Pacritinib inhibits proliferation of primary effusion lymphoma cells and production of viral interleukin-6 induced cytokines.

Primary effusion lymphoma (PEL) and a form of multicentric Castleman's disease (MCD) are both caused by Kaposi sarcoma herpesvirus (KSHV). There is a critical need for improved therapies for these disorders. The IL-6/JAK/STAT3 pathway plays an important role in the pathogenesis of both PEL and KSHV-MCD. We explored the potential of JAK inhibitors for use in PEL and KSHV-MCD, and found that pacritinib was superior to others in inhibiting the growth of PEL cell lines. Pacritinib induced apoptosis in PEL cells and inhibited STAT3 and NF-κB activity as evidenced by reduced amount of phosphorylated moieties. Pacritinib also inhibits FLT3, IRAK1, and ROS1; studies utilizing other inhibitors of these targets revealed that only FLT3 inhibitors exhibited similar cell growth inhibitory effects. FLT3's likely contribution to pacritinib's cell growth inhibition was further demonstrated by siRNA knockdown of FLT3. RNA sequencing and RT-PCR showed that many key host genes including cyclins and IL-6 were downregulated by pacritinib, while KSHV genes were variably altered. Finally, pacritinib suppressed KSHV viral IL-6-induced human IL-6 and IL-10 production in peripheral blood mononuclear cells, which may model an important step in KSHV-MCD pathogenesis. These results suggest that pacritinib warrants testing for the treatment of KSHV-MCD and PEL.

Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer.

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work. Our efforts have resulted in a potent PARP1 degrader D6 (DC50 = 25.23 nM) with high selectivity due to nitrogen heterocyclic linker generating multiple interactions with the PARP1-CRBN PPI surface, specifically. Moreover, D6 exhibited strong cytotoxicity to triple negative breast cancer cell line MDA-MB-231 (IC50 = 1.04 µM). And the proteomic results showed that the antitumor mechanism of D6 was found that intensifies DNA damage by intercepting the CDC25C-CDK1 axis to halt cell cycle transition in triple-negative breast cancer cells. Furthermore, in vivo study, D6 showed a promising PK property with moderate oral absorption activity. And D6 could effectively inhibit tumor growth (TGI rate = 71.4 % at 40 mg/kg) without other signs of toxicity in MDA-MB-321 tumor-bearing mice. In summary, we have identified an original scaffold and potent PARP1 PROTAC that provided a novel intervention strategy for the treatment of triple-negative breast cancer.

Dual Charge-Transfer Channels Harmonize Carrier Separation for Efficient U(VI) Photoreduction.

The low efficient transfer of photogenerated electrons to an active catalytic site is a pivotal problem for the photoreduction of highly soluble hexavalent uranium [U(VI)] to low soluble tetravalent uranium [U(IV)]. Herein, we successfully synthesized a TiO2-x/1T-MoS2/reduced graphene oxide heterojunction (T2-xTMR) with dual charge-transfer channels by exploiting the difference in Fermi levels between the heterojunction interfaces, which induced multilevel separation of photogenerated carriers. Theoretical and experimental results demonstrate that the presence of the electron buffer layer promoted the efficient migration of photogenerated electrons between the dual charge-transfer channels, which achieved effective separation of photogenerated carriers in physical/spatial dimensions and significantly extended the lifetime of photogenerated electrons. The migration of photogenerated electrons to the active catalytic site after multilevel spatial separation enabled the T2-xTMR dual co-photocatalyst to remove 97.4% of the high concentration of U(VI) from the liquid-phase system within 80 min. This work provides a practical reference for utilizing multiple co-catalysts to accomplish directed spatial separation of photogenerated carriers.

Advances of targeting the YAP/TAZ-TEAD complex in the hippo pathway for the treatment of cancers.

The Hippo pathway is an evolutionarily conserved signaling pathway that plays critical roles in the tumorigenesis and progression of breast cancer, oral cancer, rectal cancer, colloid cancer, and so on. YAP/TAZ-TEAD complex is a key knot in the Hippo pathway regulating cell proliferation and stem cell functions. Activation or overexpression of this complex has been proved to lead to cell transformation, proliferation and eventually cancerization. In this review, the association between the alterations of hippo pathway and tumorigenesis of various cancer had been elucidated. The structural basis of YAP/TAZ-TEAD complex is analyzed, and the targeting inhibitors are summarized within the medicinal chemistry classification. Moreover, we have also discussed the clinical status and current challenges of these drug candidates, and provide guidance for the future development of inhibitors targeting this pathway, especially YAP/TAZ-TEAD complex.

Structural and Optical Properties of High Entropy (La,Lu,Y,Gd,Ce)AlO3 Perovskite Thin Films.

Mixtures of Ce-doped rare-earth aluminum perovskites are drawing a significant amount of attention as potential scintillating devices. However, the synthesis of complex perovskite systems leads to many challenges. Designing the A-site cations with an equiatomic ratio allows for the stabilization of a single-crystal phase driven by an entropic regime. This work describes the synthesis of a highly epitaxial thin film of configurationally disordered rare-earth aluminum perovskite oxide (La0.2 Lu0.2 Y0.2 Gd0.2 Ce0.2 )AlO3 and characterizes the structural and optical properties. The thin films exhibit three equivalent epitaxial domains having an orthorhombic structure resulting from monoclinic distortion of the perovskite cubic cell. An excitation of 286.5 nm from Gd3+ and energy transfer to Ce3+ with 405 nm emission are observed, which represents the potential for high-energy conversion. These experimental results also offer the pathway to tunable optical properties of high-entropy rare-earth epitaxial perovskite films for a range of applications.

Insulators' Identification and Missing Defect Detection in Aerial Images Based on Cascaded YOLO Models.

Insulators identification and their missing defect detection are of paramount importance for the intelligent inspection of high-voltage transmission lines. As the backgrounds are complex, some insulators may be occluded, and the missing defect of the insulator is so small that it is not easily detected from aerial images with different backgrounds. To address the above issues, in this study, a cascaded You Only Look Once (YOLO) models are mainly explored to perform insulators and their defect detection in aerial images. Firstly, the datasets used for insulators location and missing defect detection are created. Secondly, a new model is proposed to locate the position of insulators, which is improved in the feature extraction network and multisacle prediction network based on previous YOLOv3-dense model. An improved YOLOv4-tiny model is used to conduct missing defect detection on the detected insulators. And then, the proposed YOLO models are trained and tested on the built datasets, respectively. Finally, the final models are cascaded for insulators identification and their missing defect detection. The average precision of missing defect detection can reach 98.4%, which is 5.2% higher than that of faster RCNN and 10.2% higher than that of SSD. The running time of the cascaded YOLO models for missing defect detection can reach 106 frames per second. Extensive experiments demonstrate that the proposed deep learning models achieve good performance in insulator identification and its missing defect detection from the inspection of high-voltage transmission lines.

Dexmedetomidine prolongs the duration of local anesthetics when used as an adjuvant through both perineural and systemic mechanisms: a prospective randomized double-blinded trial.

BACKGROUND: To study the respective peripheral and systemic mechanisms of action of dexmedetomidine, as adjuvant to regional anesthesia, we compared dexmedetomidine added to ropivacaine for mid-forearm nerve blocks, to either systemic-only dexmedetomidine, and to a control with no dexmedetomidine. METHODS: Sixty patients undergoing hand surgery were randomly divided into three groups (n = 20 per group). Each group underwent a triple-nerve (median, radial and ulnar) mid-forearm blocks with 0.75% ropivacaine. In the DexP group, 60 µg of dexmedetomidine were added to the anesthetic mixture, while in the DexIV group, they were intravenously infused. Normal saline as a placebo was used, either as adjuvant, or intravenously. All patients underwent also a supraclavicular block with 1.5% lidocaine for tourniquet pain. The main outcomes were the duration of analgesia and the duration of sensory blockade separately for each nerve termination of the upper limb, and the duration of motor blockade of the upper limb. Tolerance was assessed by blood pressure and heart rate, and the report of adverse events. RESULTS: Duration of analgesia was longer in the DexP group, in comparison to the two other groups (P < 0.001), while it was similar in the DexIV and the control group. For cutaneous territories targeted by the three mid-forearm blocks, the between-group differences behaved similarly. For the other cutaneous territories (musculocutaneous and posterior brachial cutaneous nerves), duration of sensory blockade was shorter in the control group than in the two dexmedetomidine groups. For duration of motor blockade, the between-group differences behaved similarly. Both blood pressure and heart rate were reduced in the DexP and the DexIV groups, compared to the control. CONCLUSIONS: Dexmedetomidine used as an adjuvant to regional anesthesia may act mostly though a perineural mechanism, especially for the sensory aspects of anesthesia. A systemic action might however explain other clinical effects. TRIAL REGISTRATION: ChiCTR-IOR-17011149 , date of registration: 16/04/2017.

CDK4/6 inhibitors sensitize gammaherpesvirus-infected tumor cells to T-cell killing by enhancing expression of immune surface molecules.

BACKGROUND: The two oncogenic human gammaherpesviruses, Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), both downregulate immune surface molecules, such as MHC-I, ICAM-1, and B7-2, enabling them to evade T-cell and natural killer cell immunity. Both also either encode for human cyclin homologues or promote cellular cyclin activity, and this has been shown to be important for proliferation and survival of gammaherpesvirus-induced tumors. CDK4/6 inhibitors, which are approved for certain breast cancers, have been shown to enhance expression of MHC-I in cell lines and murine models of breast cancer, and this was attributed to activation of interferons by endogenous retrovirus elements. However, it was not known if this would occur in gammaherpesvirus-induced tumors in which interferons are already activated. METHODS: Multiple KSHV/EBV-infected cell lines were treated with CDK4/6 inhibitors. The growth of viable cells and expression of surface markers was assessed. T cell activation stimulated by the treated cells was assayed by a T-cell activation bioassay. Both viral and host gene expression was surveyed using RT-qPCR. RESULTS: Three CDK4/6 inhibitors, abemaciclib, palbociclib, and ribociclib, inhibited cell growth in KSHV-induced primary effusion lymphoma (PEL) and EBV positive Burkitt's lymphoma (BL) cell lines, and KSHV-infected human umbilical vein endothelial cells (HUVECs). Moreover, CDK4/6 inhibitors increased mRNA and surface expression of MHC-I in all three and prevented downregulation of MHC-I surface expression during lytic replication in KSHV-infected cells. CDK4/6 inhibitors also variably increased mRNA and surface expression of ICAM-1 and B7-2 in the tested lines. Abemaciclib also significantly enhanced T-cell activation induced by treated PEL and BL cells. Certain gammaherpesvirus genes as well as endogenous retrovirus (ERV) 3-1 genes were enhanced by CDK4/6 inhibitors in most PEL and BL lines and this enhancement was associated with expression of gamma interferon-induced genes including MHC-I. CONCLUSIONS: These observations provide evidence that CDK4/6 inhibitors can induce expression of surface immune markers MHC-I, B7-2, and ICAM-1 in gammaherpesvirus-infected cell lines and induce virus-specific immunity. They can thus thwart virus-induced immune evasion. These effects, along with their direct effects on KSHV- or EBV-induced tumors, provide a rational for the clinical testing of these drugs in these tumors.

Rapid Pressureless Sintering of Glasses.

Silica glasses have wide applications in industrial fields due to their extraordinary properties, such as high transparency, low thermal expansion coefficient, and high hardness. However, current methods of fabricating silica glass generally require long thermal treatment time (up to hours) and complex setups, leading to high cost and slow manufacturing speed. Herein, to obtain high-quality glasses using a facile and rapid method, an ultrafast high-temperature sintering (UHS) technique is reported that requires no additional pressure. Using UHS, silica precursors can be densified in seconds due to the large heating rate (up to 102 K s-1 ) of closely placed carbon heaters. The typical sintering time is as short as ≈10 s, ≈1-3 orders of magnitude faster than other methods. The sintered glasses exhibit relative densities of > 98% and high visible transmittances of ≈90%. The powder-based sintering process also allows rapid doping of metal ions to fabricate colored glasses. The UHS is further extended to sinter other functional glasses such as indium tin oxide (ITO)-doped silica glass, and other transparent ceramics such as Gd-doped yttrium aluminum garnet. This study demonstrates an UHS proof-of-concept for the rapid fabrication of high-quality glass and opens an avenue toward rapid discovery of transparent materials.

Single cell atlas for 11 non-model mammals, reptiles and birds.

The availability of viral entry factors is a prerequisite for the cross-species transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Large-scale single-cell screening of animal cells could reveal the expression patterns of viral entry genes in different hosts. However, such exploration for SARS-CoV-2 remains limited. Here, we perform single-nucleus RNA sequencing for 11 non-model species, including pets (cat, dog, hamster, and lizard), livestock (goat and rabbit), poultry (duck and pigeon), and wildlife (pangolin, tiger, and deer), and investigated the co-expression of ACE2 and TMPRSS2. Furthermore, cross-species analysis of the lung cell atlas of the studied mammals, reptiles, and birds reveals core developmental programs, critical connectomes, and conserved regulatory circuits among these evolutionarily distant species. Overall, our work provides a compendium of gene expression profiles for non-model animals, which could be employed to identify potential SARS-CoV-2 target cells and putative zoonotic reservoirs.

Single and Repeated Intrapleural Ropivacaine Administration: A Plasma Concentration and Pharmacodynamics Study.

BACKGROUND: Intrapleural analgesia has been increasingly recommended for postoperative analgesia after thoracic surgery. However, the analgesic effect provided by a single intrapleural administration is time limited. This study reports the efficacy and safety of repeated intrapleural 0.75% ropivacaine administration after thoracoscopic surgery. METHODS: Twenty patients were randomly divided into two groups: a single administration group receiving a single intrapleural injection of 0.75% ropivacaine 15 mL (single administration group, SA group), and a repeated administration group with an intrapleural injection of 0.75% ropivacaine 15 mL every 4h for 4 doses (repeated administration group, RA group). The primary outcomes of this study were the peak plasma concentration of ropivacaine and 24h morphine consumption. The secondary outcomes were pain score, patient satisfaction, extubation time, hospital length of stay, and adverse reactions. RESULTS: In SA group, the highest plasma concentration after intrapleural administration of 0.75% ropivacaine 15 mL was 1345±364 µg/L. The highest plasma concentration in RA group after the fourth administration was 1864±492 µg/L. The 24h morphine consumption in RA group was significantly less than that in SA group (9.0±5.66 vs 15.9±3.48 mg, P=0.004). The NRS scores at rest and while coughing of patients in RA group were significantly lower than those in SA group at 5, 9, 13, 17 and 24h after operation. The patients in RA group had higher satisfaction than those in SA group. There was no significant difference in postoperative adverse events, drainage tube placement days and hospital length of stay between the two groups. CONCLUSION: Repeated intrapleural administration with 0.75% ropivacaine, 15 mL every 4h for 4 doses after video-assisted thoracoscopic lobectomies, can provide a more durable and more effective analgesic effect than single intrapleural administration. Repeated intrapleural administration of ropivacaine is an effective postoperative method of analgesia resulting in higher patient satisfaction. Moreover, it was also able to keep the plasma concentration of ropivacaine within a possible safe range. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR-IOR-17010560.

Inhibition of the Extracellular Signal-Regulated Kinase/Ribosomal S6 Kinase Cascade Limits Chlamydia trachomatis Infection.

Chlamydiatrachomatis is the cause of the most common bacterial sexually transmitted infection worldwide. Azithromycin is effective in treating chlamydial infection; however, resistance to this antibiotic is increasing, and it is important that new therapeutic strategies are developed. In this study, we demonstrated that inhibitors targeting each kinase in the extracellular signal-regulated kinase/ribosomal S6 kinase cascade significantly decreased the size and number of inclusions as well as the number of infectious progeny. The suppressive effects of the inhibitors were observed across the Chlamydia serotypes D, E, F, and L1 and across HeLa, McCoy, and Vero host cells. When combined with azithromycin, all the inhibitors exerted a synergistic suppressive effect on chlamydial infection. Knockdown experiments using small interfering RNA demonstrated that extracellular signal-regulated kinase 1/2 and ribosomal S6 kinase 1 were crucial for chlamydial infection. Moreover, BVD-523, a first-in-class extracellular signal-regulated kinase 1/2 inhibitor currently undergoing a phase II clinical trial, suppressed chlamydial infection both in cell culture and in a mouse model. These observations demonstrated not only that the extracellular signal-regulated kinase/ribosomal S6 kinase pathway plays a critical role in chlamydial infection but also that these kinases have potential as targets for host-directed therapy against C. trachomatis.

Hierarchical Suppression Based Matched Filter for Hyperspertral Imagery Target Detection.

Target detection in hyperspectral imagery (HSI) aims at extracting target components of interest from hundreds of narrow contiguous spectral bands, where the prior target information plays a vital role. However, the limitation of the previous methods is that only single-layer detection is carried out, which is not sufficient to discriminate the target parts from complex background spectra accurately. In this paper, we introduce a hierarchical structure to the traditional algorithm matched filter (MF). Because of the advantages of MF in target separation performance, that is, the background components are suppressed while preserving the targets, the detection result of MF is used to further suppress the background components in a cyclic iterative manner. In each iteration, the average output of the previous iteration is used as a suppression criterion to distinguish these pixels judged as backgrounds in the current iteration. To better stand out the target spectra from the background clutter, HSI spectral input and the given target spectrum are whitened and then used to construct the MF in the current iteration. Finally, we provide the corresponding proofs for the convergence of the output and suppression criterion. Experimental results on three classical hyperspectral datasets confirm that the proposed method performs better than some traditional and recently proposed methods.

Elevated Exhaustion Levels of NK and CD8+ T Cells as Indicators for Progression and Prognosis of COVID-19 Disease.

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) induced Coronavirus Disease 2019 (COVID-19) has posed a global threat to public health. The immune system is crucial in defending and eliminating the virus and infected cells. However, immune dysregulation may result in the rapid progression of COVID-19. Here, we evaluated the subsets, phenotypic and functional characteristics of natural killer (NK) and T cells in patients with COVID-19 and their associations with disease severity. Methods: Demographic and clinical data of COVID-19 patients enrolled in Wuhan Union Hospital from February 25 to February 27, 2020, were collected and analyzed. The phenotypic and functional characteristics of NK cells and T cells subsets in circulating blood and serum levels of cytokines were analyzed via flow cytometry. Then the LASSO logistic regression model was employed to predict risk factors for the severity of COVID-19. Results: The counts and percentages of NK cells, CD4+ T cells, CD8+ T cells and NKT cells were significantly reduced in patients with severe symptoms. The cytotoxic CD3-CD56dimCD16+ cell population significantly decreased, while the CD3-CD56dimCD16- part significantly increased in severe COVID-19 patients. More importantly, elevated expression of regulatory molecules, such as CD244 and programmed death-1 (PD-1), on NK cells and T cells, as well as decreased serum cytotoxic effector molecules including perforin and granzyme A, were detected in patients with COVID-19. The serum IL-6, IL-10, and TNF-α were significantly increased in severe patients. Moreover, the CD3-CD56dimCD16- cells were screened out as an influential factor in severe cases by LASSO logistic regression. Conclusions: The functional exhaustion and other subset alteration of NK and T cells may contribute to the progression and improve the prognosis of COVID-19. Surveillance of lymphocyte subsets may in the future enable early screening for signs of critical illness and understanding the pathogenesis of this disease.

Improved YOLO-V3 with DenseNet for Multi-Scale Remote Sensing Target Detection.

Remote sensing targets have different dimensions, and they have the characteristics of dense distribution and a complex background. This makes remote sensing target detection difficult. With the aim at detecting remote sensing targets at different scales, a new You Only Look Once (YOLO)-V3-based model was proposed. YOLO-V3 is a new version of YOLO. Aiming at the defect of poor performance of YOLO-V3 in detecting remote sensing targets, we adopted DenseNet (Densely Connected Network) to enhance feature extraction capability. Moreover, the detection scales were increased to four based on the original YOLO-V3. The experiment on RSOD (Remote Sensing Object Detection) dataset and UCS-AOD (Dataset of Object Detection in Aerial Images) dataset showed that our approach performed better than Faster-RCNN, SSD (Single Shot Multibox Detector), YOLO-V3, and YOLO-V3 tiny in terms of accuracy. Compared with original YOLO-V3, the mAP (mean Average Precision) of our approach increased from 77.10% to 88.73% in the RSOD dataset. In particular, the mAP of detecting targets like aircrafts, which are mainly made up of small targets increased by 12.12%. In addition, the detection speed was not significantly reduced. Generally speaking, our approach achieved higher accuracy and gave considerations to real-time performance simultaneously for remote sensing target detection.

Ganoderic acid A attenuates high-fat-diet-induced liver injury in rats by regulating the lipid oxidation and liver inflammation.

Ganoderic Acid A (GA) has many pharmacological effects such as anti-tumor, antibacterial, anti-inflammatory, and immunosuppressive effects. However, the protective effect of GA on liver injury has not been reported. This study aimed to investigate the action of GA on insufficient methionine and choline combined with high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) in rats. NAFLD model was established by insufficient methionine and choline combined with high fat feeding to rats. The levels of Acetyl-CoA carboxylase, fatty acid synthase, sterol regulatory element binding protein, liver X receptors, AMP-activated protein kinase, peroxisome proliferator-activated receptor α, PPARg coactivator 1α and NF-κB pathway in the liver were detected by western blot. The results of this study demonstrated that the expression of GA can not only significantly decrease the live weight and liver weight per body weight of HFD mice, but also restore the alanine aminotransferase, aspartate aminotransferase, total bilirubin levels, triglyceride and cholesterol in serum. In addition, the expression of GA increased the levels of high-density lipoprotein cholesterol in serum, ameliorated pathological changes and decreased NAS score of mice's liver. In conclusion, the treatment with GA could improve NAFLD in rats by regulating the levels of signaling events involved in free fatty acid production, lipid oxidation and liver inflammation.

Low temperature self-densification of high strength bulk hexagonal boron nitride.

Hexagonal boron nitride (hBN) ceramics are expected to have wide applications at high temperatures as both a structural and functional material. However, because of its flake structure and general inertness, it is currently impossible to sinter hBN powder to a dense bulk (with a relative density of above 96%) even at 2000 °C. Here, we report dense bulk hBN with 97.6% theoretical density achieved at a lower preparation temperature (1700 °C) via a self-densifying mechanism without sintering additives. During the sintering process, cubic boron nitride particles incorporated into the hBN flake powders transform into BN onions with a significant volume increase, thus filling in voids among the hBN flakes and highly densifying the hBN bulks. The resulting dense hBN ceramics possess 2-3 times the strength of traditional hBN ceramics. This phase-transition-induced volume expansion strategy could lead to dense sintered compacts with high performance in other ceramic systems.

Comparison of programmed intermittent bolus infusion and continuous infusion for postoperative patient-controlled analgesia with thoracic paravertebral block catheter: a randomized, double-blind, controlled trial.

BACKGROUND AND OBJECTIVES: In this randomized, double-blind, controlled study, we hypothesized that programmed intermittent bolus infusion (PIBI) of local anesthetic for continuous paravertebral block (PVB), combined with patient-controlled analgesia (PCA), provided better pain control, better patient satisfaction, and decreased in local anesthetic consumption when compared with a continuous infusion (CI) combined with PCA, after video-assisted thoracoscopic unilateral lung resection surgery. METHODS: Preoperatively, patients undergoing video-assisted thoracoscopic unilateral lung resection surgery received ipsilateral paravertebral catheters inserted at the level of thoracic vertebrae 4 and 5. All the subjects received an initial bolus of 15 mL 0.375% ropivacaine via the catheters. Subjects were randomized to receive 0.2 % ropivacaine 8 mL/h as either PIBI (n=17) or CI (n=17) combined with a PCA pump. The pain scores, frequency of PCA, local anesthetic consumption, patient satisfaction, and the need for rescue analgesia with tramadol were recorded until 48 hours postoperative. RESULTS: The numeric rating scale scores in the PIBI group were significantly lower than the CI group at 4, 8, 12 hours and 4, 8, 12, 24 hours postoperatively, at rest, and during coughing, respectively. PCA local anesthetic consumption (30 mg (20-60 mg) vs 120 mg (70-155 mg), p=0.000) and frequency of PCA use over 48 hours (3 (2-6) vs 12 (7-15.5), p=0.000) was lower in the PIBI group as compared with the CI group. Additionally, the PIBI group showed greater patient satisfaction. The need for tramadol rescue was similar in the two groups. CONCLUSIONS: In PVBs, local anesthetic administered as a PIBI in conjunction with PCA provided superior postoperative analgesia to a CI combined with PCA in patients undergoing video-assisted thoracoscopic unilateral lung resection surgery. CLINICAL TRIAL REGISTRATION: ChiCTR-IOR-17011253.

The full-length microRNA cluster in the intron of large latency transcript is associated with the virulence of pseudorabies virus.

Pseudorabies virus (PRV), the etiological pathogen of Aujeszky's disease, belongs to the Alphaherpesvirus subfamily. Large latency transcript (LLT), the most abundant PRV transcript, harbors a ~ 4.6 kb microRNA (miRNA) cluster-encoding intron. To investigate the function of the LLT miRNA cluster during the life cycle of PRV, we generated a miRNA cluster mutation virus (PRV-∆miR cluster) and revertant virus. Analysis of the growth kinetics of PRV-ΔmiR cluster-infected cells revealed significantly smaller plaques and lower titers than the wild-type and revertant viruses. The mutation virus exhibited increased IE180 and decreased EP0 expression. The clinical symptoms observed in mice infected with PRV-ΔmiR cluster revealed that the miRNA cluster is involved in the pathogenesis of PRV. Physical parameters, virus shedding assays, and the SN50 titers revealed that the miRNA cluster enhances PRV virulence in pigs. Collectively, our findings suggest that the full-length miRNA cluster is involved in PRV replication and virulence.

Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry.

Herpesvirus gH/gL envelope glycoprotein complexes are key players in virus entry as ligands for host cell receptors and by promoting fusion of viral envelopes with cellular membranes. Human cytomegalovirus (HCMV) has two alternative gH/gL complexes, gH/gL/gO and gH/gL/UL128,130,131A which both shape the HCMV tropism. By studying binding of HCMV particles to fibroblasts, we could for the first time show that virion gH/gL/gO binds to platelet-derived growth factor-α (PDGFR-α) on the surface of fibroblasts and that gH/gL/gO either directly or indirectly recruits gB to this complex. PDGFR-α functions as an entry receptor for HCMV expressing gH/gL/gO, but not for HCMV mutants lacking the gH/gL/gO complex. PDGFR-α-dependent entry is not dependent on activation of PDGFR-α. We could also show that the gH/gL/gO-PDGFR-α interaction starts the predominant entry pathway for infection of fibroblasts with free virus. Cell-associated virus spread is either driven by gH/gL/gO interacting with PDGFR-α or by the gH/gL/UL128,130,131A complex. PDGFR-α-positive cells may thus be preferred first target cells for infections with free virus which might have implications for the design of future HCMV vaccines or anti-HCMV drugs.