Palmitoylation of KSHV pORF55 is required for Golgi localization and efficient progeny virion production.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus etiologically associated with multiple malignancies. Both latency and sporadic lytic reactivation contribute to KSHV-associated malignancies, however, the specific roles of many KSHV lytic gene products in KSHV replication remain elusive. In this study, we report that ablation of ORF55, a late gene encoding a tegument protein, does not impact KSHV lytic reactivation but significantly reduces the production of progeny virions. We found that cysteine 10 and 11 (C10 and C11) of pORF55 are palmitoylated, and the palmytoilation is essential for its Golgi localization and secondary envelope formation. Palmitoylation-defective pORF55 mutants are unstable and undergo proteasomal degradation. Notably, introduction of a putative Golgi localization sequence to these palmitoylation-defective pORF55 mutants restores Golgi localization and fully reinstates KSHV progeny virion production. Together, our study provides new insight into the critical role of pORF55 palmitoylation in KSHV progeny virion production and offers potential therapeutic targets for the treatment of related malignancies.

Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases.

Deubiquitinases (DUBs) remove ubiquitin from substrates and play crucial roles in diverse biological processes. However, our understanding of deubiquitination in viral replication remains limited. Employing an oncogenic human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deubiquitination, we found that Ovarian tumor family deubiquitinase 4 (OTUD4) promotes KSHV reactivation. OTUD4 interacts with the replication and transcription activator (K-RTA), a key transcription factor that controls KSHV reactivation, and enhances K-RTA stability by promoting its deubiquitination. Notably, the DUB activity of OTUD4 is not required for K-RTA stabilization; instead, OTUD4 functions as an adaptor protein to recruit another DUB, USP7, to deubiquitinate K-RTA and facilitate KSHV lytic reactivation. Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new antiviral therapies.

Epstein-Barr virus-encoded miR-BART11-3p modulates the DUSP6-MAPK axis to promote gastric cancer cell proliferation and metastasis.

Epstein-Barr virus (EBV)-encoded miRNAs within the BamHI-A rightward transcript (BART) region are abundantly expressed in EBV-associated gastric cancer (EBVaGC), suggesting that they play roles in tumorigenesis. However, how these viral miRNAs contribute to the development of EBVaGC remains largely obscure. In this study, we found that EBV-encoded miR-BART11-3p targets 3' -UTR of dual-specificity phosphatase 6 (DUSP6) mRNA to upregulate ERK phosphorylation and downregulate JNK and p38 phosphorylation. By doing so, miR-BART11-3p promotes gastric cancer (GC) cell proliferation, migration, and invasion in vitro, and facilitates tumor growth in vivo. Restoration of DUSP6 expression reverses the tumor-promoting activity of miR-BART11-3p in AGS GC cells. Consistently, knockdown of DUSP6 ablates the antitumor effects of miR-BART11-3p inhibitors in EBV-positive GC cells. Furthermore, blocking ERK phosphorylation with trametinib inhibited the proliferation, migration, and invasion of miR-BART11-3p-expressing AGS cells. Administration of a miR-BART11-3p antagomir reduced the growth of EBV-positive xenograft tumors. Together, these findings reveal a novel mechanism by which EBV dysregulates MAPK pathways through an EBV-encoded microRNA to promote the development and progression of EBVaGC, which may be harnessed to develop new therapeutics to treat EBVaGC. IMPORTANCE The Epstein-Barr virus (EBV) is the first human tumor virus found to encode miRNAs, which within the BART region have been detected abundantly in EBV-associated gastric cancer (EBVaGC) and play various roles in promoting tumorigenesis. In our study, we observed that EBV-miR-BART11-3p promotes cell proliferation and induces migration and invasion in GC. Interestingly, we showed that miR-BART11-3p upregulates p-ERK and downregulates p-JNK and p-p38 by directly targeting 3'-UTR of dual-specificity phosphatase 6 (DUSP6). Restoration of DUSP6 rescues the effects generated by miR-BART11-3p in GC cells, and blocking ERK phosphorylation with Trametinib augments JNK and p38 phosphorylation and inhibits the effects of miR-BART11-3p-expressing AGS cells, suggesting that miR-BART11-3p promotes cell proliferation, migration, and invasion by modulating DUSP6-MAPK axis in EBVaGC. The findings presented in this study provide new mechanisms into the tumorigenesis in EBVaGC and new avenues for the development of therapeutic strategies to combat EBVaGC targeting miR-BART11-3p or phospho-ERK.

Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity.

Oncolytic viruses (OVs) encoding various transgenes are being evaluated for cancer immunotherapy. Diverse factors such as cytokines, immune checkpoint inhibitors, tumor-associated antigens, and T cell engagers have been exploited as transgenes. These modifications are primarily aimed to reverse the immunosuppressive tumor microenvironment. By contrast, antiviral restriction factors that inhibit the replication of OVs and result in suboptimal oncolytic activity have received far less attention. Here, we report that guanylate-binding protein 1 (GBP1) is potently induced during HSV-1 infection and restricts HSV-1 replication. Mechanistically, GBP1 remodels cytoskeletal organization to impede nuclear entry of HSV-1 genome. Previous studies have established that IpaH9.8, a bacterial E3 ubiquitin ligase, targets GBPs for proteasomal degradation. We therefore engineered an oncolytic HSV-1 to express IpaH9.8 and found that the modified OV effectively antagonized GBP1, replicated to a higher titer in vitro and showed superior antitumor activity in vivo. Our study features a strategy for improving the replication of OVs via targeting a restriction factor and achieving promising therapeutic efficacy.

Establishment and characterization of two Epstein-Barr virus-positive gastric cancer cell lines with epitheliotropic M81 strain undergoing distinct viral and altered cellular expression profiles.

Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct subtype of gastric cancer (GC) distinguished by the presence of the EBV genome and limited viral gene expression within malignant epithelial cells. EBV infection is generally thought to be a relatively late event following atrophic gastritis in carcinogenesis, which implies the heterogeneity of EBVaGC. To facilitate the study of the role of EBV in EBVaGC, we established two EBV-positive GC cell lines (AGS-EBV and HGC27-EBV) with an epitheliotropic EBV strain M81 and characterized viral and cellular gene expression profiles in comparison to SNU719, a naturally derived EBV-positive GC cell line. Like SNU719, AGS-EBV and HGC27-EBV stably maintained their EBV genomes and expressed EBV-encoded small RNAs and nuclear antigen EBNA1. Comprehensive analysis of the expression of EBV-encoded miRNAs within the BamHI-A region rightward transcript region, and the transcripts of EBV latent and lytic genes in cell lines, as well as xenografts, reveals that AGS-EBV and HGC27-EBV cells undergo distinct viral expression profiles. A very small fraction of AGS-EBV and SNU719 cells can spontaneously produce infectious progeny virions, while HGC27-EBV does not. AGS-EBV (both M81 and Akata) cells largely mimic SNU719 cells in viral gene expression profiles, and altered cellular functions and pathways perturbed by EBV infection. Phylogenetic analysis of the EBV genome shows both M81 and Akata EBV strains are closely related to clinical EBVaGC isolates. Taken together, these two newly established EBV-positive GC cell lines can serve as models to further investigate the role of EBV in different contexts of gastric carcinogenesis and identify novel therapeutics against EBVaGC.

Insomnia symptoms during the early and late stages of the COVID-19 pandemic in China: a systematic review and meta-analysis.

BACKGROUND: Evidence suggests that the outbreak of the coronavirus disease 2019 (COVID-19) and the prevention/control measures for COVID-19 may cause insomnia during the acute phase of COVID-19 pandemic in China. However, it is unclear whether insomnia sustains during the later phases of the pandemic. METHODS: We searched PubMed/Medline, EMBASE, PsycINFO and China National Knowledge Infrastructure from the 27th December 2019 to the 2nd February 2021. As early stage studies on COVID-19 pandemic in China were defined as those conducted prior to April 1st, 2020, while late stage studies were those conducted after April 1st, 2020. RESULTS: A total of 98 studies with 193,889 participants were included. The pooled prevalence of insomnia symptoms among all populations was 39.1% (95% CI 36.2-42.0%); the pooled prevalence of insomnia symptoms during the early and late stages of COVID-19 in China were 37.0% (95% CI 34.1-39.9%) and 41.8% (95% CI 33.6-50.0%), respectively. Importantly, there was no significant difference regarding the prevalence of insomnia symptoms between the early and late stages of COVID-19. Meta-regression showed that healthcare workers, COVID-19 patients, patients with chronic medical conditions and patients with mental disorders had a higher prevalence of insomnia symptoms compared to the general population. This association remained significant in healthcare workers and patients with chronic medical conditions after adjusting for age, gender, areas of high or low prevalence of COVID-19 cases, anxiety and depression. CONCLUSIONS: Over one third of our sample present insomnia symptoms during the early stage of COVID-19 pandemic in China. Interestingly, prevalence of insomnia symptoms sustains high during the late stage of the pandemic despite the control of the disease and the amelioration of its adverse effects. Our findings suggest that insomnia symptoms related to COVID-19 appear to persist of over time.

Effects of electrostatic therapy on nighttime sleep and daytime symptoms in patients with chronic insomnia: Evidences from an open label study.

Introduction: Transcranial electric stimulation (TES) is a neuromodulation approach that applies low-intensity electrical current to the brain and has been proposed as a treatment for insomnia. Electrostatic therapy is a kind of TES and people do not have a feeling of electrical stimuli when the voltage of static electricity is lower than 2,000 volts. However, no studies have examined the effects of electrostatic therapy on objective sleep and daytime symptoms in patients with insomnia. Materials and methods: Thirty chronic insomnia patients were included. All patients received a 6 week electrostatic therapy and three comprehensive assessments including two consecutive polysomnography (PSG) and daytime symptoms assessments, at pre-treatment, 3 week and 6 week of treatment. Insomnia Severity Index (ISI) was used to assess the severity of insomnia. Multiple sleep latency test (MSLT), Epworth Sleepiness Scale (ESS), and Flinders Fatigue Scale (FFS) were used to assess objective and self-reported daytime sleepiness and fatigue, respectively. Attention network test (ANT) was used to assess attention levels. Results: Total ISI scores decreased significantly at 3 weeks (p < 0.001) and 6 weeks (p < 0.001) after initiation of treatment. Furthermore, objective total sleep time (TST, p = 0.020) and sleep efficiency (SE, p = 0.009) increased and wake time after sleep onset (p = 0.012) decreased significantly after 6 weeks electrostatic therapy. Regarding daytime symptoms, ESS and FFS scores decreased significantly at 3 weeks (ESS, p = 0.047; FFS, p = 0.017) and 6 weeks (ESS, p = 0.008; FFS, p = 0.003) after initiation of treatment. Moreover, executive control improved significantly from pre-treatment to 3 weeks (p = 0.006) and 6 weeks (p = 0.013) and altering network improved significantly at 6 weeks (p = 0.003) after initiation of treatment. Secondary analyses showed that TST and SE improved significantly after electrostatic therapy in insomnia patients who slept < 390 min (all p-value < 0.05). However, no significant changes regarding TST and SE were observed in insomnia patients who slept ≥ 390 min. Conclusion: Electrostatic therapy improves both nighttime sleep and daytime symptoms in patients with chronic insomnia. The effect on objective sleep appears to be stronger in patient with objective short sleep duration. Electrostatic therapy might be a therapeutic choice for insomnia patients with difficulty maintaining sleep and not responding to behavioral treatments. Clinical trial registration: [www.clinicaltrials.gov], identifier [ChiCTR2100051590].

The Second-Generation XPO1 Inhibitor Eltanexor Inhibits Human Cytomegalovirus (HCMV) Replication and Promotes Type I Interferon Response.

Human cytomegalovirus (HCMV) is a ubiquitous opportunistic pathogen and can be life-threatening for immunocompromised individuals. There is currently no available vaccine for the prevention of HCMV- associated diseases and most of the available antiviral drugs that target viral DNA synthesis become ineffective in treating HCMV mutants that arise after long-term use in immunocompromised patients. Here, we examined the effects of Eltanexor, a second-generation selective inhibitor of nuclear export (SINE), on HCMV replication. Eltanexor effectively inhibits HCMV replication in human foreskin fibroblasts in a dose-dependent manner. Eltanexor does not significantly inhibit viral entry and nuclear import of viral genomic DNA, but rather suppress the transcript and protein levels of viral immediate-early (IE), early (E) and late (L) genes, and abolishes the production of infectious virions. We further found Eltanexor treatment promotes proteasome-mediated degradation of XPO1, which contributes to the nuclear retention of interferon regulatory factor 3 (IRF-3), resulting in increased expression of type I interferon as well as interferon stimulating genes ISG15 and ISG54. This study reveals a novel antiviral mechanism of Eltanexor which suggests it has potential to inhibit a broad spectrum of viral pathogens.

Psychological reactions and insomnia in adults with mental health disorders during the COVID-19 outbreak.

BACKGROUND: The 2019 coronavirus disease (COVID-19) has disrupted millions of lives and commerce. We investigated psychological reactions and insomnia during the COVID-19 outbreak in adults with mental health disorders (MDs). METHODS: A self-reported psychological and sleep online survey was conducted in China between February 5th to 19th, 2020. A total of 244 adults with MDs and 1116 controls matched for age, gender and sites were included. Worsened symptoms of anxiety, depressive and insomnia were defined when severity levels shifted to a more severe category compared to pre-COVID-19. RESULTS: During the COVID-19 outbreak, we found significantly increased prevalence of anxiety (MDs: 54.9% vs. 49.6%, controls: 25.5% vs. 14.3%), depression (MDs: 63.9% vs. 61.5%, controls: 29.9% vs. 21.2%) and insomnia (MDs: 66.0% vs. 57.8%, controls: 31.5% vs. 24.8%) compared to pre-COVID-19 period (all P-value < 0.001). Furthermore, adults with MDs had higher odds for developing COVID-19-related stress (OR = 3.41, 95% CI 2.49 ~ 4.67), worsened anxiety (OR = 1.95, 95% CI 1.38 ~ 2.76), depression (OR = 2.04, 95% CI 1.43 ~ 2.93) and insomnia (OR = 2.22, 95% CI 1.53 ~ 3.21) during the COVID-19 outbreak compared to controls. Moreover, higher COVID-19-related stress and lower levels of pre-COVID-19 anxiety, depressive and insomnia symptoms were predictors for worsened anxiety, depression and insomnia in adults with MDs, respectively. CONCLUSIONS: Our findings suggest that adverse psychological reactions and insomnia are more pronounced in adults with mental health disorders during the COVID-19 outbreak, thus more attention need to be provided.

Whole Genome Assembly of Human Papillomavirus by Nanopore Long-Read Sequencing.

Human papillomavirus (HPV) is a causal agent for most cervical cancers. The physical status of the HPV genome in these cancers could be episomal, integrated, or both. HPV integration could serve as a biomarker for clinical diagnosis, treatment, and prognosis. Although whole-genome sequencing by next-generation sequencing (NGS) technologies, such as the Illumina sequencing platform, have been used for detecting integrated HPV genome in cervical cancer, it faces challenges of analyzing long repeats and translocated sequences. In contrast, Oxford nanopore sequencing technology can generate ultra-long reads, which could be a very useful tool for determining HPV genome sequence and its physical status in cervical cancer. As a proof of concept, in this study, we completed whole genome sequencing from a cervical cancer tissue and a CaSki cell line with Oxford Nanopore Technologies. From the cervical cancer tissue, a 7,894 bp-long HPV35 genomic sequence was assembled from 678 reads at 97-fold coverage of HPV genome, sharing 99.96% identity with the HPV sequence obtained by Sanger sequencing. A 7904 bp-long HPV16 genomic sequence was assembled from data generated from the CaSki cell line at 3857-fold coverage, sharing 99.99% identity with the reference genome (NCBI: U89348). Intriguingly, long reads generated by nanopore sequencing directly revealed chimeric cellular-viral sequences and concatemeric genomic sequences, leading to the discovery of 448 unique integration breakpoints in the CaSki cell line and 60 breakpoints in the cervical cancer sample. Taken together, nanopore sequencing is a unique tool to identify HPV sequences and would shed light on the physical status of HPV genome in its associated cancers.

The use of renin-angiotensin-aldosterone system (RAAS) inhibitors is associated with a lower risk of mortality in hypertensive COVID-19 patients: A systematic review and meta-analysis.

Renin-angiotensin-aldosterone system (RAAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are one of the most prescribed antihypertensive medications. Previous studies showed RAAS inhibitors increase the expression of ACE2, a cellular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which provokes a concern that the use of ACEI and ARB in hypertensive individuals might lead to increased mortality and severity of coronavirus disease 2019 (COVID-19). To further investigate the effects of ACEI/ARB on COVID-19 patients, we systematically reviewed relevant studies that met predetermined inclusion criteria in search of PubMed, Embase, Cochrane Library databases, medRxiv, and bioRxiv. The search strategy included clinical data published through October 12, 2020. Twenty-six studies involving 8104 hypertensive patients in ACEI/ARB-treated group and 8203 hypertensive patients in non-ACEI/ARB-treated group were analyzed. Random-effects meta-analysis showed ACEI/ARB treatment was significantly associated with a lower risk of mortality in hypertensive COVID-19 patients (odds ratio [OR] = 0.624, 95% confidence interval [CI] = 0.457-0.852, p = .003, I2 = 74.3%). Meta-regression analysis showed that age, gender, study site, Newcastle-Ottawa Scale scores, comorbidities of diabetes, coronary artery disease, chronic kidney disease, or cancer has no significant modulating effect of ACEI/ARB treatment on the mortality of hypertensive COVID-19 patients (all p > .1). In addition, the ACEI/ARB treatment was associated with a lower risk of ventilatory support (OR = 0.682, 95% CI = 0.475-1.978, p = .037, I2 = 0.0%). In conclusion, these results suggest that ACEI/ARB medications should not be discontinued for hypertensive patients in the context of COVID-19 pandemic.

Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures.

By 27 February 2020, the outbreak of coronavirus disease 2019 (COVID-19) caused 82 623 confirmed cases and 2858 deaths globally, more than severe acute respiratory syndrome (SARS) (8273 cases, 775 deaths) and Middle East respiratory syndrome (MERS) (1139 cases, 431 deaths) caused in 2003 and 2013, respectively. COVID-19 has spread to 46 countries internationally. Total fatality rate of COVID-19 is estimated at 3.46% by far based on published data from the Chinese Center for Disease Control and Prevention (China CDC). Average incubation period of COVID-19 is around 6.4 days, ranges from 0 to 24 days. The basic reproductive number (R0 ) of COVID-19 ranges from 2 to 3.5 at the early phase regardless of different prediction models, which is higher than SARS and MERS. A study from China CDC showed majority of patients (80.9%) were considered asymptomatic or mild pneumonia but released large amounts of viruses at the early phase of infection, which posed enormous challenges for containing the spread of COVID-19. Nosocomial transmission was another severe problem. A total of 3019 health workers were infected by 12 February 2020, which accounted for 3.83% of total number of infections, and extremely burdened the health system, especially in Wuhan. Limited epidemiological and clinical data suggest that the disease spectrum of COVID-19 may differ from SARS or MERS. We summarize latest literatures on genetic, epidemiological, and clinical features of COVID-19 in comparison to SARS and MERS and emphasize special measures on diagnosis and potential interventions. This review will improve our understanding of the unique features of COVID-19 and enhance our control measures in the future.

Heterogeneous Responses of Gastric Cancer Cell Lines to Tenovin-6 and Synergistic Effect with Chloroquine.

Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer death. Approximately 15% of GC is associated with Epstein-Barr virus (EBV). GC is largely incurable with a dismal five-year survival rate. There is an urgent need to identify new therapeutic agents for the treatment of GC. Tenovin-6 was initially identified as a p53 activator, but it was later found to inhibit autophagy flux, and the protein deacetylase activity of sirtuins. Tenovin-6 shows promising therapeutic effect in various malignancies. However, it remains unknown whether Tenovin-6 is effective for GC. In this study, we found that EBV-positive and -negative GC cell lines were sensitive to Tenovin-6 but with different response times and doses. Tenovin-6 suppressed anchorage-independent growth of GC cells. Tenovin-6 induced different levels of apoptosis and phases of cell-cycle arrest depending on the cell lines with some manifesting gap 1 (G1) and others showing synthesis (S) phase cell-cycle arrest. Mechanistically, Tenovin-6 induced autophagy or p53 activation in GC cells depending on the status of TP53 gene. However, initiation of autophagy following treatment with Tenovin-6 conferred some protective effect on numerous cells. Combined treatment with Tenovin-6 and autophagy inhibitor chloroquine increased the cytotoxic effect by inducing microtubule-associated protein 1 light chain 3B (LC3B)-II accumulation, and by enhancing apoptosis and cell-cycle arrest. These results indicated that Tenovin-6 can be used as a potential therapeutic agent for GC, but the genetic background of the cancer cells might determine the response and mechanism of action. Treatment with Tenovin-6 alone or in combination with chloroquine could be a promising therapeutic approach for GC.

Upregulation of SOX11 enhances tamoxifen resistance and promotes epithelial-to-mesenchymal transition via slug in MCF-7 breast cancer cells.

Resistance to tamoxifen remains a prominent conundrum in the therapy of hormone-sensitive breast cancer. Also, the molecular underpinnings leading to tamoxifen resistance remain unclear. In the present study, we utilized the Gene Expression Omnibus database to identify that SOX11 might exert a pivotal function in conferring tamoxifen resistance of breast cancer. SOX11 was found to be markedly upregulated at both the messenger RNA and protein levels in established MCF-7-Tam-R cells compared to the parental counterparts. Moreover, SOX11 was able to activate the transcription of slug via binding to its promoter, resulting in promoting the progress of epithelial-to-mesenchymal transition and suppressing the expression of ESR1. Downregulating SOX11 expression can restore the sensitivity to 4-hydroxytamoxifen in MCF-7-Tam-R cells. Survival analysis from large sample datasets indicated that SOX11 was closely related to poorer survival in patients with breast cancer. These findings suggest a novel feature of SOX11 in contributing to tamoxifen resistance. Hence, targeting SOX11 could be a potential therapeutic strategy to tackle tamoxifen resistance in breast cancer.

Sleep disorders in Wilson disease: a systematic review and meta-analysis.

STUDY OBJECTIVES: Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism resulting in pathologic accumulation of copper in many organs and tissues. Sleep disorders are highly prevalent in patients with WD. However, both prevalence rates and severity of different sleep disorders in patients with WD vary widely. The aims of the current study were to systematically review and perform a meta-analysis of the association between WD and prevalent sleep disorders, including insomnia, rapid eye movement (REM) sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), sleep-disordered breathing (SDB), restless legs syndrome (RLS), periodic limb movement in sleep (PLM), cataplexy-like episodes (CLEs) and sleep paralysis, and objective sleep characteristics. METHODS: We performed a systematic search of PubMed, EMBase, the Cochrane Library, PsycINFO and ISI Web of Science for case-control studies. A total of 7 studies with 501 participants were included. RESULTS: We found that 54.1% of patients with WD experience sleep disorders and up to 7.65-fold higher odds compared to control patients. Specifically, patients with WD had higher rates of RBD, insomnia, and EDS based on self-reported questionnaires. No differences were observed in terms of RLS, PLM, or SDB between patients with WD and control patients. Furthermore, objective sleep disruptions based on polysomnographic studies included prolonged sleep onset latency and REM sleep onset latency, reduced total sleep time and sleep efficiency, higher percentage of stage N1 sleep and lower percentage of stage N2 sleep were observed in patients with WD. CONCLUSIONS: Our study indicates that sleep disorders are frequent in patients with WD. Future studies should examine the longitudinal association of WD with sleep disturbances.

Herpesviral infections and antimicrobial protection for Alzheimer's disease: Implications for prevention and treatment.

Accumulating evidence suggests that infections by herpesviruses might be closely linked to Alzheimer's disease (AD). Pathological hallmarks of AD brains include senile plaques induced by amyloid ß peptide (Aß) in the extracellular space and intracellular neurofibrillary tangles (NFTs) consisting of phosphorylated tau protein. The prevailing hypothesis for the mechanism of AD is amyloid cascade reaction. Recent studies revealed that infections by herpesviruses induce the similar pathological hallmarks of AD, including Aß production, phosphorylation of tau (P-tau), oxidative stress, neuroinflammation, etc. Aß peptide is regarded as one of the antimicrobial peptides, which inhibits HSV-1 replication. In the elderly, reactivation of herpesviruses might act as an initiator for amyloid cascade reaction in vulnerable individuals, triggering the neurofibrillary formation of phosphorylated tau and inducing oxidative stress and neuroinflammation, which can further contribute to the accumulation of Aß and P-tau by impairing mitochondria and autophagosome. Epidemiological studies have shown AD susceptibility genes, such as APOE-ε4 allele, are highly linked to infections by herpesviruses. Interestingly, anti-herpesviral therapy significantly reduced the risk of AD in a large population study. Given that herpesviruses are arguably the most prevalent opportunistic pathogens and often reactivate in the elderly, it is reasonable to argue reactivation of herpesviruses might be major culprits for initiating AD in individuals carrying AD susceptibility genes. In this review, we summarize epidemiological and molecular evidence that support for a hypothesis of herpesviral infections and antimicrobial protection in the development of AD, and discuss the implications for future prevention and treatment of the disease.

Complication rate of different wound closures after primary hip arthroplasty - A survey of 373 patients.

BACKGROUND: Wound closure is highly associated with wound complications and the best wound closure method was controversial in total hip arthroplasty. METHODS: We performed a retrospective study of primary hip arthroplasty and compared three types of closure method. RESULTS: 155 cases were closed using continuous subcuticular sutures then with staples, 111 using staples, 141 using interrupted sutures. 28 cases of wound complications occurred. Wound complication rates in subcuticular suture group, staple group and interrupted suture group were 1.9%, 11.7% and 8.5%, respectively (p < 0.01). CONCLUSION: Wound complication rate was significantly lower when wound was closed with continuous subcuticular suturue.

Ultralow-power near-infrared excited neodymium-doped nanoparticles for long-term in vivo bioimaging.

Lanthanide-doped luminescent nanoparticles with both emission and excitation in the near-infrared (NIR-to-NIR) region hold great promise for bioimaging. Herein, core@shell structured LiLuF4:Nd@LiLuF4 (named as Nd@Lu) nanoparticles (NPs) with highly efficient NIR emission were developed for high-performance in vivo bioimaging. Strikingly, the absolute quantum yield of Nd@Lu NPs reached as high as 32%. After coating with polyethylene glycol (PEG), the water-dispersible Nd@Lu NPs showed good bio-compatibility and low toxicity. With efficient NIR emission, the Nd@Lu NPs were clearly detectable in tissues at depths of up to 20 mm. In addition, long-term in vivo biodistribution with a high signal-to-noise ratio of 25.1 was distinctly tracked upon an ultralow-power-density excitation (10 mW cm-2) of 732 nm for the first time.

Reducing persistent polyomavirus infection increases functionality of virus-specific memory CD8 T cells.

Mouse polyomavirus (MuPyV) causes a smoldering persistent infection in immunocompetent mice. To lower MuPyV infection in acutely and persistently infected mice, and study the impact of a temporal reduction in viral loads on the memory CD8 T cell response, we created a recombinant MuPyV in which a loxP sequence was inserted into the A2 strain genome upstream of the early promoter and another loxP sequence was inserted in cis into the intron shared by all three T antigens. Using mice transgenic for tamoxifen-inducible Cre recombinase, we demonstrated that reduction in MuPyV load during persistent infection was associated with differentiation of virus-specific CD8 T cells having a superior recall response. Evidence presented here supports the concept that reduction in viral load during persistent infection can promote differentiation of protective virus-specific memory CD8 T cells in patients at risk for diseases caused by human polyomaviruses.