%) out of the nine upland varieties examined was classified as LS to M. graminicola infection, three (or 33.3%) as MS while five (or 55.6%) as HS. Five (or 33.3%) out of the 15 lowland varieties examined were classified as either less sensitive or tolerant to M. graminicola infection. One (or 11.1%) out of the nine upland varieties examined was classified as tolerant to M. graminicola infection. This study offers interesting information for the farmer regarding which rice variety should be grown in M. graminicola-infested fields under either lowland or upland conditions. © 2013 © 2013 Taylor & Francis.status: publishe

Population dynamics of Meloidogyne incognita on black pepper plants in two agro-ecological regions in Vietnam

The objective of our study was to examine the effect of local environmental conditions, especially air temperature and rainfall, in two agro-ecological regions in Vietnam on the population dynamics of Meloidogyne incognita on black pepper plants and on percentage root galling. The two study sites were situated in Cam Lo, Quang Tri province (North Central Coast) and Buon Ma Thuot, Dac Lac province (Central Highlands). At the study sites, 13 plant-parasitic nematode taxa belonging to 12 genera were identified. Ten of these taxa were present in both study sites. Helicotylenchus certus, Hemicriconemoides cocophilus and Pratylenchus coffeae were only found in Buon Ma Thuot. Based on nematode population densities, M. incognita was the most abundant taxon present. Rainfall and air temperature differed significantly between the two study sites. The most important climatic difference was rainfall: in Buon Ma Thuot, the rainy season lasted 2 months longer and the monthly rainfall during the rainy season was much higher compared to Cam Lo. Although this difference resulted in some differences in the population dynamics of M. incognita in the soil and roots of the black pepper variety Vinh Linh, the highest root population densities were observed in both study sites during the first half of the dry season. In Cam Lo, the highest percentage root galling was observed during the first half of the dry season. In Buon Ma Thuot, the highest percentage root galling was observed towards the end of the rainy season. Estimating the population densities if M. incognita to decide on the application of a management strategy should be done during the first half of the dry season. © 2012 Copyright Taylor and Francis Group, LLC.status: publishe

Awareness and Acceptance of Health Insurance, and Willingness to Pay: a Community based Study in Myanmar

Most health care spending in Myanmar is borne by means of out-of-pocket payment (OOP). A national health insurance scheme has not yet been established. This crosssectional study explored the awareness and acceptance of community related to health insurance, and their willingness to pay during February and March, 2014. Multi-stage random sampling procedure was used to recruit 1,346 household heads from 27 townships. As might be expected, the awareness of health insurance was low (8.4%; 95% CI = 7.0%, 10.0%). But following thorough explanation, the acceptance towards health insurance scheme was high (78.5%; 95% CI = 76.2%, 80.7%)