The Current and Prospective Adjuvant Therapies for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) stands as the most prevalent form of primary liver cancer and is highly invasive and easily recurs. For HCC, chemotherapy shows limited effect. The gold standard for HCC treatment includes curative surgical resection or liver transplantation. However, the recurrence rate at 5 years after liver resection is estimated at approximately 70% and even at 5 years after liver transplantation, it is 20%. Therefore, improving survival outcomes after curative surgical resection of liver cancer is crucial. This review highlights the importance of identifying risk factors for HCC recurrence following radical surgical resection and adjuvant therapy options that may reduce the recurrence risk and improve overall survival, including local adjuvant therapy (e.g., transcatheter arterial chemoembolization and radiotherapy), adjuvant systemic therapy (e.g., small molecule targeted therapy and immunotherapy), and other adjuvant therapies (e.g., chemotherapy). However, further research is needed to refine the use of these therapies and optimize their effectiveness in preventing HCC recurrence.

Acupuncture alleviates inflammatory pain by activating CXCL1/CXCR2 signaling in the primary somatosensory cortex in adjuvant induced arthritis rats. / S1脑区CXCL1/CXCR2å‚ä¸Žé’ˆåˆºæ”¹å–„ä½å‰‚æ€§å ³èŠ‚ç‚Žå¤§é¼ ç‚Žæ€§ç—›çš„ä½œç”¨æœºåˆ¶.

OBJECTIVES: To observe whether acupuncture up-regulates chemokine CXC ligand 1 (CXCL1) in the brain to play an analgesic role through CXCL1/chemokine CXC receptor 2 (CXCR2) signaling in adjuvant induced arthritis (AIA) rats, so as to reveal its neuro-immunological mechanism underlying improvement of AIA. METHODS: BALB/c mice with relatively stable thermal pain reaction were subjected to planta injection of complete Freund adjuvant (CFA) for establishing AIA model, followed by dividing the AIA mice into simple AF750 (fluorochrome) and AF750+CXCL1 groups (n=2 in each group). AF750 labeled CXCL1 recombinant protein was then injected into the mouse's tail vein to induce elevation of CXCL1 level in blood for simulating the effect of acupuncture stimulation which has been demonstrated by our past study. In vivo small animal imaging technology was used to observe the AF750 and AF750+CXCL1-labelled target regions. After thermal pain screening, the Wistar rats with stable pain reaction were subjected to AIA modeling by injecting CFA into the rat's right planta, then were randomized into model and manual acupuncture groups (n=12 in each group). Other 12 rats that received planta injection of saline were used as the control group. Manual acupuncture (uniform reinforcing and reducing manipulations) was applied to bilateral "Zusanli" (ST36) for 4×2 min, with an interval of 5 min between every 2 min, once daily for 7 days. The thermal pain threshold was assessed by detecting the paw withdrawal latency (PWL) using a thermal pain detector. The contents of CXCL1 in the primary somatosensory cortex (S1), medial prefrontal cortex, nucleus accumbens, amygdala, periaqueductal gray and rostroventromedial medulla regions were assayed by using ELISA, and the expression levels of CXCL1, CXCR2 and mu-opioid receptor (MOR) mRNA in the S1 region were detected using real time-quantitative polymerase chain reaction. The immune-fluorescence positive cellular rate of CXCL1 and CXCR2 in S1 region was observed after immunofluorescence stain. The immunofluorescence double-stain of CXCR2 and astrocyte marker glial fibrillary acidic protein (GFAP) or neuron marker NeuN or MOR was used to determine whether there is a co-expression between them. RESULTS: In AIA mice, results of in vivo experiments showed no obvious enrichment signal of AF750 or AF750+CXCL1 in any organ of the body, while in vitro experiments showed that there was a stronger fluorescence signal of CXCL1 recombinant protein in the brain. In rats, compared with the control group, the PWL from day 0 to day 7 was significantly decreased (P<0.01) and the expression of CXCR2 mRNA in the S1 region significantly increased in the model group (P<0.05), while in comparison with the model group, the PWL from day 2 to day 7, CXCL1 content, CXCR2 mRNA expression and CXCR2 content, and MOR mRNA expression in the S1 region were significantly increased in the manual acupuncture group (P<0.05, P<0.01). Immunofluorescence stain showed that CXCR2 co-stained with NeuN and MOR in the S1 region, indicating that CXCR2 exists in neurons and MOR-positive neurons but not in GFAP positive astrocytes. CONCLUSIONS: Acupuncture can increase the content of CXCL1 in S1 region, up-regulate CXCR2 on neurons in the S1 region and improve MOR expression in S1 region of AIA rats, which may contribute to its effect in alleviating inflammatory pain.

Comparison of laparoscopic common bile duct exploration plus cholecystectomy and endoscopic retrograde cholangiopancreatography followed by laparoscopic cholecystectomy for elderly patients with common bile duct stones and gallbladder stones.

BACKGROUND: Common bile duct (CBD) stones commonly occur in cholecystectomy cases. The management options include laparoscopic CBD exploration (LCBDE) or endoscopic retrograde cholangiopancreatography (ERCP) followed by laparoscopic cholecystectomy (LC). Although ERCP is fully developed, it has complications, and LCBDE is a proven alternative. This study aimed to evaluate the safety and efficacy of these treatments in elderly individuals aged ≥70 years. METHODS: A retrospective study between January 2015 and July 2022 included 160 elderly patients (aged ≥70 years) diagnosed with cholelithiasis and choledocholithiasis. The patients were divided into 1-stage (LCBDE [n = 80]) or 2-stage (ERCP followed by LC [n = 80]) treatment groups. Data collected encompassed comorbidities, symptoms, bile duct clearance, postoperative complications, and long-term outcomes for systematic analysis. RESULTS: This study analyzed 160 patients treated for CBD stones, comparing 1-stage and 2-stage groups. The 1-stage group had more female patients than the 2-stage group (57.5% vs 37.5%, respectively). The 1-stage group had a mean age of 80.55 ± 7.00 years, which was higher than the mean age in the 2-stage group. American Society of Anesthesiologists classification, Charlson Comorbidity Index, and laboratory findings were similar. Pancreatitis and cholangitis occurred after ERCP in the 2-stage group. Stone clearance rates (92.35% [1-stage group] vs 95.00% [2-stage group]) and biliary leakage incidence (7.5% [1-stage group] vs 3.0% [2-stage group]) were similar, as were postoperative complications and long-term recurrence rates (13.0% [1-stage group] vs 12.5% [2-stage group]). CONCLUSION: Our research indicates that both the combination of LCBDE and LC and the sequence of ERCP followed by LC are equally efficient and secure when treating CBD stones in elderly patients. Consequently, the 1-stage procedure may be considered the preferred treatment approach for this demographic.

Determinant of m6A regional preference by transcriptional dynamics.

N6-Methyladenosine (m6A) is the most abundant chemical modification occurring on eukaryotic mRNAs, and has been reported to be involved in almost all stages of mRNA metabolism. The distribution of m6A sites is notably asymmetric along mRNAs, with a strong preference toward the 3' terminus of the transcript. How m6A regional preference is shaped remains incompletely understood. In this study, by performing m6A-seq on chromatin-associated RNAs, we found that m6A regional preference arises during transcription. Nucleosome occupancy is remarkedly increased in the region downstream of m6A sites, suggesting an intricate interplay between m6A methylation and nucleosome-mediated transcriptional dynamics. Notably, we found a remarkable slowdown of Pol-II movement around m6A sites. In addition, inhibiting Pol-II movement increases nearby m6A methylation levels. By analyzing massively parallel assays for m6A, we found that RNA secondary structures inhibit m6A methylation. Remarkably, the m6A sites associated with Pol-II pausing tend to be embedded within RNA secondary structures. These results suggest that Pol-II pausing could affect the accessibility of m6A motifs to the methyltransferase complex and subsequent m6A methylation by mediating RNA secondary structure. Overall, our study reveals a crucial role of transcriptional dynamics in the formation of m6A regional preference.

Role of Qufeng Tongqiao Prescription in the protection of cerebral ischemia and associated molecular network mechanism.

To explore the of Qufeng Tongqiao Prescription in the treatment of cerebral ischemia-reperfusion (CIR) and associated molecular network mechanism. Venny diagram, gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis, protein-protein interaction (PPI), hub genes mining, molecular docking, combined with animal experiments and Nissl stain were performed to determine the molecular network mechanism of Qufeng Tongqiao Prescription for CIR treatment. Fifty three intersecting genes between Qufeng Tongqiao Prescription and cerebral ischemia reperfusion were acquired from Venny analysis. GO analysis showed that the main biological process (BP) was response to lipopolysaccharide, and the main cell localization (CC) process was membrane raft, while the most important molecular function (MF) process is Cytokine receptor binding. Moreover, AGE-RAGE signaling pathway in diabetic complications is the most important signaling pathway in KEGG pathway. Through molecular docking, it was found that Astragalus membranaceus was docked with MAPK14, IL4, FOS, IL6, and JUN; pueraria membranaceus was directly docked with JUN and IL4; Acorus acorus was linked to JUN and MAPK14; Ganoderma ganoderma and human were involved in JUN docking, and Ligusticum chuanqi and pueraria could not be docked with MAPK14, respectively. The results of animal experiments showed that Qufeng Tongqiao Prescription significantly improved behavioral performance and reduced the number of neuronal deaths in rats subjected to CIR, and molecular mechanisms are associated with FOS, IL-6, IL4, JUN, and MAPK14, of there, IL-6, as a vital candidator, which has been confirmed by immunostaining detection. Together, Qufeng Tongqiao Prescription has positive therapeutic effect on CIR, and the underlying mechanism is involved MAPK14, FOS, IL4, and JUN network, while IL-6 may be as a vital target.

Deep learning-based predictive classification of functional subpopulations of hematopoietic stem cells and multipotent progenitors.

BACKGROUND: Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) play a pivotal role in maintaining lifelong hematopoiesis. The distinction between stem cells and other progenitors, as well as the assessment of their functions, has long been a central focus in stem cell research. In recent years, deep learning has emerged as a powerful tool for cell image analysis and classification/prediction. METHODS: In this study, we explored the feasibility of employing deep learning techniques to differentiate murine HSCs and MPPs based solely on their morphology, as observed through light microscopy (DIC) images. RESULTS: After rigorous training and validation using extensive image datasets, we successfully developed a three-class classifier, referred to as the LSM model, capable of reliably distinguishing long-term HSCs, short-term HSCs, and MPPs. The LSM model extracts intrinsic morphological features unique to different cell types, irrespective of the methods used for cell identification and isolation, such as surface markers or intracellular GFP markers. Furthermore, employing the same deep learning framework, we created a two-class classifier that effectively discriminates between aged HSCs and young HSCs. This discovery is particularly significant as both cell types share identical surface markers yet serve distinct functions. This classifier holds the potential to offer a novel, rapid, and efficient means of assessing the functional states of HSCs, thus obviating the need for time-consuming transplantation experiments. CONCLUSION: Our study represents the pioneering use of deep learning to differentiate HSCs and MPPs under steady-state conditions. This novel and robust deep learning-based platform will provide a basis for the future development of a new generation stem cell identification and separation system. It may also provide new insight into the molecular mechanisms underlying stem cell self-renewal.

Apolipoprotein E E3/E4 genotype is associated with an increased risk of type 2 diabetes mellitus complicated with coronary artery disease.

OBJECTIVE: Dyslipidemia is a co-existing problem in patients with diabetes mellitus (DM) and coronary artery disease (CAD), and apolipoprotein E (APOE) plays an important role in lipid metabolism. However, the relationship between the APOE gene polymorphisms and the risk of developing CAD in type 2 DM (T2DM) patients remains controversial. The aim of this study was to assess this relationship and provide a reference for further risk assessment of CAD in T2DM patients. METHODS: The study included 378 patients with T2DM complicated with CAD (T2DM + CAD) and 431 patients with T2DM alone in the case group, and 351 individuals without DM and CAD were set as controls. The APOE rs429358 and rs7412 polymorphisms were genotyped by polymerase chain reaction (PCR) - microarray. Differences in APOE genotypes and alleles between patients and controls were compared. Multiple logistic regression analysis was performed after adjusting for age, gender, body mass index (BMI), history of smoking, and history of drinking to access the relationship between APOE genotypes and T2DM + CAD risk. RESULTS: The frequencies of the APOE ɛ3/ɛ4 genotype and ε4 allele were higher in the T2DM + CAD patients, and the frequencies of the APOE ɛ3/ɛ3 genotype and ε3 allele were lower than those in the controls (all p < 0.05). The T2DM + CAD patients with ɛ4 allele had higher level in low-density lipoprotein cholesterol (LDL-C) than those in patients with ɛ2 and ɛ3 allele (p < 0.05). The results of logistic regression analysis showed that age ≥ 60 years old, and BMI ≥ 24.0 kg/m2 were independent risk factors for T2DM and T2DM + CAD, and APOE ɛ3/ɛ4 genotype (adjusted odds ratio (OR) = 1.93, 95% confidence interval (CI) = 1.18-3.14, p = 0.008) and ɛ4 allele (adjusted OR = 1.97, 95% CI = 1.23-3.17) were independent risk factors for T2DM + CAD. However, the APOE genotypes and alleles were not found to have relationship with the risk of T2DM. CONCLUSIONS: APOE ε3/ε4 genotype and ε4 allele were independent risk factors for T2DM complicated with CAD, but not for T2DM.

Initial Experience with Hybrid Partial Nephrectomy with Ultrasound-guided Balloon Catheter Occlusion of the Renal Artery for Recurrent Renal Tumors.

Repeat partial nephrectomy (PN) is an effective treatment in improving the prognosis for patients with recurrent renal cancer after initial PN. However, salvage PN (sPN) is inevitably associated with a higher rate of complications, largely because of intraperitoneal adhesions and fibrosis. Here we describe three initial cases for which recurrent renal tumors were treated with a novel minimally invasive approach, namely Ultrasound-guided Renal Artery Balloon catheter Occluded Hybrid Partial Nephrectomy (UBo-HPN).With laparoscopic ultrasound (LUS) guiding a Fogarty catheter to occlude the arterial blood supply, dissection of the renal hilum and most of the abdominal cavity can be avoided. UBo-HPN was successfully performed in three patients. One case of postoperative fever (Clavien-Dindo grade II) occurred, with no other complications. The mean operative time was 106 min, with a mean warm ischemia time of 21 min. UBo-HPN may be considered a safe and effective alternative for sPN, with a minimally invasive surgical footprint and better surgical outcomes.

Design of target specific peptide inhibitors using generative deep learning and molecular dynamics simulations.

We introduce a computational approach for the design of target-specific peptides. Our method integrates a Gated Recurrent Unit-based Variational Autoencoder with Rosetta FlexPepDock for peptide sequence generation and binding affinity assessment. Subsequently, molecular dynamics simulations are employed to narrow down the selection of peptides for experimental assays. We apply this computational strategy to design peptide inhibitors that specifically target ß-catenin and NF-κB essential modulator. Among the twelve ß-catenin inhibitors, six exhibit improved binding affinity compared to the parent peptide. Notably, the best C-terminal peptide binds ß-catenin with an IC50 of 0.010 ± 0.06 µM, which is 15-fold better than the parent peptide. For NF-κB essential modulator, two of the four tested peptides display substantially enhanced binding compared to the parent peptide. Collectively, this study underscores the successful integration of deep learning and structure-based modeling and simulation for target specific peptide design.

Optimal Post-Operative Nalbuphine Dose Regimen: A Randomized Controlled Trial in Patients with Laparoscopic Cholecystectomy.

Background and Objectives: Optimal opioid analgesia is an excellent analgesia that does not present unexpected adverse effects. Nalbuphine, acting on the opioid receptor as a partial mu antagonist and kappa agonist, is considered a suitable option for patients undergoing laparoscopic surgery. Therefore, we aim to investigate the appropriate dosage of nalbuphine for post-operative pain management in patients with laparoscopic cholecystectomy. Materials and Methods: Patients were randomly categorized into low, medium, and high nalbuphine groups. In each group, a patient control device for post-operative pain control was programed with a low (0.05 mg/kg), medium (0.10 mg/kg), or high (0.20 mg/kg) nalbuphine dose as a loading dose and each bolus dose with a lockout interval of 7 min and without background infusion. Primary and secondary outcomes included the post-operative pain scale and nalbuphine consumption, and episodes of post-operative opioid-related adverse events and satisfactory scores. Results: The low-dosage group presented a higher initial self-reported pain score in comparison to the other two groups for the two hours post-op (p = 0.039) but presented lower nalbuphine consumption than the other two groups for four hours post-op (p = 0.047). There was no significant difference in the analysis of the satisfactory score and adverse events. Conclusions: An appropriate administration of nalbuphine could be 0.1 to 0.2 mg/kg at the initial four hours; this formula could be modified to a lower dosage (0.05 mg/kg) in the post-operative management of laparoscopic cholecystectomy.

Injectable Nano-Micro Composites with Anti-bacterial and Osteogenic Capabilities for Minimally Invasive Treatment of Osteomyelitis.

The effective management of osteomyelitis remains extremely challenging due to the difficulty associated with treating bone defects, the high probability of recurrence, the requirement of secondary surgery or multiple surgeries, and the difficulty in eradicating infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Hence, smart biodegradable biomaterials that provide effective and precise local anti-infection effects and can promote the repair of bone defects are actively being developed. Here, a novel nano-micro composite is fabricated by combining calcium phosphate (CaP) nanosheets with drug-loaded GelMA microspheres via microfluidic technology. The microspheres are covalently linked with vancomycin (Van) through an oligonucleotide (oligo) linker using an EDC/NHS carboxyl activator. Accordingly, a smart nano-micro composite called "CaP@MS-Oligo-Van" is synthesized. The porous CaP@MS-Oligo-Van composites can target and capture bacteria. They can also release Van in response to the presence of bacterial micrococcal nuclease and Ca2+, exerting additional antibacterial effects and inhibiting the inflammatory response. Finally, the released CaP nanosheets can promote bone tissue repair. Overall, the findings show that a rapid, targeted drug release system based on CaP@MS-Oligo-Van can effectively target bone tissue infections. Hence, this agent holds potential in the clinical treatment of osteomyelitis caused by MRSA.

[WITHDRAWN] MIML: Multiplex Image Machine Learning for High Precision Cell Classification via Mechanical Traits within Microfluidic Systems.

This paper has been withdrawn by Khayrul Islam.

Spatial distribution, source identification, and transportation paths of plutonium in the Beibu Gulf, South China Sea.

To investigate the spatial distribution and source of plutonium isotopes in the Beibu Gulf, surface sediments were collected and analyzed using sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). The activities of 239+240Pu in surface sediments ranged from 0.012 to 0.451 mBq/g (mean: 0.171 ± 0.138 mBq/g, n = 36), indicating a decreasing trend in a counterclockwise direction from the southern bay mouth. The counterclockwise decreasing trend in the south of the bay mouth is similar to the current in the Beibu Gulf. The 240Pu/239Pu atom ratios in surface sediments ranged from 0.156 to 0.283 (mean: 0.236 ± 0.031, n = 36), slightly higher than that of the global fallout value of 0.18. This suggests that the Pu in the Beibu Gulf was a combination of global fallout and Pacific Proving Ground (PPG). The average contribution of the plutonium (Pu) derived from the PPG in the sediment was estimated to be 52 % ± 24 %.

Rosavin: Research Advances in Extraction and Synthesis, Pharmacological Activities and Therapeutic Effects on Diseases of the Characteristic Active Ingredients of Rhodiola rosea L.

Rhodiola rosea L. (RRL) is a popular plant in traditional medicine, and Rosavin, a characteristic ingredient of RRL, is considered one of the most important active ingredients in it. In recent years, with deepening research on its pharmacological actions, the clinical application value and demand for Rosavin have been steadily increasing. Various routes for the extraction and all-chemical or biological synthesis of Rosavin have been gradually developed for the large-scale production and broad application of Rosavin. Pharmacological studies have demonstrated that Rosavin has a variety of biological activities, including antioxidant, lipid-lowering, analgesic, antiradiation, antitumor and immunomodulation effects. Rosavin showed significant therapeutic effects on a range of chronic diseases, including neurological, digestive, respiratory and bone-related disorders during in vitro and vivo experiments, demonstrating the great potential of Rosavin as a therapeutic drug for diseases. This paper gives a comprehensive and insightful overview of Rosavin, focusing on its extraction and synthesis, pharmacological activities, progress in disease-treatment research and formulation studies, providing a reference for the production and preparation, further clinical research and applications of Rosavin in the future.

Deep learning-based predictive classification of functional subpopulations of hematopoietic stem cells and multipotent progenitors.

Background: Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) play a pivotal role in maintaining lifelong hematopoiesis. The distinction between stem cells and other progenitors, as well as the assessment of their functions, has long been a central focus in stem cell research. In recent years, deep learning has emerged as a powerful tool for cell image analysis and classification/prediction. Methods: In this study, we explored the feasibility of employing deep learning techniques to differentiate murine HSCs and MPPs based solely on their morphology, as observed through light microscopy (DIC) images. Results: After rigorous training and validation using extensive image datasets, we successfully developed a three-class classifier, referred to as the LSM model, capable of reliably distinguishing long-term HSCs (LT-HSCs), short-term HSCs (ST-HSCs), and MPPs. The LSM model extracts intrinsic morphological features unique to different cell types, irrespective of the methods used for cell identification and isolation, such as surface markers or intracellular GFP markers. Furthermore, employing the same deep learning framework, we created a two-class classifier that effectively discriminates between aged HSCs and young HSCs. This discovery is particularly significant as both cell types share identical surface markers yet serve distinct functions. This classifier holds the potential to offer a novel, rapid, and efficient means of assessing the functional states of HSCs, thus obviating the need for time-consuming transplantation experiments. Conclusion: Our study represents the pioneering use of deep learning to differentiate HSCs and MPPs under steady-state conditions. With ongoing advancements in model algorithms and their integration into various imaging systems, deep learning stands poised to become an invaluable tool, significantly impacting stem cell research.

Establishment of a Prognostic Nomogram for Cancer-Specific Survival in Patients With Base-of-Tongue Squamous Cell Carcinoma: A Retrospective Study Based on the SEER Database.

BACKGROUND: The aim of this retrospective study was to construct and clinically apply a nomogram for cancer-specific survival (CSS) in patients diagnosed with base-of-tongue squamous cell carcinoma (BOTSCC) to predict their survival prognosis. METHODS: We collected 8448 patients diagnosed with BOTSCC during 2004-2015 from the Surveillance, Epidemiology, and End Results (SEER) database and divided 30% and 70% of them into validation and training cohorts, respectively. We utilized backward stepwise regression in the Cox model to select variables. Predictive variables were subsequently identified from the variables selected above by using multivariate Cox regression. The new survival model was compared with the American Joint Committee on Cancer (AJCC) prognosis model using the following variables: calibration curve, time-dependent area under the receiver operating characteristic curve (AUC), concordance index (C-index), integrated discrimination improvement (IDI), decision-curve analysis (DCA), and net reclassification improvement (NRI). RESULTS: A nomogram was established for predicting the CSS probability in patients with BOTSCC. Factors including sex, race, age at diagnosis, marital status, radiotherapy status, chemotherapy status, TNM AJCC stage, surgery status, tumor size, and months from diagnosis to treatment were selected through multivariate Cox regression as independent predictors of CSS. Calibration plots indicated that the model we established had satisfactory calibration ability. The AUC, C-index, IDI, DCA, and NRI results illustrated that the nomogram performed explicit prognoses more accurately than did the AJCC system alone. CONCLUSION: We identified the relevant factors affecting the survival of BOTSCC patients and analyzed the data on patients suffering from BOTSCC in the SEER database. These factors were used to construct a new nomogram to give clinical staff a more-visual prediction model for the 3-, 5-, and 8-year probabilities of CSS for patients newly diagnosed with BOTSCC, thereby aiding clinical decision making.

Aerosol Inhalation of Chimpanzee Adenovirus Vectors (ChAd68) Expressing Ancestral or Omicron BA.1 Stabilized Pre-Fusion Spike Glycoproteins Protects Non-Human Primates against SARS-CoV-2 Infection.

Current COVID-19 vaccines are effective countermeasures to control the SARS-CoV-2 virus pandemic by inducing systemic immune responses through intramuscular injection. However, respiratory mucosal immunization will be needed to elicit local sterilizing immunity to prevent virus replication in the nasopharynx, shedding, and transmission. In this study, we first compared the immunoprotective ability of a chimpanzee replication-deficient adenovirus-vectored COVID-19 vaccine expressing a stabilized pre-fusion spike glycoprotein from the ancestral SARS-CoV-2 strain Wuhan-Hu-1 (BV-AdCoV-1) administered through either aerosol inhalation, intranasal spray, or intramuscular injection in cynomolgus monkeys and rhesus macaques. Compared with intranasal administration, aerosol inhalation of BV-AdCoV-1 elicited stronger humoral and mucosal immunity that conferred excellent protection against SARS-CoV-2 infection in rhesus macaques. Importantly, aerosol inhalation induced immunity comparable to that obtained by intramuscular injection, although at a significantly lower dose. Furthermore, to address the problem of immune escape variants, we evaluated the merits of heterologous boosting with an adenovirus-based Omicron BA.1 vaccine (C68-COA04). Boosting rhesus macaques vaccinated with two doses of BV-AdCoV-1 with either the homologous or the heterologous C68-COA04 vector resulted in cross-neutralizing immunity against WT, Delta, and Omicron subvariants, including BA.4/5 stronger than that obtained by administering a bivalent BV-AdCoV-1/C68-COA04 vaccine. These results demonstrate that the administration of BV-AdCoV-1 or C68-COA04 via aerosol inhalation is a promising approach to prevent SARS-CoV-2 infection and transmission and curtail the pandemic spread.

Locally Saturated Ether-Based Electrolytes With Oxidative Stability For Li Metal Batteries Based on Li-Rich Cathodes.

Li metal batteries applying Li-rich, Mn-rich (LMR) layered oxide cathodes present an opportunity to achieve high-energy density at reduced cell cost. However, the intense oxidizing and reducing potentials associated with LMR cathodes and Li anodes present considerable design challenges for prospective electrolytes. Herein, we demonstrate that, somewhat surprisingly, a properly designed localized-high-concentration electrolyte (LHCE) based on ether solvents is capable of providing reversible performance for Li||LMR cells. Specifically, the oxidative stability of the LHCE was found to heavily rely on the ratio between salt and solvating solvent, where local-saturation was necessary to stabilize performance. Through molecular dynamics (MD) simulations, this behavior was found to be a result of aggregated solvation structures of Li+/anion pairs. This LHCE system was found to produce significantly improved LMR cycling (95.8% capacity retention after 100 cycles) relative to a carbonate control as a result of improved cathode-electrolyte interphase (CEI) chemistry from X-ray photoelectron spectroscopy (XPS), and cryogenic transmission electron microscopy (cryo-TEM). Leveraging this stability, 4 mAh cm-2 LMR||2× Li full cells were demonstrated, retaining 87% capacity after 80 cycles in LHCE, whereas the control electrolyte produced rapid failure. This work uncovers the benefits, design requirements, and performance origins of LHCE electrolytes for high-voltage Li||LMR batteries.

Identification of the SNARE complex that mediates the fusion of multivesicular bodies with the plasma membrane in exosome secretion.

Exosomes play crucial roles in local and distant cellular communication and are involved in various physiological and pathological processes. Tumour-derived exosomes are pivotal to tumorigenesis, but the precise mechanisms underlying their secretion remain elusive. In particular, the SNARE proteins that mediate the fusion of multivesicular bodies (MVBs) with the plasma membrane (PM) in tumour cells are subject to debate. In this study, we identified syntaxin-4, SNAP-23, and VAMP-7 as the SNAREs responsible for exosome secretion in MCF-7 breast cancer cells and found that a SNARE complex consisting of these SNAREs can drive membrane fusion in vitro. Deletion of any of these SNAREs in MCF-7 cells did not affect MVB biogenesis and transportation, indicating their specific involvement in MVB-PM fusion. In addition, syntaxin-4, SNAP-23, and VAMP-7 play equivalent roles in exosome secretion in both HeLa cervical cancer cells and A375 melanoma cells, suggesting their conserved function in exosome secretion. Furthermore, deletion of VAMP-7 in 4T1 mammary carcinoma cells efficiently inhibited exosome secretion and led to significant attenuation of tumour growth and lung metastasis in mouse models, implying that VAMP-7 may hold promise as a novel therapeutic target for breast cancer.

A China-developed adenovirus vector-based COVID-19 vaccine: review of the development and application of Ad5-nCov.

INTRODUCTION: The global spread of COVID-19 has prompted the development of vaccines. A recombinant adenovirus type-5 vectored COVID-19 vaccine (Ad5-nCoV) developed by Chinese scientists has been authorized for use as a prime and booster dose in China and several other countries. AREAS COVERED: We searched published articles as of 4 May 2023, on PubMed using keywords related to Adenovirus vector, vaccine, and SARS-CoV-2. We reported the progress and outcomes of Ad5-nCov, including vaccine efficacy, safety, immunogenicity based on pre-clinical trials, clinical trials, and real-world studies for primary and booster doses. EXPERT OPINION: Ad5-nCoV is a significant advancement in Chinese vaccine development technology. Evidence from clinical trials and real-world studies has demonstrated well-tolerated, highly immunogenic, and efficacy of Ad5-nCoV in preventing severe/critical COVID-19. Aerosolized Ad5-nCoV, given via a novel route, could elicit mucosal immunity and improve the vaccine efficacy, enhance the production capacity and availability, and reduce the potential negative impact of preexisting antibodies. However, additional research is necessary to evaluate the long-term safety and immunogenicity of Ad5-nCoV, its efficacy against emerging variants, its effectiveness in a real-world context of hybrid immunity, and its cost-effectiveness, particularly with respect to aerosolized Ad5-nCoV.