Dysfunction of cortical GABAergic neurons leads to sensory hyper-reactivity in a Shank3 mouse model of ASD.

Hyper-reactivity to sensory input is a common and debilitating symptom in individuals with autism spectrum disorders (ASD), but the neural basis underlying sensory abnormality is not completely understood. Here we examined the neural representations of sensory perception in the neocortex of a Shank3B-/- mouse model of ASD. Male and female Shank3B-/- mice were more sensitive to relatively weak tactile stimulation in a vibrissa motion detection task. In vivo population calcium imaging in vibrissa primary somatosensory cortex (vS1) revealed increased spontaneous and stimulus-evoked firing in pyramidal neurons but reduced activity in interneurons. Preferential deletion of Shank3 in vS1 inhibitory interneurons led to pyramidal neuron hyperactivity and increased stimulus sensitivity in the vibrissa motion detection task. These findings provide evidence that cortical GABAergic interneuron dysfunction plays a key role in sensory hyper-reactivity in a Shank3 mouse model of ASD and identify a potential cellular target for exploring therapeutic interventions

Multiple recent horizontal transfers of the cox1 intron in Solanaceae and extended co-conversion of flanking exons

Background: The most frequent case of horizontal transfer in plants involves a group I intron in the mitochondrial gene cox1, which has been acquired via some 80 separate plant-to-plant transfer events among 833 diverse angiosperms examined. This homing intron encodes an endonuclease thought to promote the intron´s promiscuous behavior. A promising experimental approach to study endonuclease activity and intron transmission involves somatic cell hybridization, which in plants leads to mitochondrial fusion and genome recombination. However, the cox1 intron has not yet been found in the ideal group for plant somatic genetics - the Solanaceae. We therefore undertook an extensive survey of this family to find members with the intron and to learn more about the evolutionary history of this exceptionally mobile genetic element. Results: Although 409 of the 426 species of Solanaceae examined lack the cox1 intron, it is uniformly present in three phylogenetically disjunct clades. Despite strong overall incongruence of cox1 intron phylogeny with angiosperm phylogeny, two of these clades possess nearly identical intron sequences and are monophyletic in intron phylogeny. These two clades, and possibly the third also, contain a co-conversion tract (CCT) downstream of the intron that is extended relative to all previously recognized CCTs in angiosperm cox1. Re-examination of all published cox1 genes uncovered additional cases of extended co-conversion and identified a rare case of putative intron loss, accompanied by full retention of the CCT. Conclusions: We infer that the cox1 intron was separately and recently acquired by at least three different lineages of Solanaceae. The striking identity of the intron and CCT from two of these lineages suggests that one of these three intron captures may have occurred by a within-family transfer event. This is consistent with previous evidence that horizontal transfer in plants is biased towards phylogenetically local events. The discovery of extended co-conversion suggests that other cox1 conversions may be longer than realized but obscured by the exceptional conservation of plant mitochondrial sequences. Our findings provide further support for the rampant-transfer model of cox1 intron evolution and recommend the Solanaceae as a model system for the experimental analysis of cox1 intron transfer in plants.Fil: Sánchez Puerta, María Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; ArgentinaFil: Abbona, Cinthia Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Biología Agrícola de Mendoza. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias. Instituto de Biología Agrícola de Mendoza; ArgentinaFil: Zhuo, Shi. Indiana University; Estados UnidosFil: Tepe, Eric J.. University of Cincinnati; Estados Unidos. University of Utah; Estados UnidosFil: Bohs, Lynn. University of Utah; Estados UnidosFil: Olmstead, Richard G.. University of Washington; Estados UnidosFil: Palmer, Jeffrey D.. Indiana University; Estados Unido

Dosage Compensation of the X Chromosomes in Bovine Germline, Early Embryos, and Somatic Tissues

Dosage compensation of the mammalian X chromosome (X) was proposed by Susumu Ohno as a mechanism wherein the inactivation of one X in females would lead to doubling the expression of the other. This would resolve the dosage imbalance between eutherian females (XX) versus male (XY) and between a single active X versus autosome pairs (A). Expression ratio of X- and A-linked genes has been relatively well studied in humans and mice, despite controversial results over the existence of upregulation of X-linked genes. Here we report the first comprehensive test of Ohno’s hypothesis in bovine preattachment embryos, germline, and somatic tissues. Overall an incomplete dosage compensation (0.5 \u3c X:A \u3c 1) of expressed genes and an excess X dosage compensation (X:A \u3e 1) of ubiquitously expressed “dosage-sensitive” genes were seen. No significant differences in X:A ratios were observed between bovine female and male somatic tissues, further supporting Ohno’s hypothesis. Interestingly, preimplantation embryos manifested a unique pattern of X dosage compensation dynamics. Specifically, X dosage decreased after fertilization, indicating that the sperm brings in an inactive X to the matured oocyte. Subsequently, the activation of the bovine embryonic genome enhanced expression of X-linked genes and increased the X dosage. As a result, an excess compensation was exhibited from the 8-cell stage to the compact morula stage. The X dosage peaked at the 16-cell stage and stabilized after the blastocyst stage. Together, our findings confirm Ohno’s hypothesis of X dosage compensation in the bovine and extend it by showing incomplete and over-compensation for expressed and “dosage-sensitive” genes, respectively

Mandibulofacial Dysostosis Attributed to a Recessive Mutation of CYP26C1 in Hereford Cattle

In spring 2020, six Hereford calves presented with congenital facial deformities attributed to a condition we termed mandibulofacial dysostosis (MD). Affected calves shared hallmark features of a variably shortened and/or asymmetric lower mandible and bilateral skin tags present 2–10 cm caudal to the commissure of the lips. Pedigree analysis revealed a single common ancestor shared by the sire and dam of each affected calf. Whole-genome sequencing (WGS) of 20 animals led to the discovery of a variant (Chr26 g. 14404993T\u3eC) in Exon 3 of CYP26C1 associated with MD. This missense mutation (p.L188P), is located in an α helix of the protein, which the identified amino acid substitution is predicted to break. The implication of this mutation was further validated through genotyping 2 additional affected calves, 760 other Herefords, and by evaluation of available WGS data from over 2500 other individuals. Only the a_ected individuals were homozygous for the variant and all heterozygotes had at least one pedigree tie to the suspect founder. CYP26C1 plays a vital role in tissue-specific regulation of retinoic acid (RA) during embryonic development. Dysregulation of RA can result in teratogenesis by altering the endothelin-1 signaling pathway affecting the expression of Dlx genes, critical to mandibulofacial development. We postulate that this recessive missense mutation in CYP26C1 impacts the catalytic activity of the encoded enzyme, leading to excess RA resulting in the observed MD phenotype

Accelerometry-Based Digital Gait Characteristics for Classification of Parkinson's Disease: What Counts?

Objective: Gait may be a useful biomarker that can be objectively measured with wearable technology to classify Parkinson's disease (PD). This study aims to: (i) comprehensively quantify a battery of commonly utilized gait digital characteristics (spatiotemporal and signal-based), and (ii) identify the best discriminative characteristics for the optimal classification of PD. Methods: Six partial least square discriminant analysis (PLS-DA) models were trained on subsets of 210 characteristics measured in 142 subjects (81 people with PD, 61 controls (CL)). Results: Models accuracy ranged between 70.42-88.73% (AUC: 78.4-94.5%) with a sensitivity of 72.84-90.12% and a specificity of 60.3-86.89%. Signal-based digital gait characteristics independently gave 87.32% accuracy. The most influential characteristics in the classification models were related to root mean square values, power spectral density, step velocity and length, gait regularity and age. Conclusions: This study highlights the importance of signal-based gait characteristics in the development of tools to help classify PD in the early stages of the disease

Steady state particle swarm

The following grant information was disclosed by the authors: Fundação para a Ciência e Tecnologia (FCT), Research Fellowship: SFRH/BPD/66876/2009. FCT PROJECT: UID/EEA/50009/2013. EPHEMECH: TIN2014-56494-C4-3-P, Spanish Ministry of Economy and Competitivity. PROY-PP2015-06: Plan Propio 2015 UGR. CEI2015-MP-V17 of the Microprojects program 2015 from CEI BioTIC Granada.This paper investigates the performance and scalability of a new update strategy for the particle swarm optimization (PSO) algorithm. The strategy is inspired by the Bak–Sneppen model of co-evolution between interacting species, which is basically a network of fitness values (representing species) that change over time according to a simple rule: the least fit species and its neighbors are iteratively replaced with random values. Following these guidelines, a steady state and dynamic update strategy for PSO algorithms is proposed: only the least fit particle and its neighbors are updated and evaluated in each time-step; the remaining particles maintain the same position and fitness, unless they meet the update criterion. The steady state PSO was tested on a set of unimodal, multimodal, noisy and rotated benchmark functions, significantly improving the quality of results and convergence speed of the standard PSOs and more sophisticated PSOs with dynamic parameters and neighborhood. A sensitivity analysis of the parameters confirms the performance enhancement with different parameter settings and scalability tests show that the algorithm behavior is consistent throughout a substantial range of solution vector dimensions.This work was supported by Fundação para a Ciência e Tecnologia (FCT) Research Fellowship SFRH/BPD/66876/2009 and FCT Project (UID/EEA/50009/2013), EPHEMECH (TIN2014-56494-C4-3-P, Spanish Ministry of Economy and Competitivity), PROY-PP2015-06 (Plan Propio 2015 UGR), project CEI2015-MP-V17 of the Microprojects program 2015 from CEI BioTIC Granada

Elucidating the role of ferrous ion cocatalyst in enhancing dilute acid pretreatment of lignocellulosic biomass

<p>Abstract</p> <p>Background</p> <p>Recently developed iron cocatalyst enhancement of dilute acid pretreatment of biomass is a promising approach for enhancing sugar release from recalcitrant lignocellulosic biomass. However, very little is known about the underlying mechanisms of this enhancement. In the current study, our aim was to identify several essential factors that contribute to ferrous ion-enhanced efficiency during dilute acid pretreatment of biomass and to initiate the investigation of the mechanisms that result in this enhancement.</p> <p>Results</p> <p>During dilute acid and ferrous ion cocatalyst pretreatments, we observed concomitant increases in solubilized sugars in the hydrolysate and reducing sugars in the (insoluble) biomass residues. We also observed enhancements in sugar release during subsequent enzymatic saccharification of iron cocatalyst-pretreated biomass. Fourier transform Raman spectroscopy showed that major peaks representing the C-O-C and C-H bonds in cellulose are significantly attenuated by iron cocatalyst pretreatment. Imaging using Prussian blue staining indicated that Fe²⁺ions associate with both cellulose/xylan and lignin in untreated as well as dilute acid/Fe²⁺ion-pretreated corn stover samples. Analyses by scanning electron microscopy and transmission electron microscopy revealed structural details of biomass after dilute acid/Fe²⁺ion pretreatment, in which delamination and fibrillation of the cell wall were observed.</p> <p>Conclusions</p> <p>By using this multimodal approach, we have revealed that (1) acid-ferrous ion-assisted pretreatment increases solubilization and enzymatic digestion of both cellulose and xylan to monomers and (2) this pretreatment likely targets multiple chemistries in plant cell wall polymer networks, including those represented by the C-O-C and C-H bonds in cellulose.</p

Investigation of the Spin Density Wave in NaxCoO2

Magnetic susceptibility, transport and heat capacity measurements of single crystal NaxCoO2 (x=0.71) are reported. A transition to a spin density wave (SDW) state at Tmag = 22 K is observable in all measurements, except chi(ac) data in which a cusp is observed at 4 K and attributed to a low temperature glassy phase. M(H) loops are hysteretic below 15 K. Both the SDW transition and low temperature hysteresis are only visible along the c-axis. The system also exhibits a substantial (~40%) positive magnetoresistance below this temperature. Calculations of the electronic heat capacity gamma above and below Tmag and the size of the jump in C indicate that the onset of the SDW brings about the opening of gap and the removal of part of the Fermi surface. Reduced in-plane electron-electron scattering counteracts the loss of carriers below the transition and as a result we see a net reduction in resistivity below Tmag. Sodium ordering transitions at higher temperatures are observable as peaks in the heat capacity with a corresponding increase in resistivity.Comment: 14 pages, 6 figure

Particle Motion Around Tachyon Monopole

Recently, Li and Liu have studied global monoole of tachyon in a four dimensional static space-time. We analyze the motion of massless and massive particles around tachyon monopole. Interestingly, for the bending of light rays due to tachyon monopole instead of getting angle of deficit we find angle of surplus. Also we find that the tachyon monopole exerts an attractive gravitational force towards matter.Comment: 14 pages, 7 figure

Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells

TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2?/? mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2?/? tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2?/? Lin?c-Kit+ cells shows higher mutation frequencies in Tet2?/? cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis