Miracle-dz/UniFAR-FTUs huggingface dataset:
A Case Study for Effects of Operational Taxonomic Units from Intracellular Endoparasites and Ciliates on the Eukaryotic Phylogeny: Phylogenetic Position of the Haptophyta in Analyses of Multiple Slowly Evolving Genes

Recent multigene phylogenetic analyses have contributed much to our understanding of eukaryotic phylogeny. However, the phylogenetic positions of various lineages within the eukaryotes have remained unresolved or in conflict between different phylogenetic studies. These phylogenetic ambiguities might have resulted from mixtures or integration from various factors including limited taxon sampling, missing data in the alignment, saturations of rapidly evolving genes, mixed analyses of short- and long-branched operational taxonomic units (OTUs), intracellular endoparasite and ciliate OTUs with unusual substitution etc. In order to evaluate the effects from intracellular endoparasite and ciliate OTUs co-analyzed on the eukaryotic phylogeny and simplify the results, we here used two different sets of data matrices of multiple slowly evolving genes with small amounts of missing data and examined the phylogenetic position of the secondary photosynthetic chromalveolates Haptophyta, one of the most abundant groups of oceanic phytoplankton and significant primary producers. In both sets, a robust sister relationship between Haptophyta and SAR (stramenopiles, alveolates, rhizarians, or SA [stramenopiles and alveolates]) was resolved when intracellular endoparasite/ciliate OTUs were excluded, but not in their presence. Based on comparisons of character optimizations on a fixed tree (with a clade composed of haptophytes and SAR or SA), disruption of the monophyly between haptophytes and SAR (or SA) in the presence of intracellular endoparasite/ciliate OTUs can be considered to be a result of multiple evolutionary reversals of character positions that supported the synapomorphy of the haptophyte and SAR (or SA) clade in the absence of intracellular endoparasite/ciliate OTUs.
Novel insights into SMALED2: BICD2 mutations increase microtubule stability and cause defects in axonal and NMJ development

Bicaudal D2 (BICD2) encodes a highly conserved motor adaptor protein that regulates the dynein-dynactin complex in different cellular processes. Heterozygous mutations in BICD2 cause autosomal dominant lower extremity-predominant spinal muscular atrophy-2 (SMALED2). Although, various BICD2 mutations have been shown to alter interactions with different binding partners or the integrity of the Golgi apparatus, the specific pathological effects of BICD2 mutations underlying SMALED2 remain elusive. Here, we show that the fibroblasts derived from individuals with SMALED2 exhibit stable microtubules. Importantly, this effect was observed regardless of where the BICD2 mutation is located, which unifies the most likely cellular mechanism affecting microtubules. Significantly, overexpression of SMALED2-causing BICD2 mutations in the disease-relevant cell type, motor neurons, also results in an increased microtubule stability which is accompanied by axonal aberrations such as collateral branching and overgrowth. To study the pathological consequences of BICD2 mutations in vivo, and to address the controversial debate whether two of these mutations are neuron or muscle specific, we generated the first Drosophila model of SMALED2. Strikingly, neuron-specific expression of BICD2 mutants resulted in reduced neuromuscular junction size in larvae and impaired locomotion of adult flies. In contrast, expressing BICD2 mutations in muscles had no obvious effect on motor function, supporting a primarily neurological etiology of the disease. Thus, our findings contribute to the better understanding of SMALED2 pathology by providing evidence for a common pathomechanism of BICD2 mutations that increase microtubule stability in motor neurons leading to increased axonal branching and to impaired neuromuscular junction development.
Protein kinase A determines platelet life span and survival by regulating apoptosis

Apoptosis delimits platelet life span in the circulation and leads to storage lesion, which severely limits the shelf life of stored platelets. Moreover, accumulating evidence indicates that platelet apoptosis provoked by various pathological stimuli results in thrombocytopenia in many common diseases. However, little is known about how platelet apoptosis is initiated or regulated. Here, we show that PKA activity is markedly reduced in platelets aged in vitro, stored platelets, and platelets from patients with immune thrombocytopenia (ITP), diabetes, and bacterial infections. Inhibition or genetic ablation of PKA provoked intrinsic programmed platelet apoptosis in vitro and rapid platelet clearance in vivo. PKA inhibition resulted in dephosphorylation of the proapoptotic protein BAD at Ser155, resulting in sequestration of prosurvival protein BCL-XL in mitochondria and subsequent apoptosis. Notably, PKA activation protected platelets from apoptosis induced by storage or pathological stimuli and elevated peripheral platelet levels in normal mice and in a murine model of ITP. Therefore, these findings identify PKA as a homeostatic regulator of platelet apoptosis that determines platelet life span and survival. Furthermore, these results suggest that regulation of PKA activity represents a promising strategy for extending platelet shelf life and has profound implications for the treatment of platelet number-related diseases and disorders.
COCONUT SHELL AS PARTIAL REPLACEMENT OF COARSE AGGREGATE

The rising cost of construction material is a matter of concern. The reason for increase in cost is high demand of concrete and scarcity of raw material. Hence the concrete technologists must search for some economical alternative to the coarse aggregate. In this study, M 20 grade of concrete was produced by replacing granite by coconut shell. Forty five cubes were casted and their compressive strength and densities were evaluated at 7, 14 and 28 days. The density and compressive strength of concrete reduced as the percentage replacement increased. Concrete produced by 2.5%, 5%, 7.5%, 10% replacement attained 28 days compressive strength of 19.71,19.53,19.08,18.91 respectively. These results showed that Coconut shell concrete can be used in reinforced concrete construction. Its utilization is cost effective and eco friendly
Combined use of protein biomarkers and network analysis unveils deregulated regulatory circuits in Duchenne muscular dystrophy

Although the genetic basis of Duchenne muscular dystrophy has been known for almost thirty years, the cellular and molecular mechanisms characterizing the disease are not completely understood and an efficacious treatment remains to be developed. In this study we analyzed proteomics data obtained with the SomaLogic technology from blood serum of a cohort of patients and matched healthy subjects. We developed a workflow based on biomarker identification and network-based pathway analysis that allowed us to describe different deregulated pathways. In addition to muscle-related functions, we identified other biological processes such as apoptosis, signaling in the immune system and neurotrophin signaling as significantly modulated in patients compared with controls. Moreover, our network-based analysis identified the involvement of FoxO transcription factors as putative regulators of different pathways. On the whole, this study provided a global view of the molecular processes involved in Duchenne muscular dystrophy that are decipherable from serum proteome.
Identification of potential therapeutic targets in prostate cancer through a cross‐species approach

Genetically engineered mouse models of cancer can be used to filter genome‐wide expression datasets generated from human tumours and to identify gene expression alterations that are functionally important to cancer development and progression. In this study, we have generated RNAseq data from tumours arising in two established mouse models of prostate cancer, PB‐Cre/PtenloxP/loxP and p53loxP/loxPRbloxP/loxP, and integrated this with published human prostate cancer expression data to pinpoint cancer‐associated gene expression changes that are conserved between the two species. To identify potential therapeutic targets, we then filtered this information for genes that are either known or predicted to be druggable. Using this approach, we revealed a functional role for the kinase MELK as a driver and potential therapeutic target in prostate cancer. We found that MELK expression was required for cell survival, affected the expression of genes associated with prostate cancer progression and was associated with biochemical recurrence.
Preferences for Very Low and Very High Voice Pitch in Humans

Manipulations of voice pitch have been shown to alter attractiveness ratings, but whether preferences extend to very low or very high voice pitch is unknown. Here, we manipulated voice pitch in averaged men's and women's voices by 2 Hz intervals to create a range of male and female voices speaking monopthong vowel sounds and spanning a range of frequencies from normal to very low and very high pitch. With these voices, we used the method of constant stimuli to measure preferences for voice. Nineteen university students (ages: 20–25) participated in three experiments. On average, men preferred high-pitched women's voices to low-pitched women's voices across all frequencies tested. On average, women preferred men's voices lowered in pitch, but did not prefer very low men's voices. The results of this study may reflect selection pressures for men's and women's voices, and shed light on a perceptual link between voice pitch and vocal attractiveness.
Textured insoles reduce vertical loading rate and increase subjective plantar sensation in overground running

Abstract The effect of textured insoles on kinetics and kinematics of overground running was assessed. 16 male injury-free-recreational runners attended a single visit (age 23 ± 5 yrs; stature 1.78 ± 0.06 m; mass 72.6 ± 9.2 kg). Overground 15-m runs were completed in flat, canvas plimsolls both with and without textured insoles at self-selected velocity on an indoor track in an order that was balanced among participants. Average vertical loading rate and peak vertical force (Fpeak) were captured by force platforms. Video footage was digitised for sagittal plane hip, knee and ankle angles at foot strike and mid stance. Velocity, stride rate and length and contact and flight time were determined. Subjectively rated plantar sensation was recorded by visual scale. 95% confidence intervals estimated mean differences. Smallest worthwhile change in loading rate was defined as standardised reduction of 0.54 from a previous comparison of injured versus non-injured runners. Loading rate decreased (−25 to −9.3 BW s−1; 60% likely beneficial reduction) and plantar sensation was increased (46–58 mm) with the insole. Fpeak (−0.1 to 0.14 BW) and velocity (−0.02 to 0.06 m s−1) were similar. Stride length, flight and contact time were lower (−0.13 to −0.01 m; −0.02 to−0.01 s; −0.016 to −0.006 s) and stride rate was higher (0.01–0.07 steps s−1) with insoles. Textured insoles elicited an acute, meaningful decrease in vertical loading rate in short distance, overground running and were associated with subjectively increased plantar sensation. Reduced vertical loading rate could be explained by altered stride characteristics.
The Ghosts in the Computer: The Role of Agency and Animacy Attributions in “Ghost Controls”

Three studies evaluated the role of 4-year-old children's agency- and animacy-attributions when learning from a computerized ghost control (GC). In GCs, participants observe events occurring without an apparent agent, as if executed by a “ghost” or unobserved causal forces. Using a touch-screen, children in Experiment 1 responded to three pictures in a specific order under three learning conditions: (i) trial-and-error (Baseline), (ii) imitation and (iii) Ghost Control. Before testing in the GC, children were read one of three scripts that determined agency attributions. Post-test assessments confirmed that all children attributed agency to the computer and learned in all GCs. In Experiment 2, children were not trained on the computer prior to testing, and no scripts were used. Three different GCs, varying in number of agency cues, were used. Children failed to learn in these GCs, yet attributed agency and animacy to the computer. Experiment 3 evaluated whether children could learn from a human model in the absence of training under conditions where the information presented by the model and the computer was either consistent or inconsistent. Children evidenced learning in both of these conditions. Overall, learning in social conditions (Exp. 3) was significantly better than learning in GCs (Exp. 2). These results, together with other published research, suggest that children privilege social over non-social sources of information and are generally more adept at learning novel tasks from a human than from a computer or GC.
The use of BRAF V600E mutation‐specific immunohistochemistry in pediatric Langerhans cell histiocytosis

BRAF p.V600E mutations are detected in greater than 50% of pediatric Langerhans cell histiocytosis (LCH) lesions. However, the use of mutation‐specific BRAF V600E immunohistochemistry (IHC) as a surrogate for molecular testing in pediatric LCH is unknown. We tested the mutation‐specific BRAF V600E monoclonal antibody (clone VE1) in formalin‐fixed, paraffin‐embedded LCH samples from 26 pediatric patients (14 males and 12 females, ages 7 mo–17 y) using allele‐specific real‐time polymerase chain reaction (PCR) with a limit of detection of 0.5% as the comparative gold standard. BRAF VE1 staining was scored for both intensity (0‐3+) and percentage of immunoreactive tumor cells (0%‐100%). BRAF VE1 immunoreactivity was determined using both lenient (≥1+, ≥1%) and stringent (≥2+, ≥10%) scoring criteria. Using lenient‐scoring criteria, we found that the sensitivity and specificity of IHC compared with allele‐specific real‐time PCR were 100.0% and 18.2%, respectively. The poor specificity of lenient IHC analysis was attributable to weak, 1+ staining in both BRAF‐mutated and wild‐type LCH. Using stringent‐scoring criteria, we found that specificity improved to 100.0% at the expense of sensitivity that decreased to 80.0%. Stringent scoring generated 3 false‐negative results, but in all cases, neoplastic tissue comprised less than 5% of the stained section and/or the specimen was decalcified. In conclusion, highly sensitive molecular assays remain the gold standard for BRAF mutation analysis in LCH paraffin‐embedded lesions. To avoid false‐positive results, unequivocal VE1 staining of 2+ intensity in greater than or equal to 10% neoplastic histiocytes is required. However, negative VE1 results require additional studies to exclude false‐negatives, and stringent‐scoring criteria may not be optimal for scant or decalcified specimens.
S-sulfocysteine/NMDA receptor–dependent signaling underlies neurodegeneration in molybdenum cofactor deficiency

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive inborn error of metabolism characterized by neurodegeneration and death in early childhood. The rapid and progressive neurodegeneration in MoCD presents a major clinical challenge and may relate to the poor understanding of the molecular mechanisms involved. Recently, we reported that treating patients with cyclic pyranopterin monophosphate (cPMP) is a successful therapy for a subset of infants with MoCD and prevents irreversible brain damage. Here, we studied S-sulfocysteine (SSC), a structural analog of glutamate that accumulates in the plasma and urine of patients with MoCD, and demonstrated that it acts as an N-methyl D-aspartate receptor (NMDA-R) agonist, leading to calcium influx and downstream cell signaling events and neurotoxicity. SSC treatment activated the protease calpain, and calpain-dependent degradation of the inhibitory synaptic protein gephyrin subsequently exacerbated SSC-mediated excitotoxicity and promoted loss of GABAergic synapses. Pharmacological blockade of NMDA-R, calcium influx, or calpain activity abolished SSC and glutamate neurotoxicity in primary murine neurons. Finally, the NMDA-R antagonist memantine was protective against the manifestation of symptoms in a tungstate-induced MoCD mouse model. These findings demonstrate that SSC drives excitotoxic neurodegeneration in MoCD and introduce NMDA-R antagonists as potential therapeutics for this fatal disease.
Expression of Multiple Artificial MicroRNAs from a Chicken miRNA126-Based Lentiviral Vector

Background The use of RNAi in both basic and translational research often requires expression of multiple siRNAs from the same vector. Methods/Principal Findings We have developed a novel chicken miR126-based artificial miRNA expression system that can express one, two or three miRNAs from a single cassette in a lentiviral vector. We show that each of the miRNAs expressed from the same lentiviral vector is capable of potent inhibition of reporter gene expression in transient transfection and stable integration assays in chicken fibroblast DF-1 cells. Transduction of Vero cells with lentivirus expressing two or three different anti-influenza miRNAs leads to inhibition of influenza virus production. In addition, the chicken miR126-based expression system effectively inhibits reporter gene expression in human, monkey, dog and mouse cells. These results demonstrate that the flanking regions of a single primary miRNA can support processing of three different stem-loops in a single vector. Conclusions/Significance This novel design expands the means to express multiple miRNAs from the same vector for potent and effective silencing of target genes and influenza virus.
Developments in control systems for rotary left ventricular assist devices for heart failure patients: a review

From the moment of creation to the moment of death, the heart works tirelessly to circulate blood, being a critical organ to sustain life. As a non-stopping pumping machine, it operates continuously to pump blood through our bodies to supply all cells with oxygen and necessary nutrients. When the heart fails, the supplement of blood to the body's organs to meet metabolic demands will deteriorate. The treatment of the participating causes is the ideal approach to treat heart failure (HF). As this often cannot be done effectively, the medical management of HF is a difficult challenge. Implantable rotary blood pumps (IRBPs) have the potential to become a viable long-term treatment option for bridging to heart transplantation or destination therapy. This increases the potential for the patients to leave the hospital and resume normal lives. Control of IRBPs is one of the most important design goals in providing long-term alternative treatment for HF patients. Over the years, many control algorithms including invasive and non-invasive techniques have been developed in the hope of physiologically and adaptively controlling left ventricular assist devices and thus avoiding such undesired pumping states as left ventricular collapse caused by suction. In this paper, we aim to provide a comprehensive review of the developments of control systems and techniques that have been applied to control IRBPs.
Pulmonary vascular effect of insulin in a rodent model of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is associated with metabolic derangements including insulin resistance, although their effects on the cardiopulmonary disease are unclear. We hypothesized that insulin resistance promotes pulmonary hypertension (PH) development and mutations in type 2 bone morphogenetic protein receptor (BMPR2) cause cellular insulin resistance. Using a BMPR2 transgenic murine model of PAH and two models of inducible diabetes mellitus, we explored the impact of hyperglycemia and/or hyperinsulinemia on development and severity of PH. We assessed insulin signaling and insulin-mediated glucose uptake in human endothelial cells with and without mutations in BMPR2. PH developed in control mice fed a Western diet and PH in BMPR2 mutant mice was increased by Western diet. Pulmonary artery pressure correlated strongly with fasting plasma insulin but not glucose. Reactive oxygen species were increased in lungs of insulin-resistant animals. BMPR2 mutation impaired insulin-mediated endothelial glucose uptake via reduced glucose transporter translocation despite intact insulin signaling. Experimental hyperinsulinemia is strongly associated with PH in both control and BMPR2-mutant mice, though to a greater degree in those with BMPR2 mutation. Human pulmonary endothelial cells with BMPR2 mutation have evidence of reduced glucose uptake due to impaired glucose transporter translocation. These experiments support a role for hyperinsulinemia in pulmonary vascular disease.
Evaluation of the chromosome 2q37.3 gene CENTG2 as an autism susceptibility gene

Autism is a highly heritable neurodevelopmental syndrome with a complex genetic etiology for which no disease genes have yet been definitively identified. We ascertained three subjects with autism spectrum disorders and chromosome 2q37.3 terminal deletions, and refined the deletion breakpoint regions using polymorphism mapping and fluorescence in situ hybridization (FISH) probes. We then genotyped polymorphic markers downstream from the breakpoint region in a sample of autism affected sibling pair families. Both the chromosomal breakpoints and linkage analyses focused our attention on the gene centaurin gamma‐2 (CENTG2), an attractive candidate gene based also on its function and pattern of expression. We therefore assessed CENTG2 for its involvement in autism by (1) screening its exons for variants in 199 autistic and 160 non‐autistic individuals, and (2) genotyping and assessing intra‐genic polymorphisms for linkage and linkage disequilibrium (LD). The exon screen revealed a Ser → Gly substitution in one proband, an Arg → Gly substitution in another, and a number of additional variants unique to the autism families. No unique variants were found in the control subjects. The genotyping produced strong evidence for linkage from two intronic polymorphisms, with a maximum two‐point HLOD value of 3.96 and a posterior probability of linkage (PPL) of 51%. These results were contradicted, however, by substantially weaker evidence for linkage from multi‐point analyses and by no evidence of LD. We conclude, therefore, that 2q37.3 continues to be a region of interest for autism susceptibility, and that CENTG2 is an intriguing candidate gene that merits further scrutiny for its role in autism. © 2005 Wiley‐Liss, Inc.
Intervention With the Mother–Infant Relationship Reduces Cell Proliferation in the Locus Coeruleus of Female Rat Pups

The Locus Coeruleus (LC) is a noradrenergic nucleus involved in several neuroendocrine and behavioral functions. During the neonatal period, the LC is critical for olfactory learning. Full development occurs during the early postnatal period. Environmental interventions after birth may affect neurogenesis. In rats, the neonatal handling procedure has been used as a model to analyze the effects of environmental intervention early in life. It has been related to several long-lasting behavioral and neuroendocrine changes. The present study analyzed the effects of handling on the number of neurons, cellular proliferation, and apoptosis in the LC of 11-day-old female rats. Wistar rat pups were submitted to brief maternal separation followed by handling (1 min per day from postnatal day [PND] 1 to 10). On PND 11, the LC was analyzed using immunohistochemistry for NeuN and BrdU, TUNEL staining, and electron microscopy. The intervention reduced the number of neurons in the LC but showed no significant change in the number of apoptotic cells, as measured by the TUNEL technique. However, the number of proliferating cells was significantly lower in the handled rat pups as compared with the nonhandled ones. This study demonstrates that the infant LC is sensitive to changes in maternal behavior. A seemingly mild environmental intervention during the neonatal period may reprogram the development of the LC, altering cell proliferation.