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Octonionic representation of O(9, 1) with special emphasis placed on the analytic properties of octonionic functions is investigated.

Age and estrogens may impact the mobility of N-methyl-D-aspartate receptors (NMDARs) in hippocampal synapses. Here, we used serial section immunogold electron microscopy to examine whether phosphorylated tyrosine 1472 NR2B (pY1472), which is involved in the surface expression of NMDARs, is altered in the dorsal hippocampus of young (3-4 months old) and aged ( similar to 24 months old) ovariectomized rats treated with 17 beta-estradiol or vehicle for 2 days. The number of gold particles labeling pY1472 was higher in presynaptic and postsynaptic compartments of aged rats with low estradiol (vehicle-treated) compared to other groups. In terminals, pY1472 levels were elevated in aged rats but reduced by estradiol treatment to levels seen in young rats. Conversely, the mitochondria number was lower in aged females but was restored to young levels by estradiol. In the postsynaptic density and dendritic spines, estradiol reduced pY1472 in young and aged rats. As phosphorylation at Y1472 blocks NR2B endocytosis, reduction of pY1472 by estradiol suggests another mechanism through which estrogen enhances synaptic plasticity by altering localization of NMDAR subunits within synapses. (C) 2018 Elsevier Inc. All rights reserved.

The 11-subunit eukaryotic replicative helicase CMG (Cdc45, Mcm2-7, GINS) tightly binds Mcm10, an essential replication protein in all eukaryotes. Here we show that Mcm10 has a potent strand-annealing activity both alone and in complex with CMG. CMG-Mcm10 unwinds and then reanneals single strands soon after they have been unwound in vitro. Given the DNA damage and replisome instability associated with loss of Mcm10 function, we examined the effect of Mcm10 on fork regression. Fork regression requires the unwinding and pairing of newly synthesized strands, performed by a specialized class of ATP-dependent DNA translocases. We show here that Mcm10 inhibits fork regression by the well-known fork reversal enzyme SMARCAL1. We propose that Mcm10 inhibits the unwinding of nascent strands to prevent fork regression at normal unperturbed replication forks, either by binding the fork junction to form a block to SMARCAL1 or by reannealing unwound nascent strands to their parental template. Analysis of the CMG-Mcm10 complex by cross-linking mass spectrometry reveals Mcm10 interacts with six CMG subunits, with the DNA-binding region of Mcm10 on the N-face of CMG. This position on CMG places Mcm10 at the fork junction, consistent with a role in regulating fork regression.

N-6-methyladenosine (m(6)A) is the most prevalent internal methylation in messenger RNA (mRNA). This biochemically reversible modification is deposited by m(6)A methyltransferases, removed by m(6)A demethylases and recognized by different RNA-binding proteins. Depending on the localization of m(6)A and its reader proteins, an array of cellular processes ranging from RNA maturation and export in nucleus, to degradation and translation in cytoplasm, can be affected and consequently lead to diverse cell fates. The essential role of m(6)A in normal tissue development as well as tumor progression has been revealed in the past few years, emphasizing an additional layer of gene expression regulation.

Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. We identified two ADAMTS9 mutations (c.4575_4576de1 [p.Gln1525Hisfs*60] and c.194C>G [p.Thr65Arg]) that appear to cause NPHP-RC. Although ADAMTS9 is known to be a secreted extracellular metalloproteinase, we found that ADAMTS9 localized near the basal bodies of primary cilia in the cytoplasm. Heterologously expressed wild-type ADAMTS9, in contrast to mutant proteins detected in individuals with NPHP-RC, localized to the vicinity of the basal body. Loss of ADAMTS9 resulted in shortened cilia and defective sonic hedgehog signaling. Knockout of Adamts9 in IMCD3 cells, followed by spheroid induction, resulted in defective lumen formation, which was rescued by an overexpression of wild-type, but not of mutant, ADAMTS9. Knockdown of adamts9 in zebrafish recapitulated NPHP-RC phenotypes, including renal cysts and hydrocephalus. These findings suggest that the identified mutations in ADAMTS9 cause NPHP-RC and that ADAMTS9 is required for the formation and function of primary cilia.

Conditional knockout (KO) mouse models are invaluable for elucidating the physiological roles of platelets. The Platelet factor 4-Cre recombinase (Pf4-Cre) transgenic mouse is the current model of choice for generating megakaryocyte/platelet-specific KO mice. Platelets and leukocytes work closely together in a wide range of disease settings, yet the specific contribution of platelets to these processes remains unclear. This is partially a result of the Pf4-Cre transgene being expressed in a variety of leukocyte populations. To overcome this issue, we developed a Gp1ba-Cre transgenic mouse strain in which Cre expression is driven by the endogenous Gp1ba locus. By crossing Gp1ba-Cre and Pf4-Cre mice to the mT/mG dual-fluorescence reporter mouse and performing a head-to-head comparison, we demonstrate more stringent megakaryocyte lineage-specific expression of the Gp1ba-Cre transgene. Broader tissue expression was observed with the Pf4-Cre transgene, leading to recombination in many hematopoietic lineages, including monocytes, macrophages, granulocytes, and dendritic and B and T cells. Direct comparison of phenotypes of Csk, Shp1, or CD148 conditional KO mice generated using either the Gp1ba-Cre or Pf4-Cre strains revealed similar platelet phenotypes. However, additional inflammatory and immunological anomalies were observed in Pf4-Cre-generated KO mice as a result of nonspecific deletion in other hematopoietic lineages. By excluding leukocyte contributions to phenotypes, the Gp1ba-Cre mousewill advance our understanding of the role of platelets in inflammation and other pathophysiological processes in which platelet-leukocyte interactions are involved.

In November 2017, a formal debate on the role of bacteria in the pathogenesis of hidradenitis suppurativa (HS) was held at the 2nd Symposium on Hidradenitis Suppurativa Advances (SHSA) in Detroit, Michigan. In this report, we present both sides of the argument as debated at the SHSA meeting and then discuss the potential role of bacteria as classic infectious pathogens versus an alternative pathogenic role as activators of dysregulated commensal bacterial-host interactions. Although there was consensus that bacteria play a role in pathogenesis and thus are pathogenic, there was a compelling discussion about whether bacteria in HS incite an infectious disease as we classically understand it or whether bacteria might play a different role in HS pathogenesis.

The 2nd Annual Symposium on Hidradenitis Suppurativa Advances (SHSA) took place on 03-05 November 2017 in Detroit, Michigan, USA. This symposium was a joint meeting of the Hidradenitis Suppurativa Foundation (HSF Inc.) founded in the USA, and the Canadian Hidradenitis Suppurativa Foundation (CHSF). This was the second annual meeting of the SHSA with experts from different disciplines arriving from North America, Europe and Australia, in a joint aim to discuss most recent innovations, practical challenges and potential solutions to issues related in the management and care of Hidradenitis Suppurativa patients. The last session involved clinicians, patients and their families in an effort to educate them more about the disease.

Interest in the nonlinear properties of multi-mode optical waveguides has seen a recent resurgence on account of the large dimensionality afforded by the platform. The large volume of modes in these waveguides provides a new spatial degree of freedom for phase matching nonlinear optical processes. However, this spatial dimension is quantized, which narrows the conversion bandwidths of intermodal processes and constrains spectral and temporal tailoring of the light. Here we show that by engineering the relative group velocity within the spatial dimension, we can tailor the phase-matching bandwidth of intermodal parametric nonlinearities. We demonstrate group-velocity-tailored parametric nonlinear mixing between higher-order modes in a multi-mode fiber with gain bandwidths that are more than an order of magnitude larger than that previously thought possible for intermodal four-wave mixing. As evidence of the technological utility of this methodology, we seed this process to generate the first high-peak-power wavelength-tunable all-fiber quasi-CW laser in the Ti:sapphire wavelength regime. More generally, with the combination of intermodal interactions, which dramatically expand the phase-matching degrees of freedom for nonlinear optics, and intermodal group-velocity engineering, which enables tailoring of the bandwidth of such interactions, we showcase a platform for nonlinear optics that can be broadband while being wavelength agnostic. (C) 2018 Chinese Laser Press