Neutrophil­to­lymphocyte ratio reflects lung injury in thoracic radiotherapy and immune checkpoint inhibitors combination therapy with different sequences.

The combination of thoracic radiotherapy and immune checkpoint inhibitors (ICIs) has emerged as a novel treatment approach for malignant tumors. However, it is important to consider the potential exacerbation of lung injury associated with this treatment modality. The neutrophil-to-lymphocyte ratio (NLR), an inflammatory marker, holds promise as a non-invasive indicator for assessing the toxicity of this combination therapy. To investigate this further, a study involving 80 patients who underwent thoracic radiotherapy in conjunction with ICIs was conducted. These patients were divided into two groups: The concurrent therapy group and the sequential therapy group. A logistic regression analysis was conducted to ascertain risk factors for grade ≥2 pneumonitis. Following propensity score matching, the NLR values were examined between the concurrent group and the sequential group to evaluate any disparity. A mouse model of radiation pneumonitis was established, and ICIs were administered at varying time points. The morphological evaluation of lung injury was conducted using H&E staining, while the NLR values of peripheral blood were detected through flow cytometry. Logistic regression analysis revealed that radiation dosimetric parameters (mean lung dose, total dose and V20), the inflammatory index NLR at the onset of pneumonitis, and treatment sequences (concurrent or sequential) were identified as independent predictors of grade ≥2 treatment-related pneumonitis. The results of the morphological evaluation indicated that the severity of lung tissue injury was greater in cases where programmed cell death protein 1 (PD-1) blockade was administered during thoracic radiotherapy, compared with cases where PD-1 blockade was administered 14 days after radiotherapy. Moreover, the present study demonstrated that the non-invasive indicator known as the NLR has the potential to accurately reflect the aforementioned injury.

Point-to-Point Efficient Grafting Improved Compatibility of Boron-Based Fuel-Rich Propellants.

Due to the high mass calorific value, boron powder is widely used in energetic material systems such as solid propellants and ignition powders. Especially, boron powder has very broad application prospects in the field of fuel-rich propellants. However, due to the cross-linking reaction between the boric acid contained on the surface of boron powder and an adhesive called hydroxylated polybutadiene (HTPB), the viscosity of the propellant mixture system increases sharply, which seriously affects the preparation of the propellant. In this paper, "click chemistry" is intended to be used to graft the functional groups on the surface of boron powder to reduce the viscosity of the boron powder and HTPB in the initial mixing stage. In addition, a rheometer was used to test the viscosity of the boron powder and the HTPB system. The test results showed that compared to the viscosity of the raw boron powder system at 24.1 Pa·s, the mixing termination viscosity of the grafted sample was 17.1 Pa·s, a decrease of 29.0%.

Honokiol alleviates radiation-induced premature ovarian failure via enhancing Nrf2.

BACKGROUND: The ovary is highly sensitive to radiation, and patients receiving radiotherapy are at significant risk of premature ovarian failure (POF). This study aimed to explore the radioprotective effect of honokiol (HKL) on ionizing radiation (IR)-induced POF. METHODS: Female C57BL/6 mice were administered intraperitoneally with vehicle or HKL once daily for 7 days. On day 7, the mice in the IR and HKL+IR groups were exposed to 3.2 Gy whole-body radiation for one hour after the intraperitoneal injection and sacrificed 12 or 72 h after radiation exposure. The gonadosomatic index (GSI) was calculated. Blood samples were collected for enzyme-linked immunosorbent assay (ELISA). Ovaries were harvested for histological examination, immunohistochemistry, immunofluorescence, TUNEL, western blot, and qPCR. The fertility assessment was evaluated by calculating live offspring number. RESULTS: The optimum dose of HKL against radiation was 10 mg/kg via intraperitoneal injection. POF was induced 72 h after irradiation with significantly downregulated proliferating cell nuclear antigen (PCNA). The numbers of primordial and preantral follicles decreased significantly after irradiation (p < .001), whereas the number of atretic follicles increased (p < .001). The serum levels of estradiol (E2 ) and anti-Müllerian hormone (AMH) decreased to 50% of the control group after irradiation (p < .05). Moreover, the GSI after irradiation was 27% lower than in the control group (p < .05). The number of offspring in the IR group dropped by 50% compared with the control group (p < .05). HKL pretreatment protected the animals' fertility, GSI, PCNA, serum levels of E2 and AMH, and the number of primordial and preantral follicles. Significant upregulation of apoptosis-related proteins such as Pho-P53, Bax, Cyto C, C-caspase-3, C-PARP, and pyroptosis-related proteins such as Pho-NF-κB p65, NLRP3, caspase-1, IL-1ß, and IL-18 was observed after irradiation, while the expression of Bcl-2 decreased. HKL pretreatment prevented these changes. After irradiation, malondialdehyde (MDA), Nrf2, and HO-1 were upregulated. HKL treatment activated the expression of Nrf2 and HO-1 and promoted the nucleus translocation of Nrf2. Furthermore, HKL did not affect ovarian reserves under physiological conditions. CONCLUSIONS: HKL ameliorated IR-induced POF by inhibiting apoptosis and pyroptosis by enhancing Nrf2 expression and translocation.

Mesomycoplasma ovipneumoniae from goats with respiratory infection: pathogenic characteristics, population structure, and genomic features.

BACKGROUND: Mycoplasma ovipneumoniae is a critical pathogen that causes respiratory diseases that threaten Caprini health and cause economic damage. A genome-wide study of M. ovipneumoniae will help understand the pathogenic characteristics of this microorganism. RESULTS: Toxicological pathology and whole-genome sequencing of nine M. ovipneumoniae strains isolated from goats were performed using an epidemiological survey. These strains exhibited anterior ventral lung consolidation, typical of bronchopneumonia in goats. Average nucleotide identity and phylogenetic analysis based on whole-genome sequences showed that all M. ovipneumoniae strains clustered into two clades, largely in accordance with their geographical origins. The pan-genome of the 23 M. ovipneumoniae strains contained 5,596 genes, including 385 core, 210 soft core, and 5,001 accessory genes. Among these genes, two protein-coding genes were annotated as cilium adhesion and eight as paralog surface adhesins when annotated to VFDB, and no antibiotic resistance-related genes were predicted. Additionally, 23 strains carried glucosidase-related genes (ycjT and group_1595) and glucosidase-related genes (atpD_2), indicating that M. ovipneumoniae possesses a wide range of glycoside hydrolase activities. CONCLUSIONS: The population structure and genomic features identified in this study will facilitate further investigations into the pathogenesis of M. ovipneumoniae and lay the foundation for the development of preventive and therapeutic methods.

Traditional Chinese medicine residues promote the growth and quality of Salvia miltiorrhiza Bunge by improving soil health under continuous monoculture.

Continuous monoculture of crops has resulted in reduced yields and quality, as well as soil deterioration. Although traditional Chinese medicine residues (TCMRs) are known to promote plant growth and soil health, few studies have investigated their effectiveness in continuous monoculture soils. Here, we studied the impact of chemical fertilizers (CF) and four TCMRs with antibacterial activities on the growth of S. miltiorrhiza (a widely used medicinal plant in China), accumulation of active ingredients in plants, and soil health under continuous monoculture conditions. Compared with no fertilizer (CK) and CF, fermented Sophora flavescens radix residue (SFRf) and fermented and unfermented Moutan cortex residue (MCRf and MCRu, respectively) resulted in a reduction of the disease index of root rot, while CF did not. The CF and four TCMR treatments increased the accumulation of nitrogen (N) (42.8-124.6% and 17.0-101.7%), phosphorous (P) (19.8-74.7% and 8.3-27.4%), and potassium (K) (104.1-212.0% and 9.3-51.8%) in shoots and roots compared to CK. The differences in nutrient accumulation between the CF and TCMR treatments were statistically insignificant, excepted for the N accumulation in the roots. All fertilization treatments increased plant biomass compared to CK, with increases of 25.57-89.86% and 2.62-35.28% in shoots and roots, respectively. The SFRf treatment exhibited the most significant enhancement in both shoot and root biomass. CF significantly reduced the accumulation of seven active ingredients in roots by 23.90-78.95% compared to CK, whereas each TCMR increased accumulation of certain active ingredients. The TCMR treatments effectively improved the health of deteriorated soil by enhancing soil physicochemical properties, restoring the balance of the microbial community, recruiting beneficial bacteria, and reducing the relative abundance of the pathogen Fusarium. The SFRf treatment exhibited superior performance in improving soil health than other treatments. Overall, the TCMRs outperformed CF in restoring soil health and promoting the yield and quality of S. miltiorrhiza. These findings offer guidance for improving the health of continuous cropping soil and recycling TCMRs.

Microglial voltage-dependent anion channel 1 signaling modulates sleep deprivation-induced transition to chronic postsurgical pain.

STUDY OBJECTIVES: This study verified that sleep deprivation before and after skin/muscle incision and retraction (SMIR) surgery increased the risk of chronic pain and investigated the underlying roles of microglial voltage-dependent anion channel 1 (VDAC1) signaling. METHODS: Adult mice received 6 hours of total sleep deprivation from 1 day prior to SMIR until the third day after surgery. Mechanical and heat-evoked pain was assessed before and within 21 days after surgery. Microglial activation and changes in VDAC1 expression and oligomerization were measured. Minocycline was injected to observe the effects of inhibiting microglial activation on pain maintenance. The VDAC1 inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and oligomerization inhibitor VBIT-4 were used to determine the roles of VDAC1 signaling on microglial adenosine 5' triphosphate (ATP) release, inflammation (IL-1ß and CCL2), and chronicity of pain. RESULTS: Sleep deprivation significantly increased the pain duration after SMIR surgery, activated microglia, and enhanced VDAC1 signaling in the spinal cord. Minocycline inhibited microglial activation and alleviated sleep deprivation-induced pain maintenance. Lipopolysaccharide (LPS)-induced microglial activation was accompanied by increased VDAC1 expression and oligomerization, and more VDAC1 was observed on the cell membrane surface compared with control. DIDS and VBIT-4 rescued LPS-induced microglial ATP release and IL-1ß and CCL2 expression. DIDS and VBIT-4 reversed sleep loss-induced microglial activation and pain chronicity in mice, similar to the effects of minocycline. No synergistic effects were found for minocycline plus VBIT-4 or DIDS. CONCLUSIONS: Perioperative sleep deprivation activated spinal microglia and increases the risk of chronic postsurgical pain in mice. VDAC1 signaling regulates microglial activation-related ATP release, inflammation, and chronicity of pain.

The Therapeutic Application of Stem Cells and Their Derived Exosomes in the Treatment of Radiation-Induced Skin Injury.

Radiation-induced skin injury (RISI) is a serious concern for nuclear accidents and cancer radiotherapy, which seriously affects the quality of life of patients. This injury differs from traditional wounds due to impaired healing and the propensity to recurrence and is divided into acute and chronic phases on the basis of the injury time. Unfortunately, there are few effective therapies for preventing or mitigating this injury. Over the last few decades, various studies have focused on the effects of stem cell-based therapies to address the tissue repair and regeneration of irradiated skin. These stem cells modulate inflammation and instigate tissue repair by differentiating into specific kinds of cells or releasing paracrine factors. Stem cell-based therapies, including bone marrow-derived stem cells (BMSCs), adipose-derived stem cells (ADSCs) and stromal vascular fraction (SVF), have been reported to facilitate wound healing after radiation exposure. Moreover, stem cell-derived exosomes have recently been suggested as an effective and cell-free approach to support skin regeneration, circumventing the concerns respecting direct application of stem cells. Based on the literature on stem cell-based therapies for radiation-induced skin injury, we summarize the characteristics of different stem cells and describe their latest animal and clinical applications, as well as potential mechanisms. The promise of stem-cell based therapies against radiation-induced skin injury contribute to our response to nuclear events and smooth progress of cancer radiotherapy.

Immunological pathogenesis of Bovine E. coli infection in a model of C. elegans.

BACKGROUND: Cattle industry is critical for China's livestock industry, whereas E. coli infection and relevant diseases could lead huge economic loss. Traditional mammalian models would be costly, time consuming and complicated to study pathological changes of bovine E. coli. There is an urgent need for a simple but efficient animal model to quantitatively evaluate the pathological changes of bovine-derived E. coli in vivo. Caenorhabditis elegans (C. elegans) has a broad host range of diverse E. coli strains with advantages, including a short life cycle, a simple structure, a transparent body which is easily visualized, a well-studied genetic map, an intrinsic immune system which is conservable with more complicated mammalians. RESULTS: Here, we considered that O126 was the dominant serotype, and a total of 19 virulence factors were identified from 41 common E. coli virulence factors. Different E. coli strains with diverse pathogenicity strengths were tested in C. elegans in E. coli with higher pathogenicity (EC3/10), Nsy-1, Sek-1 and Pmk-1 of the p38 MAPK signaling pathway cascade and the expression of the antimicrobial peptides Abf-3 and Clec-60 were significantly up-regulated comparing with other groups. E. coli with lower pathogenicity (EC5/13) only activated the expression of Nsy-1 and Sek-1 genes in the p38 MAPK signaling pathway, Additionally, both groups of E. coli strains caused significant upregulation of the antimicrobial peptide Spp-1. CONCLUSION: Thirteen E. coli strains showed diverse pathogenicity in nematodes and the detection rate of virulence factors did not corresponding to the virulence in nematodes, indicating complex pathogenicity mechanisms. We approved that C. elegans is a fast and convenient detection model for pathogenic bacteria virulence examinations.

Rheological Impact of Particle Size Gradation on GAP Propellant Slurries.

Over the years, widespread interest has been placed on rheological properties to reflect the processability of propellant slurries. Particle gradation technology plays an essential role in the improvement of the processability of propellant slurries. In this article, rheological properties of glycidyl azide polymer (GAP) propellant slurries were measured by dynamic rheological measurements with a rheometer. Submicron-sized (d 50 = 0.221 µm) and micron-sized (d 50 = 33.02 µm) CL-20 particles and ultrafine (d 50 = 2.40 µm) and micron-sized (d 50 = 341.69 µm) AP particles were utilized to investigate the influence of the addition of CL-20 and particle size gradation on rheological properties. The test results demonstrate that the LVE region remains almost invariable while the yield transition process is delayed when the relative content of submicron-sized CL-20 increases from 10 to 20%. The values of G', G″, and |η*| increase with increasing submicron-sized CL-20. Despite this, the value of |η*| can be effectively reduced to about the same value as the slurries with bimodal AP by the size gradation of CL-20. In addition, particle porosity appears to be a suitable parameter to predict trends concerning the rheological properties of the GAP propellant slurries.

CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage.

Recently, Toll-like receptors (TLRs) have been extensively studied in radiation damage, but the inherent defects of high toxicity and low efficacy of most TLR ligands limit their further clinical transformation. CRX-527, as a TLR4 ligand, has rarely been reported to protect against radiation. We demonstrated that CRX-527 was safer than LPS at the same dose in vivo and had almost no toxic effect in vitro. Administration of CRX-527 improved the survival rate of total body irradiation (TBI) to 100% in wild-type mice but not in TLR4-/- mice. After TBI, hematopoietic system damage was significantly alleviated, and the recovery period was accelerated in CRX-527-treated mice. Moreover, CRX-527 induced differentiation of HSCs and the stimulation of CRX-527 significantly increased the proportion and number of LSK cells and promoted their differentiation into macrophages, activating immune defense. Furthermore, we proposed an immune defense role for hematopoietic differentiation in the protection against intestinal radiation damage, and confirmed that macrophages invaded the intestines through peripheral blood to protect them from radiation damage. Meanwhile, CRX-527 maintained intestinal function and homeostasis, promoted the regeneration of intestinal stem cells, and protected intestinal injury from lethal dose irradiation. Furthermore, After the use of mice, we found that CRX-527 had no significant protective effect on the hematopoietic and intestinal systems of irradiated TLR4-/- mice. in conclusion, CRX-527 induced differentiation of HSCs protecting the intestinal epithelium from radiation damage.

PITPNC1 promotes the thermogenesis of brown adipose tissue under acute cold exposure.

Brown adipose tissue (BAT) plays an essential role in non-shivering thermogenesis. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1) is identified as a lipid transporter that reciprocally transfers phospholipids between intracellular membrane structures. However, the physiological significance of PITPNC1 and its regulatory mechanism remain unclear. Here, we demonstrate that PITPNC1 is a key player in thermogenesis of BAT. While Pitpnc1-/- mice do not differ with wildtype mice in body weight and insulin sensitivity on either chow or high-fat diet, they develop hypothermia when subjected to acute cold exposure at 4°C. The Pitpnc1-/- brown adipocytes exhibit defective ß-oxidation and abnormal thermogenesis-related metabolism pathways in mitochondria. The deficiency of lipid mobilization in Pitpnc1-/- brown adipocytes might be the result of excessive accumulation of phosphatidylcholine and a reduction of phosphatidic acid. Our findings have uncovered significant roles of PITPNC1 in mitochondrial phospholipid homeostasis and BAT thermogenesis.

Preclinical immunogenicity and efficacy of a candidate COVID-19 vaccine based on a vesicular stomatitis virus-SARS-CoV-2 chimera.

BACKGROUND: To investigate a vaccine technology with potential to protect against coronavirus disease 2019 (COVID-19) and reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with a single vaccine dose, we developed a SARS-CoV-2 candidate vaccine using the live vesicular stomatitis virus (VSV) chimeric virus approach previously used to develop a licensed Ebola virus vaccine. METHODS: We generated a replication-competent chimeric VSV-SARS-CoV-2 vaccine candidate by replacing the VSV glycoprotein (G) gene with coding sequence for the SARS-CoV-2 Spike glycoprotein (S). Immunogenicity of the lead vaccine candidate (VSV∆G-SARS-CoV-2) was evaluated in cotton rats and golden Syrian hamsters, and protection from SARS-CoV-2 infection also was assessed in hamsters. FINDINGS: VSV∆G-SARS-CoV-2 delivered with a single intramuscular (IM) injection was immunogenic in cotton rats and hamsters and protected hamsters from weight loss following SARS-CoV-2 challenge. When mucosal vaccination was evaluated, cotton rats did not respond to the vaccine, whereas mucosal administration of VSV∆G-SARS-CoV-2 was found to be more immunogenic than IM injection in hamsters and induced immunity that significantly reduced SARS-CoV-2 challenge virus loads in both lung and nasal tissues. INTERPRETATION: VSV∆G-SARS-CoV-2 delivered by IM injection or mucosal administration was immunogenic in golden Syrian hamsters, and both vaccination methods effectively protected the lung from SARS-CoV-2 infection. Hamsters vaccinated by mucosal application of VSV∆G-SARS-CoV-2 also developed immunity that controlled SARS-CoV-2 replication in nasal tissue. FUNDING: The study was funded by Merck Sharp & Dohme, Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and The International AIDS Vaccine Initiative, Inc. (IAVI), New York, USA. Parts of this research was supported by the Biomedical Advanced Research and Development Authority (BARDA) and the Defense Threat Reduction Agency (DTRA) of the US Department of Defense.

The Protective Effects of Apigenin Against Radiation-Induced Intestinal Injury.

Radiation-induced intestinal injury (RIII) restricts the therapeutic efficacy of radiotherapy in abdominal or pelvic malignancies. Also, intestinal injury is a major cause of death following exposure to high doses of radiation in nuclear accidents. No safe and effective prophylactics or therapeutics for RIII are currently available. Here, we reported that the apigenin, a natural dietary flavone, prolonged the survival in c57 mice after lethal irradiation. Apigenin pretreatment brought about accelerated restoration of crypt-villus structure, including enhanced regenerated crypts, more differentiated epithelium cells, and increased villus length. In addition, intestinal crypt cells in the apigenin-treated group exhibited more proliferation and less apoptosis. Furthermore, apigenin increased the expression of Nrf2 and its downstream target gene HO-1, and decreased oxidative stress after irradiation. In conclusion, our findings demonstrate the radioprotective efficacy of apigenin. Apigenin has the potential to be used as a radioprotectant in cancer therapy and nuclear accidents.

Dimethyl Sulfoxide Attenuates Radiation-Induced Testicular Injury through Facilitating DNA Double-Strand Break Repair.

The testis is susceptible to ionizing radiation, and male infertility and sexual dysfunction are prevalent problems after whole-body or local radiation exposure. Currently, there is no approved agent for the prevention or treatment of radiation-induced testicular injury. Herein, we investigated the radioprotective effect of dimethyl sulfoxide (DMSO), an organosulfur compound that acts as a free radical scavenger, on testicular injury. Treatment of mice with a single dose of DMSO prior to 5 Gy irradiation restored sex hormones and attenuated the reduction in testis weight. Histological analyses revealed that DMSO alleviated the distorted architecture of seminiferous tubules and promoted seminiferous epithelium regeneration following irradiation. Moreover, DMSO provided quantitative and qualitative protection for sperm and preserved spermatogenesis and fertility in male mice. Mechanistically, DMSO treatment enhanced GFRα-1+ spermatogonial stem cell and c-Kit+ spermatogonial survival and regeneration after radiation. DMSO also alleviated radiation-induced oxidative stress and suppressed radiation-induced germ cell apoptosis in vivo and in vitro. Additionally, DMSO efficiently reduced DNA damage accumulation and induced the expression of phosph-BRCA1, BRCA1, and RAD51 proteins, indicating that DMSO facilitates DNA damage repair with a bias toward homologous recombination. In summary, our findings demonstrate the radioprotective efficacy of DMSO on the male reproductive system, which warrants further studies for future application in the preservation of male fertility during conventional radiotherapy and nuclear accidents.

The hydrogen storage nanomaterial MgH2 improves irradiation-induced male fertility impairment by suppressing oxidative stress.

OBJECTIVE: This study aimed to reveal the protective effect of hydrogen storage nanomaterial MgH2 on radiation-induced male fertility impairment. METHODS: The characterization of MgH2 were analyzed by scanning electron microscopy (SEM) and particle size analyzer. The safety of MgH2 were evaluated in vivo and in vitro. The radioprotective effect of MgH2 on the reproductive system were analyzed in mice, including sperm quality, genetic effect, spermatogenesis, and hormone secretion. ESR, flow cytometry and western blotting assay were used to reveal the underlying mechanisms. RESULTS: MgH2 had an irregular spherical morphology and a particle size of approximately 463.2 nm, and the content of Mg reached 71.46%. MgH2 was safe and nontoxic in mice and cells. After irradiation, MgH2 treatment significantly protected testicular structure, increased sperm density, improved sperm motility, reduced deformity rates, and reduced the genetic toxicity. Particularly, the sperm motility were consistent with those in MH mice and human semen samples. Furthermore, MgH2 treatment could maintain hormone secretion and testicular spermatogenesis, especially the generation of Sertoli cells, spermatogonia and round sperm cells. In vitro, MgH2 eliminated the [·OH], suppressed the irradiation-induced increase in ROS production, and effectively alleviated the increase in MDA contents. Moreover, MgH2 significantly ameliorated apoptosis in testes and cells and reversed the G2/M phase cell cycle arrest induced by irradiation. In addition, MgH2 inhibited the activation of radiation-induced inflammation and pyroptosis. CONCLUSION: MgH2 improved irradiation-induced male fertility impairment by eliminating hydroxyl free radicals. Mice fertility and function were evaluated with or without MgH2 treatment after 5 Gy irradiation. MgH2 had the ability of hydroxyl radicals scavenging and MDA suppressing in testicular tissue induced by irradiation. Further, MgH2 could participate in spermatogenesis and protect sperm development in three stages: the generation of Sertoli cells (Sox-9+), spermatogonia (Stra8+) and round sperm cells (Crem+). Moreover, MgH2 alleviated the decrease of testosterone secreted by interstitial cells after irradiation. In addition, MgH2 suppressed apoptosis, pyroptosis and inflammatory response and alleviated cell cycle arrest by mediating IR-induced ROS.

A novel high throughput assay to quantify Epstein-Barr virus neutralizing antibody activity against B-cell and epithelial cell infections for vaccine and therapeutic developments.

Epstein-Barr Virus (EBV) is the causative agent of infectious mononucleosis and has been associated with a variety of malignancies. In vivo, EBV infects B cells and epithelial cells. However, the current EBV neutralization assays, especially those against B cell infection, are low throughput, laborious and lack of sensitivity. In this study, we optimized the EBV-GFP based micro-neutralization assay by selecting the most susceptible cell substrates, Akata 4E3 for B cell and HEK293T for epithelial cell. The newly developed procedure is high throughput. The cell type specific neutralization was confirmed using monoclonal antibodies specific to gp350 and gH/gL/gp42. A panel of human sera was also tested. Natural human EBV seropositive sera could neutralize EBV in both B cell and epithelial cell assays efficiently with a majority of human sera generating near 100% EBV neutralization. The EBV neutralizing antibody titers were highly correlated with antibodies specific to gp350, gH, EBV total proteins, and to a less degree with antibodies against gp42. Collectively, we demonstrated this improved neutralization assay is suitable to evaluating the humoral responses elicited by EBV vaccine candidates in preclinical animal models or in large-scale human trials.

Dopamine-derived nanoparticles for the protection of irradiation-induced intestinal injury by maintaining intestinal homeostasis.

Radiotherapy of abdominal and pelvic tumors almost inevitably injures the intestine by oxidative stress and causes inflammation. Regrettably, traditional radioprotective agents for irradiation (IR) induced intestinal injury suffer from challenges such as poor solubility, unsatisfactory bioactivity and undesired adverse reactions, which significantly limit their usefulness. Polydopamine nanoparticles (PDA-NPs) have shown promising potential in scavenging reactive oxygen species (ROS) and suppressing inflammation. In this study, PDA-NPs were prepared by a simple method and their physical properties were characterized. Mice received two doses of PDA-NPs by oral gavage 22 h apart, and were irradiated with X-rays 2 h after the last gavage. The protective effect of PDA-NPs and possible mechanisms of protection against IR-induced intestinal injury were explored. The results showed that PDA-NPs were spherical and well dispersed, with good shape uniformity, compact structure, good colloid dispersion stability, concentration-dependent light absorption, and accurate quantification. Importantly, PDA-NPs reduced mortality and prolonged the average survival time of mice after IR. Furthermore, PDA-NPs protected mice from IR-induced injury to crypt-villus units and maintained intestinal barrier function in the intestine. In particular, PDA-NPs significantly inhibited the depletion of Lgr5+ intestinal stem cells (ISCs) and promoted cell regeneration after IR, which indicated that the regeneration ability of ISCs was maintained and the repair of intestinal structure and function was promoted. Finally, PDA-NPs significantly suppressed the apoptosis, inflammatory pyroptosis and DNA damage of intestinal cells induced by ionizing radiation. Altogether, our study suggested that PDA-NPs may have great potential in protecting the intestines from ionizing radiation damage.

Disulfiram Protects Against Radiation-Induced Intestinal Injury in Mice.

Radiation-induced intestinal injury (RIII) occurs after high doses of radiation exposure. RIII restricts the therapeutic efficacy of radiotherapy in cancer and increases morbidity and mortality in nuclear disasters. Currently, there is no approved agent for the prevention or treatment of RIII. Here, we reported that the disulfiram, an FDA-approved alcohol deterrent, prolonged the survival in mice after lethal irradiation. Pretreatment with disulfiram inhibited proliferation within 24 h after irradiation, but improved crypt regeneration at 3.5 days post-irradiation. Mechanistically, disulfiram promoted Lgr5+ intestinal stem cells (ISCs) survival and maintained their ability to regenerate intestinal epithelium after radiation. Moreover, disulfiram suppresses DNA damage accumulation, thus inhibits aberrant mitosis after radiation. Unexpectedly, disulfiram treatment did not inhibit crypt cell apoptosis 4 h after radiation and the regeneration of crypts from PUMA-deficient mice after irradiation was also promoted by disulfiram. In conclusion, our findings demonstrate that disulfiram regulates the DNA damage response and survival of ISCs through affecting the cell cycle. Given its radioprotective efficacy and decades of application in humans, disulfiram is a promising candidate to prevent RIII in cancer therapy and nuclear accident.

Structural basis for HCMV Pentamer recognition by neuropilin 2 and neutralizing antibodies.

Human cytomegalovirus (HCMV) encodes multiple surface glycoprotein complexes to infect a variety of cell types. The HCMV Pentamer, composed of gH, gL, UL128, UL130, and UL131A, enhances entry into epithelial, endothelial, and myeloid cells by interacting with the cell surface receptor neuropilin 2 (NRP2). Despite the critical nature of this interaction, the molecular determinants that govern NRP2 recognition remain unclear. Here, we describe the cryo-EM structure of NRP2 bound to Pentamer. The high-affinity interaction between these proteins is calcium dependent and differs from the canonical carboxyl-terminal arginine (CendR) binding that NRP2 typically uses. We also determine the structures of four neutralizing human antibodies bound to the HCMV Pentamer to define susceptible epitopes. Two of these antibodies compete with NRP2 binding, but the two most potent antibodies recognize a previously unidentified epitope that does not overlap the NRP2-binding site. Collectively, these findings provide a structural basis for HCMV tropism and antibody-mediated neutralization.

Clinical Analysis of the Treatment of Primary Trigeminal Neuralgia by Percutaneous Balloon Compression.

PURPOSE: To summarize the technical points and clinical effects of percutaneous balloon compression (PBC) in the treatment of primary trigeminal neuralgia. METHODS: The clinical data of 13 patients with trigeminal neuralgia who received PBC from April 2020 to July 2021 were retrospectively analyzed. VAS, VRS-4 and PPI were used to evaluate the postoperative pain relief. Different postoperative complications were analyzed. RESULTS: All patients had a smooth operation, the inflation volume of the balloon was 0.7 ml, the average compression time was 120 s, and there was no balloon rupture during the operation. On the day after operation, 12 patients (92.3%) had complete pain relief, and 1 patient (7.7%) was not satisfied with pain relief, but the pain disappeared 2 weeks after the operation. After operation, there were 12 patients with facial numbness in the affected side (92.3%), 3 patients with masseter muscle weakness (23.0%), 1 patient with herpes around the mouth (7.6%), and 1 patient with diplopia (7.6%). CONCLUSION: PBC is an effective minimally invasive surgical method for the treatment of primary trigeminal neuralgia. It is suitable for the elderly and infirm people, those who cannot tolerate general anesthesia or are afraid of surgery, and patients who had undergone surgery but relapsed after surgery. However, it is necessary to pay attention to the serious facial numbness and postoperative masticatory weakness. These discomforts are generally relieved after half a year.