Miracle-dz/UniFAR-FTUs huggingface dataset:
Multivariate Associations of Fluid Intelligence and NAA

Abstract Understanding the neural and metabolic correlates of fluid intelligence not only aids scientists in characterizing cognitive processes involved in intelligence, but it also offers insight into intervention methods to improve fluid intelligence. Here we use magnetic resonance spectroscopic imaging (MRSI) to measure N‐acetyl aspartate (NAA), a biochemical marker of neural energy production and efficiency. We use principal components analysis (PCA) to examine how the distribution of NAA in the frontal and parietal lobes relates to fluid intelligence. We find that a left lateralized frontal‐parietal component predicts fluid intelligence, and it does so independently of brain size, another significant predictor of fluid intelligence. These results suggest that the left motor regions play a key role in the visualization and planning necessary for spatial cognition and reasoning, and we discuss these findings in the context of the Parieto‐Frontal Integration Theory of intelligence.
E3 ubiquitin ligase Mule targets β-catenin under conditions of hyperactive Wnt signaling

Significance Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, is crucial for normal cell functions, and its deregulation can culminate in cancer. Several surveillance mechanisms have evolved as a precautionary measure to ensure proper development and the avoidance of cancer. Here we reveal that the E3 ubiquitin ligase Mule can target β-catenin for degradation to stop the Wnt signal during constitutive activation. Significantly, our data indicate that a combined loss of Mule and Apc accelerates the conversion of normal intestinal stem cells into cancer stem cells, paving the way to colorectal cancer development. It may be possible to use this knowledge to manipulate Mule, β-catenin, or Wnt pathway functions to reduce cancer initiation. Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell self-renewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates β-catenin levels. Stabilization and nuclear localization of β-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule’s influence on oncogenesis by showing that Mule interacts directly with β-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to fine-tune the Wnt pathway and provides multiple safeguards against tumorigenesis.
A Phase I First-in-Human Trial of Bardoxolone Methyl in Patients with Advanced Solid Tumors and Lymphomas

Purpose: Bardoxolone methyl, a novel synthetic triterpenoid and antioxidant inflammation modulator, potently induces Nrf2 and inhibits NF-κB and Janus-activated kinase/STAT signaling. This first-in-human phase I clinical trial aimed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and appropriate dose for phase II studies; characterize pharmacokinetic and pharmacodynamic parameters; and assess antitumor activity. Experimental Design: Bardoxolone methyl was administered orally once daily for 21 days of a 28-day cycle. An accelerated titration design was employed until a grade 2–related adverse event occurred. A standard 3 + 3 dose escalation was then employed until the MTD was reached. Single dose and steady-state plasma pharmacokinetics of the drug were characterized. Assessment of Nrf2 activation was examined in peripheral blood mononuclear cells (PBMC) by measuring NAD(P)H:quinone oxidoreductase (NQO1) mRNA levels. Immunohistochemical assessment of markers of inflammation, cell cycle, and apoptosis was carried out on tumor biopsies. Results: The DLTs were grade 3 reversible liver transaminase elevations. The MTD was established as 900 mg/d. A complete tumor response occurred in a mantle cell lymphoma patient, and a partial response was observed in an anaplastic thyroid carcinoma patient. NQO1 mRNA levels increased in PBMCs, and NF-κB and cyclin D1 levels decreased in tumor biopsies. Estimated glomerular filtration rate (eGFR) was also increased. Conclusions: Bardoxolone methyl was well tolerated with an MTD of 900 mg/d. The increase in eGFR suggests that bardoxolone methyl might be beneficial in chronic kidney disease. Objective tumor responses and pharmacodynamic effects were observed, supporting continued development of other synthetic triterpenoids in cancer. Clin Cancer Res; 18(12); 3396–406. ©2012 AACR.
Multidimensional symptom clusters: an exploratory factor analysis in advanced chronic kidney disease.

AIMS To explore the existence of symptom clusters in advanced chronic kidney disease. BACKGROUND People with chronic kidney disease commonly report multiple symptoms. However, the complex relationships among these symptoms are still poorly understood. DESIGN Cross-sectional. METHODS A total of 436 people with stage 4 and 5 chronic kidney disease were recruited from three tertiary hospitals during 2013-2014. Participants completed the Chronic Kidney Disease-Symptom Burden Index that assesses four symptom dimensions (occurrence, distress, severity and frequency) of 32 symptoms. Exploratory factor analysis was used to identify symptom clusters across each symptom dimension. Core symptoms in each cluster were determined based on stability across dimensions and clinical plausibility. A high cutoff of 0·50 for factor loading was used for all analyses. RESULTS Five symptom clusters were consistently identified across all symptom dimensions: fluid volume symptoms, neuromuscular symptoms, gastrointestinal symptoms, sexual symptoms and psychological symptoms. Overall, clusters ranged from 2-10 symptoms. Several symptoms were also interconnected with multiple clusters. Fatigue cross-loaded on all five clusters, whereas sleep disturbance and restless leg symptoms cross-loaded across three clusters. CONCLUSIONS Adopting a symptom cluster approach has the potential to significantly advance symptom assessment and nursing care for people in advanced stages of chronic kidney disease. Routine clinical assessment and management strategies targeted at the cluster level should have synergistic effects in reducing symptoms. Fatigue is a pervasive symptom in advanced chronic kidney disease that is interconnected with global symptom burden, suggesting better management of symptom clusters may also reduce fatigue.
A study on students’ acceptance of mobile phone use to seek health information in South Africa

Background: In South Africa, inequitable access to healthcare information has made many young people with limited resources more vulnerable to health risks. Mobile phones present a unique opportunity to address this problem due to the high penetration of mobile phones in South Africa and the popularity of these devices among young adults. Objective: This research sought to examine the adoption of mobile phones to access health information among students at a traditional university in the Eastern Cape, South Africa. Method: A cross-sectional survey approach was used to collect information from a convenience sample of 202 university students (58 males; 104 females), the majority (71.3%) of whom were aged between 18 and 27 years and of Black African ethnicity (75.2%). The unified theory of acceptance and use of technology (UTAUT) framework formed the theoretical foundation for the questionnaire. A research model was developed to test the hypotheses that behavioural intention to use a mobile phone to access health information would be influenced by: perceived usefulness (PU), perceived effort, social influence (SI), attitude towards technology (AT) and mobile phone experience. Results: Factor analyses indicated that the research model explained 36% of the variance in behavioural intention to use mobile devices to search for health-related queries, with PU being the largest predictor, followed by mobile experience, SI, and AT. Perceived effort did not make a statistically significant contribution. Conclusion: Using mobile phones to disseminate health information to students is a useful, convenient, and cost-effective health-promotion strategy. This research has contributed to the body of knowledge concerning the applicability of the UTAUT framework to study the adoption of technology and provided useful information to guide future research and implementation of mHealth initiatives.
EAACI guidelines on allergen immunotherapy: Executive statement

The allergist's community has recently celebrated 100 year of Allergen Immunotherapy (AIT). Unfortunately the implemention of this treatment is still impaired by some challenges. With the diversity of definitions, methodology and different allergen products used, research studies have produced conflicting outcomes. This has resulted in confusion about the benefits and risks of AIT amongst policymakers and professionals, as well as in the variable availability of AIT products, regulation and reimbursement policies globally. In 2015 EAACI initiated the AIT Guidelines project as part of the Presidential plan in order to settle the controversies. This article is protected by copyright. All rights reserved.
Using microsecond single-molecule FRET to determine the assembly pathways of T4 ssDNA binding protein onto model DNA replication forks

Significance A microsecond-resolved single-molecule FRET method was used to monitor the binding and unbinding of the ssDNA binding protein (gene product 32) of the T4 bacteriophage replication complex to biologically relevant primer-template DNA constructs. A unique multitime correlation function analysis was applied to the resulting sparse data, which permitted the investigation of the kinetics and mechanisms of noncooperative and cooperative protein binding, unbinding, and “sliding. ” Our results indicate that noncooperatively bound monomer proteins dissociate on the timescale of tens of milliseconds, which is consistent with the known rate of nucleotide addition during DNA replication. The rapid dissociation of the monomer suggests that sliding is a much more likely mechanism for translocation of cooperatively bound clusters of indeterminate size. DNA replication is a core biological process that occurs in prokaryotic cells at high speeds (∼1 nucleotide residue added per millisecond) and with high fidelity (fewer than one misincorporation event per 107 nucleotide additions). The ssDNA binding protein [gene product 32 (gp32)] of the T4 bacteriophage is a central integrating component of the replication complex that must continuously bind to and unbind from transiently exposed template strands during DNA synthesis. We here report microsecond single-molecule FRET (smFRET) measurements on Cy3/Cy5-labeled primer-template (p/t) DNA constructs in the presence of gp32. These measurements probe the distance between Cy3/Cy5 fluorophores that label the ends of a short (15-nt) segment of ssDNA attached to a model p/t DNA construct and permit us to track the stochastic interconversion between various protein bound and unbound states. The length of the 15-nt ssDNA lattice is sufficient to accommodate up to two cooperatively bound gp32 proteins in either of two positions. We apply a unique multipoint time correlation function analysis to the microsecond-resolved smFRET data obtained to determine and compare the kinetics of various possible reaction pathways for the assembly of cooperatively bound gp32 protein onto ssDNA sequences located at the replication fork. The results of our analysis reveal the presence and translocation mechanisms of short-lived intermediate bound states that are likely to play a critical role in the assembly mechanisms of ssDNA binding proteins at replication forks and other ss duplex junctions.
Online Bayesian Phylogenetic Inference: Theoretical Foundations via Sequential Monte Carlo

Abstract Phylogenetics, the inference of evolutionary trees from molecular sequence data such as DNA, is an enterprise that yields valuable evolutionary understanding of many biological systems. Bayesian phylogenetic algorithms, which approximate a posterior distribution on trees, have become a popular if computationally expensive means of doing phylogenetics. Modern data collection technologies are quickly adding new sequences to already substantial databases. With all current techniques for Bayesian phylogenetics, computation must start anew each time a sequence becomes available, making it costly to maintain an up-to-date estimate of a phylogenetic posterior. These considerations highlight the need for an online Bayesian phylogenetic method which can update an existing posterior with new sequences. Here, we provide theoretical results on the consistency and stability of methods for online Bayesian phylogenetic inference based on Sequential Monte Carlo (SMC) and Markov chain Monte Carlo. We first show a consistency result, demonstrating that the method samples from the correct distribution in the limit of a large number of particles. Next, we derive the first reported set of bounds on how phylogenetic likelihood surfaces change when new sequences are added. These bounds enable us to characterize the theoretical performance of sampling algorithms by bounding the effective sample size (ESS) with a given number of particles from below. We show that the ESS is guaranteed to grow linearly as the number of particles in an SMC sampler grows. Surprisingly, this result holds even though the dimensions of the phylogenetic model grow with each new added sequence.
Environmental Training And Synaptic Functions In Young And Old Brain: A Presynaptic Perspective.

BACKGROUND Aging is an unavoidable, physiological process that reduces the complexity and the plasticity of the synaptic contacts in central nervous system (CNS), having profound implications for human wellbeing. The term "cognitive reserve" refers to central cellular adaptations that augment the resilience of human brain to damage and aging. The term "Cognitive training" indicates the cultural, social and physical stimulations proposed as add-on therapy for the cure of central neurological diseases. "Cognitive training" reinforces the "cognitive reserve" permitting to counteract brain impairments and rejuvenating synaptic complexity. The research has begun investigating the clinical impact of the "cognitive training" in aged people, but additional work is needed to definitively assess its effectiveness. In particular, there is a need to understand, by a preclinical point of view, whether "cognitive training" promotes compensatory effects or, alternatively, if it elicits genuine recovery of neuronal defects. Although the translation from rodent studies to the clinical situation could be difficult, the results from pre-clinical models are of high clinical relevance, since they should allow a better understanding of the effects of environmental interventions in aging-associated chronic derangements in mammals. CONCLUSION Data in literature and the recent results obtained in our laboratory concerning the impact of environmental stimulation on the presynaptic release of noradrenaline, glutamate and gamma amino butyric acid (GABA) suggest that these neurotransmitters undergo different adaptations during aging and that they are differently tuned by "cognitive training". The impact of "cognitive training" on neurotransmitter exocytosis might account for the cellular events involved in reinforcement of "cognitive reserve" in young and old animals.
On the Convergence of Decomposition Methods for Multistage Stochastic Convex Programs

We prove the almost-sure convergence of a class of sampling-based nested decomposition algorithms for multistage stochastic convex programs in which the stage costs are general convex functions of the decisions and uncertainty is modelled by a scenario tree. As special cases, our results imply the almost-sure convergence of stochastic dual dynamic programming, cutting-plane and partial-sampling CUPPS algorithm, and dynamic outer-approximation sampling algorithms when applied to problems with general convex cost functions.
Visualization of Multidimensional Data in Nursing Science

Nursing scientists have long been interested in complex, context-dependent questions addressing individual- and population-level challenges in health and illness. These critical questions require multilevel data (e.g., genetic, physiologic, biologic, behavioral, affective, and social). Advances in data-gathering methods have resulted in the collection of large sets of complex, multifaceted, and often non-comparable data. Scientific visualization is a powerful methodological tool for facilitating understanding of these multidimensional data sets. Our purpose is to demonstrate the utility of scientific visualization as a method for identifying associations, patterns, and trends in multidimensional data as exemplified in two studies. We describe a brief history of visual analysis, processes involved in scientific visualization, and opportunities and challenges in the use of visualization methods. Scientific visualization can play a crucial role in helping nurse scientists make sense of the structure and underlying patterns in their data to answer vital questions in the field.
Development of Family Medicine training in Botswana: Views of key stakeholders in Ngamiland

Background Family Medicine training commenced in Botswana in 2011, and Maun was one of the two sites chosen as a training complex. If it is to be successful there has to be investment in the training programme by all stakeholders in healthcare delivery in the district. Aim The aim of the study was to explore the attitudes of stakeholders to initiation of Family Medicine training and their perspectives on the future roles of family physicians in Ngami district, Botswana. Setting Maun and the surrounding Ngami subdistrict of Botswana. Methods Thirteen in-depth interviews were conducted with purposively selected key stakeholders in the district health services. Data were recorded, transcribed and analysed using the framework method. Results Participants welcomed the development of Family Medicine training in Maun and expect that this will result in improved quality of primary care. Participants expect the registrars and family physicians to provide holistic health care that is of higher quality and expertise than currently experienced, relevant research into the health needs of the community, and reduced need for referrals. Inadequate personal welfare facilities, erratic ancillary support services and an inadequate complement of mentors and supervisors for the programme were some of the gaps and challenges highlighted by participants. Conclusion Family Medicine training is welcomed by stakeholders in Ngamiland. With proper planning introduction of the family physician in the district is expected to result in improvement of primary care.
A Computational Model of Major Depression: the Role of Glutamate Dysfunction on Cingulo‐Frontal Network Dynamics

Abstract Major depression disease (MDD) is associated with the dysfunction of multinode brain networks. However, converging evidence implicates the reciprocal interaction between midline limbic regions (typified by the ventral anterior cingulate cortex, vACC) and the dorso‐lateral prefrontal cortex (dlPFC), reflecting interactions between emotions and cognition. Furthermore, growing evidence suggests a role for abnormal glutamate metabolism in the vACC, while serotonergic treatments (selective serotonin reuptake inhibitor, SSRI) effective for many patients implicate the serotonin system. Currently, no mechanistic framework describes how network dynamics, glutamate, and serotonin interact to explain MDD symptoms and treatments. Here, we built a biophysical computational model of 2 areas (vACC and dlPFC) that can switch between emotional and cognitive processing. MDD networks were simulated by slowing glutamate decay in vACC and demonstrated sustained vACC activation. This hyperactivity was not suppressed by concurrent dlPFC activation and interfered with expected dlPFC responses to cognitive signals, mimicking cognitive dysfunction seen in MDD. Simulation of clinical treatments (SSRI or deep brain stimulation) counteracted this aberrant vACC activity. Theta and beta/gamma oscillations correlated with network function, representing markers of switch‐like operation in the network. The model shows how glutamate dysregulation can cause aberrant brain dynamics, respond to treatments, and be reflected in EEG rhythms as biomarkers of MDD.
Brain Activity and Network Interactions Linked to Valence‐Related Differences in the Impact of Emotional Distraction

Abstract Previous investigations showed that the impact of negative distraction on cognitive processing is linked to increased activation in a ventral affective system (VAS) and simultaneous deactivation in a dorsal executive system (DES). However, less is known about the influences of positive valence and different arousal levels on these effects. FMRI data were recorded while participants performed a working memory (WM) task, with positive and negative pictures presented as distracters during the delay between the memoranda and probes. First, positive distraction had reduced impact on WM performance, compared with negative distraction. Second, fMRI results identified valence‐specific effects in DES regions and overlapping arousal and valence effects in VAS regions, suggesting increased impact of negative distraction and enhanced engagement of coping mechanisms for positive distraction. Third, a valence‐related rostro‐caudal dissociation was identified in medial frontal regions associated with the default‐mode network (DMN). Finally, these DMN regions showed increased functional connectivity with DES regions for negative compared with positive distraction. Overall, these findings suggest that, while both positive and negative distraction engage partly similar arousal‐dependent mechanisms, their differential impact on WM performance is linked to dissociations in the engagement of, and coupling between, regions associated with emotion processing and higher lever cognitive control.
Influence of dentistry professionals and oral health assistance protocols on intensive care unit nursing staff. A survey study

Patients admitted to intensive care units (ICU) often lack oral health assistance,(1-3) with a direct influence on oral health problems related to higher morbidity and mortality. Poor oral health can lead to clinical problems such as locally spreading infections, respiratory tract infections, higher costs of ICU admissions, and higher use of medications such as antibiotics, which can result in the establishment of bacterial resistance and opportunistic infections. (3-8) Considering the value of oral health in preventing complications for ICU patients, it is important to implement oral healthcare protocols in the ICU. This study aimed to evaluate the influence of oral health care protocols, the routine activity of dental professionals, the oral healthcare knowledge of ICU staff and the methods used to provide this care to ICU patients. We tested the hypothesis that oral care protocols and training positively affect oral healthcare practice in the ICU.