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Porcine deltacoronavirus (PDCoV) is one of the most important enteropathogenic pathogens, and it causes enormous economic losses to the global commercial pork industry. PDCoV was initially reported in Hong Kong (China) in 2012 and subsequently emerged in swine herds with diarrhea in Ohio (USA) in 2014. Since then, it has spread to Canada, South Korea, mainland China, and several Southeast Asian countries. Information about the epidemiology, evolution, prevention, and control of PDCoV and its prevalence in China has not been comprehensively reported, especially in the last five years. This review is an update of current information on the general characteristics, epidemiology, geographical distribution, and evolutionary relationships, and the status of PDCoV vaccine development, focusing on the prevalence of PDCoV in China and vaccine research in particular. Together, this information will provide us with a greater understanding of PDCoV infection and will be helpful for establishing new strategies for controlling this virus worldwide.

Existing evidence has demonstrated that epigenetic modifications (including DNA methylation, histone modifications, and microRNAs), which are associated with the occurrence and development of tumors, can directly or indirectly regulate autophagy. In particular, nuclear events induced by several epigenetic regulators can regulate the autophagic process and expression levels of tumor-associated genes, thereby promoting tumor progression. Tumor-associated microRNAs, including oncogenic and tumor-suppressive microRNAs, are of great significance to autophagy during tumor progression. Targeting autophagy with emerging epigenetic drugs is expected to be a promising therapeutic strategy for human tumors. From this perspective, we aim to summarize the role of epigenetic modification in the autophagic process and the underlying molecular mechanisms of tumorigenesis. Furthermore, the regulatory efficacy of epigenetic drugs on the autophagic process in tumors is also summarized. This perspective may provide a theoretical basis for the combined treatment of epigenetic drugs/autophagy mediators in tumors.

We herein report the identification, structural optimization, and structure-activity relationship of thieno[2,3-d]pyrimidine derivatives as a novel kind of selective vascular endothelial growth factor receptor 3 (VEGFR3) inhibitors. N-(4-Chloro-3-(trifluoromethyl)phenyl)-4-(6-(4-(4-methylpiperazin-1-yl)phenyl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxamide (38k) was the most potent VEGFR3 inhibitor (IC50 = 110.4 nM) among developed compounds. Compared with VEGFR1 and VEGFR2, VEGFR3 was approximately 100 times more selective. Here, compound 38k significantly inhibited proliferation and migration of VEGF-C-induced human dermal lymphatic endothelial cells (HDLEC), MDA-MB-231, and MDA-MB-436 cells by inactivating the VEGFR3 signaling pathway. Additionally, 38k induced cell apoptosis and a prolonged G1/S-phase in MDA-MB-231 and MDA-MB-436 cells. It also presented acceptable pharmacokinetic characteristics in Sprague-Dawley (SD) rats with an oral bioavailability of 30.9%. In the xenograft model in vivo, 38k effectively inhibited breast cancer growth by suppressing the VEGFR3 signaling pathway. 38k pronouncedly resisted the formation of pulmonary metastatic nodules in mice. Collectively, 38k may be a promising therapeutic agent of metastatic breast cancer.

Bone is one of the most common sites of breast cancer metastasis and a major cause of high mortality in these patients. Thus, further understanding the molecular mechanisms regulating breast cancer-induced osteolysis is critical for the development of more effective treatments. In this study, we demonstrated that important roles sterol regulatory element-binding protein 2 (SREBP-2) play in osteoclast formation a function, and in breast cancer metastasis. SREBP-2 expression was found to be induced during the early stages of osteoclast formation under the control of the RANKL/cAMP-response element binding protein (CREB) signaling cascade. SREBP-2 is subsequently translocated into the nucleus where it participates with other transcriptional factors to induce the expression of NFATc1 required for mature osteoclast formation. Additionally, SREBP-2 was also found to be highly expressed in breast cancer tissues and correlated with a poor prognosis. SREBP-2 was similarly under the transcriptional control of CREB and its induction regulates the expression of matrix metalloproteinases (MMPs), key degradative enzymes involved in bone metastases by breast cancer cells. Accordingly, targeting of SREBP-2 with Fatostatin which specifically inhibits SCAP (SREBP cleavage-activating protein) and prevents SREBP activation, attenuated breast cancer-induced osteolysis in vivo. Collectively, our results suggest that SREBP-2 plays a critical role in regulating osteoclastogenesis and contributes to breast cancer-induced osteolysis. Thus, SREBP-2 inhibition is a potential therapeutic approach for breast cancer patients with osteolytic bone lesions.

Balance of osteoclast formation is regulated by the receptor activator of NF-κB ligand and extracellular negative regulators such as IFN-γ and IFN-β. However, very little is known about the intrinsic negative regulatory factors of osteoclast differentiation. Recently, the paired-box homeodomain transcription factor Pax6 was shown to negatively regulate receptor activator of NF-κB ligand-mediated osteoclast differentiation. However, the mechanism underlying this regulation is still unclear. In this study, we show that a p38 inhibitor (VX-745) up-regulates the expression of Pax6 during osteoclast differentiation. Subsequently, we found that β-catenin could bind to the proximal region of Pax6 promoter to induce its expression, and this action could be impaired by p38-induced ubiquitin-mediated degradation of β-catenin. Our results suggest that Pax6 is regulated by a novel p38/β-catenin pathway. Pax6 can further regulate the nuclear translocation of NF of activated T cells, cytoplasmic 1. Our study indicates that this novel p38/β-catenin/Pax6 axis contributes to negative regulation of osteoclastogenesis. In addition, our study proposes a novel approach to treat osteoclast-related diseases through the use of VX-745 complemented with the β-catenin activator SKL2001.-Jie, Z., Shen, S., Zhao, X., Xu, W., Zhang, X., Huang, B., Tang, P., Qin, A., Fan, S., Xie, Z. Activating β-catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK.

Background: Recent findings indicated a high comorbidity between attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), as well as shared genetic influences on them. The latter might contribute at least partly to the former clinical scenario. This study aimed at investigating whether SHANK genes were potential pleiotropic genes to the two said disorders, underlying their genetic overlap.Methods: This study recruited 298 boys with ADHD (including 256 family trios of 1 ADHD boy and his 2 biological parents), 134 boys with ASD, 109 boys with both ADHD and ASD, and 232 typically developing boys as community controls. They were aged between 6 and 11 years old.Results: There was no significant difference in allele frequency of a number of single nucleotide polymorphisms (SNPs) in SHANK2/SHANK3 between the three clinical groups (ADHD, ASD, and ADHD + ASD) and between the two control groups (community controls and pseudo-controls), respectively. The three clinical groups and the two control groups were thus, respectively, combined. A comparison between the two aggregated samples identified significant evidence of disease association for three SHANK2 SNPs with both ADHD and ASD, even after multiple testing correction: rs11236616 (OR = 0.762, permuted p = 0.0376), rs7106631 (OR = 0.720, permuted p = 0.0034), and rs9888288 (OR = 0.770, permuted p = 0.0407). Comparisons among individual groups pointed to a similar trend of findings.Conclusion:SHANK2 could be considered a potential pleiotropic gene underlying the genetic overlap between ADHD and ASD. This might contribute partly to their high comorbidity in the afflicted children.

A 28-year-old woman with vaginal discharge was admitted to the hospital. Colposcopy examination found several ulcers with pus in the vagina. Biopsy demonstrated extranodal natural killer/T-cell lymphoma. PET/CT scan was subsequently performed for staging. It revealed intense FDG uptake in the vagina. No FDG-avid lesion was seen in the rest of the body. A primary vaginal extranodal natural killer/T-cell lymphoma was diagnosed.

Intervertebral disc degeneration (IDD) is closely related to loss of the extracellular matrix (ECM), apoptosis and inflammation in nucleus pulposus cells (NPCs). It has been reported that Zinc finger protein A20/TNFAIP3 (A20) can inhibit the activity of the NF-κB pathway and promote autophagy. Therefore, we speculated that A20 can regulate inflammation and ameliorate IDD through autophagy mediated by NF-κB in human NPCs. Our results indicated that the expression of A20 and inflammatory factors in IDD tissues was increased. A20 is an essential negative regulator in the NF-κB pathway. Constructed adenoviral shRNA and overexpression vectors for A20 could effectively regulate the inflammation, autophagy, and activity of NF-κB, which in turn affected the progression of IDD. Inhibition of NF-κB on the basis of knocking down A20 results in increased autophagy, suggesting that A20-regulated autophagy was mediated by NF-κB. In vivo, A20 overexpression could ameliorate the progression of IDD and promote autophagy at the same time, while deletion of A20 leads to low levels of autophagy and severe degeneration. In summary, A20 plays an important role in inhibiting inflammation through autophagy mediated by NF-κB in NPCs and ameliorating IDD.

P21-activated kinase 1 (PAK1) is associated with cell proliferation, survival and migration. Deregulation of PAK1 activity is involved in various human diseases, including cancer, inflammation, and neurological disorders. Using a high-throughput virtual screening, we identified the 1H-pyrazolo [3,4-d]pyrimidine scaffold as a promising lead for targeting PAK1. We designed and synthesized a focused library through a structure-based strategy. A novel potent PAK1 inhibitor, ZMF-10, was discovered, which presented an IC50 value of 174 nM with a good selectivity. In addition, ZMF-10 could inhibit PAK1-ERK signaling to suppress MDA-MB-231 cells proliferation with an IC50 value of 3.48 μM for 48 h. Subsequently, ZMF-10 was documented to induce cell apoptosis. Interestingly, according to the RNASeq-based analyses, we substantiated that ZMF-10 induced significant ER-Stress, suppressed migration via FOXO3 activation, JNK1/2, ERK1/2 and AKT signaling inhibition. Together, these results demonstrate that ZMF-10 is a novel PAK1 inhibitor triggering apoptosis, ER stress and anti-migration effect in MDA-MB-231 cells, which may provide a candidate lead for the development of novel potent inhibitors of PAK1.

Study design A rat model of multifidus muscles injury and atrophy after posterior lumbar spine surgery. Objective We determined the effect of ascorbic acid (AA) on the postoperative multifidus muscles in rat model. Summary of background data Previous studies show oxidative stress and inflammation are two main molecular mechanisms in multifidus muscle injury and atrophy after posterior lumbar surgery. AA may have a protective effect in postoperative multifidus muscles. Methods Rats were divided into sham surgery, control surgery, and surgery plus AA groups. Multifidus muscles of the control and AA groups were excised from the osseous structures. The muscles were retracted continuously for 2 hours. In the sham and AA groups, AA was administered via oral gavage daily in the first week. In each group, the oxidative stress was evaluated by measuring malondialdehyde (MDA) and Total superoxide dismutase (T-SOD). The inflammation, fat degeneration, or fibrosis of multifidus muscle were evaluated by quantitative real-time polymerase chain reaction (q-PCR), histology, or immunohistochemical analysis. Results T-SOD activity was significantly lower in the control group than that in the AA group in the first week. MDA levels were significantly higher in the AA group. Interleukin-6 and tumor necrosis factor-α in multifidus muscles also showed significant differences when treated with AA. The inflammation score on histology was significantly lower in the AA group postoperatively in the first week. In the long run, marker genes for fibrosis and fat degeneration, and fibrosis and fat degeneration scores, were significantly lower in the AA than the control group on days 14 and 28 postoperatively. Conclusion In conclusion, AA attenuated the oxidative stress and inflammation response in the postoperative multifidus muscles, and remarkable differences were observed from the histological assessment and related marker genes expression. Our results provided important insight into the anti-inflammatory and anti-oxidative effects of AA in the postoperative multifidus muscles. Level of evidence N/A.

Objective: We examined adulthood diagnostic, functioning, and social outcomes of childhood ADHD in a Hong Kong Chinese clinical sample. Method: We identified from the central registry 499 Chinese adults clinically diagnosed with ADHD aged 6 to 12 in 2002-2005 in four Hong Kong child psychiatric centers. Assessments included ADHD Clinical Diagnostic Scale (ACDS), Structured Clinical Interview for DSM Disorders (SCID), and World Health Organization Disability Assessment Schedule (WHO-DAS). Results: Eligible participants = 499. One hundred forty-five completed assessments, two deceased, six incarcerated, 100 had invalid contact, 83 declined, 34 emigrated, and 129 unable to attend. Mean follow-up duration = 14.9 years. Nonrespondents were slightly younger (19.78 vs. 20.53, p < .001). In all, 83.1% of all participants currently met Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) ADHD criteria (36.8% inattentive subtype (IA), 43% combined, 3.3% hyperactive/impulsive subtype (H/I) ). One third of persistent ADHD participants currently received care. ADHD persistence was associated with significantly increased psychiatric comorbidity (49.5% vs. 22.7%, p = .02) and poor academic and social outcomes. ADHD persistence and comorbidity independently predicted impairment. Conclusion: Adulthood-persistence of clinically presented childhood ADHD is common and impairing in Hong Kong Chinese.

Applying fertilizer through drip irrigation system is a very important method to save fertilizer and labour. Three manifold layouts (water supply in one end for transversal drip tapes (M1), water supply in both ends for transversal drip tapes (M2) and water supply in one end for longitudinal drip tapes (M3)) and four different fertilizer solution concentrations (50.00 g L−1 (C1), 66.67 g L−1 (C2), 100 g L−1 (C3) and 200 g L−1 (C4)) were selected to investigated the effect of the manifold and concentration on water fertigation uniformity. Results showed that the emitter at the extreme end of the manifold needed more time to clean the rudimental fertilizer in the drip tapes. The minimal flushing time increased from 8 to 13, 4 to 7 and 7 to 12 min with increasing the fertilizer concentration from C1 to C4 for M1, M2 and M3, respectively. The drip irrigation system needed more time for flushing to reduce the risk of emitter clogging when a higher fertilizer solution concentration was applied. In order of performance, M2 had the highest water and fertilizer uniformity, followed by M3 and lastly by M1. The fertilizer solution concentration had no significant effect on water distribution. However, it had a significant effect on fertilizer distribution. The mass of the applied fertilizer for the drip tapes close to the inlet increased with increasing fertilizer solution concentration from C1 to C4, which indicated that higher fertilizer solution concentration can result in lower fertilizer distribution uniformity. There was a significant effect of the manifold layout on water uniformity. The fertilizer concentration and the interaction between manifold layout and concentration had no significant effect on the water uniformity. Similarly, both the manifold layout and concentration had a significant effect on fertilizer uniformity. The interaction between manifold layout and concentration had a significant effect on the Christiansen’s uniformity (CU) and distribution uniformity (DU) for fertilizer, whilst, a significant effect on emission uniformity (EU) was not found. The manifold layout and fertilizer solution concentration should therefore be considered in the design and operation of fertigation system.

Pervaporation membranes made from polyethersulfone (PESU), polyphenylsulfone (PPSU), polytrimethylphenylethersulfone (T-PESU) and hydrophilic PESU-co-Pluronic (H-PESU) polymers were evaluated for dehydration of ethanol and methanol. Fundamental characteristics of pore structure, free volume, d-spacing, water contact angle, water and ethanol uptakes were investigated and correlated with their dehydration performance. The H-PESU membrane shows the best ethanol dehydration performance due to its synergetic combination of the strengths from both rigid hydrophobic PESU and flexible hydrophilic Pluronic moieties. It has the highest water permeability of 0.322 mg m−1 h−1 kPa−1 which is 2–6 times higher than other three membranes because the hydrophilic Pluronic moiety may form special water transport channels. It also has a comparable mole-based selectivity of 685 due to the rigid hydrophobic PESU moiety that prevents the membrane from uncontrolled swelling. Long-term tests evidence the operating stability of both H-PESU and PESU membranes. In addition, the methanol dehydration performance of these membranes is superior to the other reported polymeric membranes. The water in the permeate can be concentrated to 86.8%. These promising preliminary results suggest that these polyarylether (PAE) membranes have great potential for ethanol and methanol dehydration.

Osteoporosis develops because of impaired bone formation and/or excessive bone resorption. Although the pharmacological treatment of osteoporosis has been extensively developed, alternative treatments are still needed. Here, we showed that oridonin (ORI), a diterpenoid isolated from Rabdosia rubescens, can suppress osteoclastogenesis and enhance osteogenesis. ORI inhibited the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast formation and bone resorption through the inhibition of p65 nuclear translocation. ORI-induced inhibition of this translocation led to an increase in osteoblast differentiation and mineralization through the promotion of Smad1/Smad5 phosphorylation. Further analyses demonstrated that the inhibition of p65 nuclear translocation is due to the suppression of IκBα phosphorylation and the induced proteasomal degradation of interferon-related development regulator 1 (Ifrd1), a transcriptional corepressor that is involved in the suppression of NF-κB nuclear translocation. Moreover, mice treated with ORI at catabolic and anabolic windows showed a considerable attenuation of ovariectomy (OVX)-induced osteoporosis. Taken together, our findings reveal that ORI protects against OVX-induced bone loss via inhibiting osteoclastic bone resorption but enhancing osteoblastic bone formation through abolishing both Ifrd1-mediating and IκBα-mediated p65 nuclear translocation. These results show the potential of ORI for treatment of osteoporosis and highlight Ifrd1 as a another novel promising target for anti-osteoporotic drugs. © 2017 American Society for Bone and Mineral Research.

Intervertebral disc degeneration causes low back pain.Interleukin-1β (IL-1β) is a well-known inflammatory mediator that is involved in disc degeneration but its molecular mechanisms on catabolic and anabolic events in nucleus pulposus (NP) cells remain unclear. Krüppel-like factor 5 (KLF5) is associated with inflammation and was previously shown to cause cartilage degradation. In this study, we revealed that KLF5 is involved in IL-1β activated NF-kB cascade by enhancing both p65 phosphorylation and p65 acetylation. Moreover, the catabolic effect of KLF5 can be abolished by transforming growth factor-β (TGF-β) via promoting the proteasomal degradation of KLF5. Therefore, a KLF5 inhibitor ML264 was further proved to synergize with TGF-β to attenuate IL-1β-induced intervertebral disc degeneration. These results indicate the critical role of KLF5 in regulating intervertebral disc metabolism and suggest KLF5 inhibitor such as ML264 as potential compound for treatment of degenerative disc disease.

Rheumatoid arthritis (RA), a disease that causes joint destruction and bone erosion, is related to osteoclast activity. RA is generally treated with methotrexate (MTX). In this study, a MTX–Alendronate (ALN) conjugate was synthesized and characterized. The conjugate dramatically inhibited osteoclast formation and bone resorption compared with MTX and ALN used alone or in combination. Due to the characteristics of ALN, the MTX–ALN conjugate can adhere to the exposed bone surface and enhance drug accumulation in the pathological region for targeted therapy against osteoclastogenesis. Additionally, MTX was rapidly released in the presence of lysozyme under mildly acidic conditions, similar to inflammatory tissue and osteoclast-surviving conditions, which contributes to inflammatory inhibition; this was confirmed by the presence of pro-inflammatory cytokines. Our study highlights the use of the MTX–ALN conjugate as a potential therapeutic approach for RA by targeting osteoclastogenesis.

We presented a case of primary lymphoma of the sternoclavicular joint. A 67-year-old woman with a history of swelling at the sternoclavicular joint region was considered as osteoarthritis initially. Chest CT found a soft tissue mass around the sternoclavicular joint. Biopsy demonstrated diffuse large B-cell lymphoma. The subsequent FDG PET/CT revealed FDG-avid articular destruction with surrounding soft tissue mass without any other abnormal findings, suggesting a primary extranodal lymphoma of sternoclavicular joint.

Mandy H Chan,1 Patrick WL Leung,2 Ting-pong Ho,3 Se-fong Hung,4 Chi-chiu Lee,5 Chun-pan Tang,5 Ka-chai Cheung,2 Fung-yee Ching,2 Fefe HK Chan,6 Lu-hua Chen,2 Merce Garcia-Barcelo,7 Pak-chung Sham3 1Department of Clinical Psychology, Kowloon Hospital, Hospital Authority, 2Department of Psychology, The Chinese University of Hong Kong, 3Department of Psychiatry, University of Hong Kong, 4Department of Psychiatry, The Chinese University of Hong Kong, 5Department of Psychiatry, Kwai Chung Hospital, Hospital Authority, 6Department of Clinical Psychology, Alice Ho Mui Ling Nethersole Hospital, Hospital Authority, 7Department of Surgery, University of Hong Kong, Hong Kong, People’s Republic of China Background: Methylphenidate (MPH) has been found to be an effective medication for attention-deficit/hyperactivity disorder (ADHD). However, there are neither consistent nor sufficient findings on whether psychiatric comorbidities and associated cognitive functions of ADHD are related to treatment response to MPH in ADHD children.Objectives: This study investigated whether psychiatric comorbidities, IQ, and neurocognitive deficits are related to treatment response to MPH in ADHD children. In some ways, it is preferable to have a drug that the effectiveness of which to a disorder is not affected by its associated cognitive functions and psychiatric comorbidities. On the other hand, it is likely that the baseline symptom severity of ADHD is associated with the effectiveness of MPH treatment on the symptoms post treatment.Methods: A total of 149 Chinese boys (aged 6–12years) with ADHD, combined type, and normal IQ participated in this study. Assessment of ADHD symptom severity was conducted pre and post MPH treatment, while assessment of psychiatric comorbidities, IQ, and neurocognitive deficits was performed in a non-medicated condition. Treatment response was defined as the ADHD symptom severity post MPH treatment.Results: Results indicated that MPH treatment was effective, significantly improving the ADHD condition. Yet, comorbid disorders, IQ, and neurocognitive deficits were not related to MPH treatment response on ADHD symptoms. These findings indicated that the effectiveness of MPH was not affected by psychiatric comorbidities and associated cognitive functions of ADHD. Instead, as expected, it was the baseline symptom severity that was mainly related to the treatment response, ie, the milder the baseline condition, the better the treatment response.Conclusion: The current findings positively endorse the widespread clinical use of MPH for treating ADHD. It improves the behavioral symptoms of ADHD regardless of varying psychiatric comorbidities, IQ, and neurocognitive deficits. Keywords: ADHD, psychiatric comorbidities, cognitive functions, treatment response, methylphenidate

Osteoporosis is caused by an imbalance between bone formation and bone resorption. Receptor activator of nuclear factor-κB ligand (RANKL) promotes the activity and differentiation of osteoclasts via activating the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. IMD 0354 is a selective molecular inhibitor of inhibitor of NF-κB kinase subunit beta (IKKβ) and effective for treatment of acute and subacute inflammatory diseases through the suppression of NF-κB activation. However, the effect of IMD 0354 on bone homeostasis is unknown. In this study, we demonstrated that IMD 0354 significantly attenuated ovariectomy-induced bone loss and inhibited osteoclastogenesis in mice, whereas bone formation was not affected. Additionally, IMD 0354 dramatically inhibited osteoclast differentiation and function induced by RANKL and macrophage colony-stimulating factor in bone marrow monocytes as verified by tartrate-resistant acid phosphatase (TRAP) staining as well as bone resorption assay in vitro. Subsequently, we found that activation of NF-κB signaling and the ERK/c-Fos axis were blunted during osteoclast formation induced by RANKL. Transcription factors nuclear factor of activated T cells c1 (NFATc1) and c-Fos were suppressed with the decreased expression of osteoclast-related genes by IMD 0354. Our findings suggest that IMD 0354 could be a potential preventive and therapeutic drug for osteoporosis.

Modic changes are the MRI signal changes of degenerative lumbar vertebral endplate and which lead to or accelerate intervertebral disc degeneration. NLRP3, caspase-1, and interleukin-1β (IL-1β) play a pivotal role in the pathogenesis of many inflammatory diseases, such as osteoarthritis. However, the roles of IL-1β and its activators caspase-1 and NLRP3 are unclear in the degenerative endplate. We asked: (1) What are the degenerative changes of the histologic features and chondrogenic markers’ gene expressions between the cartilaginous endplates of patients with Modic changes and trauma (control)? (2) How does the NLRP3/caspase-1/IL-1β axis in the cartilaginous endplates of patients with Modic changes compare with control (trauma) specimens? Surgical specimens of cartilaginous endplates were divided into Modic changes (n = 56) and the trauma control (n = 16) groups. Hematoxylin and eosin and safranin O staining of cartilaginous endplate tissues were done to evaluate the extracellular matrix. Reverse transcription-polymerase chain reaction was performed on these tissues to investigate mRNA expression of type II collagen (Col II), SOX-9, matrix metalloproteinase-3, and a disintegrin like and metalloproteinase thrombospondin type I motifs-5. NLRP3, caspase-1, and IL-1β were evaluated by reverse transcription-polymerase chain reaction and immunohistochemistry. Hematoxylin and eosin and safranin O staining showed the extracellular matrix degraded in the cartilaginous endplates of patients with Modic changes but not in the control cartilaginous endplates. Chondrogenic Col II (p = 0.024) and SOX9 (p = 0.053) were downregulated in the Modic changes group compared with the control group. In contrast to the control group, the transcriptional levels of NLRP3 (p < 0.001), caspase-1 (p = 0.054), and IL-1β (p = 0.001) were all upregulated in the Modic changes group. The expression of NLRP3, caspase-1, and IL-1β was upregulated in the patients with low back pain and Modic changes on MRI compared with patients with vertebral burst fracture without degenerative changes on MRI. The data suggest the NLRP3/caspase-1/IL-1β axis may be implicated in lumbar cartilaginous endplate degeneration. The NLRP3/caspase-1/IL-1β axis is active in cartilaginous endplates of patients with Modic changes and inflammatory cascades can exacerbate the cartilaginous endplate degeneration which may act as a trigger for intervertebral disc degeneration and low back pain. If these findings can be confirmed by others, we hope that new and effective therapy could be developed directed against this target.

Pamapimod (PAM) is a novel selective p38 mitogen-activated protein (MAP) kinase inhibitor proved to be effective in rheumatoid arthritis in phase 2 clinical trial. However, its effect on osteoclast-associated osteoporosis and the underlying mechanisms remain unclear. In this study, we showed that PAM suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation via inhibition of p38 phosphorylation and subsequent c-Fos and nuclear factor of activated T cells c1 (NFATc1) expression. In addition, the downregulated NFATc1 leads to reduced expression of its targeting gene disintegrin and metalloproteinase domain-containing protein 12 (ADAM12), which was further proven to be critical for osteoclastic bone resorption. Therefore, we treated ovariectomized (OVX) mice with PAM and revealed a protective effect of PAM on osteoporosis in vivo. In conclusion, our results demonstrated PAM can prevent OVX-induced bone loss through suppression of p38/NFATc1-induced osteoclast formation and NFATc1/ADAM12-associated bone resorption. © 2018 American Society for Bone and Mineral Research.

Background Attention Deficit/Hyperactivity Disorder (ADHD) is characterized with inattention, hyperactivity and impulsivity, while Autism Spectrum Disorder (ASD) is characterized with impaired social communication and interaction, restricted and repetitive patterns of behavior and activities. Phenotypically, both appear to be quite different. However, clinically it has been found that 20–50% ADHD children meet diagnostic criteria for ASD, while 30–80% ASD children meet diagnostic criteria for ADHD. These rates of comorbidity between the two disorders imply that they may share underlying etiologies. Although recent evidence has suggested a genetic overlap between ADHD and ASD, little progress has been made so far to identify the specific genes involved. The shank synaptic scaffold proteins, which are encoded by SHANK genes and located at the post-synaptic density of glutamatergic synapses, have been reported to be associated with a number of psychiatric disorders, including ADHD and ASD, separately. The aim of the current study is to investigate whether there is a genetic overlap between ADHD and ASD in SHANK genes. Methods In the present study, only male children with Chinese ethnicity, aged between 6 to 12 years, were included. 298 ADHD family trios (including ADHD children without ASD and their biological fathers and mothers), 134 ASD children without ADHD, and 109 children with both ASD and ADHD were recruited from public hospitals in Hong Kong. 232 normal control children were recruited from local primary schools. A number of single-nucleotide polymorphisms (SNPs) from SHANK2 and SHANK3 were selected for genotyping. After quality control, 14 SNPs from SHANK2 and 7 SNPs from SHANK3 were included for data analyses. For ADHD family trios’ data, we constructed ADHD cases and matched pseudo-control, which were based on transmitted and un-transmitted parental alleles using the Haplotype-Relative-Risk (HRR) principle. The pseudo-control supplemented the normal control to increase the statistical power. Likewise, ASD children with or without ADHD were also paired with samples of normal control and pseudo-control for association analysis. PLINK and KGG were used for statistical association analyses at SNP-level and gene-level, respectively. Results When association analysis was done between ADHD children without ASD and samples of normal control and pseudo-control, the T allele of rs7106631 of SHANK2 significantly decreased the ADHD risk (p=0.001, OR=0.70). When allele frequencies’ comparisons were conducted between ASD children with or without ADHD and samples of normal control and pseudo-control, the same protective effect of rs7106631 T allele was identified with OR=0.74 (p=0.011). Further association analysis conducted between all clinical children (i.e., ADHD children without ASD & ASD children with or without ADHD) and samples of normal control and pseudo-control yielded more significant results for rs7106631 (p=0.0003, OR=0.72). Additionally, significant associations were found for other SHANK2 SNPs, namely, rs7113016 (p=0.027), rs1073294 (p=0.008), rs11236616 (p=0.003), rs10899158 (p=0.048), and rs9888288 (p=0.004). However, no significant result was detected for SNPs of SHANK3. Subsequent gene-level analysis based on whole dataset suggested the significant role of SHANK2 in both ADHD and ASD (gene-level p=0.003). Discussion Consistent with previous findings in Western populations, this current study provides additional evidence for the significant association of SHANK2 with ASD from a Chinese population. A new finding rarely reported in previous studies is the association of SHANK2 with ADHD. This implies a shared genetic susceptibility between ADHD and ASD. Both disorders do share a number of characteristics, including male preponderance, increased level of oxidative stress, and abnormal neuronal connectivity, reflecting potentially common underlying neurodevelopmental abnormality. Speculatively, the identification of SHANK2 from this current candidate gene study as associating to both ADHD and ASD may provide the common genetic etiology to explain their shared characteristics and higher-than-chance comorbidity. Further studies examining the functional abnormalities of the identified gene, SHANK2, are warranted in the future.

Various virulence-associated genes or pathogenicity island are responsible for determining the pathogenicity of Escherichia coli strains. However, the correlation of the number and combination patterns of virulence-associated genes in Escherichia coli strains with their pathogenicity remains largely unknown. In this work, 581 chicken Escherichia coli strains were isolated from 1045 liver samples of dead chickens from 50 chicken farms at four provinces in China during 2007-2012. Based on the pathogenic test of SPF chickens, 320 chickens pathogenic Escherichia coli isolates were identified as highly (n = 193), intermediate (n = 98) and low pathogenic (n = 29) strains, respectively. Furthermore, the number of virulence genes in the 320 chicken pathogenic and 50 non-pathogenic Escherichia coli strains was examined. Our results reveal that thirteen virulence genes in Escherichia coli strains were detected, and all strains carried at least two or more than two virulence-associated genes. This study also suggests that highly pathogenic E. coli strains simultaneously carried at least 8 to13 virulence genes while intermediate pathogenic strains carried at least 5 to 8 virulence genes. The number of virulence-associated genes detected in highly pathogenic strains showed there were more significant differences than that in low pathogenic strains (P irp2, fyuA, and colV in high pathogenic strains was significantly higher than that in low and non-pathogenic strains (P irp2, fyuA, iucA, iucD, iutA, papC, iss, tsh, and colV were more often detected in highly and intermediate pathogenic E. coli strains. Taken together, our results provide evidences demonstrating that the pathogenicity of Escherichia coli strains is closely associated with the number and combination patterns of virulence-associated genes.

Intervertebral disc degeneration (IVDD) is a multifactorial disease and responsible for many spine related disorders, causes disability in the workforce and heavy social costs all over the world. Honokiol, a low molecular weight natural product, could penetrate into and distribute in IVDs to achieve therapeutic effect in a rat tail model. Therefore, the present study was undertaken to examine the antiinflammatory, antioxidation and IVD-protective effect of honokiol using nucleus pulposus cells and investigate its mechanisms to provide a new basis for future clinical treatment of IVDD. In the current study, we demonstrated that honokiol inhibits the H2O2-induced apoptosis (caspase-9, caspase-3, and bax), levels of oxidative stress mediators (ROS, MDA), expression of inflammatory mediators (Interleukin-6, COX-2, and iNOS), major matrix degrading proteases (MMP-3, MMP-13, ADAMTS5, and ADAMTS4) associated with nucleus pulposus degradation. Furthermore, we found nucleus pulposus protective ability of honokiol by up-regulating extra cellular matrix anabolic factors like type II collagen (Col II) and SOX9 in nucleus pulposus. We also found that honokiol suppressed the phosphorylation of NF-kB and JNK, and activation of TXNIP-NLRP3 inflammasome in H2O2-stimulated nucleus pulposus cells, thereby inhibiting the activation of downstream inflammatory mediators such as Interleukin-1β. Furthermore, honokiol showed a cartilage protective effect in the progression of IVDD in a rat model induced by puncture. Thus, our results demonstrate that honokiol inhibited the H2O2 induced apoptosis, oxidative stress, and inflammatory responses through the depression of TXNIP/NLRP3/caspase-1/ Interleukin − 1β signaling axis and the activation of NF-kB and JNK. Honokiol possess nucleus pulposus protective properties and may be of value in suppressing the pathogenesis of IVDD.

The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.

Free-standing graphene oxide (GO) thin films have been assembled by a pressurized ultrafiltration method. The GO films exhibit a layered microstructure with high structural stability and hydrophilicity, as analyzed by XPS, FESEM, XRD, positron annihilation spectroscopy (PAS), etc. The effects of ultrafiltration pressure and feed composition on the film׳s microstructure and pervaporation performance for dehydration of ethanol were investigated and correlated with XRD and PAS observations. Experimental results suggest that the interlaminar spacing is determined by both packing density of GO nanosheets and water content in the feed solution. The packing density is sensitively affected by the ultrafiltration pressure applied during film formation. By tuning the ultrafiltration pressure, a high separation performance with water permeability of 13,800 Barrer (1 Barrer=3.348×10 − 19 kmol m m − 2 s − 1 Pa − 1 ) and water/ethanol selectivity of 227 is achieved for dehydration of an 85 wt% ethanol aqueous solution at 24 °C. Additionally, the total permeability varied from 50 to 113,000 Barrer by increasing the water content in the feed from 0 to 100 wt%. As a result, the ideal water/ethanol selectivity calculated from single-component feed tests is about 2260 which is much higher than the selectivity obtained from binary-component feed tests. This discrepancy is probably attributed to the effect of intermolecular hydrogen bonding between water molecules and the functional groups on GO nanosheets that enlarges the interlaminar spacing and allows more ethanol transport through the GO film. The interactions among the GO nanosheets and the feed components enable the film to effectively dehydrate ethanol via pervaporation.

Rationale: Dieulafoy disease of the bronchus is a rare vascular deformity. To the best of our knowledge, reports of these involving both lung vascular are hitherto absent. Patient concerns: A 67-year-old male was admitted to our department due to agnogenic hemoptysis. Diagnoses: Bronchoscopy was performed and some smooth, pulsatile nodular lesions were found in the middle and lower lobes, Computed tomography angiography of the bronchial artery confirmed a left bronchial artery arising from the aortic arch at T4 level, and both bronchial arteries were dilated and tortuous. Interventions: Bronchial artery embolization was performed successfully. Outcomes: The patient was discharged with no hemoptysis. In addition, patient is under follow-up until today without any further incidents. Lessons: This case reminds us that Dieulafoy disease of the bronchus could be a potential etiology for unexplained hemoptysis. The clinician should be aware of this disease when bronchoscopy revealed multiple some smooth, pulsatile nodular lesions, thereafter, bronchoscope biopsy should be avoided, as it could lead to fatal hemoptysis.

In the present study, the prevalence of antimicrobial-resistant chicken Escherichia coli strains and the resistance genes in E. coli was investigated. For this purpose, 1002 chicken E. coli strains isolated from layer and broiler flocks in Shaanxi, Henan and Gansu provinces in China during 2007-2012 were examined. Antimicrobial susceptibility of these E. coli strains against 18 antimicrobials was determined by the Kirby-Bauer disk diffusion method. Eight out of the twenty antimicrobial resistance genes were detected by polymerase chain reaction (PCR). The sequences of the resistance genes in chicken E. coli strains were compared with the previously published sequences. Our results revealed that the antimicrobial resistance prevalence of E. coli strains in western China to ampicillin, doxycycline, tetracycline and nalidixic acid were consistently kept at 62-100%. The E. coli resistance to nalidixic acid and ciprofloxacin had an increasing trend, as high as 100% for nalidixic acid while the resistance prevalence to gentamicin had a decreasing trend. The detection rates of the genes for tetA, tetB, blaTEM, and aac(3)-II in chicken E. coli strains were positively correlated with their antimicrobial resistance (P

In this work, pervaporation membranes made of sulfonated polyphenylsulfone (sPPSU) materials were developed and applied for C1–C4 alcohols dehydration. Compared to their non-sulfonated polyphenylsulfone (PPSU) counterpart, the membranes from sulfonated materials can achieve both a higher permeability and a higher selectivity. Fundamentals of PPSU membranes with different degrees of sulfonation are investigated by employing different analytic instruments. Polymer chains of sPPSU membranes get stiffer than those of PPSU membrane due to the favorable interaction between –SO 3 H groups. Moreover, sPPSU membranes maintain similarly excellent mechanical properties and display slightly higher hydrophilicity compared with non-sulfonated PPSU membrane. The pervaporation characteristics and the temperature dependence of sPPSU membranes are examined with respect to the dehydration of an ethanol/water mixture. It is found that, for sPPSU membranes, permeation flux and permeability increase while separation factor and selectivity decreases with an increase in temperature. Activation energies based on flux ( E J ) and permeability ( E P ) are also found to rise with increasing degree of sulfonation, which reveal that dehydration performance of sPPSU membranes is more sensitive to operating temperature than that of PPSU membranes. Sorption analyses indicate that membrane separation performance is mainly attributed to the preferential diffusion of feed components through membranes. Dehydration of C1–C4 alcohols by pervaporation through these PPSU based membranes was subsequently studied. Interestingly, it can be observed that flux can be maintained above 30 g/m 2 h while separation factor follows the order of IPA>n-BuOH>EtOH>MeOH. Especially, it can reach to a separation factor above 11 at 60 °C for methanol dehydration, which is better than most other polymeric membranes, indicating a great potential to be applied for methanol purification in the industry.

BackgroundChildren with attention-deficit hyperactivity disorder (ADHD) have difficulties with executive function and impulse control which may improve with age.AimsTo map the brain correlates of executive function in ADHD and determine age-related changes in reaction times and brain volumes.MethodAttention-deficit hyperactivity disorder and control groups were compared on the change task measures of response inhibition (stop signal reaction time, SSRT) and shifting (change response reaction time, CRRT). Voxel-wise magnetic resonance imaging (MRI) correlations of reaction times and grey matter volume were determined, along with bivariate correlations of reaction times, brain volumes and age.ResultsIndividuals in the ADHD group had longer SSRTs and CRRTs. Anterior cingulate, striatal and medial temporal volumes highly correlated with SSRT. Striatal and cerebellar volumes strongly correlated with CRRT. Older children had faster reaction times and larger regional brain volumes. In controls, orbitofrontal, medial temporal and cerebellar volumes correlated with CRRT but not SSRT. Neither reaction times nor regional brain volumes were strongly age-dependent.ConclusionsOur evidence supports delayed brain maturation in ADHD and implies that some features of ADHD improve with age.

Background: Psychometric properties of the Chinese version of CBCL, TRF, and YSR were understudied. This study aimed at examining their test–retest reliability and criterion validity. Methods: Three Chinese community and clinic samples were recruited in Hong Kong. The parents, teachers, and youths respectively completed the CBCL, TRF, and YSR. Results: The Chinese CBCL, TRF, and YSR were test–retest reliable and valid. However, there was score/case attenuation at retest. CBCL and TRF appeared to screen externalizing and ADHD problems better, while YSR screened internalizing problems better. Conclusions: Clinicians should be cautious about score/case attenuation at retest while using CBCL, TRF, and YSR to chart patients’ progress. They should also recognize their different strengths in screening various disorders.

This study examined the prevalence and risk of psychiatric disturbances and suicidal behaviours among the peers of suicide attempters and completers. The subjects were selected from high schools with and without history of student suicides in the past 3 years. The psychiatric disturbances (as measured by the YSR and CBCL), suicidal behaviours, drug use, and a wide range of potential risk factors were measured. About a quarter of the peers of suicide completers and attempters were probable psychiatric cases and 15-21% of them reported suicidal acts. The increased risk of psychiatric disturbances and suicidal behaviours were still evident after controlling for age, sex, and potential risk factors. The presence of psychiatric disturbances could not wholly account for the increased odds of suicidal behaviours. Peers of suicide attempters carried a higher risk than peers of suicide completers. The close friends of suicide completers were particularly at risk of internalising problems, whereas the close friends of suicide attempters were at high risk of externalising problems. The peers of suicide completers and attempters represent a high-risk group for psychiatric disturbances and suicidal behaviours. The specific association of different types of psychiatric disturbances in the peers of suicide completers and attempters suggested that different risk mechanisms might be in operation within these peer groups.

To provide preliminary prevalence estimates of common DSM-IV (Diagnostic and Statistical Manual of Mental Disorders—4th Edition) disorders in a sample of Hong Kong Chinese adolescents. 541 Chinese adolescents were recruited from Grades 7, 8 and 9 of 28 mainstream high schools in Hong Kong (mean age=13.8 years; SD=1.2). The adolescents and their parents were separately administered the Youth and Parent versions of DISC-IV (Diagnostic Interview Schedule for Children-Version 4), respectively. Based upon both symptom and impairment criteria, as required by DSM-IV, the overall prevalence estimate of DSM-IV disorders in our sample of Chinese adolescents was 16.4%. Estimates for such individual disorders/diagnostic groupings as anxiety disorders, depressive disorders, attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD), and substance use disorders were 6.9, 1.3, 3.9, 6.8, 1.7, and 1.1%, respectively. These rates were largely compatible with those reported in previous studies with perhaps lower rates of generalized anxiety disorder (GAD), depressive disorders, CD, and substance use disorders, but a higher rate of ODD. The rate of ADHD was somewhat higher, but this might reflect the current DSM-IV diagnostic practice. The rate of anxiety disorders was not as high as predicted from some previous questionnaire surveys. The application of an impairment criterion had discernible impacts on prevalence estimates, greater on anxiety and substance use disorders, but smaller on depressive and disruptive behavior disorders. There was a lack of gender difference in rates of ODD and CD. While the findings reported here are broadly compatible with those of other studies, there may be cross-cultural differences in rates of some individual disorders, e.g., GAD, depressive disorders, ODD, CD, and substance use disorders, as well as in gender difference regarding rates of ODD and CD. However, exact comparison between studies is confounded by methodological differences in sample characteristics, measures, and case definition. Standardization of methodology in epidemiological surveys should allow more precise identification of any within- or between-culture variations in prevalence estimation.

Background: Despite the huge youth population, there is a lack of psychiatric diagnostic instruments with reported psychometric properties in Chinese. This study reports the development of the Chinese version of DISC-IV and examines its test–retest reliability. Method: Seventy-eight parents and 79 youths (mean age 13.1 years) attending child psychiatric clinics were interviewed twice using the Chinese DISC-IV (Diagnostic Interview Schedule for Children-IV) about 22 days apart. Results: The kappa coefficients were good to excellent for obsessive compulsive disorder (OCD) (both youth (Y) and parent (P) versions), major depressive disorder (MDD) (P), attention deficit hyperactivity disorder (ADHD) (P); fair for anxiety disorder (P), oppositional defiant disorder (ODD) (P, Y), MDD (Y); but poor for anxiety disorder (Y) and ADHD (Y). Parent informants had better test–retest reliability than youth informants. Conclusions: The Chinese DISC-IV had comparable test–retest reliability with the original English version.

The DISC Predictive Scales-4.32 (DPS-4.32) were short-forms of the Diagnostic Interview Schedule for Children-IV (DISC-IV). The psychometric properties of DPS-4.32 were tested on two Chinese samples: a clinic sample of 83 children/youths, and a community sample of 541 youths. Both Parent and Youth DPS-4.32 exhibited good-to-excellent test-retest reliability. Their screening efficiency was examined respectively against DSM-IV diagnoses of the full-length Parent and Youth DISC-IV. Results indicated large AUCs (Area under Receiver—Operating Charateristic Curve), as well as high sensitivity, specificity, and negative predictive values, supporting the capability of DPS-4.32 to differentiate cases from noncases. DPS-4.32 held promise as efficient short-forms of DISC-IV, screening DSM-IV diagnoses. They were also applicable to the Chinese population, demonstrating their cross-cultural applicability.

The subcellular distribution of the soluble flavohaemoglobin (HMP) of Escherichia coli has been determined. Cells over-expressing HMP from the cloned hmp gene on a multicopy plasmid were fractionated by osmotic shock and lysozyme treatment. Spectral analysis of subcellular fractions showed the CO-binding haemoprotein to be cytoplasmic. However, Western blotting using antibody raised to purified HMP revealed approximately 30% of the protein to be periplasmic in the over-expressing strain. Western analysis also revealed substantial levels of periplasmic HMP in a strain expressing only chromosomally encoded protein but none in an hmp mutant. The results are discussed in relation to protein function and the similar distribution reported for Vitreoscilla globin.