(±)-hypermonanones A-G, seven pairs of monoterpenoid polyprenylated acylphloroglucinol enantiomers from Hypericum monanthemum.

Seven pairs of undescribed monoterpenoid polyprenylated acylphloroglucinol enantiomers [(±)-hypermonanones A-G (1-7)], together with three known analogues, were identified from the whole plant of Hypericum monanthemum Hook. The structures of these compounds were determined by analyses of their UV, HRESIMS, 1D/2D NMR spectroscopic data, and NMR calculations. The absolute configurations of these compounds were assigned by ECD calculations after chiral HPLC separation. Diverse monoterpene moieties were fused at C-3/C-4 of the dearomatized acylphloroglucinol core, which led to 3,4-dihydro-2H-pyran-integrated angular or linear type 6/6/6 tricyclic skeletons in 1-7. Compounds (-)-2 and (+)-2 exhibited significant NO inhibitory activity against LPS induced RAW264.7 cells with the IC50 values of 7.07 ± 1.02 µM and 11.39 ± 0.24 µM, respectively.

Theoretical and experimental studies on channel impulse response of short-range non-line-of-sight ultraviolet communications.

A theoretical channel impulse response (CIR) model of short-range non-line-of-sight (NLOS) ultraviolet communications (UVC) in noncoplanar geometry under the single-scatter condition is proposed. Simulation results obtained from the widely accepted Monte-Carlo (MC)-based channel model of NLOS UVC are provided to verify corresponding theoretical results obtained from the proposed theoretical single-scatter CIR model. Additionally, an outdoor experiment with a light-emitting diode (LED) as the light source is first designed to measure the channel step response of NLOS UVC and to further validate the proposed theoretical single-scatter CIR model. By varying the different parameters of the transmitter and the receiver, such as the baseline range, the inclination angle, the azimuth angle, the beam divergence angle, and the field-of-view angle, the results of the proposed theoretical single-scatter CIR model and the MC-based channel model are exhibited and further analyzed in detail. Results indicate that the computational time cost by the proposed theoretical single-scatter CIR model is decreased to less than 0.6% of the MC-based one with comparable accuracy in assessing the temporal characteristics of NLOS UVC channels. Additionally, theoretical results obtained from the proposed theoretical single-scatter CIR model manifest satisfactory agreement with corresponding experimental measurements.

tert-Butyl Nitrite-Induced Radical Nitrile Oxidation Cycloaddition: Synthesis of Isoxazole/Isoxazoline-Fused Benzo 6/7/8-membered Oxacyclic Ketones.

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through Csp3-H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N-O fragment donor.

Long non-coding RNA NRSN2-AS1 promotes ovarian cancer progression through targeting PTK2/ß-catenin pathway.

As a common malignant tumor among women, ovarian cancer poses a serious threat to their health. This study demonstrates that long non-coding RNA NRSN2-AS1 is over-expressed in ovarian cancer tissues using patient sample and tissue microarrays. In addition, NRSN2-AS1 is shown to promote ovarian cancer cell proliferation and metastasis both in vitro and in vivo. Mechanistically, NRSN2-AS1 stabilizes protein tyrosine kinase 2 (PTK2) to activate the ß-catenin pathway via repressing MG-53-mediated ubiquitinated degradation of PTK2, thereby facilitating ovarian cancer progression. Rescue experiments verify the function of the NRSN2-AS1/PTK2/ß-catenin axis and the effects of MG53 on this axis in ovarian cancer cells. In conclusion, this study demonstrates the key role of the NRSN2-AS1/PTK2/ß-catenin axis for the first time and explores its potential clinical applications in ovarian cancer.

Rectosigmoid intussusception due to large submucosal lipoma mimicking rectal prolapse.

Rectosigmoid intussusception is a rare cause of bowel obstruction, accounting for only approximately 1%-2% of all bowel obstruction cases. While intussusception in adults typically occurs intra-abdominally and presents with signs and symptoms of intestinal obstruction, in rare cases, it can mimic a rectal prolapse if the intussusceptum protrudes through the anal canal. We herein report a case where an octogenarian woman presented with rectosigmoid intussusception through the anal canal, due to a sigmoid colon submucosal lipoma, who eventually required an open Hartmann's procedure. Patients with rectal prolapse symptoms should be carefully examined to rule out intussuscepting masses as a differential, as it would necessitate earlier surgical intervention.

Hyperxylones A and B, two polycyclic polyprenylated acylphloroglucinols with a benzoyl substituted bicyclo[3.2.1]octane core from Hypericum beanii.

Two new polycyclic polyprenylated acylphloroglucinols (PPAPs) possessing a rare benzoyl substituted bicyclo[3.2.1]octane core, hyperxylones A (1) and B (2), along with three new dearomatized isoprenylated acylphloroglucinols (DIAPs), hyperxylones C - E (3-5), were isolated from the roots of Hypericum beanii. The structures of 1-5 were determined by high-resolution electrospray ionization mass spectroscopy (HRESIMS) and 1D/2D nuclear magnetic resonance (NMR) spectroscopic analyses, gauge-independent atomic orbital (GIAO) NMR calculations, and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were biomimetically semi-synthesized starting from 5 and 4, respectively, enabling the correct stereochemical assignment of 5 and 4. Moreover, compounds 1 and 2 showed anti-nonalcoholic steatohepatitis (NASH) activity by inhibiting lipid deposition in L02 cells; compounds 3 and 5 exhibited nitric oxide (NO) inhibitory activity in lipopolysaccharides (LPS)-induced RAW264.7 cells.

Structural characteristics of a low molecular weight velvet antler protein and the anti-tumor activity on S180 tumor-bearing mice.

Velvet antler is a traditional Chinese medicine with various pharmacological values, which is an important raw material for traditional Chinese medicinal wine. Nevertheless, the chemical compositions and bioactivities of velvet antler residue used for making medicinal wine are rarely reported, leading to a waste of resources. In this study, a velvet antler protein (VA-pro) was extracted from velvet antler residue by simulating the gastrointestinal digestion, and its composition, structural characteristics and in vivo anti-tumor activities were determined and investigated. VA-pro possessed high purity with a relatively low molecular weight as 22.589 kDa under HPLC, one- and two-dimensional electrophoresis, and it contained high contents of Pro, Gly, Glu and Ala. Besides, the secondary structure of VA-pro was dominated by ß-turn and ß-sheet, and VA-pro possessed similar protein sequence, isoelectric point and amino acid compositions to hypothetical protein G4228_020061. The in vivo results substantiated that VA-pro could improve the body weights and immune organ indices, increase the expressions of sera cytokines and regulate the distributions of T and B lymphocytes subsets in peripheral blood of S180 tumor-bearing mice. Furthermore, VA-pro could effectively inhibit solid S180 tumors growth by inducing S phase cell cycle arrest mediated through mitochondria. To summarize, our study provided theoretical support that VA-pro had the potential to be used as an immunopotentiator in immunocompromised or cancer-bearing hosts.

CPLX2 Regulates Ferroptosis and Apoptosis Through NRF2 Pathway in Human Hepatocellular Carcinoma Cells.

Understanding the principle of regulated cell death (RCD) such as ferroptosis and apoptosis provides opportunities to overcome sorafenib resistance of HCC. Complexin II (CPLX2) is involved in calcium-dependent fusion of vesicles and plasma membrane, and recent studies showed CPLX2 is involved in cancer progression. However, the expression and function of CPLX2 are unclear in hepatocellular carcinoma (HCC). qPCR and western blotting assays were used to detect the levels of CPLX2. MTT and colony formation assays were used to detect cell viability. The contents of iron, ROS, MDA, and GSH were used to evaluate the function of CPLX2 on ferroptosis, while the flow cytometry and TUNEL assays were used to evaluate the role of CPLX2 on apoptosis. Our analysis showed CPLX2 is significantly upregulated in HCC, which predicts poor overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), and disease-specific survival (DSS) for patients with HCC. Further function enrichment analysis of genes related to CPLX2 showed CPLX2 is involved in the NRF2 pathway. Downregulation of CPLX2 can inhibit NRF2 expression and the transcription of its downstream genes, which confirms that CPLX2 is involved in NRF2 pathway. Cell viability assay showed that ferroptosis and apoptosis inhibitors can reverse the inhibition effect of CPLX2-knockdown on cell survival, respectively. And downregulation of CPLX2 significantly promotes the contents of iron, ROS, and MDA, while inhibiting the GSH level of HCC cell lysate, suggesting CPLX2 involved in ferroptosis. Moreover, downregulation of CPLX2 promotes the apoptosis of HCC cells by flow cytometry and TUNEL assay. And upregulation of NRF2 can partly reverse the inhibitory effect of CPLX2-downregulation on ferroptosis and apoptosis. Finally, we found downregulation of CPLX2 aggravates cell death induced by sorafenib. CPXL2 regulates ferroptosis and apoptosis through NRF2 pathway, and CPLX2 knockdown promotes cell death induced by sorafenib. CPLX2 might be an effective target for therapy patients with HCC.

Identifying Diagnostic and Prognostic Differentially Expressed Genes of Gastric Cancer Based on Bioinformatics Analyses of RNA-seq Data.

Background: The abnormal expression of genes in serum may be associated with early diagnosis of patients with malignant tumors. This study was designed to screen for significantly differentially expressed genes (DEGs) that may be associated with gastric cancer using bioinformatic methods. Methods: RNA-seq data from gastric cancers were downloaded from the TCGA and GEO databases, and 1903 secretory genes were downloaded from the HPA database. The diagnostic secretory RNAs of gastric cancer were screened using least absolute shrinkage and selection operator regression analysis. Univariate Cox regression analysis was used to evaluate the prognostic significance of the results. Biological functions were performed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Then, 640 cases of gastric cancer and paracancerous tissues were collected, and immunohistochemistry (IHC) was used to detect the expression of COL4A1. Results: In total, 25 upregulated differentially expressed genes (DEGs) were identified, which were secreted mainly in the blood and cell matrices. Six secretory genes (OLFM4, CEMIP, APOC1, CST1, COL4A1, and CD55) with diagnostic significance were identified, and the enrichment scores of these six genes were significantly associated with tumor stage. In addition, we found that increased COL4A1 expression might be associated with a poor prognosis in patients with gastric cancer. Based on GO and KEGG analyses, we found COL4A1-related DEGs were mainly enriched in connective tissue development, collagen fibrous tissue-related processes, extracellular structure, extracellular matrix (ECM) tissue, and related to the ECM receptor-related pathway, focal adhesion, and PI3K-Akt signaling pathway. Moreover, the results of immunohistochemical analyses showed that the COL4A1 protein level in gastric cancers was also higher than in the matched paracancerous tissues. Conclusions: In this study, we found six upregulated secretory genes, including OLFM4, CEMIP, APOC1, CST1, COL4A1, and CD55 which we hypothesized to be significant DEGs for the diagnosis of gastric cancer. Our data also suggest that COL4A1 may play an important role in the diagnosis and prognosis of gastric cancer.

Positive association between triglyceride glucose index and central systolic blood pressure among hypertensive adults.

BACKGROUND: While studies have suggested the association between triglyceride-glucose (TyG) index, a reliable surrogate for insulin resistance and hypertension data are limited to the correlation of TyG and central blood pressure. This study aims to test the hypothesis that a higher TyG index is associated with elevated central systolic blood pressure (cSBP). METHODS: A total of 9249 Chinese hypertensive adults from the H-type Hypertension and Stroke Prevention and Control Project were analyzed in this study. cSBP was measured noninvasively using an A-Pulse CASPro device. TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Smoothing curve and multivariate linear regression models [beta coefficient (ß) with 95% CI] were applied to analyze the association between TyG index and cSBP. Subgroup analyses were conducted to explore potential modifications to such a correlation. RESULTS: The overall mean TyG index is 8.8 ± 0.7, and the total mean cSBP is 131.3 ± 12.8 mmHg. TyG index was observed to be independently and positively associated with cSBP among the total population (ß = 0.92, 95% CI: 0.53-1.31, P < 0.001), and participants who do not use antihypertensive drugs (ß = 1.03, 95% CI: 0.46-1.60, P < 0.001), which is in accordance with the result of the smoothing curve. The association between TyG index and cSBP appears robust in all tested subgroups. CONCLUSIONS: TyG index is positively and independently associated with cSBP among hypertensive adults. Our study result suggests that TyG index might serve as an effective marker for vascular function.

[Characterization of VOCs Emissions from Caged Broiler House in Winter].

Volatile organic compound (VOCs) emissions from poultry and livestock facilities affect the surrounding environmental quality and human health. However, VOCs emissions from broiler houses have been less characterized, and studies of related dominant odorants, carcinogenic risk, and ozone formation potential are still lacking. To fill this research gap, VOCs pollutants emitted from a broiler house were investigated in this study. The VOCs emission characteristics of the broiler house during three different periods of broiler growth (early, middle, and later) were analyzed using gas chromatography-mass spectrometry. The results showed that 77 types of VOCs were detected, including 16 types of halogenated hydrocarbons, 21 types of alkanes, 5 types of olefins, 12 types of aromatic hydrocarbons, 15 types of oxygenated volatile organic compounds (OVOCs), and 8 types of sulfides. During the entire 42-day growth period, the concentrations of halogenated hydrocarbons, alkanes, olefin, aromatic hydrocarbons, and OVOCs in the broiler house showed few changes. However, with the growth of broilers, the intake of sulfur-containing amino acids and the fecal emission coefficient increased, resulting in the gradual conversion of the VOCs to sulfide. Therefore, emissions of sulfur-containing VOCs increased in the early and middle growth periods. Moreover, the increase in ventilation in the house during the later growth period resulted in a decrease in the sulfur-containing VOCs concentrations. The dominant odorants in the broiler house were naphthalene, ethyl acetate, acetaldehyde, carbon disulfide, dimethyl disulfide, methanethiol, methanethiol, and thiophene. Methanethiol had the highest odorous values, ranging from 2172.4 to 19090.9. Meanwhile, there were acceptable levels of carcinogenic risk in the early and middle growth periods, with a lifetime cancer risk (LCR) of 7.7×10-6 and 4.5×10-6, respectively. The average ozone formation potential (OFP) was (1458.9±787.4) µg·m-3. The results of this study can provide a scientific basis for the monitoring of malodorous substances and formulation of emission reduction strategies in broiler production.

Modular Assembly of MXene Frameworks for Noninvasive Disease Diagnosis via Urinary Volatiles.

Volatile organic compounds (VOCs) in urine are valuable biomarkers for noninvasive disease diagnosis. Herein, a facile coordination-driven modular assembly strategy is used for developing a library of gas-sensing materials based on porous MXene frameworks (MFs). Taking advantage of modules with diverse composition and tunable structure, our MFs-based library can provide more choices to satisfy gas-sensing demands. Meanwhile, the laser-induced graphene interdigital electrodes array and microchamber are laser-engraved for the assembly of a microchamber-hosted MF (MHMF) e-nose. Our MHMF e-nose possesses high-discriminative pattern recognition for simultaneous sensing and distinguishing of complex VOCs. Furthermore, with the MHMF e-nose being a plug-and-play module, a point-of-care testing (POCT) platform is modularly assembled for wireless and real-time monitoring of urinary volatiles from clinical samples. By virtue of machine learning, our POCT platform achieves noninvasive diagnosis of multiple diseases with a high accuracy of 91.7%, providing a favorable opportunity for early disease diagnosis, disease course monitoring, and relevant research.

Individual and joint effects of borderline ankle-brachial index and high plasma total homocysteine on all-cause death in hypertensive adults.

BACKGROUND: The cardiovascular hazards of total homocysteine (tHcy) are long known. In addition, despite the acknowledgment on the importance of low ankle-brachial index (ABI) (< 0.9), borderline ABI (0.91-0.99) was once commonly overlooked. This study aims to explore the independent and joint effect of tHcy level and borderline ABI on all-cause death in hypertensive population. METHODS: This study included 10,538 participants from China H-type Hypertension Registry Study. ABI was described into two groups: normal ABI (1.00-1.40) and borderline ABI. tHcy level was also divided into two groups: < 15.02 and ≥ 15.02 µmo/L. Four groups were analyzed, using COX proportional hazard regression model, separately and pairwise to observe the independent and joint effect on all-cause death. RESULTS: A total of 126 (1.2%) deaths were observed in the 1.7 years follow-up time. Borderline ABI has a higher predicted risk of death than normal ABI (HR = 1.87, 95%CI: 1.17-3.00) after adjusting for potential covariates. Compare with tHcy level < 15.02 µmo/L (low tHcy), those with tHcy ≥ 15.02 µmo/L (high tHcy) had higher risk to event outcome (HR = 1.99, 95% CI: 1.30-3.05). According to the cumulative hazard curve, group with borderline ABI and high tHcy level has significantly higher altitude and larger increasing rate over follow-up period compare to other groups. Among those with borderline ABI, participants with high tHcy had higher death risk than those with low tHcy, nevertheless, no significant different between borderline and normal ABI among those with low tHcy levels. CONCLUSIONS: Borderline ABI and tHcy level both have independent predictive value on all-cause death. The combined group of borderline ABI and high tHcy has highest risk factor of outcomes, which suggested the mutual additive value of borderline ABI and tHcy. More attention should be given to the importance of borderline ABI in hypertensive population, especially with elevated tHcy level.

Ångstrom-scale silver particles potently combat SARS-CoV-2 infection by suppressing the ACE2 expression and inflammatory responses.

The SARS-CoV-2 pandemic has become a severe global public health event, and the development of protective and therapeutic strategies is urgently needed. Downregulation of angiotensin converting enzyme 2 (ACE2; one of the important SARS-CoV-2 entry receptors) and aberrant inflammatory responses (cytokine storm) are the main targets to inhibit and control COVID-19 invasion. Silver nanomaterials have well-known pharmaceutical properties, including antiviral, antibacterial, and anticancer properties. Here, based on a self-established metal evaporation-condensation-size graded collection system, smaller silver particles reaching the Ångstrom scale (AgÅPs) were fabricated and coated with fructose to obtain a stabilized AgÅP solution (F-AgÅPs). F-AgÅPs potently inactivated SARS-CoV-2 and prevented viral infection. Considering the application of anti-SARS-CoV-2, a sterilized F-AgÅP solution was produced via spray formulation. In our model, the F-AgÅP spray downregulated ACE2 expression and attenuated proinflammatory factors. Moreover, F-AgÅPs were found to be rapidly eliminated to avoid respiratory and systemic toxicity in this study as well as our previous studies. This work presents a safe and potent anti-SARS-CoV-2 agent using an F-AgÅP spray.

The infectivity and pathogenicity of hepatitis A virus live-attenuated vaccine strain H2 in type I interferon receptor-deficient mice.

Hepatitis A virus (HAV) live-attenuated vaccine H2 strain has been approved for clinical use for decades with ideal safety profiles in nonhuman primate models and humans. Recently, type I interferon (IFN) receptor-deficient mice were shown to be susceptible to HAV infection. Herein, we sought to determine the infection and replication dynamics of the H2 in Ifnar-/- mice that lack type I IFN receptor. Following intravenous injection, the H2 failed to cause obvious clinical symptoms in Ifnar-/- mice, and no significant upregulation in serum alanine aminotransferase (ALT) levels was observed. Notably, the histopathological examination showed that there were significant focal infiltrations of lymphocytes and neutrophils in the portal area, but no focal necrosis was observed in liver tissues. Viral RNAs sustained in the liver, and the infectious virus could be recovered from the liver tissue until 42 days post-infection. More importantly, H2 infection induced obvious viremia and persistent viral shedding in feces. In addition, robust HAV-specific humoral immune responses were induced in Ifnar-/- mice. Overall, our study revealed the safety profile of H2 in Ifnar-/- mice, which not only helps understand the attenuation mechanism of H2, but also expands the application of the Ifnar-/- mouse model for HAV studies.

Modeling of ultraviolet propagation from air to human epidermis with wavelength range of 200-300 nm.

Ultraviolet (UV) technology plays an important role in the fields of sterilization, disinfection, and short-range wireless optical communications. In this Letter, a theoretical model to determine the UV radiation intensity (UVRI) on human skin is put forward based on the Monte Carlo method, where the UV wavelength ranges from 200 to 300 nm. Meanwhile, the UVRI evaluation algorithm is provided to reproduce the simulation results. Furthermore, the penetration depth of UV radiation in the human epidermis is investigated, which can be used to assess whether UV radiation causes damage to human health. Simulation results coincide with the existing experimental results that the 222-nm UV radiation is harmless to humans at the given dose of 1.7 mJ/cm2. This work provides theoretical guidelines for the power control of a UV system when humans are in the vicinity.

Single-collision-induced path loss model of reflection-assisted non-line-of-sight ultraviolet communications.

By considering both scattering and reflection events as collision-induced events (CIEs), an analytical path loss model of reflection-assisted non-line-of-sight (NLOS) ultraviolet communications (UVC) is proposed with single CIE incorporated, which refers to the single-collision-induced (SCI) path loss model. More specifically, the analytical expressions of the received optical energy resulting from single-scatter and single-reflection events in reflection-assisted NLOS UVC are respectively derived. Then, in terms of those two expressions, the expression of the proposed SCI path loss model is obtained. Finally, Monte-Carlo (MC) simulations and experimental results are given to verify the correctness and effectiveness of the proposed SCI path loss model. The results manifest that the proposed SCI path loss model can work well in both coplanar and noncoplanar geometry of the reflection-assisted NLOS UVC.

The Slack Channel Regulates Anxiety-Like Behaviors via Basolateral Amygdala Glutamatergic Projections to Ventral Hippocampus.

Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. In the present study, we find that the global Slack KO male mice exhibit anxious behaviors, whereas the Slack Y777H male mice manifest anxiolytic behaviors. The expression of Slack channels is rich in basolateral amygdala (BLA) glutamatergic neurons and downregulated in chronic corticosterone-treated mice. In addition, electrophysiological data show enhanced excitability of BLA glutamatergic neurons in the Slack KO mice and decreased excitability of these neurons in the Slack Y777H mice. Furthermore, the Slack channel deletion in BLA glutamatergic neurons is sufficient to result in enhanced avoidance behaviors, whereas Kcnt1 gene expression in the BLA or BLA-ventral hippocampus (vHPC) glutamatergic projections reverses anxious behaviors of the Slack KO mice. Our study identifies the role of the Slack channel in controlling anxious behaviors by decreasing the excitability of BLA-vHPC glutamatergic projections, providing a potential target for anxiolytic therapies.SIGNIFICANCE STATEMENT Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. Here, we examined the behaviors of loss- and gain-of-function of Slack channel mice in elevated plus maze and open field tests and found the anxiolytic role of the Slack channel. By altering the Slack channel expression in the specific neuronal circuit, we demonstrated that the Slack channel played its anxiolytic role by decreasing the excitability of BLA-vHPC glutamatergic projections. Our data reveal the role of the Slack channel in the regulation of anxiety, which may provide a potential molecular target for anxiolytic therapies.

Lipid nanoparticle-encapsulated mRNA antibody provides long-term protection against SARS-CoV-2 in mice and hamsters.

Monoclonal antibodies represent important weapons in our arsenal to against the COVID-19 pandemic. However, this potential is severely limited by the time-consuming process of developing effective antibodies and the relative high cost of manufacturing. Herein, we present a rapid and cost-effective lipid nanoparticle (LNP) encapsulated-mRNA platform for in vivo delivery of SARS-CoV-2 neutralization antibodies. Two mRNAs encoding the light and heavy chains of a potent SARS-CoV-2 neutralizing antibody HB27, which is currently being evaluated in clinical trials, were encapsulated into clinical grade LNP formulations (named as mRNA-HB27-LNP). In vivo characterization demonstrated that intravenous administration of mRNA-HB27-LNP in mice resulted in a longer circulating half-life compared with the original HB27 antibody in protein format. More importantly, a single prophylactic administration of mRNA-HB27-LNP provided protection against SARS-CoV-2 challenge in mice at 1, 7 and even 63 days post administration. In a close contact transmission model, prophylactic administration of mRNA-HB27-LNP prevented SARS-CoV-2 infection between hamsters in a dose-dependent manner. Overall, our results demonstrate a superior long-term protection against SARS-CoV-2 conferred by a single administration of this unique mRNA antibody, highlighting the potential of this universal platform for antibody-based disease prevention and therapy against COVID-19 as well as a variety of other infectious diseases.

Repetitive Mild Closed Head Injury in Adolescent Mice Is Associated with Impaired Proteostasis, Neuroinflammation, and Tauopathy.

Repetitive mild traumatic brain injury (mTBI) in children and adolescents leads to acute and chronic neurologic sequelae and is linked to later life neurodegenerative disease. However, the biological mechanisms connecting early life mTBI to neurodegeneration remain unknown. Using an adolescent mouse repetitive closed head injury model that induces progressive cognitive impairment in males and anxiety in females in the absence of overt histopathology, we examined transcriptional and translational changes in neurons isolated from sham and injured brain in the chronic phase after injury. At 14 months, single-nuclei RNA sequencing of cortical brain tissue identified disruption of genes associated with neuronal proteostasis and evidence for disrupted ligand-receptor signaling networks in injured mice. Western blot analysis of isolated neurons showed evidence of inflammasome activation and downstream IL-1ß processing, as previously demonstrated in acute CNS injury models, and accumulation of misfolded, hyperphosphorylated tau, and changes in expression of proteins suggestive of impaired translation in males but not in females. At 6 months, injured IL-1 receptor 1 (IL-1R1) KO mice, which are protected from postinjury cognitive deficits, had decreased accumulation of pro-IL-1ß and misfolded tau in cortex and cerebellum, suggesting that IL-1R1 is upstream of inflammasome priming (defined as increase in pro-IL-1ß) and abnormal tau phosphorylation. Together, our findings provide evidence for neuronal inflammasome activation and impaired proteostasis as key mechanisms linking repetitive mTBI in adolescence to later life neurologic dysfunction and neurodegeneration.SIGNIFICANCE STATEMENT Repetitive mild closed head injury in adolescent male mice leads to impaired proteostasis, tau phosphorylation, and inflammasome activation in neurons later in adulthood through mechanisms involving IL-1 receptor 1. The data are the first to link repetitive mild traumatic brain injury in adolescence to neurodegeneration and suggest molecular targets and pathways to prevent neurologic sequelae in the chronic period after injuries.