Recurrent deletions of ULK4 in schizophrenia : a gene crucial for neuritogenesis and neuronal motility

Peer reviewedPublisher PD

The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination.

Background: Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of axonal regrowth and remyelination. More recently, they have also been highlighted as a modulator of macrophage infiltration into the central nervous system in experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. Methods: We interrogated results from single nucleotide polymorphisms (SNPs) lying in or close to genes regulating CSPG metabolism in the summary results from two publicly available systematic studies of multiple sclerosis (MS) genetics. A demyelinating injury model in the spinal cord of exostosin-like 2 (EXTL2)-/- mice was used to investigate the effects of dysregulation of EXTL2 on remyelination. Cell cultures of bone marrow-derived macrophages and primary oligodendrocyte precursor cells and neurons were supplemented with purified CSPGs or conditioned media to assess potential mechanisms of action. Results: The strongest evidence for genetic association was seen for SNPs mapping to the region containing the glycosyltransferase exostosin-like 2 (EXTL2), an enzyme that normally suppresses CSPG biosynthesis. Six of these SNPs showed genomewide significant evidence for association in one of the studies with concordant and nominally significant effects in the second study. We then went on to show that a demyelinating injury to the spinal cord of EXTL2-/- mice resulted in excessive deposition of CSPGs in the lesion area. EXTL2-/- mice had exacerbated axonal damage and myelin disruption relative to wildtype mice, and increased representation of microglia/macrophages within lesions. In tissue culture, activated bone marrow derived macrophages from EXTL2-/- mice overproduce tumor necrosis factor α (TNFα) and matrix metalloproteinases (MMPs). Conclusions: These results emphasize CSPGs as a prominent modulator of neuroinflammation and they highlight CSPGs accumulating in lesions in promoting axonal injury.Canadian Institutes of Health Sciences Alberta/Novartis Translational Research Fund Multiple Sclerosis Society of Canad

MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma

<p>Abstract</p> <p>Background</p> <p>MiR-221 and miR-222 (miR-221/222) are frequently up-regulated in various types of human malignancy including glioblastoma. Recent studies have reported that miR-221/222 regulate cell growth and cell cycle progression by targeting p27 and p57. However the underlying mechanism involved in cell survival modulation of miR-221/222 remains elusive.</p> <p>Results</p> <p>Here we showed that miR-221/222 inhibited cell apoptosis by targeting pro-apoptotic gene PUMA in human glioma cells. Enforced expression of miR-22/222 induced cell survival whereas knockdown of miR-221/222 rendered cells to apoptosis. Further, miR-221/222 reduced PUMA protein levels by targeting PUMA-3'UTR. Introducing PUMA cDNA without 3'UTR abrogated miR-221/222-induced cell survival. Notably, knockdown of miR-221/222 induces PUMA expression and cell apoptosis and considerably decreases tumor growth in xenograft model. Finally, there was an inverse relationship between PUMA and miR-221/222 expression in glioma tissues.</p> <p>Conclusion</p> <p>To our knowledge, these data indicate for the first time that miR-221/222 directly regulate apoptosis by targeting PUMA in glioblastoma and that miR-221/222 could be potential therapeutic targets for glioblastoma intervention.</p

A simulation study on the measurement of D0-D0bar mixing parameter y at BES-III

We established a method on measuring the \dzdzb mixing parameter $y$ for BESIII experiment at the BEPCII $e^+e^-$ collider. In this method, the doubly tagged $\psi(3770) \to D^0 \overline{D^0}$ events, with one $D$ decays to CP-eigenstates and the other $D$ decays semileptonically, are used to reconstruct the signals. Since this analysis requires good $e/\pi$ separation, a likelihood approach, which combines the $dE/dx$, time of flight and the electromagnetic shower detectors information, is used for particle identification. We estimate the sensitivity of the measurement of $y$ to be 0.007 based on a $20fb^{-1}$ fully simulated MC sample.Comment: 6 pages, 7 figure

The glycosyltransferase EXTL2 promotes proteoglycan deposition and injurious neuroinflammation following demyelination

Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024Abstract: Background: Chondroitin sulfate proteoglycans (CSPGs) are potent inhibitors of axonal regrowth and remyelination. More recently, they have also been highlighted as a modulator of macrophage infiltration into the central nervous system in experimental autoimmune encephalomyelitis, an inflammatory model of multiple sclerosis. Methods: We interrogated results from single nucleotide polymorphisms (SNPs) lying in or close to genes regulating CSPG metabolism in the summary results from two publicly available systematic studies of multiple sclerosis (MS) genetics. A demyelinating injury model in the spinal cord of exostosin-like 2 deficient (EXTL2-/-) mice was used to investigate the effects of dysregulation of EXTL2 on remyelination. Cell cultures of bone marrow-derived macrophages and primary oligodendrocyte precursor cells and neurons were supplemented with purified CSPGs or conditioned media to assess potential mechanisms of action. Results: The strongest evidence for genetic association was seen for SNPs mapping to the region containing the glycosyltransferase exostosin-like 2 (EXTL2), an enzyme that normally suppresses CSPG biosynthesis. Six of these SNPs showed genome-wide significant evidence for association in one of the studies with concordant and nominally significant effects in the second study. We then went on to show that a demyelinating injury to the spinal cord of EXTL2−/− mice resulted in excessive deposition of CSPGs in the lesion area. EXTL2−/− mice had exacerbated axonal damage and myelin disruption relative to wild-type mice, and increased representation of microglia/macrophages within lesions. In tissue culture, activated bone marrow-derived macrophages from EXTL2−/− mice overproduce tumor necrosis factor α (TNFα) and matrix metalloproteinases (MMPs). Conclusions: These results emphasize CSPGs as a prominent modulator of neuroinflammation and they highlight CSPGs accumulating in lesions in promoting axonal injury

An emerging PB2-627 polymorphism increases the pandemic potential of avian influenza virus by breaking through ANP32 host restriction in mammalian and avian hosts

Alterations in the PB2-627 domain could substantially increase the risk of an avian influenza virus (AIV) pandemic. So far, a well-known mammalian mutation PB2-E627K has not been maintained in AIV in poultry, which limits the spread of AIVs from avian to humans. Here, we discovered a variant, PB2-627V, which combines the properties of avian-like PB2-627E and human-like PB2-627K, overcoming host restrictions and posing a risk for human pandemics. Specifically, by screening the global PB2 sequences, we discovered a new independent cluster with PB2-627V emerged in the 2010s, which is prevalent in various avian, mammalian, and human isolates of AIVs, including H9N2, H7N9, H3N8, 2.3.4.4b H5N1, and other subtypes. And, the increasing prevalence of PB2-627V in poultry is accompanied by a rise in human infection cases with this variant. Then we systematically assessed its host adaptation, fitness, and transmissibility across three subtypes of AIVs (H9N2, H7N9, and H3N8) in different host models, including avian and human cells, chickens, mice, and ferrets where infections naturally occur. We found that PB2-627V facilitates AIVs to efficiently infect and replicate in chickens and mice by utilizing both avian- and human-origin ANP32A proteins. Importantly, and like PB2-627K, PB2-627V promotes efficient transmission between ferrets through respiratory droplets. Deep sequencing in passaged chicken samples and transmitted ferret samples indicates that PB2-627V remains stable across the two distinct hosts and has a high potential for long-term prevalence in avian species. Therefore, the mutation has the ability to continue spreading among poultry and can also overcome the barrier between birds and humans, greatly enhancing the likelihood of AIVs infecting humans. Given the escalating global spread of AIVs, it is crucial to closely monitor influenza viruses carrying PB2-627V to prevent a pandemic

Identification of TMPRSS3

Hereditary hearing loss is characterized by a high degree of genetic heterogeneity. Mutations in the TMPRSS3 (transmembrane protease, serine 3) gene cause prelingual (DFNB10) or postlingual (DFNB8) deafness. In our previous study, three pathogenic mutations in TMPRSS3 were identified in one Chinese family. To evaluate the importance of TMPRSS3 mutations in recessive deafness among the Chinese, we screened 150 autosomal recessive nonsyndromic hearing loss (ARNSHL) families and identified 6 that carried seven causative TMPRSS3 mutations, including five novel mutations (c.809T>A, c.1151T>G, c.1204G>A, c.1244T>C, and c.1250G>A) and two previously reported mutations (c.323-6G>A and c.916G>A). Each of the five novel mutations was classified as severe, by both age of onset and severity of hearing loss. Together with our previous study, six families were found to share one pathogenic mutation (c.916G>A, p.Ala306Thr). To determine whether this mutation arose from a common ancestor, we analyzed six short tandem repeat (STR) markers spanning the TMPRSS3 gene. In four families, we observed linkage disequilibrium between p.Ala306Thr and STR markers. Our results indicate that mutations in TMPRSS3 account for about 4.6% (7/151) of Chinese ARNSHL cases lacking mutations in SLC26A4 or GJB2 and that the recurrent TMPRSS3 mutation p.Ala306Thr is likely to be a founder mutation

Overexpression and Small Molecule-Triggered Downregulation of CIP2A in Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide, with a five-year overall survival rate of only 15%. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies. However, whether CIP2A can be a new drug target for lung cancer is largely unclear.Normal and malignant lung tissues were derived from 60 lung cancer patients from southern China. RT-PCR, Western blotting and immunohistochemistry were used to evaluate the expression of CIP2A. We found that among the 60 patients, CIP2A was undetectable or very low in paratumor normal tissues, but was dramatically elevated in tumor samples in 38 (63.3%) patients. CIP2A overexpression was associated with cigarette smoking. Silencing CIP2A by siRNA inhibited the proliferation and clonogenic activity of lung cancer cells. Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down-regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells.Our findings strongly indicate that CIP2A could be an effective target for lung cancer drug development, and the therapeutic potentials of CIP2A-targeting agents warrant further investigation