The flexible DC power network has the characteristics of low inertia and low damping, which makes the DC fault short-circuit current rise quickly. The existing research schemes by adding current limiting devices and improving converter topology will increase the investment cost. To reduce the breaking current of the DC circuit breaker (DCCB), an adaptive current limiting strategy for a modular multilevel converter (MMC) is proposed in this paper. Firstly, considering that the analytical formula of fault current in a flexible DC power grid is difficult to obtain, a fault current prediction method based on deep neural networks (DNN) is proposed in this paper. Secondly, based on the prediction of fault current, a matching strategy of MMC submodule input coefficient which ADAPTS to fault severity is proposed. Finally, a four-terminal flexible DC grid simulation model is built on the PSCAD/EMTDC platform to verify the effectiveness of the proposed adaptive current limiting control strategy. The simulation results show that the proposed adaptive current limiting control strategy reduces the breaking current of DCCB by 53.3%, 33.3%, and 16.1%, respectively. The proposed strategy is sensitive and effective to different fault locations and transition resistance.

Background: Peripheral T-cell lymphomas (PTCLs) are a highly heterogeneous group of aggressive malignant lymphomas, usually exhibit a poor prognosis, with a 5-year survival <50%, the risk of relapse remains quite high and relapsed or refractory (R/R) patients have been shown to have a very dismal outcome. Immunotherapy with anti-PD-1 antibodies may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. So far the largest study (Gxplore-002) including 102 patients with R/R PTCL showed that anti-PD-1 antibody is safe and has promising activity with overall response rate (ORR) of 40.4%. However, the depth of remission and long term prognosis are not satisfied with complete response rate (CRR) of 14.6% and the median progression-free survival of 2.7 months. Combination therapy is a potential strategy to increase the efficacy. Epigenetic agents may promote effect of anti-PD-1 antibody by stimulating antigen presentation, enhancing the migration of T cells to the tumor microenvironment, restoring T cell activation. These rationales support the combination of anti-PD-1 antibody and epigenetic agents. Therefore, the combination of sintilimab (anti-PD-1 antibody) and chidamide (histone deacetylase inhibitors, HDACi), azacitidine (hypomethylating agents, HMA) may have potent synergy in treating patients with relapsed or refractory PTCLs. Methods: This is a single-arm-phase II clinical trial for patients with relapsed or refractory PTCLs. Patients with at least one line of standard therapy are required. Prior HDACi or PD-1/PD-L1 antibodies or HMA is allowed. Patients with CNS disease or cutaneous T-cell lymphoma are excluded. Eligible patients will be treated with sintilimab (200 mg IV Q3W on day 1) in combination with chidamide (30 mg PO BIW on d1 and d4) and azacitidine (100 mg SC Q3W days 1-7). Cycles repeat every 3 weeks for up to 24 months in the absence of disease progression, death, unacceptable toxicity, hematopoietic stem cell transplantation, withdrawal of informed consent, other reasons specified in the protocol or the decision of the researcher. After completion of study treatment, participants are followed up at 90 days for safety and then every 90 days for survival. The study intends to enroll approximately 30 patients. Considering the safety of patients, the first 6 patients will be recruited slowly, if a DLT is observed in 2 of 6 patients, the investigators will decide to reduce the dose of chidamide to 20 mg, otherwise, all patients use 30 mg chidamide. The primary objective is ORR; the secondary objectives are CRR, duration of response (DOR), progression-free survival (PFS), overall survival(OS) and adverse events; the exploratory objective is the correlation of clinical response with the expression of PD-L1, CD4, CD8, CD68 in tumor environment. Clinical trial information: NCT04052659 The research was funded by: Innovent Biologics Inc. Keywords: Combination Therapies, Immunotherapy, Aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor, significantly improved clinical benefit in many solid tumours. TQB2450 is an engineered anti-programmed death-ligand 1 antibody. This study aimed to assess the safety and effect of TQB2450 plus anlotinib in patients with advanced solid tumour. This phase Ib study, which included a dose-escalating phase and an expansion phase, enrolled patients with advanced or metastatic solid tumour who had standard treatment failure or no standard treatment between June 2019 and January 2020. Eligible patients were firstly enrolled into sequential dose-escalating cohorts including 10mg and 12mg anlotinib plus TQB2450 following the conventional 3+3 design. If the starting dose of 10mg anlotinib led to ≥2 dose-limiting toxicities (DLTs), 8mg anlotinib would be administered. After the dose-escalating phase completed, eligible patients were enrolled into the expansion cohort. The primary outcomes were safety and objective response rate (ORR). In the dose-escalating phase, the first 3 eligible patients received 10mg anlotinib plus TQB2450 had no DLTs in the first cycle, neither did the 3 patients who received 12mg anlotinib plus TQB2450. Then the expansion phase started, 16 patients were enrolled and received 12mg anlotinib plus TQB2450. Of the 22 patients included, there are 6 patients with small cell lung cancer (SCLC), 8 patients with non-small cell lung cancer, 2 patients with colorectal cancer, 2 patients with breast cancer, 2 patients with ovarian cancer, 1 patient with thymic carcinoma and 1 patient with cervical cancer. Of Those patients, ORR was 32.8% and Disease control rate was 81.8%. Four SCLC patient had PR and 1 SCLC patient had stable disease. Ten ≥3 grade AEs were observed (Table).Table:The ≥3 grade AEs≥3 grade AEs10mg anlotinib plus TQB2450, n=312mg anlotinib plus TQB2450, n=19Hypertriglyceridemia14Dyspnea1Pericardial effusion1Oropharyngeal and gingival pain1Decreased lymphocyte count1Elevation of γ-glutamyltransferase1 Open table in a new tab 12mg anlotinib plus TQB2450 showed an acceptable safety profile and promising results in patients with advanced solid tumour. The phase Ib study is ongoing to investigate the safety and effect.

Many viruses previously have been shown to have pressurized genomes inside their viral protein shell, termed the capsid. This pressure results from the tight confinement of negatively charged viral nucleic acids inside the capsid. However, the relevance of capsid pressure to viral infection has not been demonstrated. In this work, we show that the internal DNA pressure of tens of atmospheres inside a herpesvirus capsid powers ejection of the viral genome into a host cell nucleus. To our knowledge, this provides the first demonstration of a pressure-dependent mechanism of viral genome penetration into a host nucleus, leading to infection of eukaryotic cells.

Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients.

We report on the properties and function of two herpes simplex virus-1 (HSV-1) microRNAs (miRNAs) designated "miR-H28" and "miR-H29." Both miRNAs accumulate late in productive infection at a time when, for the most part, viral DNA and proteins have been made. Ectopic expression of miRNA mimics in human cells before infection reduced the accumulation of viral mRNAs and proteins, reduced plaque sizes, and at vey low multiplicities of infection reduced viral yields. The specificity of the miRNA mimics was tested in two ways. First, ectopic expression of mimics carrying mutations in the seed sequence was ineffective. Second, in similar tests two viral miRNAs made early in productive infection also had no effect. Both miR-H28 and miR-H29 are exported from infected cells in exosomes. A noteworthy finding is that both miR-H28 and miR-H29 were absent from murine ganglia harboring latent virus but accumulated in ganglia in which the virus was induced to reactivate. The significance of these findings rests on the principle that the transmission of HSV from person to person is by physical contact between the infected tissues of the donor and those of uninfected recipient. Diminished size of primary or recurrent lesions could be predicted to enhance person-to-person transmission. Reduction in the amount of reactivating latent virus would reduce the risk of retrograde transport to the CNS but would not interfere with anterograde transport to a site at or near the site of initial infection.

The Compact Pulsed Hadron Source (CPHS) project that was launched in September 2009 at Tsinghua University has reached a first commissioning stage in conjunction with ongoing activities to fulfill the eventual design goal of a similar to 10(13) n/s epithermal-to-cold neutron yield for education, instrumentation development, and industrial applications. Here, we report the latest progress on the commissioning and applications of 3MeV proton and neutron beam lines in the last one and half years, and the design, fabrication, engineering of the 13 MeV/16kW proton accelerator system.

A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSVs express a long noncoding RNA, a latency-associated transcript (LAT), which plays a key role in maintaining latently infected neurons, but not viral proteins. To investigate the events leading to reactivation, we examined the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to nerve growth factor (NGF) or delayed reactivation in medium containing NGF and epidermal growth factor (EGF). Here we report the discovery that activating transcription factor 3 (ATF3), a stress response protein, profoundly affects the interaction of HSV with its host. Specifically, (i) ATF3 is induced by stress, such as inhibition of protein synthesis or infection; (ii) in infected cells, ATF3 enhances the accumulation of LAT by acting on the response elements in the promoter of the LAT precursor RNA; (iii) ATF3 is induced nearly 100-fold in ganglionic organ cultures; and (iv) ATF3 plays a key role in the maintenance of the latent state, inasmuch as expression of ATF3 bereft of the C-terminal activation domain acts as a dominant negative factor, inducing HSV gene expression in ganglionic organ cultures harboring latent virus and incubated in medium containing NGF and EGF. Thus, ATF3 is a component of a cluster of cellular proteins that together with LAT maintain the integrity of the neurons harboring latent virus.

The key events in herpes simplex virus (HSV) infections are (i) replication at a portal of entry into the body modeled by infection of cultured cells; (ii) establishment of a latent state characterized by a sole latency-associated transcript and microRNAs (miRNAs) modeled in murine peripheral ganglia 30 d after inoculation; and (iii) reactivation from the latent state modeled by excision and incubation of ganglia in medium containing anti-NGF antibody for a timespan of a single viral replicative cycle. In this report, we examine the pattern of synthesis and accumulation of 18 HSV-1 miRNAs in the three models. We report the following: (i) H2-3P, H3-3P, H4-3P, H5-3P, H6-3P, and H7-5P accumulated in ganglia harboring latent virus. All but H4-3P were readily detected in productively infected cells, and most likely they originate from three transcriptional units. (ii) H8-5P, H15, H17, H18, H26, and H27 accumulated during reactivation. Of this group, only H26 and H27 could be detected in productively infected cells. (iii) Of the 18 we have examined, only 10 miRNAs were found to accumulate above background levels in productively infected cells. The disparity in the accumulation of miRNAs in cell culture and during reactivation may reflect differences in the patterns of regulation of viral gene expression during productive infection and during reactivation from the latent state.

STING (stimulator of IFN genes) activates the IFN-dependent innate immune response to infection on sensing the presence of DNA in cytosol. The quantity of STING accumulating in cultured cells varies; it is relatively high in some cell lines [e. g., HEp-2, human embryonic lung fibroblasts (HEL), and HeLa] and low in others (e. g., Vero cells). In a preceding publication we reported that STING was stable in four cell lines infected with herpes simplex virus 1 and that it was actively stabilized in at least two cell lines derived from human cancers. In this report we show that STING is exported from HEp-2 cells to Vero cells along with virions, viral mRNAs, microRNAs, and the exosome marker protein CD9. The virions and exosomes copurified. The quantity of STING and CD9 exported from one cell line to another was inoculum-size-dependent and reflected the levels of STING and CD9 accumulating in the cells in which the virus inoculum was made. The export of STING, an innate immune sensor, and of viral mRNAs whose major role may be in silencing viral genes in latently infected neurons, suggests that the virus has evolved mechanisms that curtail rather than foster the spread of infection under certain conditions.

The Compact Pulsed Hadron Source (CPHS) project that was launched in September 2009 at Tsinghua University has reached a first commissioning stage in conjunction with on-going activities to fulfill the eventual design goal of a ∼1013 n/s epithermal-to-cold neutron yield for education, instrumentation development, and industrial applications. Here, we report the latest progress on the design, fabrication, engineering of the 13 MeV/16kW proton accelerator system, the neutron target station and neutron beamlines, especially regarding the successful delivery of the first 3-MeV proton beam and the realization of the first neutron generation in 2013.

ABSTRACT Herpes simplex virus 1 (HSV-1)-infected cell protein 0 (ICP0) is a multifunctional protein that plays a key role in overcoming numerous facets of host innate immunity. A key function of ICP0 that requires an intact RING finger domain is that of an ubiquitin E3 ligase: ICP0 interacts with at least three ubiquitin-conjugating enzymes of which one, UbcH5a, is required for degradation of PML and SP100. A preceding report showed that ICP0 is highly unstable at very early times after infection but becomes stable at later times. We report here that (i) the degradation of ICP0 is not infected cell specific, (ii) the degradation does not require the interaction of ICP0 with either UbcH5a, UbcH6, or UbcH9, (iii) ICP0 is degraded both early and late in cells infected with a mutant lacking the U L 13 protein kinase, (iv) ICP0 encoded by wild-type virus or the ΔU L 13 mutant is stable in cells transfected with a plasmid encoding U L 13 before infection, (v) ICP0 carrying mutations in the RING finger domain is stable both early and late in infection, and, finally, (vi) in cells infected with both wild type and RING finger mutant only the wild-type ICP0 is rapidly degraded at early times. The results suggest that the stability of ICP0 is mediated by the U L 13 protein kinase and that the target of proteolysis is a site at or near the RING domain of ICP0. IMPORTANCE ICP0, a major regulatory protein of HSV-1, turns over rapidly early in infection but becomes stable at late times. We report that stabilization requires the presence of U L 13 protein kinase and that an ICP0 with mutations in RING finger is stable. In mixed infections mutant ICP0 is stable, whereas the wild-type ICP0 is degraded. Our findings suggest that the lifestyle of HSV-1 requires an ICP0 that turns over rapidly if late proteins are absent.

HSVs transit from vigorous replication at the portal of entry into the body to a latent state in sensory neurons in which only noncoding (e.g., latency-associated transcript) and micro-RNAs are expressed. In productive infection, viral genes must be sequentially derepressed at two checkpoints. A leading role in the repression of viral genes is carried out by histone deacetylase (HDAC)/corepressor element-1 silencing transcription factor (CoREST)/lysinespecific demethylase1(LSD1)/RE1-silencing transcription factor (REST) repressor complex (HCLR). Previously, we reported that to define the role of the components of the HCLR complex in the establishment of latency, we constructed recombinant virus (R112) carrying a dominant-negative REST that bound response elements in DNA but could not recruit repressive proteins. This recombinant virus was unable to establish latency. In the current studies, we constructed a virus (R111) carrying WT REST with a WT genome. We report the following findings: (a) R111 readily established latent infection in trigeminal ganglia; however, although the amounts of viral DNAs in latently infected neurons were similar to those of WT virus, the levels of latency-associated transcript and micro-RNAs were 50- to 100-fold lower; (b) R111 did not spontaneously reactivate in ganglionic organ cultures; however, viral genes were expressed if the synthesis of REST was blocked by cycloheximide; and (c) histone deacetylase inhibitors reactivated the WT parent but not the R111 recombinant virus. The results suggest that REST plays a transient role in the establishment of latency but not in reactivation and suggest the existence of at least two phases at both establishment and reactivation.

A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSV expresses a long noncoding RNA and a set of microRNAs, but viral proteins are not expressed. The mechanism by which latent HSV reactivates is unknown. A key question is, what is the mechanism of reactivation in the absence of tegument proteins that enable gene expression in productive infection? Elsewhere we have reported the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to NGF or delayed reactivation in medium containing NGF and EGF. We also reported that in the ganglionic organ cultures incubated in medium containing antibody to NGF, all viral genes are derepressed at once without requiring de novo protein synthesis within the time frame of a single replicative cycle. Here we report that latent HSV in ganglia immersed in medium containing NGF and EGF is reactivated by (i) broad spectrum as well as specific histone deacetylase 1 or histone deacetylase 4 inhibitors, (ii) activation of p300/CBP, and (iii) either STAT3 carrying the substitution of tyrosine 705 to phenylalanine or an inhibitor of STAT3. Conversely, reactivation of latent HSV was blocked by p300/CBP inhibitor in medium containing antibody to NGF. The results suggest that (i) STAT3 is required for the maintenance of the latent state and interference with its functions leads to reactivation and (ii) p300/CBP is essential for HSV reactivation.

REST is a key component of the HDAC1 or 2, CoREST, LSD1, REST (HCLR) repressor complex. The primary function of the HCLR complex is to silence neuronal genes in non-neuronal cells. HCLR plays a role in regulating the expression of viral genes in productive infections as a donor of LDS1 for expression of α genes and as a repressor of genes expressed later in infection. In sensory neurons the HCLR complex is involved in the silencing of viral genome in the course of establishment of latency. The thesis of this article is that (a) sensory neurons evolved a mechanism to respond to the presence and suppress the transmission of infectious agents from the periphery to the CNS and (b) HSV evolved subservience to the HCLR with at least two objectives: to maintain a level of replication consistent with maximal person-to-person spread and to enable it to take advantage of neuronal innate immune responses to survive and be available for reactivation shielded from adaptive immune responses of the host.

Background Paroxysmal kinesigenic choreoathetosis (PKC) is characterised by recurrent and brief attacks of involuntary movement, inherited as an autosomal dominant trait with incomplete penetrance. A PKC locus has been previously mapped to the pericentromeric region of chromosome 16 (16p11.2-q12.1), but the causative gene remains unidentified. Methods/results Deep sequencing of this 30 Mb region enriched with array capture in five affected individuals from four Chinese PKC families detected two heterozygous PRRT2 insertions (c.369dupG and c.649dupC), producing frameshifts and premature stop codons (p.S124VfsX10 and p.R217PfsX8, respectively) in two different families. Sanger sequencing confirmed these two mutations and revealed a missense PRRT2 mutation (c.859G→A, p.A287T) in one of the two remaining families. This study also sequenced PRRT2 in 29 sporadic cases affected with PKC and identified mutations in 10 cases, including six with the c.649dupC mutation. Most variants were truncating mutations, consistent with loss-of-function and haploinsufficiency. Conclusion The present study identifies PRRT2 as the gene mutated in a subset of PKC, and suggests that PKC is genetically heterogeneous.

Herpes simplex viruses replicate at the portal of entry into the body and are transported retrograde to sensory neurons in which they can establish a silent, latent infection characterized by the expression of a noncoding latency-associated transcript and a set of microRNAs. At the portal of entry into the body and in cell culture a viral protein, VP16, recruits cellular proteins that initiate a sequential derepression of several kinetic classes of viral genes. Earlier studies have shown that upon reactivation of latent virus in ganglionic organ cultures all genes are derepressed at once, thus obviating the need for VP16 to initiate sequential derepression of viral genes. One hypothesis that could explain the data is that the massive reactivation of all classes of viral genes is the consequence of activation of an apoptotic pathway. Here we show that two proapoptotic drugs, dexamethasone and 2[[3-(2,3-dichlorophenoxy)propyl]amino]-ethanol, each accelerates viral gene expression in ganglionic organ cultures. We also show that in cultured cells apoptosis induced by dexamethasone accelerates viral gene expression and accumulation of infectious virus. The results are surprising in light of the relatively large number of viral proteins that independently block apoptosis induced by viral gene products or exogenous agents. The results suggest that the virus may rely on apoptosis to exit from latency but that apoptosis may be detrimental for virus replication or spread at the portal of entry into the body.

In cell cultures, HSV-1 replication is initiated by recruitment by virion protein 16 of transcriptional factors and histone-modifying enzymes to immediate early (α) gene promoters. HSV establishes latent infections characterized by suppression of viral gene expression except for latency-associated transcripts (LATs) and miRNAs. The latent virus reactivates in stressed neurons. A fundamental question is how reactivation initiates in the absence of virion protein 16. We report the following findings in the ganglion explant model. (i) Anti-nerve growth factor antibody accelerated the reactivation of latent virus. Viral mRNAs were detected as early as 9 h after explantation. (ii) After explantation the amounts of viral mRNAs increased whereas amounts of miRNAs and LATs decreased. The decrease in miRNAs and LATs required ongoing protein synthesis, raising the possibility that LAT and miRNAs were degraded by a viral gene product. (iii) The expression of viral genes in explanted ganglia was disordered rather than sequentially ordered as in infected cells in culture. These findings suggest that in reactivating ganglia gene expression is totally derepressed and challenge the current models in that establishment of or exit from latency could not be dependent on the suppression or activation of single or small clusters of viral genes. Finally, miRNAs and LATs reached peak levels 9–11 d after corneal inoculation, thus approximating the pattern of virus replication in these ganglia. These findings suggest that the patterns of accumulation of LATs and miRNAs reflect many different stages in the infection of neurons.

The fundamental question posed here is why in dorsal root ganglia herpes simplex viruses (HSV) can establish a silent infection in which only latency associate transcripts (LAT) and miRNAs are expressed and the neuronal cell survives whereas in non-neuronal cells HSV replicates and destroys the infected cells. Current evidence indicates that in productive infection there are two checkpoints. The first is at activation of α genes and requires a viral protein (VP16) that recruits HCF-1, Oct1, LSD1, and the CLOCK histone acetyl transferase to demethylate histones and initiate transcription. The second checkpoint involves activation of β and γ genes. An α protein, ICP0, activates transcription by displacing HDAC1 or 2 from the HDAC/CoREST/LSD1/REST repressor complex at its DNA binding sites. Current data suggest that in dorsal root ganglia VP16 and HCF-1 are not translocated to neuronal nucleus and that the HDAC/CoREST/LSD1/REST complex is not suppressed-a first step in silencing of the viral genome and establishment of heterochromatin. The viral genome remains in a state of equilibrium with respect to viral gene expression. The function of both LAT and the micro RNAs is to silence low level expression of viral genes that could reactivate the latent genomes.