Miracle-dz/UniFAR-FTUs huggingface dataset:
Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease

Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.
Cohort Profile Cohort Profile : Stratifying Resilience and Depression Longitudinally ( STRADL ) : a questionnaire follow-up of Generation Scotland : Scottish Family Health Study ( GS : SFHS )

Cohort Profile: Stratifying Resilience and Depression Longitudinally (STRADL): a questionnaire follow-up of Generation Scotland: Scottish Family Health Study (GS:SFHS) LB Navrady,* MK Wolters, DJ MacIntyre, T-K Clarke, AI Campbell, AD Murray, KL Evans, J Seckl, C Haley, K Milburn, JM Wardlaw, DJ Porteous, IJ Deary and AM McIntosh Division of Psychiatry, University of Edinburgh, Edinburgh, UK, School of Informatics, University of Edinburgh, Edinburgh, UK, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK, Generation Scotland, Centre for Genetics and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK, Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, UK, Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK, Endocrinology Unit, Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, UK, MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK, Health Informatics Centre, University of Dundee, Dundee, UK, Brain Research Imaging Centre, School of Clinical Sciences, University of Edinburgh, Edinburgh, UK and Department of Psychology, University of Edinburgh, Edinburgh, UK
Paper-based sensors for rapid detection of virulence factor produced by Pseudomonas aeruginosa

Pyocyanin is a toxin produced by Pseudomonas aeruginosa. Here we describe a novel paper-based electrochemical sensor for pyocyanin detection, manufactured with a simple and inexpensive approach based on electrode printing on paper. The resulting sensors constitute an effective electrochemical method to quantify pyocyanin in bacterial cultures without the conventional time consuming pretreatment of the samples. The electrochemical properties of the paper-based sensors were evaluated by ferri/ferrocyanide as a redox mediator, and showed reliable sensing performance. The paper-based sensors readily allow for the determination of pyocyanin in bacterial cultures with high reproducibility, achieving a limit of detection of 95 nM and a sensitivity of 4.30 μA/μM in standard culture media. Compared to the similar commercial ceramic based sensors, it is a 2.3-fold enhanced performance. The simple in-house fabrication of sensors for pyocyanin quantification allows researchers to understand in vitro adaptation of P. aeruginosa infections via rapid screenings of bacterial cultures that otherwise are expensive and time-consuming.
Antiretroviral Therapy Enrollment Characteristics and Outcomes Among HIV-Infected Adolescents and Young Adults Compared with Older Adults — Seven African Countries, 2004–2013

Although scale-up of antiretroviral therapy (ART) since 2005 has contributed to declines of about 30% in the global annual number of human immunodeficiency (HIV)-related deaths and declines in global HIV incidence, estimated annual HIV-related deaths among adolescents have increased by about 50% and estimated adolescent HIV incidence has been relatively stable. In 2012, an estimated 2,500 (40%) of all 6,300 daily new HIV infections occurred among persons aged 15-24 years. Difficulty enrolling adolescents and young adults in ART and high rates of loss to follow-up (LTFU) after ART initiation might be contributing to mortality and HIV incidence in this age group, but data are limited. To evaluate age-related ART retention challenges, data from retrospective cohort studies conducted in seven African countries among 16,421 patients, aged ≥15 years at enrollment, who initiated ART during 2004-2012 were analyzed. ART enrollment and outcome data were compared among three groups defined by age at enrollment: adolescents and young adults (aged 15-24 years), middle-aged adults (aged 25-49 years), and older adults (aged ≥50 years). Enrollees aged 15-24 years were predominantly female (81%-92%), commonly pregnant (3%-32% of females), unmarried (54%-73%), and, in four countries with employment data, unemployed (53%-86%). In comparison, older adults were more likely to be male (p<0.001), employed (p<0.001), and married, (p<0.05 in five countries). Compared with older adults, adolescents and young adults had higher LTFU rates in all seven countries, reaching statistical significance in three countries in crude and multivariable analyses. Evidence-based interventions to reduce LTFU for adolescent and young adult ART enrollees could help reduce mortality and HIV incidence in this age group.
Bacterial Infections in Neonates, Madagascar, 2012–2014

Severe bacterial infections are a leading cause of death among neonates in low-income countries, which harbor several factors leading to emergence and spread of multidrug-resistant bacteria. Low-income countries should prioritize interventions to decrease neonatal infections; however, data are scarce, specifically from the community. To assess incidence, etiologies, and antimicrobial drug–resistance patterns of neonatal infections, during 2012–2014, we conducted a community-based prospective investigation of 981 newborns in rural and urban areas of Madagascar. The incidence of culture-confirmed severe neonatal infections was high: 17.7 cases/1,000 live births. Most (75%) occurred during the first week of life. The most common (81%) bacteria isolated were gram-negative. The incidence rate for multidrug-resistant neonatal infection was 7.7 cases/1,000 live births. In Madagascar, interventions to improve prevention, early diagnosis, and management of bacterial infections in neonates should be prioritized.
Four simple rules that are sufficient to generate the mammalian blastocyst

Early mammalian development is both highly regulative and self-organizing. It involves the interplay of cell position, predetermined gene regulatory networks, and environmental interactions to generate the physical arrangement of the blastocyst with precise timing. However, this process occurs in the absence of maternal information and in the presence of transcriptional stochasticity. How does the preimplantation embryo ensure robust, reproducible development in this context? It utilizes a versatile toolbox that includes complex intracellular networks coupled to cell—cell communication, segregation by differential adhesion, and apoptosis. Here, we ask whether a minimal set of developmental rules based on this toolbox is sufficient for successful blastocyst development, and to what extent these rules can explain mutant and experimental phenotypes. We implemented experimentally reported mechanisms for polarity, cell—cell signaling, adhesion, and apoptosis as a set of developmental rules in an agent-based in silico model of physically interacting cells. We find that this model quantitatively reproduces specific mutant phenotypes and provides an explanation for the emergence of heterogeneity without requiring any initial transcriptional variation. It also suggests that a fixed time point for the cells’ competence of fibroblast growth factor (FGF)/extracellular signal—regulated kinase (ERK) sets an embryonic clock that enables certain scaling phenomena, a concept that we evaluate quantitatively by manipulating embryos in vitro. Based on these observations, we conclude that the minimal set of rules enables the embryo to experiment with stochastic gene expression and could provide the robustness necessary for the evolutionary diversification of the preimplantation gene regulatory network.
Fatigue in Patients with Multiple Sclerosis: Is It Related to Pro- and Anti-Inflammatory Cytokines?

Objective. To investigate the pathophysiological role of pro- and anti-inflammatory cytokines in primary multiple sclerosis-related fatigue. Methods. Fatigued and non-fatigued patients with multiple sclerosis (MS) were recruited and their cytokine profiles compared. Patients with secondary fatigue were excluded. Fatigue was assessed with the self-reported Checklist Individual Strength (CIS20r), subscale fatigue. A CIS20r fatigue cut-off score of 35 was applied to differentiate between non-fatigued (CIS20r fatigue ≤34) and fatigued (CIS20r fatigue ≥35) patients with MS. Blood was collected to determine the serum concentrations of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, IL-12p70, IL-17, TNFα, and IFN-γ) and anti-inflammatory cytokines (IL-4, IL-5, IL-10, and IL-13). We controlled for the confounding effect of age, gender, duration of MS, disease severity, type of MS, and use of immunomodulatory drugs. Results. Similar cytokine levels were observed between MS patients with (n = 21) and without fatigue (n = 14). Adjusted multiple regression analyses showed a single significant positive relationship, that of IL-6 with CIS20r fatigue score. The explained variance of the IL-6 model was 21.1%, once adjusted for the confounding effect of age. Conclusion. The pro-inflammatory cytokine interleukin-6 (IL-6) may play a role in the pathophysiology of primary fatigue in patients with MS. Trial Registrations. ISRCTN69520623, ISRCTN58583714, and ISRCTN82353628.
Genetic Architecture of White Matter Hyperintensities Differs in Hypertensive and Nonhypertensive Ischemic Stroke

Background and Purpose— Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. Methods— WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. Results— A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99×10−5); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). Conclusions— A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction.
Problems identified by dual sensory impaired older adults in long-term care when using a self-management program: A qualitative study

Objective To gain insights into the problems of dual sensory impaired older adults in long-term care. Insights into these problems are essential for developing adequate policies which address the needs of the increasing population of dual sensory impaired older adults in long-term care. Methods A qualitative study was conducted in parallel with a cluster randomized controlled trial. Dual sensory impaired older adults in the intervention group (n = 47, age range 82–98) were invited by a familiar nurse to identify the problems they wanted to address. Data were taken from the semi-structured intervention diaries in which nurses noted the older adults’ verbal responses during a five-month intervention period in 17 long-term care homes across the Netherlands. The data were analyzed using descriptive statistics and qualitative content analysis based on the Grounded Theory. Findings The 47 dual sensory impaired older adults identified a total of 122 problems. Qualitative content analysis showed that the older adults encountered participation problems and problems controlling what happens in their personal environment. Three categories of participation problems emerged: (1) existential concerns of not belonging or not being able to connect with other people, (2) lack of access to communication, information and mobility, and (3) the desire to be actively involved in care delivery. Two categories of control-in-personal-space problems emerged: (1) lack of control of their own physical belongings, and (2) lack of control regarding the behavior of nurses providing daily care in their personal environment. Conclusions The invasive problems identified indicate that dual sensory impaired older adults experience great existential pressures on their lives. Long-term care providers need to develop and implement policies that identify and address these problems, and be aware of adverse consequences of usual care, in order to improve dual sensory impaired residents’ autonomy and quality of life.
Müllerian inhibiting substance/anti-Müllerian hormone: A novel treatment for gynecologic tumors

Müllerian inhibiting substance (MIS), also called anti-Müllerian hormone (AMH), is a member of the transforming growth factor-β super-family of growth and differentiation response modifiers. It is produced in immature Sertoli cells in male embryos and binds to MIS/AMH receptors in primordial Müllerian ducts to cause regression of female reproductive structures that are the precursors to the fallopian tubes, the surface epithelium of the ovaries, the uterus, the cervix, and the upper third of the vagina. Because most gynecologic tumors originate from Müllerian duct-derived tissues, and since MIS/AMH causes regression of the Müllerian duct in male embryos, it is expected to inhibit the growth of gynecologic tumors. Purified recombinant human MIS/AMH causes growth inhibition of epithelial ovarian cancer cells and cell lines in vitro and in vitro via MIS receptor-mediated mechanism. Furthermore, several lines of evidence suggest that MIS/AMH inhibits proliferation in tissues and cell lines of other MIS/AMH receptor-expressing gynecologic tumors such as cervical, endometrial, breast, and in endometriosis as well. These findings indicate that bioactive MIS/AMH recombinant protein should be tested in patients against tumors expressing the MIS/AMH receptor complex, perhaps beginning with ovarian cancer because it has the worst prognosis. The molecular tools to identify MIS/AMH receptor expressing ovarian and other cancers are in place, thus, it is possible to select patients for treatment. An MIS/AMH ELISA exists to follow administered doses of MIS/AMH, as well. Clinical trials await the production of sufficient supplies of qualified recombinant human MIS/AMH for this purpose.
Social modulation of decision-making: a cross-species review

Taking decisions plays a pivotal role in daily life and comprises a complex process of assessing and weighing short-term and long-term costs and benefits of competing actions. Decision-making has been shown to be affected by factors such as sex, age, genotype, and personality. Importantly, also the social environment affects decisions, both via social interactions (e.g., social learning, cooperation and competition) and social stress effects. Although everyone is aware of this social modulating role on daily life decisions, this has thus far only scarcely been investigated in human and animal studies. Furthermore, neuroscientific studies rarely discuss social influence on decision-making from a functional perspective such as done in behavioral ecology studies. Therefore, the first aim of this article is to review the available data of the influence of the social context on decision-making both from a causal and functional perspective, drawing on animal and human studies. Also, there is currently still a gap between decision-making in real life where influences of the social environment are extensive, and decision-making as measured in the laboratory, which is often done without any (deliberate) social influences. However, methods are being developed to bridge this gap. Therefore, the second aim of this review is to discuss these methods and ways in which this gap can be increasingly narrowed. We end this review by formulating future research questions.
A Common Representation of Spatial Features Drives Action and Perception: Grasping and Judging Object Features within Trials

Spatial features of an object can be specified using two different response types: either by use of symbols or motorically by directly acting upon the object. Is this response dichotomy reflected in a dual representation of the visual world: one for perception and one for action? Previously, symbolic and motoric responses, specifying location, has been shown to rely on a common representation. What about more elaborate features such as length and orientation? Here we show that when motoric and symbolic responses are made within the same trial, the probability of making the same symbolic and motoric response is well above chance for both length and orientation. This suggests that motoric and symbolic responses to length and orientation are driven by a common representation. We also show that, for both response types, the spatial features of an object are processed independently. This finding of matching object-processing characteristics is also in agreement with the idea of a common representation driving both response types.
Recombinant snakebite antivenoms: A cost-competitive solution to a neglected tropical disease?

Snakebite envenoming is a major public health burden in tropical parts of the developing world. In sub-Saharan Africa, neglect has led to a scarcity of antivenoms threatening the lives and limbs of snakebite victims. Technological advances within antivenom are warranted, but should be evaluated not only on their possible therapeutic impact, but also on their cost-competitiveness. Recombinant antivenoms based on oligoclonal mixtures of human IgG antibodies produced by CHO cell cultivation may be the key to obtaining better snakebite envenoming therapies. Based on industry data, the cost of treatment for a snakebite envenoming with a recombinant antivenom is estimated to be in the range USD 60–250 for the Final Drug Product. One of the effective antivenoms (SAIMR Snake Polyvalent Antivenom from the South African Vaccine Producers) currently on the market has been reported to have a wholesale price of USD 640 per treatment for an average snakebite. Recombinant antivenoms may therefore in the future be a cost-competitive alternative to existing serum-based antivenoms.
Accurate self-correction of errors in long reads using de Bruijn graphs

Motivation: New long read sequencing technologies, like PacBio SMRT and Oxford NanoPore, can produce sequencing reads up to 50 000 bp long but with an error rate of at least 15%. Reducing the error rate is necessary for subsequent utilization of the reads in, e.g. de novo genome assembly. The error correction problem has been tackled either by aligning the long reads against each other or by a hybrid approach that uses the more accurate short reads produced by second generation sequencing technologies to correct the long reads. Results: We present an error correction method that uses long reads only. The method consists of two phases: first, we use an iterative alignment‐free correction method based on de Bruijn graphs with increasing length of k‐mers, and second, the corrected reads are further polished using long‐distance dependencies that are found using multiple alignments. According to our experiments, the proposed method is the most accurate one relying on long reads only for read sets with high coverage. Furthermore, when the coverage of the read set is at least 75×, the throughput of the new method is at least 20% higher. Availability and Implementation: LoRMA is freely available at http://www.cs.helsinki.fi/u/lmsalmel/LoRMA/. Contact: leena.salmela@cs.helsinki.fi
Lexical representation explains cortical entrainment during speech comprehension

Results from a recent neuroimaging study on spoken sentence comprehension have been interpreted as evidence for cortical entrainment to hierarchical syntactic structure. We present a simple computational model that predicts the power spectra from this study, even though the model’s linguistic knowledge is restricted to the lexical level, and word-level representations are not combined into higher-level units (phrases or sentences). Hence, the cortical entrainment results can also be explained from the lexical properties of the stimuli, without recourse to hierarchical syntax.
Patient‐centred physical therapy is (cost‐) effective in increasing physical activity and reducing frailty in older adults with mobility problems: a randomized controlled trial with 6 months follow‐up

Despite the well‐known health benefits of physical activity, it is a great challenge to stay physically active for frail–older adults with mobility limitations. The aim of this study was to test the (cost‐) effectiveness of a patient‐centred physical therapy strategy (Coach2Move) in which individualized treatment (motivational interviewing, physical examination, individualized goal setting, coaching and advice on self management, and physical training) is combined to increase physical activity level and physical fitness and, thereby, to decrease the level of frailty.