Cdk5rap2 Interacts with Pericentrin to Maintain the Neural Progenitor Pool in the Developing Neocortex

Primary autosomal-recessive microcephaly (MCPH) and Majewski osteodysplastic primordial dwarfism type II (MOPDII) are both genetic diseases that result in decreased brain size at birth. MCPH is thought to arise from alterations in the size of the neural progenitor pool, but the cause of this defect has not been thoroughly explored. We find that one of the genes associated with MCPH, Cdk5rap2, is highly expressed in the neural progenitor pool and that its loss results in a depletion of apical progenitors and increased cell-cycle exit leading to premature neuronal differentiation. We link Cdk5rap2 function to the pericentriolar material protein pericentrin, loss of function of which is associated with MOPDII. Depletion of pericentrin in neural progenitors phenocopies effects of Cdk5rap2 knockdown and results in decreased recruitment of Cdk5rap2 to the centrosome. Our findings uncover a common mechanism, involving aberrations in the neurogenesis program, that may underlie the development of microcephaly in multiple diseases.National Institutes of Health (U.S.) (grant NS37007)Howard Hughes Medical Institute (Investigator

From Luzon Strait to Dongsha Plateau: Stages in the Life of an Internal Wave

Tidal currents in Luzon Strait south of Taiwan generate some of the largest internal waves anywhere in the ocean. Recent collaborative efforts between oceanographers from the United States and Taiwan explored the generation, evolution, and characteristics of these waves from their formation in the strait to their scattering and dissipation on Dongsha Plateau and the continental slope of mainland China. Nonlinear internal waves affect offshore engineering, navigation, biological productivity, and sediment resuspension. Observations within Luzon Strait identified exceptionally large vertical excursions of density (as expressed primarily in temperature profiles) and intense turbulence as tidal currents interact with submarine ridges. In the northern part of the strait, the ridge spacing is close to the internal semidiurnal tidal wavelength, allowing wave generation at both ridges to contribute to amplification of the internal tide. Westward radiation of semidiurnal internal tidal energy is predominant in the north, diurnal energy in the south. The competing effects of nonlinearity, which tends to steepen the stratification, and rotational dispersion, which tends to disperse energy into inertial waves, transform waves traveling across the deep basin of the South China Sea. Rotation inhibits steepening, especially for the internal diurnal tide, but despite the rotational effect, the semidiurnal tide steepens sufficiently so that nonhydrostatic effects become important, leading to the formation of a nonlinear internal wave train. As the waves encounter the continental slope and Dongsha Plateau, they slow down, steepen further, and are modified and scattered into extended wave trains. At this stage, the waves can “break,” forming trapped cores. They have the potential to trap prey, which may account for their attraction to pilot whales, which are often seen following the waves as they advance toward the coast. Interesting problems remain to be explored and are the subjects of continuing investigations

Simultaneous Penile Gangrene and Testicular Infarction Secondary to Calciphylaxis in a Uremic Patient

We report here a 46-year-old man with end stage renal disease (ESRD) secondary to type 2 diabetes, who had been on hemodialysis for 5 years. He had a painful glans lesion for 1 week. Five days later, he also complained of right testicular pain. Computed tomography of the pelvis demonstrated calcification of both penile arteries. Scrotal sonography revealed right testicular infarction. He received partial penectomy and right orchiectomy because of progressive lesions and intractable pain. Pathologic examination revealed testicular and penile tissue with necrotizing inflammation accompanied by multifocal calcification in the tunica media, compatible with calciphylaxis. This is the first report to document simultaneous penile gangrene and testicular infarction secondary to calciphylaxis

SERPINE2, an inhibitor of plasminogen activators, is highly expressed in the human endometrium during the secretory phase

<p>Abstract</p> <p>Background</p> <p>SERPINE2, also known as protease nexin-1, belongs to the serine protease inhibitor (SERPIN) superfamily. It is one of the potent SERPINs that modulates the activity of plasminogen activators (PAs). PAs and their SERPIN inhibitors, such as SERPINB2 and SERPINE1, were expressed in the human endometrium and were implicated in implantation. However, expression data about SERPINE2 in the human endometrium is still unknown. Thus, we conducted an investigation to reveal the spatiotemporal and cellular expression of SERPINE2 in the human uterus during the menstrual cycle.</p> <p>Methods</p> <p>Seven patients who underwent a hysterectomy and samples of 120 archived patients' endometrial curettage or parts of the uterus that were formalin-fixed and embedded in paraffin. Western blotting was performed to evaluate the specificity and sensitivity of the antibody. Immunohistochemistry was conducted to localize the SERPINE2 expression site. Quantitative analysis was conducted to evaluate expression levels of SERPINE2 in various sub-phases of the menstrual cycle.</p> <p>Results</p> <p>The SERPINE2 protein was primarily detected in the uterine fluid during the mid- and late-secretory phases of the menstrual cycle. It was predominantly expressed in the luminal and glandular epithelium, less in the myometrium, and only dispersedly in certain stromal cells throughout the menstrual cycle. A quantitative analysis of expression levels of SERPINE2 in the glandular epithelium revealed that it was highly expressed in the endometrium during the secretory phase compared to the proliferative phase.</p> <p>Conclusions</p> <p>The SERPINE2 protein is highly expressed in the endometrium during the secretory phase, indicating that it may participate in tissue remodeling involved in implantation.</p

APP processing is regulated by cytoplasmic phosphorylation

Amyloid-β peptide (Aβ) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the β-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by α-secretase. The production of Aβ is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Aβ generation

Impact of cognitive behavior therapy on osteoarthritis-associated pain, insomnia, depression, fatigue, and physical function in patients with knee/hip osteoarthritis: A systematic review and meta-analysis of randomized controlled trials

BackgroundThis meta-analysis aimed at evaluating the efficacy of cognitive behavior therapy (CBT) against osteoarthritis-associated symptoms in patients with knee/hip osteoarthritis.MethodsMedline, PubMed, Cochrane Library, and EMBASE databases were searched from inception to July 2022 to identify randomized controlled trials (RCTs) comparing the efficacy of CBT with other treatment approaches in adults with confirmed knee/hip osteoarthritis. The pain intensity (primary outcome) and the secondary outcomes including insomnia severity, sleep efficiency, physical function as well as the severity of depression and fatigue were assessed at two time points (i.e., immediately after treatment and during the follow-up period). The effect size is expressed as standardized mean difference (SMD) with SMDs of &lt; 0.2, 0.2–0.5, and 0.5–0.8, and &gt; 0.8 representing negligible, small, medium, and large effect sizes, respectively.ResultsFifteen RCTs were included for analysis. Immediately after CBT intervention, meta-analysis showed similar treatment effect in pain severity [SMD = –0.46, 95% confidence interval (CI): –0.95 to 0.04, 11 studies, 1557 participants] and other symptoms including depression (SMD = –0.26, 95% CI: –0.58 to 0.06, five studies, 735 participants), fatigue (SMD = –2.44, 95% CI:–6.53 to 1.65, two RCTs, 511 participants), and physical function (SMD = –0.11, 95% CI:–0.25 to 0.02, five RCTs, 720 participants) between CBT and control groups, while there was an improvement in insomnia severity (SMD = –0.65, 95% CI: –1.06 to –0.24, four RCTs, 639 participants, medium treatment effect) and sleep efficiency (SMD = 0.32, 95% CI: 0.04 to 0.59, three RCTs, 352 patients, small treatment effect). During follow-up, CBT improved pain severity (SMD = –0.52, 95% CI: –1.03 to –0.01, eight studies, 1447 participants, medium treatment effect), insomnia (SMD = –0.43, 95% CI: –0.85 to –0.01, three RCTs, 571 participants, small treatment effect), and depression (SMD = –0.39, 95% CI: –0.59 to –0.18, four RCTs, 791 participants, small treatment effect). Nevertheless, sleep efficiency, fatigue, and physical function were not improved in the follow-up period.ConclusionOur results may suggest the durability of CBT-associated treatment benefits, supporting its role as a potential promising alternative or complementary intervention for patients with knee/hip osteoarthritis, especially against pain and insomnia. Future large-scale investigations are warranted to verify our findings.Systematic review registration[https://www.crd.york.ac.uk/prospero/], identifier [CRD42022331165]

HDAC2 Negatively Regulates Memory Formation and Synaptic Plasticity

Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment

Emerged HA and NA Mutants of the Pandemic Influenza H1N1 Viruses with Increasing Epidemiological Significance in Taipei and Kaohsiung, Taiwan, 2009–10

The 2009 influenza pandemic provided an opportunity to observe dynamic changes of the hemagglutinin (HA) and neuraminidase (NA) of pH1N1 strains that spread in two metropolitan areas -Taipei and Kaohsiung. We observed cumulative increases of amino acid substitutions of both HA and NA that were higher in the post–peak than in the pre-peak period of the epidemic. About 14.94% and 3.44% of 174 isolates had one and two amino acids changes, respective, in the four antigenic sites. One unique adaptive mutation of HA2 (E374K) was first detected three weeks before the epidemic peak. This mutation evolved through the epidemic, and finally emerged as the major circulated strain, with significantly higher frequency in the post-peak period than in the pre-peak (64.65% vs 9.28%, p<0.0001). E374K persisted until ten months post-nationwide vaccination without further antigenic changes (e.g. prior to the highest selective pressure). In public health measures, the epidemic peaked at seven weeks after oseltamivir treatment was initiated. The emerging E374K mutants spread before the first peak of school class suspension, extended their survival in high-density population areas before vaccination, dominated in the second wave of class suspension, and were fixed as herd immunity developed. The tempo-spatial spreading of E374K mutants was more concentrated during the post–peak (p = 0.000004) in seven districts with higher spatial clusters (p<0.001). This is the first study examining viral changes during the naïve phase of a pandemic of influenza through integrated virological/serological/clinical surveillance, tempo-spatial analysis, and intervention policies. The vaccination increased the percentage of E374K mutants (22.86% vs 72.34%, p<0.001) and significantly elevated the frequency of mutations in Sa antigenic site (2.36% vs 23.40%, p<0.001). Future pre-vaccination public health efforts should monitor amino acids of HA and NA of pandemic influenza viruses isolated at exponential and peak phases in areas with high cluster cases

A novel pathway regulates memory and plasticity via SIRT1 and miR-134

The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies. Its mammalian homologue, SIRT1, seems to have evolved complex systemic roles in cardiac function, DNA repair and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 has a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, whereas its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of cAMP response binding protein (CREB) expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the downregulated expression of CREB and brain-derived neurotrophic factor (BDNF), thereby impairing synaptic plasticity. These findings demonstrate a new role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signalling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of central nervous system disorders

Detection of the inferred interaction network in hepatocellular carcinoma from EHCO (Encyclopedia of Hepatocellular Carcinoma genes Online)

BACKGROUND: The significant advances in microarray and proteomics analyses have resulted in an exponential increase in potential new targets and have promised to shed light on the identification of disease markers and cellular pathways. We aim to collect and decipher the HCC-related genes at the systems level. RESULTS: Here, we build an integrative platform, the Encyclopedia of Hepatocellular Carcinoma genes Online, dubbed EHCO , to systematically collect, organize and compare the pileup of unsorted HCC-related studies by using natural language processing and softbots. Among the eight gene set collections, ranging across PubMed, SAGE, microarray, and proteomics data, there are 2,906 genes in total; however, more than 77% genes are only included once, suggesting that tremendous efforts need to be exerted to characterize the relationship between HCC and these genes. Of these HCC inventories, protein binding represents the largest proportion (~25%) from Gene Ontology analysis. In fact, many differentially expressed gene sets in EHCO could form interaction networks (e.g. HBV-associated HCC network) by using available human protein-protein interaction datasets. To further highlight the potential new targets in the inferred network from EHCO, we combine comparative genomics and interactomics approaches to analyze 120 evolutionary conserved and overexpressed genes in HCC. 47 out of 120 queries can form a highly interactive network with 18 queries serving as hubs. CONCLUSION: This architectural map may represent the first step toward the attempt to decipher the hepatocarcinogenesis at the systems level. Targeting hubs and/or disruption of the network formation might reveal novel strategy for HCC treatment