Characterization of a K+-induced conformational switch in a human telomeric DNA oligonucleotide using 2-aminopurine fluorescence

Human telomeric DNA consists of tandem repeats of the DNA sequence d(GGGTTA). Oligodeoxynucletotide telomere models such as d[A(GGGTTA)(3)GGG] (Tel22) fold in a cation-dependent manner into quadruplex structures consisting of stacked G-quartets linked by d(TTA) loops. NMR has shown that in Na(+) solutions Tel22 forms a ‘basket’ topology of four antiparallel strands; in contrast, Tel22 in K(+) solutions consists of a mixture of unknown topologies. Our previous studies on the mechanism of folding of Tel22 and similar telomere analogs utilized changes in UV absorption between 270 and 325 nm that report primarily on G-quartet formation and stacking showed that quadruplex formation occurs within milliseconds upon mixing with an appropriate cation. In the current study, we assessed the dynamics and equilibria of folding of specific loops by using Tel22 derivatives in which the dA residues were serially substituted with the fluorescent reporter base, 2-aminopurine (2-AP). Tel22 folding induced by Na(+) or K(+) assessed by changes in 2-AP fluorescence consists of at least three kinetic steps with time constants spanning a range of ms to several hundred seconds. Na(+)-dependent equilibrium titrations of Tel22 folding could be approximated as a cooperative two-state process. In contrast, K(+)-dependent folding curves were biphasic, revealing that different conformational ensembles are present in 1 mM and 30 mM K(+). This conclusion was confirmed by (1)H NMR. Molecular dynamics simulations revealed a K(+) binding pocket in Tel22 located near dA1 that is specific for the so-called hybrid-1 conformation in which strand 1 is in a parallel arrangement. The possible presence of this topologically specific binding site suggests that K(+) may play an allosteric role in regulating telomere conformation and function by modulating quadruplex tertiary structure

Group B Streptococcus vaccine development: present status and future considerations, with emphasis on perspectives for low and middle income countries.

Globally, group B Streptococcus (GBS) remains the leading cause of sepsis and meningitis in young infants, with its greatest burden in the first 90 days of life. Intrapartum antibiotic prophylaxis (IAP) for women at risk of transmitting GBS to their newborns has been effective in reducing, but not eliminating, the young infant GBS disease burden in many high income countries. However, identification of women at risk and administration of IAP is very difficult in many low and middle income country (LMIC) settings, and is not possible for home deliveries. Immunization of pregnant women with a GBS vaccine represents an alternate pathway to protecting newborns from GBS disease, through the transplacental antibody transfer to the fetus in utero. This approach to prevent GBS disease in young infants is currently under development, and is approaching late stage clinical evaluation. This manuscript includes a review of the natural history of the disease, global disease burden estimates, diagnosis and existing control options in different settings, the biological rationale for a vaccine including previous supportive studies, analysis of current candidates in development, possible correlates of protection and current status of immunogenicity assays. Future potential vaccine development pathways to licensure and use in LMICs, trial design and implementation options are discussed, with the objective to provide a basis for reflection, rather than recommendations

A complex network approach to structural inequality of educational deprivation in a Latin American country

To guarantee the human right to education established by the fourth UNESCO’s Sustainable Development Goal, a deep understanding of a big set of non-linear relationships at different scales is need it, as well as to know how they impact on learning outcomes. In doing so, current methods do not provide enough evidence about interactions and, for this reason, some researchers have proposed to model education as a complex system for considering all interactions at individual level, as well as using computer simulation and network analysis to provide a comprehensive look at the educational processes, as well as to predict the outcomes of different public policies. The highlight of this paper is modeling the structure of the inequality of a national educational system as a complex network from learning outcomes and socio-economic, ethnicity, rurality and type of school funding, for providing a better understanding and measuring of the educational gaps. This new approach might help to integrate insights improving the theoretical framework, as well as to provide valuable information about non-trivial relationships between educational and non-educational variables in order to help policymakers to implement effective solutions for the educational challenge of ensuring inclusive and equitable education.info:eu-repo/semantics/acceptedVersio

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Contemporary Discourses of Green Political Economy: A Q Method Analysis

For over two decades, the concept of sustainable development has been salient in political discourse. But its promise of reconciling economic development, social welfare, and environmental sustainability has proven rather elusive. In recent years, we've seen numerous competing concepts emerge in debates about sustainable economic development. While many advance ideas of a green economy and green growth, others talk about wellbeing, gross national happiness, inclusive wealth, harmony with nature, de-growth, steady-state economy, and buenvivir (living well). This rhetorical diversity shows that there is no single vision for reconciling environmental sustainability and economic development. But the varied terminology itself obscures actual points of agreement and disagreement. This article reports on a bilingual ‘Q study’ of international debates about sustainable economic development. It reveals that three discourses underpin these debates: Radical Transformationism; Cooperative Reformism; and Statist Progressivism. The article dissects these discourses and contextualizes their key points of contention in wider sustainability debates over the past two decades

STAT1 Hyperphosphorylation and Defective IL12R/IL23R Signaling Underlie Defective Immunity in Autosomal Dominant Chronic Mucocutaneous Candidiasis

We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency

Proliferation of Acid-Secretory Cells in the Kidney during Adaptive Remodelling of the Collecting Duct

The renal collecting duct adapts to changes in acid-base metabolism by remodelling and altering the relative number of acid or alkali secreting cells, a phenomenon termed plasticity. Acid secretory A intercalated cells (A-IC) express apical H+-ATPases and basolateral bicarbonate exchanger AE1 whereas bicarbonate secretory B intercalated cells (B-IC) express basolateral (and apical) H+-ATPases and the apical bicarbonate exchanger pendrin. Intercalated cells were thought to be terminally differentiated and unable to proliferate. However, a recent report in mouse kidney suggested that intercalated cells may proliferate and that this process is in part dependent on GDF-15. Here we extend these observations to rat kidney and provide a detailed analysis of regional differences and demonstrate that differentiated A-IC proliferate massively during adaptation to systemic acidosis. We used markers of proliferation (PCNA, Ki67, BrdU incorporation) and cell-specific markers for A-IC (AE1) and B-IC (pendrin). Induction of remodelling in rats with metabolic acidosis (with NH4Cl for 12 hrs, 4 and 7 days) or treatment with acetazolamide for 10 days resulted in a larger fraction of AE1 positive cells in the cortical collecting duct. A large number of AE1 expressing A-IC was labelled with proliferative markers in the cortical and outer medullary collecting duct whereas no labeling was found in B-IC. In addition, chronic acidosis also increased the rate of proliferation of principal collecting duct cells. The fact that both NH4Cl as well as acetazolamide stimulated proliferation suggests that systemic but not urinary pH triggers this response. Thus, during chronic acidosis proliferation of AE1 containing acid-secretory cells occurs and may contribute to the remodelling of the collecting duct or replace A-IC due to a shortened life span under these conditions

Trends in malaria morbidity among health care-seeking children under age five in Mopti and Sévaré, Mali between 1998 and 2006

<p>Abstract</p> <p>Background</p> <p>In Mali, malaria is the leading cause of death and the primary cause of outpatient visits for children under five. The twin towns of Mopti and Sévaré have historically had high under-five mortality. This paper investigates the changing malaria burden in children under five in these two towns for the years 1998-2006, and the likely contribution of previous interventions aimed at reducing malaria.</p> <p>Methods</p> <p>A retrospective analysis of daily outpatient consultation records from urban community health centres (CSCOMs) located in Mopti and Sévaré for the years 1998-2006 was conducted. Risk factors for a diagnosis of presumptive malaria, using logistic regression and trends in presumptive malaria diagnostic rates, were assessed using multilevel analysis.</p> <p>Results</p> <p>Between 1998-2006, presumptive malaria accounted for 33.8% of all recorded consultation diagnoses (10,123 out of 29,915). The monthly presumptive malaria diagnostic rate for children under five decreased by 66% (average of 8 diagnoses per month per 1,000 children in 1998 to 2.7 diagnoses per month in 2006). The multi-level analysis related 37% of this decrease to the distribution of bed net treatment kits initiated in May of 2001. Children of the Fulani (Peuhl) ethnicity had significantly lower odds of a presumptive malaria diagnosis when compared to children of other ethnic groups.</p> <p>Conclusions</p> <p>Presumptive malaria diagnostic rates have decreased between 1998-2006 among health care-seeking children under five in Mopti and Sévaré. A bed net treatment kit intervention conducted in 2001 is likely to have contributed to this decline. The results corroborate previous findings that suggest that the Fulani ethnicity is protective against malaria. The findings are useful to encourage dialogue around the urban malaria situation in Mali, particularly in the context of achieving the target of reducing malaria morbidity in children younger than five by 50% by 2011 as compared to levels in 2000.</p

Isolation in Globalizing Academic Fields: A Collaborative Autoethnography of Early Career Researchers

This study examines academic isolation – an involuntary perceived separation from the academic field to which one aspires to belong, associated with a perceived lack of agency in terms of one’s engagement with the field – as a key challenge for researchers in increasingly globalized academic careers. While prior research describes early career researchers’ isolation in their institutions, we theorize early career researchers’ isolation in their academic fields and reveal how they attempt to mitigate isolation to improve their career prospects. Using a collaborative autoethnographic approach, we generate and analyze a dataset focused on the experiences of ten early career researchers in a globalizing business academic field known as Consumer Culture Theory. We identify bricolage practices, polycentric governance practices, and integration mechanisms that work to enhance early career researchers’ perceptions of agency and consequently mitigate their academic isolation. Our findings extend discussions on isolation and its role in new academic careers. Early career researchers, in particular, can benefit from a deeper understanding of practices that can enable them to mitigate isolation and reclaim agency as they engage with global academic fields