Bimodal Remapping of Visual Grids

Spatially modulated neurons from the rat secondary visual cortex (V2) show grid-like firing patterns during freely foraging in open-field enclosures. However, the remapping of the V2 grid cells is not well understood. Here we report two classes of V2 grid cell populations with distinct remapping properties: one regular class with invariant grid field patterns, and the other bimodal class that has remapping induced by environmental manipulations such as changes in enclosure shape, size, orientation and lighting in a familiar environment. The bimodal V2 grid cell pattern remains stable regardless of the follow-up manipulations, but restores to the original firing pattern upon animal's re-entry into the familiar environment on the next day or from the novel environment. The bimodal V2 grid cells are modulated with theta frequency during the course of remapping and stabilize quickly. We also found conjunctive bistable V2 grid cells with invariant head directional tuning. Overall, our results suggest a new grid cell mechanism in V2 that is different from the medial entorhinal cortex (MEC) grid cells.

Grid Cells Lose Coherence in Realistic Environments

Spatial cognition in naturalistic environments, for freely moving animals, may pose quite different constraints from that studied in artificial laboratory settings. Hippocampal place cells indeed look quite different, but almost nothing is known about entorhinal cortex grid cells, in the wild. Simulating our self-organizing adaptation model of grid cell pattern formation, we consider a virtual rat randomly exploring a virtual burrow, with feedforward connectivity from place to grid units and recurrent connectivity between grid units. The virtual burrow was based on those observed by John B. Calhoun, including several chambers and tunnels. Our results indicate that lateral connectivity between grid units may enhance their “gridness” within a limited strength range, but the overall effect of the irregular geometry is to disable long-range and obstruct short-range order. What appears as a smooth continuous attractor in a flat box, kept rigid by recurrent connections, turns into an incoherent motley of unit clusters, flexible or outright unstable.

Interplay between Hepatitis E Virus and Host Cell Pattern Recognition Receptors

Hepatitis E virus (HEV) usually causes self-limiting acute hepatitis, but the disease can become chronic in immunocompromised individuals. HEV infection in pregnant women is reported to cause up to 30% mortality, especially in the third trimester. Additionally, extrahepatic manifestations like neuronal and renal diseases and pancreatitis are also reported during the course of HEV infection. The mechanism of HEV pathogenesis remains poorly understood. Innate immunity is the first line of defense triggered within minutes to hours after the first pathogenic insult. Growing evidence based on reverse genetics systems, in vitro cell culture models, and representative studies in animal models including non-human primates, has implicated the role of the host’s innate immune response during HEV infection. HEV persists in presence of interferons (IFNs) plausibly by evading cellular antiviral defense. This review summarizes our current understanding of recognizing HEV-associated molecular patterns by host cell Pattern Recognition Receptors (PRRs) in eliciting innate immune response during HEV infection as well as mechanisms of virus-mediated immune evasion.

Detecting the Mechanism behind the Transition from Fixed Two-Dimensional Patterned Sika Deer (Cervus nippon) Dermal Papilla Cells to Three-Dimensional Pattern

The hair follicle dermal papilla is critical for hair generation and de novo regeneration. When cultured in vitro, dermal papilla cells from different species demonstrate two distinguishable growth patterns under the conventional culture condition: a self-aggregative three dimensional spheroidal (3D) cell pattern and a two dimensional (2D) monolayer cell pattern, correlating with different hair inducing properties. Whether the loss of self-aggregative behavior relates to species-specific differences or the improper culture condition remains unclear. Can the fixed 2D patterned dermal papilla cells recover the self-aggregative behavior and 3D pattern also remains undetected. Here, we successfully constructed the two growth patterns using sika deer (Cervus nippon) dermal papilla cells and proved it was the culture condition that determined the dermal papilla growth pattern. The two growth patterns could transit mutually as the culture condition was exchanged. The fixed 2D patterned sika deer dermal papilla cells could recover the self-aggregative behavior and transit back to 3D pattern, accompanied by the restoration of hair inducing capability when the culture condition was changed. In addition, the global gene expressions during the transition from 2D pattern to 3D pattern were compared to detect the potential regulating genes and pathways involved in the recovery of 3D pattern and hair inducing capability.

Genetic Alterations in Invasive Breast Carcinoma with a Glycogen-Rich Clear Cell Pattern: A Case Report

Invasive carcinoma with a glycogen-rich clear cell pattern (IC-GRCCP) is a rare and understudied subtype of invasive breast carcinoma of no special type (IBC-NST). Here we report the molecular characteristics of a mammary IC-GRCCP diagnosed in a 69-year-old woman. Next-generation sequencing of the tumor revealed an inv(1)(p36.12,q32.1) leading to loss-of-function of ARID1A gene, a MAP2K4 truncating mutation (p.E376), MYC amplification, a variant of uncertain significance of PTPRB gene (p.D1848N) and deep deletions of NCKAP5, CCNT2, MAP3K19, LRP1B, and KMT2A. The analysis of the involved pathways shows close resemblance to the ovarian clear cell carcinoma and indicates similarities in the molecular mechanisms of development of glycogen-rich clear cell carcinomas in different organs. Our findings and the literature review suggest new potential strategies for treatment of mammary IC-GRCCP, including epigenetic therapies, checkpoint inhibitors, radiation, or other double-strand DNA breaks-inducing agents. Nevertheless, larger studies are needed to substantiate those ideas.

A unified mechanism for the control of Drosophila wing growth by the morphogens Decapentaplegic and Wingless

Development of the Drosophila wing—a paradigm of organ development—is governed by 2 morphogens, Decapentaplegic (Dpp, a BMP) and Wingless (Wg, a Wnt). Both proteins are produced by defined subpopulations of cells and spread outwards, forming gradients that control gene expression and cell pattern as a function of concentration. They also control growth, but how is unknown. Most studies have focused on Dpp and yielded disparate models in which cells throughout the wing grow at similar rates in response to the grade or temporal change in Dpp concentration or to the different amounts of Dpp “equalized” by molecular or mechanical feedbacks. In contrast, a model for Wg posits that growth is governed by a progressive expansion in morphogen range, via a mechanism in which a minimum threshold of Wg sustains the growth of cells within the wing and recruits surrounding “pre-wing” cells to grow and enter the wing. This mechanism depends on the capacity of Wg to fuel the autoregulation of vestigial (vg)—the selector gene that specifies the wing state—both to sustain vg expression in wing cells and by a feed-forward (FF) circuit of Fat (Ft)/Dachsous (Ds) protocadherin signaling to induce vg expression in neighboring pre-wing cells. Here, we have subjected Dpp to the same experimental tests used to elucidate the Wg model and find that it behaves indistinguishably. Hence, we posit that both morphogens act together, via a common mechanism, to control wing growth as a function of morphogen range.

A hybrid feature selection on AIRS method for identifying breast cancer diseases

Breast cancer may cause a death due to the late diagnosis. A cheap and accurate tool for early detection of this disease is essential to prevent fatal incidence. In general, the cheap and less invasive method to diagnose the disease could be done by biopsy using fine needle aspirates from breast tissue. However, rapid and accurate identification of the cancer cell pattern from the cell biopsy is still challenging task. This diagnostic tool can be developed using machine learning as a classification problem. The performance of the classifier depends on the interrelationship between sample sizes, some features, and classifier complexity. Thus, the removal of some irrelevant features may increase classification accuracy. In this study, a new hybrid feature selection fast correlation based feature (FCBF) and information gain (IG) was used to select features on identifying breast cancer using AIRS algorithm. The results of 10 times the crossing (CF) of our validation on various AIRS seeds indicate that the proposed method can achieve the best performance with accuracy =0.9797 and AUC=0.9777 at k=6 and seed=50.

Stability of Viscous Flow in a Curved Porous Channel with Radial Flow

In this paper, we present a linear hydrodynamic stability analysis of the fluid, flowing in a porous curved channel. The motion is due to Pressure gradient acting round the curved channel and an imposed radial flow. The analytical solution of the eigen value problem is obtained by using the Galerkin’s method, for the wide gap case. Results for critical wave number and Dean Number are obtained and are compared with earlier result. The agreement is very good. Also, the stability curve, amplitude of the radial velocity and the cell-pattern are shown on graphs. The results show that the flow is strongly stabilized by an outward radial flow and weakly stabilized by a strong inward radial flow, while it is destabilized by a weak inward radial flow. In presence of outward flow, wide gap systems show stronger stability than the small gap system.

A natural DNMT1 mutation elevates the fetal hemoglobin via epigenetic de-repression of γ-globin gene in β-thalassemia

DNA methyltransferase 1 (DNMT1) is a major epigenetic regulator of the formation of large macromolecular complexes that repress human γ-globin expression by maintaining DNA methylation. However, very little is known about the association of DNMT1 variants with β-thalassemia phenotypes. We systematically investigated associations between variants in DNMT1 and phenotypes in 1,142 β-thalassemia subjects and identified a novel missense mutation (c.2633G>A, S878F) in the bromo-adjacent homology-1 (BAH1) domain of DNMT1. We functionally characterized this mutation in CD34+ cells from patientsand engineered HuDEP-2 mutant cells. Our results demonstrate that DNMT1 phosphorylation is abrogated by substitution of serine with phenylalanine at position 878, resulting in lower stability and loss of catalytic activity. S878F mutation also attenuated the interactions of DNMT1 with BCL11A, GATA1 and HDAC1/2 and reduced the recruitment of DNMT1 to the HBG promoters, leading to epigenetic de-repression of γ-globin expression. By analyzing the F-cell pattern, we demonstrated that the effect of DNMT1 mutation on increased fetal hemoglobin (HbF) is heterocellular. Furthermore, introduction of S878F mutation into erythroid cells by CRISPR-Cas9 recapitulated γ-globin reactivation. Thus, the natural S878F DNMT1 mutation is a novel modulator of HbF synthesis and represents a potential new therapeutic target for β-hemoglobinopathies.