Site-specific fluorescence dynamics in an RNA 'thermometer' reveals the role of ribosome binding in its temperature-sensitive switch function

RNA thermometers control the translation of several heat shock and virulence genes by their temperature-sensitive structural transitions. Changes in the structure and dynamics of MiniROSE RNA, which regulates translation in the temperature range of 20–45°C, were studied by site specifically replacing seven adenine residues with the fluorescent analog, 2-aminopurine (2-AP), one at a time. Dynamic fluorescence observables of 2-AP-labeled RNAs were compared in their free versus ribosome-bound states for the first time. Noticeably, position dependence of fluorescence observables, which was prominent at 20°C, was persistent even at 45°C, suggesting the persistence of structural integrity up to 45°C. Interestingly, position-dependent dispersion of fluorescence lifetime and quenching constant at 45°C was ablated in ribosome-bound state, when compared to those at 20°C, underscoring loss of structural integrity at 45°C, in ribosome-bound RNA. Significant increase in the value of mean lifetime for 2-AP corresponding to Shine–Dalgarno sequences, when the temperature was raised from 20 to 45°C, to values seen in the presence of urea at 45°C was a strong indicator of melting of the 3D structure of MiniROSE RNA at 45°C, only when it was ribosome bound. Taken all together, we propose a model where we invoke that ribosome binding of the RNA thermometer critically regulates temperature sensing functions in MiniROSE RNA

Individualized precision targeting of dorsal attention and default mode networks with rTMS in traumatic brain injury-associated depression

At the group level, antidepressant efficacy of rTMS targets is inversely related to their normative connectivity with subgenual anterior cingulate cortex (sgACC). Individualized connectivity may yield better targets, particularly in patients with neuropsychiatric disorders who may have aberrant connectivity. However, sgACC connectivity shows poor test-retest reliability at the individual level. Individualized resting-state network mapping (RSNM) can reliably map inter-individual variability in brain network organization. Thus, we sought to identify individualized RSNM-based rTMS targets that reliably target the sgACC connectivity profile. We used RSNM to identify network-based rTMS targets in 10 healthy controls and 13 individuals with traumatic brain injury-associated depression (TBI-D). These RSNM targets were compared with consensus structural targets and targets based on individualized anti-correlation with a group-mean-derived sgACC region ( sgACC-derived targets ). The TBI-D cohort was also randomized to receive active (n = 9) or sham (n = 4) rTMS to RSNM targets with 20 daily sessions of sequential high-frequency left-sided stimulation and low-frequency right-sided stimulation. We found that the group-mean sgACC connectivity profile was reliably estimated by individualized correlation with default mode network (DMN) and anti-correlation with dorsal attention network (DAN). Individualized RSNM targets were thus identified based on DAN anti-correlation and DMN correlation. These RSNM targets showed greater test-retest reliability than sgACC-derived targets. Counterintuitively, anti-correlation with the group-mean sgACC connectivity profile was also stronger and more reliable for RSNM-derived targets than for sgACC-derived targets. Improvement in depression after RSNM-targeted rTMS was predicted by target anti-correlation with the portions of sgACC. Active treatment also led to increased connectivity within and between the stimulation sites, the sgACC, and the DMN. Overall, these results suggest that RSNM may enable reliable individualized rTMS targeting, although further research is needed to determine whether this personalized approach can improve clinical outcomes

Realizing the Nishimori transition across the error threshold for constant-depth quantum circuits

Preparing quantum states across many qubits is necessary to unlock the full potential of quantum computers. However, a key challenge is to realize efficient preparation protocols which are stable to noise and gate imperfections. Here, using a measurement-based protocol on a 127 superconducting qubit device, we study the generation of the simplest long-range order -- Ising order, familiar from Greenberger-Horne-Zeilinger (GHZ) states and the repetition code -- on 54 system qubits. Our efficient implementation of the constant-depth protocol and classical decoder shows higher fidelities for GHZ states compared to size-dependent, unitary protocols. By experimentally tuning coherent and incoherent error rates, we demonstrate stability of this decoded long-range order in two spatial dimensions, up to a critical point which corresponds to a transition belonging to the unusual Nishimori universality class. Although in classical systems Nishimori physics requires fine-tuning multiple parameters, here it arises as a direct result of the Born rule for measurement probabilities -- locking the effective temperature and disorder driving this transition. Our study exemplifies how measurement-based state preparation can be meaningfully explored on quantum processors beyond a hundred qubits.Comment: 16 pages, 18 figure

Developmental trajectories of cortical thickness by functional brain network: The roles of pubertal timing and socioeconomic status

The human cerebral cortex undergoes considerable changes during development, with cortical maturation patterns reflecting regional heterogeneity that generally progresses in a posterior-to-anterior fashion. However, the organizing principles that govern cortical development remain unclear. In the current study, we characterized age-related differences in cortical thickness (CT) as a function of sex, pubertal timing, and two dissociable indices of socioeconomic status (i.e., income-to-needs and maternal education) in the context of functional brain network organization, using a cross-sectional sample (n = 789) diverse in race, ethnicity, and socioeconomic status from the Lifespan Human Connectome Project in Development (HCP-D). We found that CT generally followed a linear decline from 5 to 21 years of age, except for three functional networks that displayed nonlinear trajectories. We found no main effect of sex or age by sex interaction for any network. Earlier pubertal timing was associated with reduced mean CT and CT in seven networks. We also found a significant age by maternal education interaction for mean CT across cortex and CT in the dorsal attention network, where higher levels of maternal education were associated with steeper age-related decreases in CT. Taken together, our results suggest that these biological and environmental variations may impact the emerging functional connectome

Geo-additive modelling of malaria in Burundi

Abstract Background Malaria is a major public health issue in Burundi in terms of both morbidity and mortality, with around 2.5 million clinical cases and more than 15,000 deaths each year. It is still the single main cause of mortality in pregnant women and children below five years of age. Because of the severe health and economic burden of malaria, there is still a growing need for methods that will help to understand the influencing factors. Several studies/researches have been done on the subject yielding different results as which factors are most responsible for the increase in malaria transmission. This paper considers the modelling of the dependence of malaria cases on spatial determinants and climatic covariates including rainfall, temperature and humidity in Burundi. Methods The analysis carried out in this work exploits real monthly data collected in the area of Burundi over 12 years (1996-2007). Semi-parametric regression models are used. The spatial analysis is based on a geo-additive model using provinces as the geographic units of study. The spatial effect is split into structured (correlated) and unstructured (uncorrelated) components. Inference is fully Bayesian and uses Markov chain Monte Carlo techniques. The effects of the continuous covariates are modelled by cubic p-splines with 20 equidistant knots and second order random walk penalty. For the spatially correlated effect, Markov random field prior is chosen. The spatially uncorrelated effects are assumed to be i.i.d. Gaussian. The effects of climatic covariates and the effects of other spatial determinants are estimated simultaneously in a unified regression framework. Results The results obtained from the proposed model suggest that although malaria incidence in a given month is strongly positively associated with the minimum temperature of the previous months, regional patterns of malaria that are related to factors other than climatic variables have been identified, without being able to explain them. Conclusions In this paper, semiparametric models are used to model the effects of both climatic covariates and spatial effects on malaria distribution in Burundi. The results obtained from the proposed models suggest a strong positive association between malaria incidence in a given month and the minimum temperature of the previous month. From the spatial effects, important spatial patterns of malaria that are related to factors other than climatic variables are identified. Potential explanations (factors) could be related to socio-economic conditions, food shortage, limited access to health care service, precarious housing, promiscuity, poor hygienic conditions, limited access to drinking water, land use (rice paddies for example), displacement of the population (due to armed conflicts).</p

Inhibition of the JAK2/STAT3 pathway in ovarian cancer results in the loss of cancer stem cell-like characteristics and a reduced tumor burden

Background Current treatment of ovarian cancer patients with chemotherapy leaves behind a residual tumor which results in recurrent ovarian cancer within a short time frame. We have previously demonstrated that a single short-term treatment of ovarian cancer cells with chemotherapy in vitro resulted in a cancer stem cell (CSC)-like enriched residual population which generated significantly greater tumor burden compared to the tumor burden generated by control untreated cells. In this report we looked at the mechanisms of the enrichment of CSC-like residual cells in response to paclitaxel treatment. Methods The mechanism of survival of paclitaxel-treated residual cells at a growth inhibitory concentration of 50% (GI50) was determined on isolated tumor cells from the ascites of recurrent ovarian cancer patients and HEY ovarian cancer cell line by in vitro assays and in a mouse xenograft model. Results Treatment of isolated tumor cells from the ascites of ovarian cancer patients and HEY ovarian cancer cell line with paclitaxel resulted in a CSC-like residual population which coincided with the activation of Janus activated kinase 2 (JAK2) and signal transducer and activation of transcription 3 (STAT3) pathway in paclitaxel surviving cells. Both paclitaxel-induced JAK2/STAT3 activation and CSC-like characteristics were inhibited by a low dose JAK2-specific small molecule inhibitor CYT387 (1 μM) in vitro. Subsequent, in vivo transplantation of paclitaxel and CYT387-treated HEY cells in mice resulted in a significantly reduced tumor burden compared to that seen with paclitaxel only-treated transplanted cells. In vitro analysis of tumor xenografts at protein and mRNA levels demonstrated a loss of CSC-like markers and CA125 expression in paclitaxel and CYT387-treated cell-derived xenografts, compared to paclitaxel only-treated cell-derived xenografts. These results were consistent with significantly reduced activation of JAK2 and STAT3 in paclitaxel and CYT387-treated cell-derived xenografts compared to paclitaxel only-treated cell derived xenografts. Conclusions This proof of principle study demonstrates that inhibition of the JAK2/STAT3 pathway by the addition of CYT387 suppresses the ‘stemness’ profile in chemotherapy-treated residual cells in vitro, which is replicated in vivo, leading to a reduced tumor burden. These findings have important implications for ovarian cancer patients who are treated with taxane and/or platinum-based therapies. Keywords: Ovarian carcinoma, Cancer stem cell, Metastasis, Ascites, Chemoresistance, Recurrence, JAK2/STAT3 pathwa

Regional inequalities in under-5 mortality in Nigeria: a population-based analysis of individual- and community-level determinants

<p>Abstract</p> <p>Background</p> <p>Regions with geographically diverse ecology and socioeconomic circumstances may have different disease exposures and child health outcomes. This study assessed variations in the risks of death in children under age 5 across regions of Nigeria and determined characteristics at the individual and community levels that explain possible variations among regions.</p> <p>Methods</p> <p>Multilevel Cox proportional hazards analysis was performed using a nationally representative sample of 6,029 children from 2,735 mothers aged 15-49 years and nested within 365 communities from the 2003 Nigeria Demographic and Health Survey. Hazard ratios (HR) with 95% confidence intervals (CI) were used to express measures of association among the characteristics. Variance partition coefficients and Wald statistic were used to express measures of variation.</p> <p>Results</p> <p>Patterns of under-5 mortality cluster within families and communities. The risks of under-5 deaths were significantly higher for children of mothers residing in the South South (Niger Delta) region (HR: 1.30; 95% CI: 1.76-2.20) and children of mothers residing in communities with a low proportion of mothers attending prenatal care by a doctor (HR: 1.36; 95% CI: 1.15-1.86). In addition, the cross-level interaction between mothers' education and community prenatal care by a doctor was associated with a more than 40% higher risk of dying (HR: 1.41; 95% CI: 1.21-1.78).</p> <p>Conclusion</p> <p>The findings suggest the need to differentially focus on community-level interventions aimed at increasing maternal and child health care utilization and improving the socioeconomic position of mothers, especially in disadvantaged regions such as the South South (Niger Delta) region. Further studies on community-levels determinants of under-5 mortality are needed.</p

Quantum bits with Josephson junctions

Already in the first edition of this book (Barone and Paterno, "Fundamentals and Physics and Applications of the Josephson Effect", Wiley 1982), a great number of interesting and important applications for Josephson junctions were discussed. In the decades that have passed since then, several new applications have emerged. This chapter treats one such new class of applications: quantum optics and quantum information processing (QIP) based on superconducting circuits with Josephson junctions. In this chapter, we aim to explain the basics of superconducting quantum circuits with Josephson junctions and demonstrate how these systems open up new prospects, both for QIP and for the study of quantum optics and atomic physics.Comment: 30 pages, 10 figures. Book chapter for a new edition of Barone and Paterno's "Fundamentals and Physics and Applications of the Josephson Effect". Final versio