Bacterial chemotaxis without gradient-sensing

Models for chemotaxis are based on gradient sensing of individual organisms. The key contribution of Keller and Segel is showing that erratic movements of individuals may result in an accurate chemotaxis phenomenon as a group. In this paper we provide another option to understand chemotactic behavior when individuals do not sense the gradient of chemical concentration by any means. We show that, if individuals increase their motility to find food when they are hungry, an accurate chemotactic behavior may obtained without sensing the gradient. Such a random dispersal has been suggested by Cho and Kim and is called starvation driven diffusion. This model is surprisingly similar to the original derivation of Keller-Segel model. A comprehensive picture of traveling band and front solutions is provided with numerical simulations.Comment: 19 pages, 4 figure

Impaired DNA-binding affinity of novel PAX6 mutations

Mutations in human PAX6 gene are associated with various congenital eye malformations including aniridia, foveal hypoplasia, and congenital nystagmus. These various phenotypes may depend on the mutation spectrums that can affect DNA-binding affinity, although this hypothesis is debatable. We screened PAX6 mutations in two unrelated patients with congenital nystagmus, and measured DNA-binding affinity through isothermal titration calorimetry (ITC). To elucidate phenotypic differences according to DNA-binding affinity, we also compared DNA-binding affinity among the previously reported PAX6 missense mutations within the linker region between two subdomains of the paired domain (PD). We identified two novel mutations of PAX6 gene: c.214G >T (p.Gly72Cys) and c.249_250delinsCGC (p.Val84Alafs*8). Both were located within the linker region between the two subdomains of the PD. ITC measurement revealed that the mutation p.Val84Alafs*8 had no DNA-binding affinity, while the p.Gly72Cys mutation showed a decreased binding affinity (Kd = 0.58 mu M) by approximately 1.4 times compared to the wild type-PAX6 (Kd = 0.41 mu M). We also found that there was no close relationship between DNA-binding affinity and phenotypic differences. Our results suggest that the DNA-binding affinity alone might be insufficient to determine PAX6-related phenotypes, and that other modifier genes or environmental factors might affect phenotypes of the PAX6 gene

Genotype and Phenotype Spectrum of FRMD7-Associated Infantile Nystagmus Syndrome

PURPOSE. We investigate the genotype and phenotype spectrum of FRMD7-associated infantile nystagmus syndrome in Korean probands. METHODS. A total of 37 patients with infantile nystagmus syndrome were recruited prospectively for genetic analysis. We performed polymerase chain reaction (PCR)-based direct sequencing and haplotype analysis for FRMD7. Detailed ophthalmic examinations and eye movement recordings were compared between FRMD7 and non-FRMD7 groups. RESULTS. In 13 (35%) of 37 patients, five different mutations of FRMD7 were detected: start codon mutation c.1A>G, splice site mutation c.162thorn6T>C, and three missense mutations (c.575A>C, c.722A>G, and c.875T>C). The latter mutation was identified in seven unrelated patients, and always was accompanied with two single nucleotide polymorphisms of exon 12 (rs6637934, rs5977623). Compared to non-FRMD7 groups, a cup-to-disc ratio was significantly decreased in FRMD7 groups (P < 0.001), and a disc-macula distance to disc diameter ratio markedly increased in the FRMD7 group (P = 0.015). Most patients in the FRMD7 group had at least two types of the nystagmus waveforms, and the most common type was unidirectional jerk nystagmus (75%), such as pure jerk and jerk with extended foveation, followed by pendular (25%), bidirectional jerk (19%), and dual jerk (6%) nystagmus. No significant differences were observed between FRMD7 and non-FRMD7 groups in terms of the nystagmus waveform, presence of periodic alternating nystagmus, and mean foveation time. CONCLUSIONS. We identified five FRMD7 mutations in 35% of our infantile nystagmus syndrome cohort, expanding its mutational spectrum. The missense mutation c.875T>C may be a common mutation arisen from the founder effect in Korea. Optic nerve dysplasia associated with FRMD7 mutations suggests that the abnormal development of afferent visual systems may affect neural circuitry within the oculomotor syste

Structural basis for inhibition of the replication licensing factor Cdt1 by geminin

To maintain chromosome stability in eukaryotic cells, replication origins must be licensed by loading mini-chromosome maintenance (MCM2-7) complexes once and only once per cell cycle. This licensing control is achieved through the activities of geminin and cyclin-dependent kinases. Geminin binds tightly to Cdt1, an essential component of the replication licensing system, and prevents the inappropriate reinitiation of replication on an already fired origin. The inhibitory effect of geminin is thought to prevent the interaction between Cdt1 and the MCM helicase. Here we describe the crystal structure of the mouse geminin-Cdt1 complex using tGeminin (residues 79-157, truncated geminin) and tCdt1 (residues 172-368, truncated Cdt1). The amino-terminal region of a coiled-coil dimer of tGeminin interacts with both N-terminal and carboxy-terminal parts of tCdt1. The primary interface relies on the steric complementarity between the tGeminin dimer and the hydrophobic face of the two short N-terminal helices of tCdt1 and, in particular, Pro 181, Ala 182, Tyr 183, Phe 186 and Leu 189. The crystal structure, in conjunction with our biochemical data, indicates that the N-terminal region of tGeminin might be required to anchor tCdt1, and the C-terminal region of tGeminin prevents access of the MCM complex to tCdt1 through steric hindrance.close847

Application of Deep Reinforcement Learning to Dynamic Verification of DRAM Designs

This paper presents a deep neural network based test vector generation method for dynamic verification of memory devices. The proposed method is built on reinforcement learning framework, where the action is input stimulus on device pins and the reward is coverage score of target circuitry. The developed agent efficiently explores high-dimensional and large action space by using policy gradient method with ??-nearest neighbor search, transfer learning, and replay buffer. The generated test vectors attained the coverage score of 100% for fifteen representative circuit blocks of modern DRAM design. The output vector length was only 7% of the human-created vector length

Augmented ERAD (ER-associated degradation) activity in chondrocytes is necessary for cartilage development and maintenance

Chondrocytes secrete massive extracellular matrix (ECM) molecules that are produced, folded, and modified in the endoplasmic reticulum (ER). Thus, the ER-associated degradation (ERAD) complex???which removes misfolded and unfolded proteins to maintain proteostasis in the ER??? plays an indispensable role in building and maintaining cartilage. Here, we examined the necessity of the ERAD complex in chondrocytes for cartilage formation and maintenance. We show that ERAD gene expression is exponentially increased during chondrogenesis, and disruption of ERAD function causes severe chondrodysplasia in developing embryos and loss of adult articular cartilage. ERAD complex malfunction also causes abnormal accumulation of cartilage ECM molecules and subsequent chondrodysplasia. ERAD gene expression is decreased in damaged cartilage from patients with osteoarthritis (OA), and disruption of ERAD function in articular cartilage leads to cartilage destruction in a mouse OA model

Ubiquitous Detection of Gram-Positive Bacteria with Bioorthogonal Magnetofluorescent Nanoparticles

The ability to rapidly diagnose gram-positive pathogenic bacteria would have far reaching biomedical and technological applications. Here we describe the bioorthogonal modification of small molecule antibiotics (vancomycin and daptomycin), which bind to the cell wall of gram-positive bacteria. The bound antibiotics conjugates can be reacted orthogonally with tetrazine-modified nanoparticles, <i>via</i> an almost instantaneous cycloaddition, which subsequently renders the bacteria detectable by optical or magnetic sensing. We show that this approach is specific, selective, fast and biocompatible. Furthermore, it can be adapted to the detection of intracellular pathogens. Importantly, this strategy enables detection of entire classes of bacteria, a feat that is difficult to achieve using current antibody approaches. Compared to covalent nanoparticle conjugates, our bioorthogonal method demonstrated 1–2 orders of magnitude greater sensitivity. This bioorthogonal labeling method could ultimately be applied to a variety of other small molecules with specificity for infectious pathogens, enabling their detection and diagnosis

Improvement of the Symmetry and Linearity of Synaptic Weight Update by Combining the InGaZnO Synaptic Transistor and Memristor

Obtaining symmetrical and highly linear synapse weight update characteristics of analog resistive switching devices is critical for attaining high performance and energy efficiency of the neural network system. In this work, based on the two-terminal one transistor-one memristor (1T1M) block, the improvement of the symmetry and linearity of synaptic weight update is demonstrated by combining the InGaZnO synaptic transistor and memristor. Due to the symmetric and linear weight update characteristic, a pattern recognition accuracy of 88&#x0025; is achieved after 50 epochs in the on-chip learning simulation of the hand-written digit images (MNIST) data set. The proposed 1T1M device saves the hardware burden and additional power consumption required to implement non-identical programming pulses