Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms.

BACKGROUND: Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role of PCSK9 in macrophage activation and vein graft failure is largely unknown, especially through LDLR-independent mechanisms. This study aimed to explore a novel mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion. METHODS: We used Ldlr-/- mice to examine the LDLR-independent roles of circulating PCSK9 in experimental vein grafts. Adeno-associated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) induced hepatic PCSK9 overproduction. To explore novel inflammatory targets of PCSK9, we used systems biology in Ldlr-/- mouse macrophages. RESULTS: In Ldlr-/- mice, AAV-PCSK9 increased circulating PCSK9, but did not change serum cholesterol and triglyceride levels. AAV-PCSK9 promoted vein graft lesion development when compared with control AAV. In vivo molecular imaging revealed that AAV-PCSK9 increased macrophage accumulation and matrix metalloproteinase activity associated with decreased fibrillar collagen, a molecular determinant of atherosclerotic plaque stability. AAV-PCSK9 induced mRNA expression of the pro-inflammatory mediators IL-1ß (interleukin-1 beta), TNFα (tumor necrosis factor alpha), and MCP-1 (monocyte chemoattractant protein-1) in peritoneal macrophages underpinned by an in vitro analysis of Ldlr-/- mouse macrophages stimulated with endotoxin-free recombinant PCSK9. A combination of unbiased global transcriptomics and new network-based hyperedge entanglement prediction analysis identified the NF-κB (nuclear factor-kappa B) signaling molecules, lectin-like oxidized LOX-1 (LDL receptor-1), and SDC4 (syndecan-4) as potential PCSK9 targets mediating pro-inflammatory responses in macrophages. CONCLUSIONS: Circulating PCSK9 induces macrophage activation and vein graft lesion development via LDLR-independent mechanisms. PCSK9 may be a potential target for pharmacologic treatment for this unmet medical need.

Differential inducibility of transmembrane peptidoglycan recognition proteins (PGRPs) by bacterial challenges in the earthworm, Eisenia andrei.

Peptidoglycan recognition proteins (PGRPs) and Toll-like receptors (TLRs) are highly conserved pattern recognition receptors (PRRs). Earthworms possess genes encoding TLRs that specifically respond to Gram-positive bacteria. In addition, several PGRPs have been recently identified, which are predicted to exhibit amidase activity but lack receptor function. In lophotrochozoans, a membrane-bound PRR responsible for detecting Gram-negative bacteria remains unidentified. This study reveals several novel transmembrane peptidoglycan recognition proteins (Ean-PGRPLs) in earthworms, whose mRNA expression increases in response to Gram-negative but not Gram-positive bacteria. This indicates that Ean-PGRPLs may serve as a PRR associated with intracellular signaling for Gram-negative bacteria.

Artemisia argyi extract exerts antioxidant properties and extends the lifespan of Drosophila melanogaster.

BACKGROUND: Chinese mugwort (Artemisia argyi) possesses extensive pharmacological activities associated with anti-tumour, antioxidative and anti-inflammatory effects. The present study aimed to investigate the antioxidant and anti-ageing effects of A. argyi extract (AAE) on the fruit fly (Drosophila melanogaster) ageing model by detecting antioxidant enzyme activities and the mRNA level of antioxidant genes. RESULTS: AAE could significantly lengthen the mean lifespan, 50% survival days, and maximum lifespan of D. melanogaster, especially when the amount of AAE added reached 6.68 mg mL-1, the mean lifespan of both female and male flies increased by 23.74% and 22.30%, respectively, indicating the effective life extension effect of AAE. At the same time, AAE could improve the climbing ability and tolerance to hydrogen peroxide in D. melanogaster. In addition, the addition of AAE effectively increased the activities of copper-zinc-containing superoxide dismutase, manganese-containing superoxide dismutase and catalase in D. melanogaster and reduced the contents of malondialdehyde. Moreover, when reared with diets containing AAE, the expression of antioxidant-related genes SOD1, SOD2 and CAT was up-regulated in D. melanogaster and down-regulated for MTH genes. CONCLUSION: The study indicates that AAE effectively enhances the antioxidant capacity of D. melanogaster and has potential applications as an antioxidant and anti-ageing agent in the nutraceutical industry. © 2024 Society of Chemical Industry.

Comparison of the efficacy and safety of tocilizumab, sarilumab, and olokizumab in patients with active rheumatoid arthritis: a network meta-analysis of randomized controlled trials.

OBJECTIVE: This study compared the relative efficacy and safety of olokizumab, tocilizumab, and sarilumab in rheumatoid arthritis (RA) patients who were intolerant or responding inadequately to methotrexate (MTX). METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of olokizumab, tocilizumab, and sarilumab in RA patients who were intolerant or responding inadequately to MTX. RESULTS: Six RCTs comprising 4439 patients met the inclusion criteria. Tocilizumab, sarilumab, olokizumab, and adalimumab treatments achieved a significant American College of Rheumatology 20% (ACR20) response rate compared with placebo. However, tocilizumab was associated with the most favorable surface area using the cumulative ranking curve (SUCRA) for the ACR20 response rate. The ranking probability based on the SUCRA indicated that tocilizumab treatment had the highest probability of providing the best ACR20 response rate, followed by sarilumab, olokizumab every 2 weeks (Q2W), olokizumab Q4W, adalimumab 40 mg, and placebo. The ACR50 and 70 response rates showed a distribution pattern similar to that of the ACR20 response rate. However, olokizumab Q4W had a higher ranking probability than olokizumab Q2W. The SUCRA rating showed that the placebo was the best intervention with the least adverse events (AEs) and withdrawal due to AEs, followed by interleukin­6 inhibitors. CONCLUSION: Tocilizumab, sarilumab, and olokizumab are more effective than adalimumab and have similar efficacy and safety in RA patients with inadequate responses to MTX.

Progress Toward Measles Elimination - Worldwide, 2000-2022.

Measles is a highly contagious, vaccine-preventable disease that requires high population immunity for transmission to be interrupted. All six World Health Organization regions have committed to eliminating measles; however, no region has achieved and sustained measles elimination. This report describes measles elimination progress during 2000-2022. During 2000-2019, estimated coverage worldwide with the first dose of measles-containing vaccine (MCV) increased from 72% to 86%, then declined to 81% in 2021 during the COVID-19 pandemic, representing the lowest coverage since 2008. In 2022, first-dose MCV coverage increased to 83%. Only one half (72) of 144 countries reporting measles cases achieved the measles surveillance indicator target of two or more discarded cases per 100,000 population in 2022. During 2021-2022, estimated measles cases increased 18%, from 7,802,000 to 9,232,300, and the number of countries experiencing large or disruptive outbreaks increased from 22 to 37. Estimated measles deaths increased 43% during 2021-2022, from 95,000 to 136,200. Nonetheless, an estimated 57 million measles deaths were averted by vaccination during 2000-2022. In 2022, measles vaccination coverage and global surveillance showed some recovery from the COVID-19 pandemic setbacks; however, coverage declined in low-income countries, and globally, years of suboptimal immunization coverage left millions of children unprotected. Urgent reversal of coverage setbacks experienced during the COVID-19 pandemic can be accomplished by renewing efforts to vaccinate all children with 2 MCV doses and strengthening surveillance, thereby preventing outbreaks and accelerating progress toward measles elimination.

Comparative efficacy and safety of tumor necrosis factor inhibitors and their biosimilars in patients with rheumatoid arthritis having an insufficient response to methotrexate : A network meta-analysis.

OBJECTIVE: This study aimed to compare the effectiveness and safety of tumor necrosis factor inhibitor (TNFI) biosimilars to TNFI originators in patients with active rheumatoid arthritis (RA) who responded inadequately to methotrexate (MTX). METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) to compare the effectiveness and safety of TNFI biosimilars to TNFIs in patients with RA who had not responded adequately to MTX. RESULTS: A total of 18 RCTs (8 adalimumab, 7 infliximab, and 3 etanercept) comprising 4039 patients randomized to TNFI biosimilars and 3905 to TNFI treatment were included. The American College of Rheumatology 20% improvement (ACR20) response rate was significantly higher for TNFI biosimilar-treated patients than for TNFI-treated patients (odds ratio, OR 1.140, 95% confidence interval, CI 1.031-1.261, P = 0.011); however, subgroup analysis by the TNFI type showed that the ACR20 response rates were not different among the biosimilars of adalimumab, infliximab, and etanercept compared with the originators. The ACR50 response rate was significantly higher for TNFI biosimilar-treated patients than for TNFI treated patients (OR 1.096, 95% CI 1.001-1.200, P = 0.047). Subgroup analysis by the TNFI type showed that the ACR50 response rates did not differ among the biosimilars of adalimumab and infliximab compared with the originators; however, the ACR50 response rate was significantly higher in etanercept biosimilar-treated patients than in etanercept-treated patients (OR 1.406, 95% CI 1.111-1.780, P = 0.005). No significant difference was observed between the TNFI biosimilars and TNFIs as per ACR70. There was no significant difference in the number of patients who experienced adverse events (AEs) between TNFI biosimilars and TNFIs (OR 0.961, 95% CI 0.876-1.055, P = 0.402); however, subgroup analysis by the TNFI type showed that the adalimumab biosimilar caused fewer AEs than adalimumab (OR 0.865, 95% CI 0.756-0.989, P = 0.034). Serious AEs and withdrawals due to AEs did not differ between TNFI biosimilars and TNFIs. CONCLUSION: This meta-analysis showed that TNFI biosimilars had an overall comparable efficacy and safety profile compared with their originators in RA patients.

Systems Approach to Discovery of Therapeutic Targets for Vein Graft Disease: PPARα Pivotally Regulates Metabolism, Activation, and Heterogeneity of Macrophages and Lesion Development.

BACKGROUND: Vein graft failure remains a common clinical challenge. We applied a systems approach in mouse experiments to discover therapeutic targets for vein graft failure. METHODS: Global proteomics and high-dimensional clustering on multiple vein graft tissues were used to identify potential pathogenic mechanisms. The PPARs (peroxisome proliferator-activated receptors) pathway served as an example to substantiate our discovery platform. In vivo mouse experiments with macrophage-targeted PPARα small interfering RNA, or the novel, selective activator pemafibrate demonstrate the role of PPARα in the development and inflammation of vein graft lesions. In vitro experiments further included metabolomic profiling, quantitative polymerase chain reaction, flow cytometry, metabolic assays, and single-cell RNA sequencing on primary human and mouse macrophages. RESULTS: We identified changes in the vein graft proteome associated with immune responses, lipid metabolism regulated by the PPARs, fatty acid metabolism, matrix remodeling, and hematopoietic cell mobilization. PPARα agonism by pemafibrate retarded the development and inflammation of vein graft lesions in mice, whereas gene silencing worsened plaque formation. Pemafibrate also suppressed arteriovenous fistula lesion development. Metabolomics/lipidomics, functional metabolic assays, and single-cell analysis of cultured human macrophages revealed that PPARα modulates macrophage glycolysis, citrate metabolism, mitochondrial membrane sphingolipid metabolism, and heterogeneity. CONCLUSIONS: This study explored potential drivers of vein graft inflammation and identified PPARα as a novel potential pharmacological treatment for this unmet medical need.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2021.

All six World Health Organization (WHO) regions have committed to eliminating measles.* The Immunization Agenda 2021-2030 (IA2030)† aims to achieve the regional targets as a core indicator of impact and positions measles as the tracer of a health system's ability to deliver essential childhood vaccines. IA2030 highlights the importance of ensuring rigorous measles surveillance systems to document immunity gaps and achieve 95% coverage with 2 timely doses of measles-containing vaccine (MCV) among children. This report describes progress toward measles elimination during 2000-2021 and updates a previous report (1). During 2000-2021, estimated global coverage with a first MCV dose (MCV1) increased from 72% to a peak of 86% in 2019, but decreased during the COVID-19 pandemic to 83% in 2020 and to 81% in 2021, the lowest MCV1 coverage recorded since 2008. All countries conducted measles surveillance, but only 47 (35%) of 135 countries reporting discarded cases§ achieved the sensitivity indicator target of two or more discarded cases per 100,000 population in 2021, indicating surveillance system underperformance in certain countries. Annual reported measles incidence decreased 88% during 2000-2016, from 145 to 18 cases per 1 million population, then rebounded to 120 in 2019 during a global resurgence (2), before declining to 21 in 2020 and to 17 in 2021. Large and disruptive outbreaks were reported in 22 countries. During 2000-2021, the annual number of estimated measles deaths decreased 83%, from 761,000 to 128,000; an estimated 56 million measles deaths were averted by vaccination. To regain progress and achieve regional measles elimination targets during and after the COVID-19 pandemic, accelerating targeted efforts is necessary to reach all children with 2 MCV doses while implementing robust surveillance and identifying and closing immunity gaps to prevent cases and outbreaks.

Novel Molecular Genetic Etiology of Asymmetric Hearing Loss: Autosomal-Dominant LMX1A Variants.

INTRODUCTION: Sensorineural hearing loss is the most common sensory disorder in humans. Genetic analyses have greatly increased our understanding of the pathogenic mechanisms in play. Thus, characterization of audiologic phenotypes by the genetic etiology may aid elucidation of the etiologies of certain types of inherited hearing loss. Further, delineation of specific audiologic phenotypes based on the genetic etiology aids our understanding of some types of inherited hearing loss in terms of the prediction of clinical course, revelation of genotype-phenotype correlations, and application of appropriate audiologic rehabilitation. Here, we describe the interesting audiologic characteristics of LMX1A -associated deafness, which revealed significant asymmetry between two ears. METHODS: Among 728 probands of which genomic DNA went through exome sequencing regardless of any specific audiologic phenotypes, probands for which exome sequencing was performed and a causative LMX1A variant was found were all included. Five LMX1A -associated DFNA7 families (approximately 0.7%), the pedigrees of whom indicated autosomal-dominant hearing loss, were identified, and segregation was studied using Sanger sequencing. The affected individuals underwent comprehensive evaluations, including medical history reviews, physical examinations, imaging, and auditory phenotyping. We functionally characterized the novel LMX1A variants via computational structural modeling and luciferase reporter assays. RESULTS: Among 728 probands of which genomic DNA went through exome sequencing, we identified four novel LMX1A heterozygous variants related to DFNA7 (c.622C>T:p.Arg208*, c.719A>G:p.Gln240Arg, c.721G>A:p.Val241Met, and c.887dup:p.Gln297Thrfs*41) and one harboring a de novo heterozygous missense LMX1A variant (c.595A>G;p.Arg199Gly) previously reported. It is important to note that asymmetric hearing loss was identified in all probands and most affected individuals, although the extent of asymmetry varied. Structural modeling revealed that the two missense variants, p.Gln240Arg and p.Val241Met, affected conserved residues of the homeodomain, thus attenuating LMX1A-DNA interaction. In addition, Arg208*-induced premature termination of translation destroyed the structure of the LMX1A protein, including the DNA-binding homeodomain, and p.Gln297Thrfs*41 led to the loss of the C-terminal helix involved in LIM2 domain interaction. Compared with the wild-type protein, all mutant LMX1A proteins had significantly reduced transactivation efficiency, indicating that the ability to elicit transcription of the downstream target genes of LMX1A was severely compromised. Thus, in line with the American College of Medical Genetics and Genomics guideline specified to genetic hearing loss, the four novel LMX1A variants were identified as "pathogenic" (p.Arg208* and p.Gln297Thrfs*41), "likely pathogenic" (p.Val241Met), and as a "variant of uncertain significance'' (p.Gln240Arg). CONCLUSION: For the first time, we suggest that LMX1A is one of the candidate genes which, if altered, could be associated with dominantly inherited asymmetric hearing loss. We also expand the genotypic spectrum of disease-causing variants of LMX1A causing DFNA7 by doubling the number of LMX1A variants reported thus far in the literature.

Surface Functionalization of Surfactant-Free Particles: A Strategy to Tailor the Properties of Nanocomposites for Enhanced Thermoelectric Performance.

The broad implementation of thermoelectricity requires high-performance and low-cost materials. One possibility is employing surfactant-free solution synthesis to produce nanopowders. We propose the strategy of functionalizing "naked" particles' surface by inorganic molecules to control the nanostructure and, consequently, thermoelectric performance. In particular, we use bismuth thiolates to functionalize surfactant-free SnTe particles' surfaces. Upon thermal processing, bismuth thiolates decomposition renders SnTe-Bi2 S3 nanocomposites with synergistic functions: 1) carrier concentration optimization by Bi doping; 2) Seebeck coefficient enhancement and bipolar effect suppression by energy filtering; and 3) lattice thermal conductivity reduction by small grain domains, grain boundaries and nanostructuration. Overall, the SnTe-Bi2 S3 nanocomposites exhibit peak z T up to 1.3 at 873 K and an average z T of ≈0.6 at 300-873 K, which is among the highest reported for solution-processed SnTe.

Synthesis and biological activity of selenopsammaplin A and its analogues as antitumor agents with DOT1L inhibitory activity.

Disruptor of telomeric silencing-1 like (DOT1L) is a histone H3 methyltransferase which specifically catalyzes the methylation of histone H3 lysine-79 residue. Recent findings demonstrate that DOT1L is abnormally overexpressed and the upregulated DOT1L evokes the proliferation and metastasis in human breast cancer cells. Therefore, the DOT1L inhibitor is considered a promising strategy to treat breast cancers. Non-nucleoside DOT1L inhibitors, selenopsammaplin A and its analogues, were firstly reported in the present study. Selenopsammaplin A was newly designed and synthesized with 25% overall yield in 8 steps from 3-bromo-4-hydroxybenzaldahyde, and thirteen analogues of selenopsammaplin A were prepared for structure-activity relationship studies of their cytotoxicity against cancer cells and inhibitory activity toward DOT1L for antitumor potential. All synthetic selenopsammaplin A analogues exhibited the higher cytotoxicity compared to psammaplin A with up to 6 - 60 times depending on cancer cells, and most analogues showed significant inhibitory activities against DOT1L. Among the prepared analogues, the phenyl analogue (10) possessed the most potent activity with both cytotoxicity and inhibition of DOT1L. Compound 10 also exhibited the antitumor and antimetastatic activity in an orthotopic mouse metastasis model implanted with MDA-MB-231 human breast cancer cells. These biological findings suggest that analogue 10 is a promising candidate for development as a cancer chemotherapeutic agent in breast cancers.

Modiolar Proximity of Slim Modiolar Electrodes and Cochlear Duct Length: Correlation for Potential Basis of Customized Cochlear Implantation With Perimodiolar Electrodes.

OBJECTIVES: Recent studies have shown that cochlear duct length (CDL) varies among individuals and could significantly influence the final position of the electrode and its trajectory in the cochlea. Given this, we hypothesized that the degree of modiolar proximity of novel slim modiolar electrodes, such as CI532 and CI632, can also be affected by CDL. To test this hypothesis, we retrospectively evaluated individual CDL to determine if there is any significant correlation of CDL with degree of modiolar proximity. METHODS: Fifty-one ears from 38 subjects implanted with slim modiolar electrodes by a single surgeon through the round window approach using the pull-back technique were included. Our cohort was classified according to the deafness onset (congenital versus postlingual) and the degree of modiolar proximity (less versus tight) with reference to the spiral diameter made by the slim modiolar electrodes in situ on transorbital x ray. We then analyzed the CDL and its metrics using a readily available surgical preplanning tool (OTOPLAN) to obtain comparable data. RESULTS: Among 30 ears associated with congenital deafness, 9 ears (30%) showed less modiolar proximity, while none of the 21 ears from 19 subjects with postlingual deafness exhibited "less modiolar proximity" based on our criteria. In this study, CDL showed significant variation among subjects. Importantly, a significant inverse correlation between spiral diameter and CDL (ρ = -0.581, p < 0.001) was found, showing that shorter CDLs have longer spiral diameter and less modiolar proximity. Moreover, further pull-back technique characterized by pulling out the electrode a little bit more in cases with shorter CDL, if not always, exhibited tighter modiolar proximity. CONCLUSION: A preponderance of less modiolar proximity of the electrode was observed exclusively among congenital deafness cases, demonstrated by a less tight spiral configuration even under the pull-back technique. Our data suggest that shorter CDL is associated with a less tight spiral configuration of slim modiolar electrodes postoperatively. Depending on the insertion technique, the differential degree of modiolar proximity of slim modiolar electrodes can be alleviated in cases with short CDL, which justifies cochlear duct length-based customized insertion of slim modiolar electrodes.

Comparative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for active rheumatoid arthritis.

WHAT IS KNOWN AND OBJECTIVE: Several clinical trials have attempted to evaluate the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy in patients with active rheumatoid arthritis (RA), but their relative efficacy and safety as monotherapy remain unclear due to the lack of data from head-to-head comparison trials. The relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for rheumatoid arthritis (RA) were assessed. METHODS: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) and examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy relative to placebo in patients with RA. RESULTS AND DISCUSSION: Five RCTs comprising 1547 patients met the inclusion criteria. Compared with placebo, tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy showed a significantly higher American College of Rheumatology 20% (ACR20) response rate. Peficitinib 150 mg monotherapy showed the highest ACR20 response rate (odds ratio, 17.24.39; 95% credible interval, 6.57-51.80). The ranking probability based on the surface under the cumulative ranking curve indicated that peficitinib 150 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by peficitinib 100 mg, filgotinib 200 mg, filgotinib 100 mg, tofacitinib 5 mg, upadacitinib 15 mg, baricitinib 4 mg and placebo. However, the number of patients who experienced serious adverse events did not differ significantly between the JAK inhibitors, except for tofacitinib 5 mg, and placebo. WHAT IS NEW AND CONCLUSION: All five JAK inhibitors-tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib-were efficacious monotherapy interventions for active RA, and differences were noted in their efficacy and safety in monotherapy.

Association of physical and psychological health status between chronic obstructive pulmonary disease patients and their family caregivers.

We performed this cross-sectional study with 72 chronic obstructive pulmonary disease (COPD) patients and their family caregivers to analyze relationship of physical and psychological health status between COPD patients and caregivers. Most caregivers were female (100%). Caregiver depression and burden were significantly associated with caregiving hours. In path analysis, the higher the patient's social support, the higher the patient's self-efficacy. The higher the patient's self-efficacy, the lower the care burden of the caregiver. Based on our results, there was a significant correlation of physical and psychological factors between patients and family caregivers.

Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein.

Extracellular deposition of amyloid-beta (Aß) peptide, a metabolite of sequential cleavage of amyloid precursor protein (APP), is a critical step in the pathogenesis of Alzheimer's disease (AD). While death-associated protein kinase 1 (DAPK1) is highly expressed in AD brains and its genetic variants are linked to AD risk, little is known about the impact of DAPK1 on APP metabolism and Aß generation. In this study, we demonstrated a novel effect of DAPK1 in the regulation of APP processing using cell culture and mouse models. DAPK1, but not its kinase deficient mutant (K42A), significantly increased human Aß secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased Aß secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Aß. In Tg2576 APPswe-overexpressing mice, knockout of DAPK1 shifted APP processing toward non-amyloidogenic pathway and decreased Aß generation. Finally, in AD brains, elevated DAPK1 levels showed co-relation with the increase of APP phosphorylation. Combined together, these results suggest that DAPK1 promotes the phosphorylation and amyloidogenic processing of APP, and that may serve a potential therapeutic target for AD.

Hippocampal VEGF is necessary for antidepressant-like behaviors but not sufficient for antidepressant-like effects of ketamine in rats.

We investigated the effects of ketamine on both the temporal and spatial profiles of neural precursor cells located in the hippocampus, and on antidepressant-like behaviors in rats. A single dose of ketamine resulted in a significant increase in the number of 5-bromo-2-deoxyuridine-positive (BrdU(+)) cells in the dentate gyrus (DG) of rats at 24h, but not at 28days, after treatment completion. Ketamine caused antidepressant-like behaviors in the forced swim test (FST) and novelty suppressed feeding test (NSFT). Viral-mediated hippocampal knockdown of vascular endothelial growth factor (VEGF) produced depressive-like behaviors in the FST and NSFT, which were partially recovered by ketamine to the level observed in the control group. The behavioral effects of VEGF knock down were accompanied by a decrease in hippocampal neurogenesis, which was also partially recovered by ketamine. Our results suggest that basal hippocampal VEGF expression is necessary for ketamine-induced antidepressant-like behaviors in rats, but ketamine-induced VEGF expression only partially contributes to hippocampal neurogenesis and the antidepressant-like effects of ketamine.

MxaJ structure reveals a periplasmic binding protein-like architecture with unique secondary structural elements.

MxaJ is a component of type II methanol dehydrogenase (MDH) that mediates electron transfer during methanol oxidation in methanotrophic bacteria. However, little is known about how MxaJ structurally cooperates with MDH and Cytochrome cL . Here, we report for the first time the crystal structure of MxaJ. MxaJ consists of eight α-helices and six ß-strands, and resembles the "bi-lobate" folding architecture found in periplasmic binding proteins. Distinctive features of MxaJ include prominent loops and a ß-strand around the hinge region supporting the ligand-binding cavity, which might provide a more favorable framework for interacting with proteins rather than small molecules. Proteins 2017; 85:1379-1386. © 2017 Wiley Periodicals, Inc.

Association of patient age with high-risk pathologic features in papillary thyroid cancer.

BACKGROUND: Certain patient demographics and histopathologic features are risk factors for papillary thyroid cancer (PTC) recurrence after initial treatment. Our objective was to determine whether very young age is associated with aggressive pathologic features in patients with PTC. MATERIALS AND METHODS: A retrospective analysis was performed for PTC patients who underwent surgical treatment at the University of Michigan between 2006 and 2012. Patients with known distant metastases were excluded. Demographics, high-risk pathologic features (capsular or vascular invasion, extrathyroidal extension, lymph node metastases, and extranodal extension), and disease recurrence were analyzed. RESULTS: 632 PTC patients were included in the analysis. Median age was 49 y (range 10-87). Tumors in patients aged <25 y had higher rates of extranodal extension (P = 0.002) compared with patients aged 25-44 y. Patients aged <25 y had more vascular invasion (P < 0.001) and lymph node metastasis (P = 0.001) than tumors in patients aged between 45-75 y. Patients aged >75 y had higher rates of vascular invasion (P < 0.001) and extrathyroidal extension (P = 0.001) compared with patients aged 45-75 y and more extrathyroidal extension (P < 0.001) than patients aged 25-44 y. There were no differences in tumor characteristics between the <25 and >75 age groups. CONCLUSIONS: PTC patients aged <25 y of age or older than 75 y exhibit higher rates of aggressive histopathologic features compared to PTC patients aged between 25-75 y.

Epidurographic Findings Following Percutaneous Epidural Adhesiolysis Failed to Correlate with Level of Pain Reduction in Patients with Lumbar Spinal Stenosis.

Background: Spinal stenosis is characterized by narrowing of the spinal canal, with mechanical compression of spinal nerve roots. The latter may cause low back pain and/or leg pain, as well as neurogenic claudication. Epidural steroid injection is commonly used to treat patients with lumbar spinal stenosis (LSS), but percutaneous epidural adhesiolysis has been utilized when symptoms prove refractory. Our goal was to assess the relationship between improvement shown on epidurogram and subjective patient response to adhesiolysis. Methods: For this prospective study, 78 patients with degenerative LSS were enrolled. Each subject underwent magnetic resonance imaging of the lumbar spine, with all therapeutic procedures conducted in the operating room. Two weeks later, a second epidurography was performed. Second epidurography was conducted to assess any change in epidural filling defects. Outcome measures were obtained using the visual analogue scale (VAS) score at two weeks, one month, and three months post-treatment. Results: All of the 78 study participants (mean age = 60.9 years, range = 34-85 years) displayed epidural filling defects at baseline. After percutaneous adhesiolysis, epidurographic filling defects were absent in 73% of patients. In the presence or absence of filling defects, mean VAS scores were 5.2 and 4.5, respectively, at two weeks' follow-up. No significant correlation between postprocedural VAS score and status of filling defects (yes or no) was evident during the three-month follow-up period. Conclusion: In patients with LSS, epidurographic findings following percutaneous epidural adhesiolysis failed to correlate with level of pain reduction achieved.

Recent progress on correlated electron systems with strong spin-orbit coupling.

The emergence of novel quantum ground states in correlated electron systems with strong spin-orbit coupling has been a recent subject of intensive studies. While it has been realized that spin-orbit coupling can provide non-trivial band topology in weakly interacting electron systems, as in topological insulators and semi-metals, the role of electron-electron interaction in strongly spin-orbit coupled systems has not been fully understood. The availability of new materials with significant electron correlation and strong spin-orbit coupling now makes such investigations possible. Many of these materials contain 5d or 4d transition metal elements; the prominent examples are iridium oxides or iridates. In this review, we succinctly discuss recent theoretical and experimental progress on this subject. After providing a brief overview, we focus on pyrochlore iridates and three-dimensional honeycomb iridates. In pyrochlore iridates, we discuss the quantum criticality of the bulk and surface states, and the relevance of the surface/boundary states in a number of topological and magnetic ground states, both in the bulk and thin film configurations. Experimental signatures of these boundary and bulk states are discussed. Domain wall formation and strongly-direction-dependent magneto-transport are also discussed. In regard to the three-dimensional honeycomb iridates, we consider possible quantum spin liquid phases and unusual magnetic orders in theoretical models with strongly bond-dependent interactions. These theoretical ideas and results are discussed in light of recent resonant x-ray scattering experiments on three-dimensional honeycomb iridates. We also contrast these results with the situation in two-dimensional honeycomb iridates. We conclude with the outlook on other related systems.