Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Ca2+ Homeostasis Disruption in Rotavirus-Associated Seizures

Rotavirus infection disturbs cellular Ca2+ homeostasis by triggering an increase in Ca2+ permeation. A theoretical link between Ca2+ dysregulation and seizures in patients with rotavirus gastroenteritis has been suggested, but no prior studies have investigated this relationship. To test our hypothesis that patients with rotavirus-associated seizures have greater Ca2+ homeostasis disruption than those without seizures, we compared clinical and laboratory data—including corrected total serum Ca2+ levels—between the 2 groups. Age, gender, maximum body temperature, day of admission, levels of electrolytes except Ca2+, blood pH, and urine ketone levels were not related to seizure occurrence. Significantly lower Ca2+ levels were found among the seizure (+) group (9.22 ± 0.50 vs 9.66 ± 0.46 mg/dL, P = .01). Although Ca2+ levels were within normal ranges and did not directly cause the seizures, our results provide preliminary evidence for a relationship between Ca2+ homeostasis disruption and seizures in rotavirus patients.
Comment on “Invasive Harlequin Ladybird Carries Biological Weapons Against Native Competitors”

Conclusions about the nontarget effects of putatively invasive pathogens should be based on biologically relevant data. We disagree that the research experiments on a microsporidium isolated from Harmonia axyridis conducted by Vilcinskas et al. (Reports, 17 May 2013, p. 862) can explain the decline of native coccinellid species in the absence of such data.
In Situ Observations of Interstellar Plasma with Voyager 1

Finally Out Last summer, it was not clear if the Voyager 1 spacecraft had finally crossed the heliopause—the boundary between the heliosphere and interstellar space. Gurnett et al. (p. 1489, published online 12 September) present results from the Plasma Wave instrument on Voyager 1 that provide evidence that the spacecraft was in the interstellar plasma during two periods, October to November 2012 and April to May 2013, and very likely in the interstellar plasma continuously since the series of boundary crossings that occurred in July to August 2012. Electron densities detected by Voyager 1 show that the spacecraft is in the interstellar plasma. Launched over 35 years ago, Voyagers 1 and 2 are on an epic journey outward from the Sun to reach the boundary between the solar plasma and the much cooler interstellar medium. The boundary, called the heliopause, is expected to be marked by a large increase in plasma density, from about 0.002 per cubic centimeter (cm−3) in the outer heliosphere, to about 0.1 cm−3 in the interstellar medium. On 9 April 2013, the Voyager 1 plasma wave instrument began detecting locally generated electron plasma oscillations at a frequency of about 2.6 kilohertz. This oscillation frequency corresponds to an electron density of about 0.08 cm−3, very close to the value expected in the interstellar medium. These and other observations provide strong evidence that Voyager 1 has crossed the heliopause into the nearby interstellar plasma.
Comment on “Invasive Harlequin Ladybird Carries Biological Weapons Against Native Competitors”

We comment on the implications that Vilcinskas et al. (Reports, 17 May 2013, p. 862) attach to the finding that the exotic, invasive ladybird Harmonia axyridis carries microsporidia to which this species is insensitive but that is lethal to species that are native to the invaded areas. The authors suggest that these microsporidia might serve as “biological weapons” against the native competitors, but we cast doubt on the importance of this suggestion in the field.
An Evolutionary Morphological Approach for Financial Time Series Forecasting

This paper presents an evolutionary morphological approach for designing translation invariant operators for time series forecasting. It consists of an intelligent evolutionary model composed of a modular morphological neural network (MMNN) trained via an improved genetic algorithm (IGA) having optimal genetic operators to accelerate convergence of the genetic algorithm. The proposed design strategy searches for the minimum number of time lags to represent the time series, as well as the weights, architecture and number of modules of the MMNN. An experimental analysis is conducted with the proposed method using six real world financial time series and five well-known performance measurements, demonstrating good performance of MMNN systems for financial time series forecasting.
Clustering by fast search and find of density peaks

Discerning clusters of data points Cluster analysis is used in many disciplines to group objects according to a defined measure of distance. Numerous algorithms exist, some based on the analysis of the local density of data points, and others on predefined probability distributions. Rodriguez and Laio devised a method in which the cluster centers are recognized as local density maxima that are far away from any points of higher density. The algorithm depends only on the relative densities rather than their absolute values. The authors tested the method on a series of data sets, and its performance compared favorably to that of established techniques. Science, this issue p. 1492 Local density of points is ranked and analyzed to categorize data. Cluster analysis is aimed at classifying elements into categories on the basis of their similarity. Its applications range from astronomy to bioinformatics, bibliometrics, and pattern recognition. We propose an approach based on the idea that cluster centers are characterized by a higher density than their neighbors and by a relatively large distance from points with higher densities. This idea forms the basis of a clustering procedure in which the number of clusters arises intuitively, outliers are automatically spotted and excluded from the analysis, and clusters are recognized regardless of their shape and of the dimensionality of the space in which they are embedded. We demonstrate the power of the algorithm on several test cases.
Hyperactivity, Unexplained Speech Delay, and Coarse Facies—Is It Sanfilippo Syndrome?

Mucopolysaccharidosis-IIIB or Sanfilippo-B syndrome is caused by deficiency of lysosomal α-N-acetylglucosaminidase that leads to accumulation of heparan-sulphate and degeneration of central nervous system with progressive dementia, hyperactivity, and aggressive behavior. Mucopolysaccharidosis-III remains underdiagnosed as a cause of developmental delay and hyperactivity both in adults and children because in contrast to other mucopolysaccharidoses, they have little somatic disease, coarse facial features, hepatosplenomegaly or skeletal changes, and a high incidence of false-negative results on the urinary screening tests. We describe here a girl with the classic phenotype of mucopolysaccharidosis-IIIB to alert pediatricians to the possibility of this disorder in children with unexplained speech delay and hyperactivity and prevent unnecessary investigations.
Resident Neural Stem Cells Restrict Tissue Damage and Neuronal Loss After Spinal Cord Injury in Mice

The Good Scar We tend to think of scars as bad and, in the central nervous system, as counterproductive to recovery. Studying mice, Sabelström et al. (p. 637) prevented resident stem cells from proliferating after spinal cord injury. Without the astrocytes generated by the neural stem cells, recovery from spinal cord lesions was poorer than normal. Thus, somewhat counterintuitively, glial scarring appears to limit spinal cord damage and support the remaining cells. Glial scarring helps to maintain the integrity of the injured spinal cord in mice. Central nervous system injuries are accompanied by scar formation. It has been difficult to delineate the precise role of the scar, as it is made by several different cell types, which may limit the damage but also inhibit axonal regrowth. We show that scarring by neural stem cell–derived astrocytes is required to restrict secondary enlargement of the lesion and further axonal loss after spinal cord injury. Moreover, neural stem cell progeny exerts a neurotrophic effect required for survival of neurons adjacent to the lesion. One distinct component of the glial scar, deriving from resident neural stem cells, is required for maintaining the integrity of the injured spinal cord.
Genetic Determinants and Cellular Constraints in Noisy Gene Expression

In individual cells, transcription is a random process obeying single-molecule kinetics. Often, it occurs in a bursty, intermittent manner. The frequency and size of these bursts affect the magnitude of temporal fluctuations in messenger RNA and protein content within a cell, creating variation or “noise” in gene expression. It is still unclear to what degree transcriptional kinetics are specific to each gene and determined by its promoter sequence. Alternative scenarios have been proposed, in which the kinetics of transcription are governed by cellular constraints and follow universal rules across the genome. Evidence from genome-wide noise studies and from systematic perturbations of promoter sequences suggest that both scenarios—namely gene-specific versus genome-wide regulation of transcription kinetics—may be present to different degrees in bacteria, yeast, and animal cells.
EMRE Is an Essential Component of the Mitochondrial Calcium Uniporter Complex

EMRE Emerges Concentrations of calcium within mitochondria are tightly regulated and modulate physiological mitochondrial functions, including control of metabolism and cell death. Sancak et al. (p. 1379, published online 14 November) complete the molecular characterization of the mitochondrial calcium uniporter (MCU), the multicomponent channel that allows concentration of calcium within the organelle. They identified a small protein termed “essential MCU regulator”—or EMRE—which was required for calcium transport activity of the fully assembled uniporter. A final but essential protein component involved in maintaining mitochondrial calcium levels is discovered. The mitochondrial uniporter is a highly selective calcium channel in the organelle’s inner membrane. Its molecular components include the EF-hand–containing calcium-binding proteins mitochondrial calcium uptake 1 (MICU1) and MICU2 and the pore-forming subunit mitochondrial calcium uniporter (MCU). We sought to achieve a full molecular characterization of the uniporter holocomplex (uniplex). Quantitative mass spectrometry of affinity-purified uniplex recovered MICU1 and MICU2, MCU and its paralog MCUb, and essential MCU regulator (EMRE), a previously uncharacterized protein. EMRE is a 10-kilodalton, metazoan-specific protein with a single transmembrane domain. In its absence, uniporter channel activity was lost despite intact MCU expression and oligomerization. EMRE was required for the interaction of MCU with MICU1 and MICU2. Hence, EMRE is essential for in vivo uniporter current and additionally bridges the calcium-sensing role of MICU1 and MICU2 with the calcium-conducting role of MCU.
Nucleus Accumbens Cholinergic Interneurons Oppose Cue-Motivated Behavior

Background Environmental reward-predictive stimuli provide a major source of motivation for adaptive reward pursuit behavior. This cue-motivated behavior is known to be mediated by the nucleus accumbens core (NAc). The cholinergic interneurons in the NAc are tonically active and densely arborized and, thus, well-suited to modulate NAc function. But their causal contribution to adaptive behavior remains unknown. Here we investigated the function of NAc cholinergic interneurons in cue-motivated behavior. Methods To do this, we used chemogenetics, optogenetics, pharmacology, and a translationally analogous Pavlovian-to-instrumental transfer behavioral task designed to assess the motivating influence of a reward-predictive cue over reward-seeking actions in male and female rats. Results The data show that NAc cholinergic interneuron activity is necessary and sufficient to oppose the motivating influence of appetitive cues. Chemogenetic inhibition of NAc cholinergic interneurons augmented cue-motivated behavior. Optical stimulation of acetylcholine release from NAc cholinergic interneurons prevented cues from invigorating reward-seeking behavior, an effect that was mediated by activation of β2-containing nicotinic acetylcholine receptors. Conclusions Thus, NAc cholinergic interneurons provide a critical regulatory influence over adaptive cue-motivated behavior and, therefore, are a potential therapeutic target for the maladaptive cue-motivated behavior that marks many psychiatric conditions, including addiction and depression.
International Classification of Functioning, Disability and Health (ICF) as a Framework for Change

The International Classification of Functioning, Disability and Health (ICF) utilizes domains of body functions and structures, activities and participation, as well as environmental and personal factors to fully encapsulate the concepts of health and disability. The International Classification of Functioning, Disability and Health provides a rich and holistic understanding of functioning that is particularly valuable in the setting of childhood disability and rehabilitation. With applicability that enhances a nuanced understanding of each child within their family, school, and community, the International Classification of Functioning, Disability and Health also ensures facile and meaningful communication between professionals. Use of the International Classification of Functioning, Disability and Health promotes improved treatment plans for individual children and for larger programmatic decisions. This article demonstrates how the International Classification of Functioning, Disability and Health has reinvented the language and understanding of childhood disability and rehabilitation.
Sources of Antimicrobial Resistance

Genomic data help to elucidate the role of food animals in the spread of antimicrobial resistance in humans. [Also see Report by Mather et al.] The relentless rise in levels of antimicrobial resistance is an unfolding global public health crisis (1). Resistance to frontline antimicrobials such as fluoroquinolones, third- and fourth-generation cephalosporins, and carbapenems is a particular concern, as is multidrug resistance. The antimicrobial resistance problem is not confined to human medicine: Comparable quantities of antimicrobials are used in livestock production, and resistance is rife in that setting, too, even on organic farms that restrict drug usage (2). Such observations have led to debate about whether antimicrobial resistance in farm animals is an important source of antimicrobial resistance in humans (3, 4). On page 1514 of this issue, Mather et al. (5) shed light on this important question in the context of Salmonella Typhimurium DT104 in humans and cattle in Scotland.
IFI16 DNA Sensor Is Required for Death of Lymphoid CD4 T Cells Abortively Infected with HIV

The progressive depletion of quiescent “bystander” CD4 T cells, which are nonpermissive to HIV infection, is a principal driver of the acquired immunodeficiency syndrome (AIDS). These cells undergo abortive infection characterized by the cytosolic accumulation of incomplete HIV reverse transcripts. These viral DNAs are sensed by an unidentified host sensor that triggers an innate immune response, leading to caspase-1 activation and pyroptosis. Using unbiased proteomic and targeted biochemical approaches, as well as two independent methods of lentiviral short hairpin RNA–mediated gene knockdown in primary CD4 T cells, we identify interferon-γ–inducible protein 16 (IFI16) as a host DNA sensor required for CD4 T cell death due to abortive HIV infection. These findings provide insights into a key host pathway that plays a central role in CD4 T cell depletion during disease progression to AIDS. The intracellular sensor that triggers the death of human lymphoid CD4 T cells abortively infected with HIV is identified. [Also see Perspective by Gaiha and Brass] Sensing HIV The depletion of quiescent CD4+ T cells from lymphoid organs is a major event contributing to the development of AIDS. The accumulation of incomplete HIV DNA transcripts in the cytoplasm of these cells, which do not themselves become productively infected, is somehow sensed, which triggers cell death. Monroe et al. (p. 428, published online 19 December; see the Perspective by Gaiha and Brass) now identify the host DNA sensor as interferon-γ–inducible protein 16, which senses viral DNA and activates pyroptosis, an inflammatory cell death pathway.
Optimising multi-modal polynomial mutation operators for multi-objective problem classes

This paper presents a novel method of generating new probability distributions tailored to specific problem classes for use in optimisation mutation operators. A range of tailored operators with varying behaviours are created using the proposed technique and the evolved multi-modal polynomial distributions are found to match the performance of a tuned Gaussian distribution when applied to a mutation operator incorporated in a simple (1+1) Evolution Strategy. The generated heuristics are shown to display a range of desirable characteristics for the DTLZ test problems 1, 2 and 7; such as speed of convergence.
A particle swarm optimization algorithm based on orthogonal design

The last decade has witnessed a great interest in using evolutionary algorithms, such as genetic algorithms, evolutionary strategies and particle swarm optimization (PSO), for multivariate optimization. This paper presents a hybrid algorithm for searching a complex domain space, by combining the PSO and orthogonal design. In the standard PSO, each particle focuses only on the error propagated back from the best particle, without “communicating” with other particles. In our approach, this limitation of the standard PSO is overcome by using a novel crossover operator based on orthogonal design. Furthermore, instead of the “generating-and-updating” model in the standard PSO, the elitism preservation strategy is applied to determine the possible movements of the candidate particles in the subsequent iterations. Experimental results demonstrate that our algorithm has a better performance compared to existing methods, including five PSO algorithms and three evolutionary algorithms.
Potential of the Synthetic Lethality Principle

Elucidating the first principles of synthetic lethality in cancer, including biological context, will assist clinical translation. Most cancer mutations, including those causing a loss of function, are not directly “druggable” with conventional small-molecule drugs or biologicals, such as antibodies. Thus, despite our growing knowledge of mutations that drive cancer progression, there remains a frustrating gap in translating this information into the development of targeted treatments that kill only cancer cells. An approach that exploits a concept from genetics called “synthetic lethality” could provide a solution. But it has been over 15 years since that framework was proposed (1). Does the synthetic lethality principle still have the potential for treating cancer?
Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder

People with severe mental illness have a considerably shorter lifespan than the general population. This excess mortality is mainly due to physical illness. Next to mental illness‐related factors, unhealthy lifestyle, and disparities in health care access and utilization, psychotropic medications can contribute to the risk of physical morbidity and mortality. We systematically reviewed the effects of antipsychotics, antidepressants and mood stabilizers on physical health outcomes in people with schizophrenia, depression and bipolar disorder. Updating and expanding our prior systematic review published in this journal, we searched MEDLINE (November 2009 ‐ November 2014), combining the MeSH terms of major physical disease categories (and/or relevant diseases within these categories) with schizophrenia, major depressive disorder and bipolar disorder, and the three major psychotropic classes which received regulatory approval for these disorders, i.e., antipsychotics, antidepressants and mood stabilizers. We gave precedence to results from (systematic) reviews and meta‐analyses wherever possible. Antipsychotics, and to a more restricted degree antidepressants and mood stabilizers, are associated with an increased risk for several physical diseases, including obesity, dyslipidemia, diabetes mellitus, thyroid disorders, hyponatremia; cardiovascular, respiratory tract, gastrointestinal, haematological, musculoskeletal and renal diseases, as well as movement and seizure disorders. Higher dosages, polypharmacy, and treatment of vulnerable (e.g., old or young) individuals are associated with greater absolute (elderly) and relative (youth) risk for most of these physical diseases. To what degree medication‐specific and patient‐specific risk factors interact, and how adverse outcomes can be minimized, allowing patients to derive maximum benefits from these medications, requires adequate clinical attention and further research.
Single-Cell RNA-Seq Reveals Dynamic, Random Monoallelic Gene Expression in Mammalian Cells

Expressing One Allele at a Time Although genetic traits are often dominant or recessive, the impact of the same heterozygous genotype can vary quite a bit between individuals. Deng et al. (p. 193), analyzed global gene expression in hundreds of individual mouse cells and found that a substantial fraction of the genes only expressed one of the alleles, chosen randomly, at any given point in time. Such stochasticity in transcription increases the heterogeneity among cells and likely contributes to the phenotypic variance among individuals of identical genotype. Independent allelic transcription generates fluctuations in the single-cell transcriptome. Expression from both alleles is generally observed in analyses of diploid cell populations, but studies addressing allelic expression patterns genome-wide in single cells are lacking. Here, we present global analyses of allelic expression across individual cells of mouse preimplantation embryos of mixed background (CAST/EiJ × C57BL/6J). We discovered abundant (12 to 24%) monoallelic expression of autosomal genes and that expression of the two alleles occurs independently. The monoallelic expression appeared random and dynamic because there was considerable variation among closely related embryonic cells. Similar patterns of monoallelic expression were observed in mature cells. Our allelic expression analysis also demonstrates the de novo inactivation of the paternal X chromosome. We conclude that independent and stochastic allelic transcription generates abundant random monoallelic expression in the mammalian cell.
Pediatric Gliomatosis Cerebri: A Review of 15 Years

Gliomatosis cerebri is a rare glial tumor that carries a poor prognosis. Seen in both adults and children, gliomatosis cerebri appears to differ in these populations as with adult versus pediatric glioblastoma. We present 10 children who either presented to the Weill Cornell Medical College or enrolled in the institution’s Gliomatosis Cerebri International Registry alongside a cohort of 89 pediatric patients reported in the literature between 2000 and 2014. Age ranged from 4 months to 21 years, with a male to female ratio of 1.71. Median overall survival for patients in the registry cohort was 17 months (n = 10) and for the historic cohort was 13 months (n = 52). Overall survival was analyzed for the combined cohort and was significantly longer when presenting at age ≥10 (20 vs 10 months), for boys (18 vs 11 months), and with low-grade pathology (26.5 vs 12 months) but did not vary significantly by treatment approach.