Mapping a Systematic Ribozyme Fitness Landscape Reveals a Frustrated Evolutionary Network for Self-Aminoacylating RNA.

Molecular evolution can be conceptualized as a walk over a "fitness landscape", or the function of fitness (e.g., catalytic activity) over the space of all possible sequences. Understanding evolution requires knowing the structure of the fitness landscape and identifying the viable evolutionary pathways through the landscape. However, the fitness landscape for any catalytic biomolecule is largely unknown. The evolution of catalytic RNA is of special interest because RNA is believed to have been foundational to early life. In particular, an essential activity leading to the genetic code would be the reaction of ribozymes with activated amino acids, such as 5(4 H)-oxazolones, to form aminoacyl-RNA. Here we combine in vitro selection with a massively parallel kinetic assay to map a fitness landscape for self-aminoacylating RNA, with nearly complete coverage of sequence space in a central 21-nucleotide region. The method (SCAPE: sequencing to measure catalytic activity paired with in vitro evolution) shows that the landscape contains three major ribozyme families (landscape peaks). An analysis of evolutionary pathways shows that, while local optimization within a ribozyme family would be possible, optimization of activity over the entire landscape would be frustrated by large valleys of low activity. The sequence motifs associated with each peak represent different solutions to the problem of catalysis, so the inability to traverse the landscape globally corresponds to an inability to restructure the ribozyme without losing activity. The frustrated nature of the evolutionary network suggests that chance emergence of a ribozyme motif would be more important than optimization by natural selection.

Mutualistic Coupling Between Vocabulary and Reasoning in Young Children: A Replication and Extension of the Study by Kievit et al. (2017).

Recent work suggests that the positive manifold of individual differences may arise, or be amplified, by a mechanism called mutualism. Kievit et al. (2017) showed that a latent change score implementation of the mutualism model outperformed alternative models, demonstrating positive reciprocal interactions between vocabulary and reasoning during development. Here, we replicated these findings in a cohort of children (N = 227, 6-8 years old) and expanded the findings in three directions. First, a third wave of data was included, and the findings were robust to alternative model specifications. Second, a simulation demonstrated that data sets of similar magnitude and distributional properties could have, in principle, favored alternative models with close to 100% power. Third, we found support for the hypothesis that mutualistic-coupling effects are stronger and self-feedback parameters weaker in younger children. Together, these findings replicated the work of Kievit et al. (2017) and further support the hypothesis that mutualism supports cognitive development.

TRACING THE DEVELOPMENT OF TYPEWRITING SKILLS IN AN ADAPTIVE E-LEARNING ENVIRONMENT.

Typewriting studies which compare novice and expert typists have suggested that highly trained typing skills involve cognitive process with an inner and outer loop, which regulate keystrokes and words, respectively. The present study investigates these loops longitudinally, using multi-level modeling of 1,091,707 keystroke latencies from 62 children (M age=12.6 yr.) following an online typing course. Using finger movement repetition as indicator of the inner loop and words typed as indicator of the outer loop, practicing keystroke latencies resulted in different developmental curves for each loop. Moreover, based on plateaus in the developmental curves, the inner loop seemed to require less practice to develop than the outer loop.

Severe hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone developed as initial manifestation of human herpesvirus-6-associated acute limbic encephalitis after unrelated bone marrow transplantation.

Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation (allo-SCT) recipients and >50% of cases of severe hyponatremia are caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we present a patient with rapidly progressive severe hyponatremia as an initial sign and symptom of human herpesvirus-6-associated post-transplantation acute limbic encephalitis (HHV-6 PALE) after allo-SCT. A 45-year-old woman with acute lymphoblastic leukemia received unrelated bone marrow transplantation from a one locus-mismatched donor at the DR locus. On day 21, she developed a generalized seizure and loss of consciousness with severe hyponatremia, elevated serum antidiuretic hormone (ADH), and decreased serum osmolality. A high titer of HHV-6 DNA was detected in cerebrospinal fluid. Treatment with foscarnet sodium and hypertonic saline was started with improvement of neurological condition within several days. Although an elevated serum ADH, low serum osmolality, and high urinary osmolality persisted for 2 months, she had no other recurrent symptoms of encephalitis. Our experience suggests that hyponatremia accompanied by SIADH should be recognized as a prodromal or concomitant manifestation of HHV-6 PALE, and close monitoring of serum sodium levels in high-risk patients for HHV-6 PALE is necessary for immediate diagnosis and treatment initiation.

Phosphocreatine resynthesis during recovery in different muscles of the exercising leg by 31P-MRS.

To investigate the high-energy phosphate metabolism by (31) P-nuclear magnetic resonance spectroscopy during off-transition of exercise in different muscle groups, such as calf muscles and biceps femoris muscles, seven male long-distance runners (LDR) and nine untrained males (UT) performed both submaximal constant and incremental exercises. The relative exercise intensity was set at 60% of the maximal work rate (60%W max) during both knee flexion and plantar flexion submaximal constant load exercises. The relative areas under the inorganic phosphate (Pi ) and phosphocreatine (PCr) peaks were determined. During the 5-min recovery following the 60%W max, the time constant for the PCr off-kinetics was significantly faster in the plantar flexion (LDR: 17.3 ± 3.6 s, UT: 26.7 ± 6.7 s) than in the knee flexion (LDR: 29.7 ± 4.7 s, UT: 42.7 ± 2.8 s, P < 0.05). In addition, a significantly faster PCr off-kinetics was observed in LDR than in UT for both exercises. The ratio of Pi to PCr (Pi /PCr) during exercise was significantly lower during the plantar flexion than during the knee flexion (P < 0.01). These findings indicated that the calf muscles had relatively higher potential for oxidative capacity than that of biceps femoris muscles with an association of training status.

Tracking a multitude of abilities as they develop.

Recently, the Urnings algorithm (Bolsinova et al., 2022, J. R. Stat. Soc. Ser. C Appl. Statistics, 71, 91) has been proposed that allows for tracking the development of abilities of the learners and the difficulties of the items in adaptive learning systems. It is a simple and scalable algorithm which is suited for large-scale applications in which large streams of data are coming into the system and on-the-fly updating is needed. Compared to alternatives like the Elo rating system and its extensions, the Urnings rating system allows the uncertainty of the ratings to be evaluated and accounts for adaptive item selection which, if not corrected for, may distort the ratings. In this paper we extend the Urnings algorithm to allow for both between-item and within-item multidimensionality. This allows for tracking the development of interrelated abilities both at the individual and the population level. We present formal derivations of the multidimensional Urnings algorithm, illustrate its properties in simulations, and present an application to data from an adaptive learning system for primary school mathematics called Math Garden.

Control Theory Forecasts of Optimal Training Dosage to Facilitate Children's Arithmetic Learning in a Digital Educational Application.

Education can be viewed as a control theory problem in which students seek ongoing exogenous input-either through traditional classroom teaching or other alternative training resources-to minimize the discrepancies between their actual and target (reference) performance levels. Using illustrative data from [Formula: see text] Dutch elementary school students as measured using the Math Garden, a web-based computer adaptive practice and monitoring system, we simulate and evaluate the outcomes of using off-line and finite memory linear quadratic controllers with constraintsto forecast students' optimal training durations. By integrating population standards with each student's own latent change information, we demonstrate that adoption of the control theory-guided, person- and time-specific training dosages could yield increased training benefits at reduced costs compared to students' actual observed training durations, and a fixed-duration training scheme. The control theory approach also outperforms a linear scheme that provides training recommendations based on observed scores under noisy and the presence of missing data. Design-related issues such as ways to determine the penalty cost of input administration and the size of the control horizon window are addressed through a series of illustrative and empirically (Math Garden) motivated simulations.

Altered gene expression in leukocyte transendothelial migration and cell communication pathways in periodontitis-affected gingival tissues.

BACKGROUND AND OBJECTIVE: Gene expression is related to the pathogenesis of periodontitis and plays a crucial role in local tissue destruction and disease susceptibility. The aims of the present study were to identify the expression of specific genes and biological pathways in periodontitis-affected gingival tissue using microarray and quantitative real-time RT-PCR analyses. MATERIAL AND METHODS: Healthy and periodontitis-affected gingival tissues were taken from three patients with severe chronic periodontitis. Total RNAs from six gingival tissue samples were used for microarray analyses. Data-mining analyses, such as comparisons, gene ontology and pathway analyses, were performed and biological pathways with a significant role in periodontitis were identified. In addition, quantitative real-time RT-PCR analysis was performed on samples obtained from 14 patients with chronic periodontitis and from 14 healthy individuals in order to confirm the results of the pathway analysis. RESULTS: Comparison analyses found 15 up-regulated and 13 down-regulated genes (all of which showed a change of more than twofold in expression levels) in periodontitis-affected gingival tissues. Pathway analysis identified 15 up-regulated biological pathways, including leukocyte transendothelial migration, and five down-regulated pathways, including cell communication. Quantitative real-time RT-PCR verified that five genes in the leukocyte transendothelial migration pathway were significantly up-regulated, and four genes in the cell communication pathway were significantly down-regulated, which was consistent with pathway analysis. CONCLUSION: We identified up-regulated genes (ITGB-2, MMP-2, CXCL-12, CXCR-4 and Rac-2) and down-regulated genes (connexin, DSG-1, DSC-1 and nestin) in periodontitis-affected gingival tissues; these genes may be related to the stimulation of leukocyte transendothelial migration and to the the impairment of cell-to-cell communication in periodontitis.

Tracking with (Un)Certainty.

One of the highest ambitions in educational technology is the move towards personalized learning. To this end, computerized adaptive learning (CAL) systems are developed. A popular method to track the development of student ability and item difficulty, in CAL systems, is the Elo Rating System (ERS). The ERS allows for dynamic model parameters by updating key parameters after every response. However, drawbacks of the ERS are that it does not provide standard errors and that it results in rating variance inflation. We identify three statistical issues responsible for both of these drawbacks. To solve these issues we introduce a new tracking system based on urns, where every person and item is represented by an urn filled with a combination of green and red marbles. Urns are updated, by an exchange of marbles after each response, such that the proportions of green marbles represent estimates of person ability or item difficulty. A main advantage of this approach is that the standard errors are known, hence the method allows for statistical inference, such as testing for learning effects. We highlight features of the Urnings algorithm and compare it to the popular ERS in a simulation study and in an empirical data example from a large-scale CAL application.

Identification of testicular cancer driver genes by a cross-species comparative oncology approach.

BACKGROUND: Germ cell tumors arise in the testis, ovary, or extragonadal locations and have a wide range of histopathological and clinical presentations. The relative lack of animal models of germ cell tumors has impeded functional assessment of candidate driver genes. Previously, we described the development of testicular germ cell tumors in zebrafish carrying a mutation in bmpr1bb, a BMP family receptor, and demonstrated that human germ cell tumors have defects in BMP signaling. OBJECTIVE: To further credential the zebrafish model for studies of human germ cell tumor, and to elucidate conserved genetic programs underlying the development of germ cell tumor. MATERIALS AND METHODS: We used genetic techniques to ablate the germ cell lineage in developing fish and tested tumors for loss-of-heterozygosity of the wild-type allele of bmpr1bb. We performed comparative gene expression profiling of zebrafish and human germ cell tumors and carried out functional studies of selected genes. RESULTS: Ablation of germ cells completely prevents testis tumor formation in the fish, definitively establishing the germ cell origin of the tumors. Germ cell tumors in bmpr1bb heterozygous mutants retain the wild-type allele, indicating haploinsufficiency of bmpr1bb as the mechanism of tumor formation. Comparison of RNA-Seq and microarray data from human and zebrafish germ cell tumors revealed a unique overlapping signature shared by the zebrafish tumors with human seminomas, yolk sac tumors, and embryonal carcinomas. The most highly conserved gene set in this cross-species analysis included potential driver genes such as JUP, which we show to be essential for germ cell tumor cell growth. CONCLUSION: Our findings highlight the value of cross-species comparative oncology for the identification of candidate human cancer genes.

Formal Modeling of the Resistance to Peer Influence Questionnaire: A Comparison of Adolescent Boys and Girls With and Without Mild-to-Borderline Intellectual Disability.

Items of the Resistance to Peer Influence Questionnaire (RPIQ) have a tree-based structure. On each item, individuals first choose whether a less versus more peer-resistant group best describes them; they then indicate whether it is "Really true" versus "Sort of true" that they belong to the chosen group. Using tree-based item response theory, we show that RPIQ items tap three dimensions: A Resistance to Peer Influence (RPI) dimension and two Response Polarization dimensions. We then reveal subgroup differences on these dimensions. That is, adolescents with mild-to-borderline intellectual disability, compared with typically developing adolescents, are less RPI and more polarized in their responses. Also, girls, compared with boys, are more RPI, and, when high RPI, more polarized in their responses. Together, these results indicate that a tree-based modeling approach yields a more sensitive measure of individuals' RPI as well as their tendency to respond more or less extremely.

Influence of work rate on dynamics of O2 uptake under hypoxic conditions in humans.

AIM: It was the purpose of the investigation to determine whether an altered work rate could influence the oxygen uptake (V.O(2)) and heart rate (HR) dynamics at hypoxia and normoxia. METHODS: Ten males performed a cycle exercise with 2 repetitions of 6 min each at a constant work load while breathing one of two inspiratory O(2) fractions (FIO(2)): 0.12 (moderate hypoxia) and 0.21 (normoxia). Each test began with unloaded pedaling. This was followed by three constant loads, which were 40%, 60%, and 80% of the subject's gas exchange threshold (GET) in hypoxia (F(I)O(2) = 0.12), with the 80% GET load repeated under normoxia (room air). V.O(2) was measured on a breath-by-breath basis and beat-by-beat HR via ECG, and the half time (t1/2) of each parameter was established, following interpolation data. RESULTS: There were no remarkable differences in t1/2 V.O(2) dynamics among the 40%, 60% and 80% GET; however, the differences became significant at hypoxia compared with normoxia. The HR dynamics were significantly faster in normoxia compared with hypoxia, independent of work rates. During steady-state exercise, the alterations in HR and cardiac output (Q) using the acetylene rebreathing method depended on increases in the work rate, and a significantly increase in at 80% GET was observed when compared with normoxia. Increases of stroke volume (SV) were unaffected by altered work rates and inspired O(2) concentrations. The arteriovenous oxygen difference (Ca-vO(2)) at a steady-state of exercise increased proportionally with the work rate under hypoxia, and a much greater Ca-vO(2) was observed during normoxic exercise than under hypoxia. CONCLUSION: These results seem to suggest that in humans, O(2) uptake dynamics are affected by lower O(2), not by changing work rates at hypoxia, to which the interaction between lower O(2) utilization in exercising muscles and hypoxic-induced greater blood flow can be attributed.

A Solution to the Measurement Problem in the Idiographic Approach Using Computer Adaptive Practicing.

Molenaar's manifesto on psychology as idiographic science (Molenaar, 2004) brought the N = 1 times series perspective firmly to the attention of developmental scientists. The rich intraindividual variation in complex developmental processes requires the study of these processes at the level of the individual. Yet, the idiographic approach is all but easy in practical research. One major limitation is the collection of short interval times series of high quality data on developmental processes. In this paper, we present a novel measurement approach to this problem. We developed an online practice and monitoring system which is now used by thousands of Dutch primary school children on a daily or weekly basis, providing a new window on cognitive development. We will introduce the origin of this new instrument, called Math Garden, explain its setup, and present and discuss ways to analyze children's individual developmental pathways.

Bayesian evaluation of constrained hypotheses on variances of multiple independent groups.

Research has shown that independent groups often differ not only in their means, but also in their variances. Comparing and testing variances is therefore of crucial importance to understand the effect of a grouping variable on an outcome variable. Researchers may have specific expectations concerning the relations between the variances of multiple groups. Such expectations can be translated into hypotheses with inequality and/or equality constraints on the group variances. Currently, however, no methods are available for testing (in)equality constrained hypotheses on variances. This article proposes a novel Bayesian approach to this challenging testing problem. Our approach has the following useful properties: First, it can be used to simultaneously test multiple (non)nested hypotheses with equality as well as inequality constraints on the variances. Second, our approach is fully automatic in the sense that no subjective prior specification is needed. Only the hypotheses need to be provided. Third, a user-friendly software application is included that can be used to perform this Bayesian test in an easy manner. (PsycINFO Database Record

The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing.

In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by α-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein-protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt). RNA sequencing revealed that AMA impaired transcription and RNA splicing of Htt, which is known as an endoplasmic reticulum (ER)-stabilizing molecule. The impairment in RNA splicing and PL ratio was rescued by overexpresion of hnRNP that had been also affected by transcriptional repression. Fly genetics with suppressor or expresser of Htt and hnRNP worsened or ameliorated the decreased PL ratio by AMA, respectively. Collectively, these results suggested involvement of RNA splicing and a regulatory role of the hnRNP-Htt axis in the process of the transcriptional repression-induced necrosis.

Additional list of species of aquatic macrophytes in the lower basin of the Xingu River.

In this paper the authors present an additional list of aquatic macrophytes in the lower basin of the Xingu River.

The Balance-Scale Task Revisited: A Comparison of Statistical Models for Rule-Based and Information-Integration Theories of Proportional Reasoning.

We propose and test three statistical models for the analysis of children's responses to the balance scale task, a seminal task to study proportional reasoning. We use a latent class modelling approach to formulate a rule-based latent class model (RB LCM) following from a rule-based perspective on proportional reasoning and a new statistical model, the Weighted Sum Model, following from an information-integration approach. Moreover, a hybrid LCM using item covariates is proposed, combining aspects of both a rule-based and information-integration perspective. These models are applied to two different datasets, a standard paper-and-pencil test dataset (N = 779), and a dataset collected within an online learning environment that included direct feedback, time-pressure, and a reward system (N = 808). For the paper-and-pencil dataset the RB LCM resulted in the best fit, whereas for the online dataset the hybrid LCM provided the best fit. The standard paper-and-pencil dataset yielded more evidence for distinct solution rules than the online data set in which quantitative item characteristics are more prominent in determining responses. These results shed new light on the discussion on sequential rule-based and information-integration perspectives of cognitive development.

Alterations in land uses based on amendments to the Brazilian Forest Law and their influences on water quality of a watershed.

The amendments to the Forest Law proposed by the Brazilian government that allow partial substitution of forested areas by agricultural activities raised deep concern about the integrity of aquatic ecosystems. To assess the impacts of this alteration in land uses on the watershed, diffuse loads of total nitrogen (Nt) and total phosphorus (Pt) were estimated in Lobo Stream watershed, southeastern Brazil, based on export coefficients of the Model of Correlation between Land Use and Water Quality (MQUAL). Three scenarios were generated: scenario 1 (present scenario), with 30-meter-wide permanent preservation areas along the shore of water bodies and 50-meter-radius in springs; scenario 2, conservative, with 100-meter-wide permanent preservation areas along water bodies; and scenario 3, with the substitution of 20% of natural forest by agricultural activities. Results indicate that a suppression of 20% of forest cover would cause an increase in nutrient loads as well as in the trophic state of aquatic ecosystems of the watershed. This could result in losses of ecosystem services and compromise the quality of water and its supply for the basin. This study underlines the importance of forest cover for the maintenance of water quality in Lobo Stream watershed.

Limnological and ecological methods: approaches, and sampling strategies for middle Xingu River in the area of influence of future Belo Monte Power Plant.

In this paper the authors describe the limnological approaches, the sampling methodology, and strategy adopted in the study of the Xingu River in the area of influence of future Belo Monte Power Plant. The river ecosystems are characterized by unidirectional current, highly variable in time depending on the climatic situation the drainage pattern an hydrological cycle. Continuous vertical mixing with currents and turbulence, are characteristic of these ecosystems. All these basic mechanisms were taken into consideration in the sampling strategy and field work carried out in the Xingu River Basin, upstream and downstream the future Belo Monte Power Plant Units.

Spatial patterns of water quality in Xingu River Basin (Amazonia) prior to the Belo Monte dam impoundment.

The Xingu River, one of the most important of the Amazon Basin, is characterized by clear and transparent waters that drain a 509.685 km2 watershed with distinct hydrological and ecological conditions and anthropogenic pressures along its course. As in other basins of the Amazon system, studies in the Xingu are scarce. Furthermore, the eminent construction of the Belo Monte for hydropower production, which will alter the environmental conditions in the basin in its lower middle portion, denotes high importance of studies that generate relevant information that may subsidize a more balanced and equitable development in the Amazon region. Thus, the aim of this study was to analyze the water quality in the Xingu River and its tributaries focusing on spatial patterns by the use of multivariate statistical techniques, identifying which water quality parameters were more important for the environmental changes in the watershed. Data sampling were carried out during two complete hydrological cycles in twenty-five sampling stations. The data of twenty seven variables were analyzed by Spearman's correlation coefficients, cluster analysis (CA), and principal component analysis (PCA). The results showed a high auto-correlation between variables (> 0.7). These variables were removed from multivariate analyzes because they provided redundant information about the environment. The CA resulted in the formation of six clusters, which were clearly observed in the PCA and were characterized by different water quality. The statistical results allowed to identify a high spatial variation in the water quality, which were related to specific features of the environment, different uses, influences of anthropogenic activities and geochemical characteristics of the drained basins. It was also demonstrated that most of the sampling stations in the Xingu River basin showed good water quality, due to the absence of local impacts and high power of depuration of the river itself.