Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1.

Adhesion G protein-coupled receptors (aGPCRs) are essential for a variety of physiological processes such as immune responses, organ development, cellular communication, proliferation and homeostasis1-7. An intrinsic manner of activation that involves a tethered agonist in the N-terminal region of the receptor has been proposed for the aGPCRs8,9, but its molecular mechanism remains elusive. Here we report the G protein-bound structures of ADGRD1 and ADGRF1, which exhibit many unique features with regard to the tethered agonism. The stalk region that proceeds the first transmembrane helix acts as the tethered agonist by forming extensive interactions with the transmembrane domain; these interactions are mostly conserved in ADGRD1 and ADGRF1, suggesting that a common stalk-transmembrane domain interaction pattern is shared by members of the aGPCR family. A similar stalk binding mode is observed in the structure of autoproteolysis-deficient ADGRF1, supporting a cleavage-independent manner of receptor activation. The stalk-induced activation is facilitated by a cascade of inter-helix interaction cores that are conserved in positions but show sequence variability in these two aGPCRs. Furthermore, the intracellular region of ADGRF1 contains a specific lipid-binding site, which proves to be functionally important and may serve as the recognition site for the previously discovered endogenous ADGRF1 ligand synaptamide. These findings highlight the diversity and complexity of the signal transduction mechanisms of the aGPCRs.

La-doped Porous Fe2O3 Nanorods as Advanced Anodes for Lithium/Sodium Ion Batteries and Sulfur Host for Li-Sulfur Batteries.

Transition metal oxides are investigated as electrochemically active anodes for several years due to the merits of high specific capacity, low cost, abundant resources and controllable synthesis. But the poor cycle performances have hindered their further wide application. Herein, porous La-doped FeOOH nanorods have been synthesized through a facile hydrothermal method, which could be transformed into porous La-doped Fe2O3 (Fe2O3-La) via a simple heating process. Compared with the undoped Fe2O3, the Fe2O3-La showed larger surface area, higher specific capacities and more stable cycle performances for lithium/sodium ion batteries. In addition, as an advanced sulfur host for lithium-sulfur batteries, the Fe2O3-La also displayed much more excellent cycle and rate performances than the undoped Fe2O3. The superior electrochemical performances of the Fe2O3-La may could be attributed to the doping of La, which could induce more porous morphology and offer more reactive sites. The positive effects of La-doping for electrochemical performances of porous Fe2O3 nanorods provide novel insights for further applications of rare earth metal doping.

Rational Design of Li-Wicking Hosts for Ultrafast Fabrication of Flexible and Stable Lithium Metal Anodes.

The ever-increasing development of flexible and wearable electronics has imposed unprecedented demand on flexible batteries of high energy density and excellent mechanical stability. Rechargeable lithium (Li) metal battery shows great advantages in terms of its high theoretical energy density. However, the use of Li metal anode for flexible batteries faces huge challenges in terms of its undesirable dendrite growth, poor mechanical flexibility, and slow fabrication speed. Here, a highly scalable Li-wicking strategy is reported that allows ultrafast fabrication of mechanically flexible and electrochemically stable Li metal anodes. Through the rational design of the interface and structure of the wicking host, the mean speed of Li-wicking reaches 10 m2 min-1 , which is 1000 to 100 000 fold faster than the reported electrochemical deposition or thermal infusion methods and meets the industrial fabrication speed. Importantly, the Li-wicking process results in a unique 3D Li metal structure, which not only offers remarkable flexibility but also suppresses the dendrite formation. Paring the Li metal anode with lithium-iron phosphate or sulfur cathode yields flexible full cells that possess a high charging rate (8.0 mA cm-2 ), high energy density (300-380 Wh kg-1 ), long cycling stability (over 550 cycles), and excellent mechanical robustness (500 bending cycles).

Sex differences in changes in BMI and blood pressure in Chinese school-aged children during the COVID-19 quarantine.

There may be sex differences in BMI and blood pressure levels in school-age children, especially in the face of lifestyle changes. This study aimed to explore sex differences in changes in BMI and blood pressure in Chinese school-aged children during the COVID-19 quarantine. The cohort study of 445 school-aged children examined the change of BMI and blood pressure during the five-month quarantine. Multivariable Cox regression models were created to identify potential predictors of overweight, obesity, and elevated blood pressure (EBP). During the COVID-19 quarantine, the proportion of boys with overweight and obesity increased (P = 0.036), and the proportion of both boys and girls with Pre-EBP and EBP increased (P = 0.004 in boys; P < 0.001 in girls). The multivariate Cox regression analysis demonstrated that the setting, eating chili, parents' perception of their child's size and family doting were associated with overweight, obesity, and EBP. The study showed that BMI was more likely to increase in boys, and blood pressure increased in both boys and girls during the COVID-19 quarantine.

RVG-functionalized reduction sensitive micelles for the effective accumulation of doxorubicin in brain.

BACKGROUND: Glioblastoma is a lethal neoplasm with few effective therapy options. As a mainstay in the current treatment of glioma at present, chemotherapeutic agents usually show inadequate therapeutic efficiency due to their low blood brain barrier traversal and brain targeting, together with tumor multidrug resistance. Novel treatment strategies are thus urgently needed to improve chemotherapy outcomes. RESULTS: Here, we report that nanomedicines developed by functionalizing the neurotropic rabies virus-derived polypeptide, RVG, and loading reduction-sensitive nanomicelles (polymer and doxorubicin) enable a highly specific and efficacious drug accumulation in the brain. Interestingly, curcumin serves as the hydrophobic core of the polymer, while suppressing the major efflux proteins in doxorubicin-resistant glioma cells. Studies on doxorubicin-resistant rat glioma cells demonstrate that the RVG-modified micelles exhibit superior cell entry and antitumor activity. In vivo research further showed that RVG modified nanomicelles significantly enhanced brain accumulation and tumor inhibition rate in mice, leading to a higher survival rate with negligible systemic toxicity. Moreover, effective suppression of recurrence and pulmonary metastatic nodules were also determined after the RVG-modified nanomicelles treatment. CONCLUSIONS: The potential of RVG-modified nanomicelles for glioma was demonstrated. Brain accumulation was markedly enhanced after intravenous administration. This unique drug delivery nanoplatform to the brain provides a novel and powerful therapeutic strategy for the treatment of central nervous system disorders including glioma.

A molybdenum oxide-based degradable nanosheet for combined chemo-photothermal therapy to improve tumor immunosuppression and suppress distant tumors and lung metastases.

Molybdenum oxide (MoOx) nanosheets have drawn increasing attention for minimally invasive cancer treatments but still face great challenges, including complex modifications and the lack of efficient accumulation in tumor. In this work, a novel multifunctional degradable FA-BSA-PEG/MoOx nanosheet was fabricated (LA-PEG and FA-BSA dual modified MoOx): the synergistic effect of PEG and BSA endows the nanosheet with excellent stability and compatibility; the FA, a targeting ligand, facilitates the accumulation of nanosheets in the tumor. In addition, DTX, a model drug for breast cancer treatment, was loaded (76.49%, 1.5 times the carrier weight) in the nanosheets for in vitro and in vivo antitumor evaluation. The results revealed that the FA-BSA-PEG/MoOx@DTX nanosheets combined photothermal and chemotherapy could not only inhibit the primary tumor growth but also suppress the distant tumor growth (inhibition rate: 51.7%) and lung metastasis (inhibition rate: 93.6%), which is far more effective compared to the commercial Taxotere®. Exploration of the molecular mechanism showed that in vivo immune response induced an increase in positive immune responders, suppressed negative immune suppressors, and established an inflammatory tumor immune environment, which co-contributes towards effective suppression of tumor and lung metastasis. Our experiments demonstrated that this novel multifunctional nanosheet is a promising platform for combined chemo-photothermal therapy.

A review of stimuli-responsive polymeric micelles for tumor-targeted delivery of curcumin.

Despite a potential drug with multiple pharmacological activities, curcumin has disadvantages of the poor water solubility, rapid metabolism, low bioavailability, which considerably limit its clinical application. Currently, polymeric micelles (PMs) have gained widespread concern due to their advantageous physical and chemical properties, easy preparation, and biocompatibility. They can be used to improve drug solubility, prolong blood circulation time, and allow passive targeted drug delivery to tumor through enhanced penetration and retention effect. Moreover, studies focused on tumor microenvironment offer alternatives to design stimulus-responsive smart PMs based on low pH, high levels of glutathione, altered enzyme expression, increased reactive oxygen species production, and hypoxia. There are various external stimuli, such as light, ultrasound, and temperature. These endogenous/exogenous stimuli can be used for the research of intelligent micelles. Intelligent PMs can effectively load curcumin with improved solubility, and intelligently respond to release the drug at a controlled rate at targeted sites such as tumors to avoid early release, which markedly improves the bioavailability of curcumin. The present review is aimed to discuss and summarize recent developments in research of curcumin-loaded intelligent PMs based on endogenous and exogenous stimuli, and facilitates the development of novel delivery systems for future research.

Binary Classification of Alzheimer's Disease Using sMRI Imaging Modality and Deep Learning.

Alzheimer's disease (AD) is an irreversible devastative neurodegenerative disorder associated with progressive impairment of memory and cognitive functions. Its early diagnosis is crucial for the development of possible future treatment option(s). Structural magnetic resonance images (sMRI) play an important role to help in understanding the anatomical changes related to AD especially in its early stages. Conventional methods require the expertise of domain experts and extract hand-picked features such as gray matter substructures and train a classifier to distinguish AD subjects from healthy subjects. Different from these methods, this paper proposes to construct multiple deep 2D convolutional neural networks (2D-CNNs) to learn the various features from local brain images which are combined to make the final classification for AD diagnosis. The whole brain image was passed through two transfer learning architectures; Inception version 3 and Xception, as well as a custom Convolutional Neural Network (CNN) built with the help of separable convolutional layers which can automatically learn the generic features from imaging data for classification. Our study is conducted using cross-sectional T1-weighted structural MRI brain images from Open Access Series of Imaging Studies (OASIS) database to maintain the size and contrast over different MRI scans. Experimental results show that the transfer learning approaches exceed the performance of non-transfer learning-based approaches demonstrating the effectiveness of these approaches for the binary AD classification task.

[Characteristics of vocalization in children with autism spectrum disorder during the still-face paradigm].

OBJECTIVE: To study the characteristics of vocalization during the still-face paradigm (SFP) before the age of 2 years and their correlation with the severity of autism spectrum disorder (ASD) symptoms at diagnosis in children with ASD. METHODS: A total of 43 children aged 7-23 months, who were suspected of ASD, were enrolled as the suspected ASD group, and 37 typical development (TD) children, aged 7-23 months, were enrolled as the TD group. The frequency and durations of vocalization in the SFP were measured. The children in the suspected ASD group were followed up to the age of 2 years, and 34 children were diagnosed with ASD. Autism Diagnostic Observation Schedule (ADOS) was used to assess the severity of symptoms. The correlation of the characteristics of vocalization before the age of 2 years with the severity of ASD symptoms was analyzed. RESULTS: Compared with the TD group, the ASD group had significant reductions in the frequency and durations of meaningful vocalization and vocalization towards people and a significant increase in the duration of vocalization toward objects (P<0.05). The Spearman correlation analysis showed that in the ASD group, the frequency and durations of total vocalization, non-speech vocalization, babbling, vocalization towards people, and vocalization towards objects were negatively correlated with the score of communication in ADOS (P<0.05). The frequency and durations of total vocalization, babbling, and vocalization towards people and the duration of vocalization towards objects were negatively correlated with the score of reciprocal social interaction in ADOS (P<0.05). The frequency of total vocalization, the duration of babbling, and the frequency and duration of vocalization towards people were negatively correlated with the score of play in ADOS (P<0.05). The frequency of total vocalization and non-speech vocalization and the frequency and durations of vocalization towards people were negatively correlated with the score of stereotyped behaviors and restricted interests in ADOS (P<0.05). The multiple linear regression analysis showed that the frequency of total vocalization was a negative predictive factor for the score of communication in ADOS (P<0.001), and the duration of vocalization towards people was a negative predictive factor for the score of reciprocal social interaction in ADOS (P<0.05). CONCLUSIONS: SFP can better highlight the abnormal vocalization of ASD children before the age of 2 years, and such abnormalities can predict the severity of ASD symptoms early.

Circumferential Shaving of the Cavity in Breast-Conserving Surgery: A Randomized Controlled Trial.

BACKGROUND: This randomized controlled trial aimed to investigate the effects of circumferential shaving on reducing the intraoperative margin positivity rate (MPR) during breast-conserving surgery (BCS). METHODS: Eligible breast cancer patients were randomly assigned into no-shave and shave groups. In the no-shave group, the cavity margins were collected for assessment after the tumor resection, whereas in the shave group, a circumferential shaving was performed before collecting the cavity margins. The primary outcome was the intraoperative MPR by frozen section analysis. RESULTS: A total of 181 patients, with a median age of 49 years, were randomized. Patient characteristics at baseline were well-balanced between the two groups. The intraoperative MPRs (12.1% vs. 7.8%, p = 0.38), postoperative MPRs (16.5% vs. 7.8%, p = 0.073), intraoperative re-excision rates (26.4% vs. 23.3%, p = 0.64), second operation rates (4.4% vs. 1.1%, p = 0.34), and successful BCS rate (93.4% vs. 94.4%, p = 0.94) were all similar between the no-shave and the shave groups. The volume of the shaved tissues was significantly increased in patients with larger breast volume (p < 0.01). In patients with C-E cup breasts, the no-shave and shave groups had 16.7% and 0% (p = 0.03) intraoperative MPRs, and 22.0% and 0% (p = 0.01) postoperative MPRs, respectively. In patients with A-B cup breasts, the MPRs were similar between the two groups. The presence of the ductal carcinoma in situ component is the only determinant of margin positivity. CONCLUSIONS: Circumferential shaving did not significantly reduce the MPR in BCS. Its benefit depends on the volume of the shaved tissues and the breast. Trial registration This trial was registered at ClinicalTrials.gov (NCT02648802).

Shedding light on minipig drug metabolism - elevated amide hydrolysis in vitro.

1. In recent years, the minipig is increasingly used as a test species in non-clinical assessment of drug candidates. While there is good scientific evidence available concerning cytochrome P450-mediated metabolism in minipig, the knowledge of other metabolic pathways is more limited. 2. The aim of this study was to provide an understanding of when, why, and how drug metabolism in minipig differs from other species commonly used in non-clinical studies. In-house cross-species metabolite profile comparisons in hepatocytes and microsomes of 38 Roche development compounds were retrospectively analyzed to compare the metabolism among minipig, human, rat, dog, monkey, rabbit and mouse. 3. A significant contributor to the elevated metabolism observed for certain compounds in minipig was identified as amide hydrolysis. The hepatic amide hydrolysis activity in minipig was further investigated in subcellular liver fractions and a structure-activity relationship was established. When structural motifs according to the established SAR are excluded, coverage of major human metabolic pathways was shown to be higher in minipig than in dog, and only slightly lower than in cynomolgus monkey. 4. A strategy is presented for early identification of drug compounds which might not be suited to further investigation in minipig due to excessive hydrolytic metabolism.

Characterization of monoclonal antibodies against duck Tembusu virus E protein: an antigen-capture ELISA for the detection of Tembusu virus infection.

The E protein of flaviviruses is the primary antigen that induces protective immunity, but a monoclonal antibody (mAb) against the E protein of duck Tembusu virus (DTMUV) has never been characterized. Six hybridoma cell lines secreting DTMUV anti-E mAbs were prepared and designated 2A5, 1F3, 1G2, 1B11, 3B6, and 4F9, respectively. An immunofluorescence assay indicated that the mAbs could specifically bind to duck embryo fibroblast (DEF) cells infected with DTMUV and that the E protein was distributed in the cytoplasm of the infected cells. Immunoglobulin isotyping differentiated the mAbs as IgG1 (1G2, 1B11, 4F9, 1F3, and 2A5) and IgG2b (3B6). The mAbs were used to identify three epitopes, A (2A5, 1F3, and 1G2), B (1B11 and 4F9), and C (3B6) on the E protein on the basis of a competitive binding assay. By using mAbs 1F3 and 3B6, we developed an antigen-capture enzyme-linked immunosorbent assay (AC-ELISA) to detect E antigen from clinical samples. The AC-ELISA did not react with other known pathogens, indicating that the mAbs are specific for DTMUV. Compared to RT-PCR, the specificity and sensitivity of the AC-ELISA was 94.1 % and 98.0 %, respectively. This AC-ELISA thus represents a sensitive and rapid method for detecting DTMUV infection in birds.

Muscovy duck reovirus p10.8 protein localizes to the nucleus via a nonconventional nuclear localization signal.

BACKGROUND: It was previously report that the first open reading frame of Muscovy duck reocvirus S4 gene encodes a 95-amino-acid protein, designed p10.8, which has no sequence similarity to other known proteins. Its amino acid sequence offers no clues about its function. RESULTS: Subcellular localization and nuclear import signal of p10.8 were characterized. We found that p10.8 protein localizes to the nucleus of infected and transfected cells, suggesting that p10.8 nuclear localization is not facilitated by viral infection or any other viral protein. A functional non-canonical nuclear localization signal (NLS) for p10.8 was identified and mapped to N-terminus residues 1-40. The NLS has the ability to retarget a large cytoplasmic protein to the nucleus. CONCLUSIONS: p10.8 imported into the nucleus might via a nonconventional signal nuclear signal.

Role of regulatory non-coding RNAs in traumatic brain injury.

Traumatic brain injury (TBI) is a potentially fatal health event that cannot be predicted in advance. After TBI occurs, it can have enduring consequences within both familial and social spheres. Yet, despite extensive efforts to improve medical interventions and tailor healthcare services, TBI still remains a major contributor to global disability and mortality rates. The prompt and accurate diagnosis of TBI in clinical contexts, coupled with the implementation of effective therapeutic strategies, remains an arduous challenge. However, a deeper understanding of changes in gene expression and the underlying molecular regulatory processes may alleviate this pressing issue. In recent years, the study of regulatory non-coding RNAs (ncRNAs), a diverse class of RNA molecules with regulatory functions, has been a potential game changer in TBI research. Notably, the identification of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and other ncRNAs has revealed their potential as novel diagnostic biomarkers and therapeutic targets for TBI, owing to their ability to regulate the expression of numerous genes. In this review, we seek to provide a comprehensive overview of the functions of regulatory ncRNAs in TBI. We also summarize regulatory ncRNAs used for treatment in animal models, as well as miRNAs, lncRNAs, and circRNAs that served as biomarkers for TBI diagnosis and prognosis. Finally, we discuss future challenges and prospects in diagnosing and treating TBI patients in the clinical settings.

Loss of microRNA-15a/16-1 function promotes neuropathological and functional recovery in experimental traumatic brain injury.

The diffuse axonal damage in white matter and neuronal loss, along with excessive neuroinflammation, hinder long-term functional recovery after traumatic brain injury (TBI). MicroRNAs (miRs) are small noncoding RNAs that negatively regulate protein-coding target genes in a posttranscriptional manner. Recent studies have shown that loss of function of the miR-15a/16-1 cluster reduced neurovascular damage and improved functional recovery in ischemic stroke and vascular dementia. However, the role of the miR-15a/16-1 cluster in neurotrauma is poorly explored. Here, we report that genetic deletion of the miR-15a/16-1 cluster facilitated the recovery of sensorimotor and cognitive functions, alleviated white matter/gray matter lesions, reduced cerebral glial cell activation, and inhibited infiltration of peripheral blood immune cells to brain parenchyma in a murine model of TBI when compared with WT controls. Moreover, intranasal delivery of the miR-15a/16-1 antagomir provided similar brain-protective effects conferred by genetic deletion of the miR-15a/16-1 cluster after experimental TBI, as evidenced by showing improved sensorimotor and cognitive outcomes, better white/gray matter integrity, and less inflammatory responses than the control antagomir-treated mice after brain trauma. miR-15a/16-1 genetic deficiency and miR-15a/16-1 antagomir also significantly suppressed inflammatory mediators in posttrauma brains. These results suggest miR-15a/16-1 as a potential therapeutic target for TBI.

A novel glycoglycerolipid from Holotrichia diomphalia Bates: Structure characteristics and protective effect against DNA damage.

A lipidated polysaccharide, HDPS-2II, was isolated from the dried larva of Holotrichia diomphalia, which is used in traditional Chinese medicine. The molecular weight of HDPS-2II was 5.9 kDa, which contained a polysaccharide backbone of →4)-ß-Manp-(1 â†’ 4,6)-ß-Manp-(1 â†’ [6)-α-Glcp-(1]n â†’ 6)-α-Glcp→ with the side chain α-Glcp-(6 â†’ 1)-α-Glcp-(6 â†’ linked to the C-4 of ß-1,4,6-Manp and four types of lipid chains including 4-(4-methyl-2-(methylamino)pentanamido)pentanoic acid, 5-(3-(tert-butyl)phenoxy)hexan-2-ol, N-(3-methyl-5-oxopentan-2-yl)palmitamide, and N-(5-amino-3-methyl-5-oxopentan-2-yl)stearamide. The lipid chains were linked to C-1 of terminal α-1,6-Glcp in carbohydrate chain through diacyl-glycerol. HDPS-2II exhibited DNA protective effects and antioxidative activity on H2O2- or adriamycin (ADM)-induced Chinese hamster lung cells. Furthermore, HDPS-2II significantly ameliorated chromosome aberrations and the accumulation of reactive oxygen species (ROS), reduced γ-H2AX signaling and the expressions of NADPH oxidase (NOX)2, NOX4, P22phox, and P47phox in ADM-induced cardiomyocytes. Mechanistically, HDPS-2II suppressed ADM-induced up-regulation of NOX2 and NOX4 in cardiomyocytes, but not in NOX2 or NOX4 knocked-down cardiomyocytes, indicating that HDPS-2II could relieve intracellular DNA damage by regulating NOX2/NOX4 signaling. These findings demonstrate that HDPS-2II is a new potential DNA protective agent.

Molecular characterization of a duck Tembusu virus from China.

A new emerging flavivirus caused severe egg-drop in poultry and spread quickly across most duck-producing regions of China in 2010. Complete genome sequencing indicated that the virus genome is 10,989 nucleotides in length and possesses typical flavivirus genome organization, 5' untranslated region (UTR)-Cv-Ci-prM-M-E-NS1-NS2A-NS2B-NS3-NS4A-2K-NS4B-NS5-3'-UTR. The long open reading frame (ORF) encodes 3,425 amino acids (95-10,372 nt). The 94-nucleotide 5'-UTR is of intermediate size and the 617-nucleotide 3'-UTR is quite long relative to those of other flaviviruses. The polyprotein cleavage sites, potential glycosylation sites, distribution of cysteine residues, and 3'-UTR secondary structure were characterized. Phylogenetic analysis of the polyprotein sequences indicates that the HN isolate is closely related to Tembusu viruses of the Ntaya virus group.

Novel Carbazole-Based Porous Organic Polymer for Efficient Iodine Capture and Rhodamine B Adsorption.

A new porous organic polymer (CTF-CAR), which takes carbazole as the electron-rich center unit and thiophenes as the auxiliary group, has been synthesized through catalyst-free Schiff-base polymerization. At the same time, the structure, thermal stability, morphology, and other basic properties of the polymer were analyzed by IR, NMR, TGA, and SEM. Then, CTF-CAR was applied to iodine capture and rhodamine B adsorption. Due to its strong electron donor ability and abundant heteroatom binding sites, which have a positive effect on the interaction between the polymer network and adsorbates, CTF-CAR exhibits high uptake capacities for iodine vapor and rhodamine B as 2.86 g g-1 and 199.7 mg g-1, respectively. The recyclability test also confirmed that it has good reusability. We found that this low-cost and catalyst-free synthetic porous organic polymer has great potential for the treatment of polluted water and iodine capture.

CD8 T cell-mediated depletion of HBV surface-antigen-expressing, bilineal-differentiated liver carcinoma cells generates highly aggressive escape variants.

The expression of viral antigens in chronic hepatitis B virus (HBV) infection drives continuous liver inflammation, one of the main risk factors to develop liver cancer. HBV developed immune-suppressive functions to escape from the host immune system, but their link to liver tumor development is not well understood. Here, we analyzed if and how HBV surface antigen (HBs) expression in combined hepatocellular-cholangiocarcinoma (cHCC/iCCA) cells influences their antigenicity for CD8 T cells. We randomly isolated liver tumor tissues from AlfpCre+-Trp53fl/fl/Alb-HBs+ tg mice and established primary carcinoma cell lines (pCCL) that showed a bilineal (CK7+/HNF4α+) cHCC/iCCA phenotype. These pCCL uniformly expressed HBs (HBshi), and low levels of MHC-I (MHC-Ilo), and were transiently convertible to a high antigenicity (MHC-Ihi) phenotype by IFN-γ treatment. HBshi/pCCL induced HBs/(Kb/S190-197)-specific CD8 T cells and developed slow-growing tumors in subcutaneously transplanted C57Bl/6J (B6) mice. Interestingly, pCCL-ex cells, established from HBshi/pCCL-induced and re-explanted tumors in B6 but not those in immune-deficient Rag1-/- mice showed major alterations, like an MHC-Ihi phenotype, a prominent growth-biased gene expression signature, a significantly decreased HBs expression (HBslo) and a switch to fast-growing tumors in re-transplanted B6 or PD-1-/- hosts with an unlocked PD-1/PD-L1 control system. CD8 T cell-mediated elimination of HBshi/pCCL, together with the attenuation of the negative restraints of HBs in the tumor cells, like ER-stress, reveals a novel mechanism to unleash highly aggressive HBslo/pCCL-ex immune-escape variants. Under certain conditions, HBs-specific CD8 T-cell responses thus potentiate tumor growth, an aspect that should be considered for therapeutic vaccination strategies against chronic HBV infection and liver tumors.

Influences of Separator Thickness and Surface Coating on Lithium Dendrite Growth: A Phase-Field Study.

Li dendrite growth, which causes potential internal short circuit and reduces battery cycle life, is the main hazard to lithium metal batteries. Separators have the potential to suppress dendrite growth by regulating Li+ distribution without increasing battery weight significantly. However, the underlying mechanism is still not fully understood. In this paper, we apply an electrochemical phase-field model to investigate the influences of separator thickness and surface coating on dendrite growth. It is found that dendrite growth under thicker separators is relatively uniform and the average dendrite length is shorter since the ion concentration within thicker separators is more uniform. Moreover, compared to single layer separators, the electrodeposition morphology under particle-coated separators is smoother since the particles can effectively regulate Li ionic flux and homogenize Li deposition. This study provides significant guidance for designing separators that inhibit dendrites effectively.