Trimerized S expressed by modified vaccinia virus Ankara (MVA) confers superior protection against lethal SARS-CoV-2 challenge in mice.

The reoccurrence of successive waves of SARS-CoV-2 variants suggests the exploration of more vaccine alternatives is imperative. Modified vaccinia virus Ankara (MVA) is a virus vector exhibiting excellent safety as well as efficacy for vaccine development. Here, a series of recombinant MVAs (rMVAs) expressing monomerized or trimerized S proteins from different SARS-CoV-2 variants are engineered. Trimerized S expressed from rMVAs is found predominantly as trimers on the surface of infected cells. Remarkably, immunization of mice with rMVAs demonstrates that S expressed in trimer elicits higher levels of binding IgG and IgA, as well as neutralizing antibodies for matched and mismatched S proteins than S in the monomer. In addition, trimerized S expressed by rMVA induces enhanced cytotoxic T-cell responses than S in the monomer. Importantly, the rMVA vaccines expressing trimerized S exhibit superior protection against a lethal SARS-CoV-2 challenge as the immunized animals all survive without displaying any pathological conditions. This study suggests that opting for trimerized S may represent a more effective approach and highlights that the MVA platform serves as an ideal foundation to continuously advance SARS-CoV-2 vaccine development. IMPORTANCE: MVA is a promising vaccine vector and has been approved as a vaccine for smallpox and mpox. Our analyses suggested that recombinant MVA expressing S in trimer (rMVA-ST) elicited robust cellular and humoral immunity and was more effective than MVA-S-monomer. Importantly, the rMVA-ST vaccine was able to stimulate decent cross-reactive neutralization against pseudoviruses packaged using S from different sublineages, including Wuhan, Delta, and Omicron. Remarkably, mice immunized with rMVA-ST were completely protected from a lethal challenge of SARS-CoV-2 without displaying any pathological conditions. Our results demonstrated that an MVA vectored vaccine expressing trimerized S is a promising vaccine candidate for SARS-CoV-2 and the strategy might be adapted for future vaccine development for coronaviruses.

The microRNA/TET3/REST axis is required for olfactory globose basal cell proliferation and male behavior.

In the main olfactory epithelium (MOE), new olfactory sensory neurons (OSNs) are persistently generated to replace lost neurons throughout an organism's lifespan. This process predominantly depends on the proliferation of globose basal cells (GBCs), the actively dividing stem cells in the MOE. Here, by using CRISPR/Cas9 and RNAi coupled with adeno-associated virus (AAV) nose delivery approaches, we demonstrated that knockdown of miR-200b/a in the MOE resulted in supernumerary Mash1-marked GBCs and decreased numbers of differentiated OSNs, accompanied by abrogation of male behaviors. We further showed that in the MOE, miR-200b/a targets the ten-eleven translocation methylcytosine dioxygenase TET3, which cooperates with RE1-silencing transcription factor (REST) to exert their functions. Deficiencies including proliferation, differentiation, and behaviors illustrated in miR-200b/a knockdown mice were rescued by suppressing either TET3 or REST. Our work describes a mechanism of coordination of GBC proliferation and differentiation in the MOE and olfactory male behaviors through miR-200/TET3/REST signaling.

Efficacy and safety of tratinterol hydrochloride tablets in bronchial asthma: a randomized double-blind and multicenter clinical trial.

PURPOSE: The aim of this study was to investigate the efficacy and safety of tratinterol hydrochloride in bronchial asthma (BA) treatment. METHODS: Patients enrolled in this study were distributed randomly into a treatment group (tratinterol hydrochloride) and an active control group (procaterol hydrochloride) and were treated for 2 weeks after running-in. The end points were changes in pulmonary function and clinical symptoms after administration. Safety indices were physical examinations, laboratory testing and spontaneous reporting. FINDINGS: We enrolled 732 subjects, -365 in the treatment group and 367 in the active control group. Forced expiratory volume (FEV1), significantly increased in both group after treatment (P < 0.05). Least-squares (LS) means were -0.03/in the full-analysis set (FAS) and -0.02 in the per-protocol set (PPS) set, and 95% confidence intervals (CIs) for these sets were -0.09 to 0.03 and -0.08 to 0.04, respectively. Forced expiratory volume (FVC), morning peak expiratory flow (PEF) and asthma scores were significantly different with pretreatment (P < 0.05). There was no difference in asymptomatic days or frequency of relief medicine use (P > 0.05). No serious adverse events occurred. IMPLICATIONS: Tratinterol hydrochloride was effective, safe and not inferior to procaterol hydrochloride in treating BA.

G protein-coupled odorant receptors underlie mechanosensitivity in mammalian olfactory sensory neurons.

Mechanosensitive cells are essential for organisms to sense the external and internal environments, and a variety of molecules have been implicated as mechanical sensors. Here we report that odorant receptors (ORs), a large family of G protein-coupled receptors, underlie the responses to both chemical and mechanical stimuli in mouse olfactory sensory neurons (OSNs). Genetic ablation of key signaling proteins in odor transduction or disruption of OR-G protein coupling eliminates mechanical responses. Curiously, OSNs expressing different OR types display significantly different responses to mechanical stimuli. Genetic swap of putatively mechanosensitive ORs abolishes or reduces mechanical responses of OSNs. Furthermore, ectopic expression of an OR restores mechanosensitivity in loss-of-function OSNs. Lastly, heterologous expression of an OR confers mechanosensitivity to its host cells. These results indicate that certain ORs are both necessary and sufficient to cause mechanical responses, revealing a previously unidentified mechanism for mechanotransduction.

Mechanisms of Heshouwuyin in regulating apoptosis of testicular cells in aging rats through mitochondrial pathway.

BACKGROUND: Polygonum multiflorum has important effects on anti-aging and immunity enhancement. Many traditional Chinese medicine preparations based on Polygonum multiflorum are widely used for the clinical prevention and treatment of aging. However the mechanisms of these herb mixtures are often unknown. This study investigates the effect of Heshouwuyin, a Chinese herbal compound for invigorating the kidney, on the regulation of testicular cells apoptosis in aging rats. METHODS: In this study, 18-month-old Wistar rats served as a model of natural aging and 12-month-old rats served as a young control group. Heshouwuyin group 1 and group 2 were comprised 18-month-old rats given Heshouwuyin intragastrically for 60 days and 30 days respectively. Then testes of the young control group were isolated in the age of 12 months, the other three groups were in the age of 18 months. RESULTS: TUNEL assay showed that the rate of testicular cell apoptosis was obviously higher and Flow cytometry analysis showed that the rate of cell proliferation was significantly lower in the natural aging group than in the young control group and that intervention with Heshouwuyin could reverse this phenomenon. Therefore, we further applied microarray analysis to screen out differentially expressed genes regulated by Heshouwuyin and related to cell apoptosis. The expression of these genes was observed by quantitative fluorescence PCR, immunofluorescence staining, and western blot. The results showed that the expression of 14-3-3σ was significantly lower and that the expression of DR6, BAX, caspase-3 and Cytc were significantly higher in the natural aging group than in the young control group, but intervention with Heshouwuyin significantly reversed this phenomenon. Moreover, the curative efficacy of Heshouwuyin after 60 days was better than that of Heshouwuyin after 30 days. CONCLUSION: Our study suggests that Heshouwuyin has anti-aging effects on the testis by means of inhibiting the occurrence of apoptosis in spermatogenic cells, thus improving the spermatogenic function of the testis. This is mainly achieved by regulating the expression of key genes in the mitochondrial apoptosis pathway.

Gene Expression Profiles of Main Olfactory Epithelium in Adenylyl Cyclase 3 Knockout Mice.

Adenylyl Cyclase 3 (AC3) plays an important role in the olfactory sensation-signaling pathway in mice. AC3 deficiency leads to defects in olfaction. However, it is still unknown whether AC3 deficiency affects gene expression or olfactory signal transduction pathways within the main olfactory epithelium (MOE). In this study, gene microarrays were used to screen differentially expressed genes in MOE from AC3 knockout (AC3(-/-)) and wild-type (AC3(+/+)) mice. The differentially expressed genes identified were subjected to bioinformatic analysis and verified by qRT-PCR. Gene expression in the MOE from AC3(-/-) mice was significantly altered, compared to AC3(+/+) mice. Of the 41266 gene probes, 3379 had greater than 2-fold fold change in expression levels between AC3(-/-) and AC3(+/+) mice, accounting for 8% of the total gene probes. Of these genes, 1391 were up regulated, and 1988 were down regulated, including 425 olfactory receptor genes, 99 genes that are specifically expressed in the immature olfactory neurons, 305 genes that are specifically expressed in the mature olfactory neurons, and 155 genes that are involved in epigenetic regulation. Quantitative RT-PCR verification of the differentially expressed epigenetic regulation related genes, olfactory receptors, ion transporter related genes, neuron development and differentiation related genes, lipid metabolism and membrane protein transport etc. related genes showed that P75NTR, Hinfp, Gadd45b, and Tet3 were significantly up-regulated, while Olfr370, Olfr1414, Olfr1208, Golf, Faim2, Tsg101, Mapk10, Actl6b, H2BE, ATF5, Kirrrel2, OMP, Drd2 etc. were significantly down-regulated. In summary, AC3 may play a role in proximal olfactory signaling and play a role in the regulation of differentially expressed genes in mouse MOE.

Possible mechanism underlying the effect of Heshouwuyin, a tonifying kidney herb, on sperm quality in aging rats.

BACKGROUND: Herb mixtures are used as alternatives to hormone therapy in China for the treatment of partial androgen deficiency in aging men. However, the compositions of these herb mixtures are complex and their mechanisms are often unknown. This study investigates the effect of Heshouwuyin, a Chinese herbal compound for invigorating the kidney, on the control of testosterone secretion and sperm function. METHODS: Aged Wistar rats were administered with Heshouwuyin. A Shouwu pill group and young group were used as controls. RESULTS: Morphology, chemiluminescence, fluorescence immunohistochemistry, and western blot showed that the epididymal sperm of naturally aged rats had intact plasma membranes. They also had abnormal mitochondrial function and DNA integrity, a significant decline in serum testosterone levels, and significant pathological changes in the structure of testicular tissues. Heshouwuyin significantly improved sperm function and serum testosterone levels, and improved testicular morphology. Moreover, the curative efficacy of Heshouwuyin after 60 days was better than that of Heshouwuyin after 30 days and the Shouwu pill group. CONCLUSION: Heshouwuyin exerts an important role in controlling testosterone secretion and sperm function.

[Lower grade chronic inflammation is associated with obstructive sleep apnea syndrome in type 2 diabetes mellitus].

OBJECTIVE: To investigate whether the existence of obstructive sleep apnea syndrome (OSAS) in patients with type 2 diabetes (T2DM) is associated with low grade chronic inflammation. METHODS: Fifty-four patients hospitalized for poor glycemic control from 12/2008 to 12/2009 were divided into 2 groups, OSAS group (T2DM with OSAS, 27 cases) and NOSAS group (T2DM without OSAS, 27 cases). The control group consisted of 26 people from a health check-up program without diabetes and OSAS. Biochemical indexes were analyzed in central laboratory of the hospital. Serum tumor necrosis factor-α(TNF-α), lipopolysaccharides (LPS), monocyte chemoattractant protein-1 (MCP), and plasminogen activator inhibitor-1 (PAI) levels were determined with commercial ELISA kits. Apnea hypopnea index (AHI), the lowest pulse oxygen saturation (LSpO2) at night were measured with a portable home sleep monitor. RESULTS: Homeostasis model assessment insulin resistance index (HOMA-IR), AHI in OSAS group were higher than those in NOSAS group and control group [for HOMA-IR, 2.7 ± 1.5 vs 1.7 ± 0.9 vs 1.2 ± 0.7, and for AHI, (17.0 ± 13.0) vs (3.4 ± 1.3) vs (3.2 ± 1.2) per hour], and LSpO2 was lower than that in NOSAS group and control group [(78 ± 11)% vs (87 ± 4)% vs (89 ± 6)%]. Compared with normal control, levels of TNF-α [(0.73 ± 0.19) vs (1.97 ± 0.13) vs (1.09 ± 0.29) ng/ml], LPS [(50 ± 11) vs (303 ± 70) vs (171 ± 49) pg/ml], MCP [(302 ± 41) vs (514 ± 122) vs (473 ± 134) pg/ml] and PAI [(0.89 ± 0.25) vs (2.27 ± 0.85) vs (1.59 ± 0.13) ng/ml] in patients with OSAS and with NOSAS group increased significantly. Pearson univariate correlation analysis revealed that TNF-α and PAI were both positively associated with HOMA-IR, FBG and AHI, and negatively with LSpO2, LPS, MCP were both associated positively with FBG and AHI, and negatively with LSpO2. Multiple linear regression stepwise analysis found that TNF-α and LPS were independently associated with AHI and FBG, MCP with LSpO2, PAI with both AHI and HOMA-IR. CONCLUSIONS: Patients with diabetes and OSAS show raised level of chronic inflammatory activity.

Efficacy of neuromobilization in the treatment of low back pain: Systematic review and meta-analysis.

BACKGROUND: Low back pain (LBP) is a leading cause of disability. Neuromobilization (NM) as a physical therapy technique, offers some degree of symptom improvement. However, some studies have shown that NM can significantly reduce the symptoms of LBP, while others have failed to find similar positive effects. OBJECTIVE: This study aims to investigate the effectiveness of NM for LBP. DATA SOURCES: A literature search was conducted across five databases (MEDLINE, Embase, Cochrane Library, PubMed, and Web of Science) from their inception to December 2023. Study main measures assessed pain, disability, and straight leg raise angle to determine the degree of improvement in patients. RESULTS: Seven randomized controlled trials were included in the analysis. The findings indicated that NM interventions in patients with LBP were more effective than control groups in improving Visual Analog Scale scores (mean difference = 0.62, 95% CI (0.03, 1.21)) and Oswestry Disability Index scores (mean difference = 7.54, 95% CI (4.98, 10.10)). There was no significant difference in straight leg raise results (mean difference = 0.18, 95% CI (-0.08, 0.44)). CONCLUSIONS: NM demonstrated effectiveness in improving Visual Analog Scale and Oswestry Disability Index outcomes in patients with LBP, but straight leg raise outcomes are still uncertain and until more high-quality studies are included, the effectiveness of NM for SLR remains unknown.

The miR-669a-5p/G3BP/HDAC6/AKAP12 Axis Regulates Primary Cilia Length.

Primary cilia are conserved organelles in most mammalian cells, acting as "antennae" to sense external signals. Maintaining a physiological cilium length is required for cilium function. MicroRNAs (miRNAs) are potent gene expression regulators, and aberrant miRNA expression is closely associated with ciliopathies. However, how miRNAs modulate cilium length remains elusive. Here, using the calcium-shock method and small RNA sequencing, a miRNA is identified, namely, miR-669a-5p, that is highly expressed in the cilia-enriched noncellular fraction. It is shown that miR-669a-5p promotes cilium elongation but not cilium formation in cultured cells. Mechanistically, it is demonstrated that miR-669a-5p represses ras-GTPase-activating protein SH3-domain-binding protein (G3BP) expression to inhibit histone deacetylase 6 (HDAC6) expression, which further upregulates A-kinase anchor protein 12 (AKAP12) expression. This effect ultimately blocks cilia disassembly and leads to greater cilium length, which can be restored to wild-type lengths by either upregulating HDAC6 or downregulating AKAP12. Collectively, these results elucidate a previously unidentified miR-669a-5p/G3BP/HDAC6/AKAP12 signaling pathway that regulates cilium length, providing potential pharmaceutical targets for treating ciliopathies.

Establishment and application of a surrogate model for human Ebola virus disease in BSL-2 laboratory.

The Ebola virus (EBOV) is a member of the Orthoebolavirus genus, Filoviridae family, which causes severe hemorrhagic diseases in humans and non-human primates (NHPs), with a case fatality rate of up to 90%. The development of countermeasures against EBOV has been hindered by the lack of ideal animal models, as EBOV requires handling in biosafety level (BSL)-4 facilities. Therefore, accessible and convenient animal models are urgently needed to promote prophylactic and therapeutic approaches against EBOV. In this study, a recombinant vesicular stomatitis virus expressing Ebola virus glycoprotein (VSV-EBOV/GP) was constructed and applied as a surrogate virus, establishing a lethal infection in hamsters. Following infection with VSV-EBOV/GP, 3-week-old female Syrian hamsters exhibited disease signs such as weight loss, multi-organ failure, severe uveitis, high viral loads, and developed severe systemic diseases similar to those observed in human EBOV patients. All animals succumbed at 2-3 days post-infection (dpi). Histopathological changes indicated that VSV-EBOV/GP targeted liver cells, suggesting that the tissue tropism of VSV-EBOV/GP was comparable to wild-type EBOV (WT EBOV). Notably, the pathogenicity of the VSV-EBOV/GP was found to be species-specific, age-related, gender-associated, and challenge route-dependent. Subsequently, equine anti-EBOV immunoglobulins and a subunit vaccine were validated using this model. Overall, this surrogate model represents a safe, effective, and economical tool for rapid preclinical evaluation of medical countermeasures against EBOV under BSL-2 conditions, which would accelerate technological advances and breakthroughs in confronting Ebola virus disease.

Targeted deletion of ERK5 MAP kinase in the developing nervous system impairs development of GABAergic interneurons in the main olfactory bulb and behavioral discrimination between structurally similar odorants.

ERK5 MAP kinase is highly expressed in the developing nervous system and has been implicated in promoting the survival of immature neurons in culture. However, its role in the development and function of the mammalian nervous system has not been established in vivo. Here, we report that conditional deletion of the erk5 gene in mouse neural stem cells during development reduces the number of GABAergic interneurons in the main olfactory bulb (OB). Our data suggest that this is due to a decrease in proliferation and an increase in apoptosis in the subventricular zone and rostral migratory stream of ERK5 mutant mice. Interestingly, ERK5 mutant mice have smaller OB and are impaired in odor discrimination between structurally similar odorants. We conclude that ERK5 is a novel signaling pathway regulating developmental OB neurogenesis and olfactory behavior.

Matrix metalloproteinases and their tissue inhibitors in serum and cerebrospinal fluid of patients with moderate and severe traumatic brain injury.

OBJECTIVE: In this study, we investigated matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) in cerebrospinal fluid (CSF) and plasma of traumatic brain injury (TBI) patients. PATIENTS AND METHODS: A total of 30 patients with moderate and severe TBI and 15 age-matched controls were enrolled in this study. Plasma and CSF samples were collected within 24 h (as the initial value), at 72 and 120 h post injury. CSF and plasma MMP-9, MMP-2, TIMP-1 and TIMP-2 were estimated using ELISA. Different levels of these indexes were compared in the two groups and further investigated the correlation between each other. RESULTS: There was a significant elevation in the levels of the initial MMP-9 in the CSF (P < 0.05), which lasted for 72 h post injury. TIMP-1 kept increasing within 120 h post injury and it was different compared with TIMP-1 at 24 and 72 h post injury. Plasma levels of MMP-9, MMP-2, TIMP-1 and TIMP-2 in TBI patients were also significantly different from those in controls. Furthermore the CSF MMP-9 in patients with severe TBI was higher than that in patients with moderate TBI. In addition, there was a positive relationship between the initial MMP-9 and TIMP-1 at 120 h post injury (r = 0.614, P < 0.01). CONCLUSION: MMPs and TIMPs are increased in both CSF and plasma of TBI patients. TIMP-1 has a positive correlation with MMP-9 and the initial MMP-9 is associated with the neurological outcomes.

Mechanism, application and effect evaluation of nerve mobilization in the treatment of low back pain: A narrative review.

Lower back pain is a prevalent condition affecting people across all age groups and causing significant personal and societal burdens. While numerous treatments exist, nerve mobilization has emerged as a promising approach for managing lower back pain. Nerve mobilization involves applying gentle and rhythmic movements to the affected nerves, promoting normal nerve function and releasing tension. It has been well documented that nerve mobilization can be effective in reducing pain and improving function in patients with lower back pain, but the underlying mechanisms have not been clarified. This study aims to review the mechanisms of nerve mobilization in the management of lower back pain, its application, and effectiveness evaluation, and provide a potential solution for managing lower back pain.

Exploring the latest advancements in physical therapy techniques for treating cervical spondylosis patients: A narrative review.

Cervical spondylosis is a widespread medical condition that significantly impacts patients' quality of life. Treatment options include surgical and conservative approaches, with conservative treatment often being the preferred choice. Rehabilitation therapy is an essential component of conservative treatment, and advancements in technology have the way to the development of new physiotherapy techniques. The effectiveness of treatment largely hinges on the patient's ability to improve their dysfunction. This study aims to provide valuable insights into the use of new physical therapy techniques, such as Sling Exercises Training (SET), fascia manipulation, muscle energy technique (MET), and proprioceptive neuromuscular facilitation (PNF), that aid the rehabilitation of cervical spondylosis. By scrutinizing the current research status of these techniques, this study aims to present innovative ideas enhancing the rehabilitation process and outcomes for patients suffering from cervical spondylosis.

Durability Performance and Corrosion Mechanism of New Basalt Fiber Concrete under Organic Water Environment.

Under corrosive environments, concrete material properties can deteriorate significantly, which can seriously affect structural safety. Therefore, it has important engineering applications to improve the durability performance at a lower economic cost. This paper proposes a new, highly durable concrete using inexpensive construction materials such as basalt fiber, sodium methyl silicate, and inorganic aluminum salt waterproofing agent. With the massive application of sewage treatment projects, the problem of concrete durability degradation is becoming more and more serious. In this paper, five types of concrete are developed for the sewage environment, and the apparent morphology and fine structure of the specimens after corrosion in sewage were analyzed. The density, water absorption, and compressive strength were measured to investigate the deterioration pattern of concrete properties. It was found that ordinary concrete was subject to significant corrosion, generating large deposits of algae on the surface and accompanied by sanding. The new concrete showed superior corrosion resistance compared to conventional concrete. Among other factors, the inorganic aluminum salt waterproofing agent effect was the most prominent. The study found that the strength of ordinary concrete decreased by about 15% in the test environment, while the new concrete had a slight increase. Comprehensive evaluation showed that the combination of basalt fiber and inorganic aluminum salt waterproofing agent had the best effect. Its use is recommended.

Gut microbiota is associated with spatial memory and seed-hoarding behavior of South China field mice (Apodemus draco).

Background: Scatter-hoarding animals store food in multiple locations within their home range and rely on spatial memory for subsequent localization and retrieval. The relationship between memory and scatter-hoarding behavior has been widely demonstrated, but the association of gut microbiota with spatial memory and seed-hoarding behavior of animals remains unclear. Methods: In this study, by using enclosure behavior tests, memory tests including an object location test (OLT) and a novel object recognition test (NORT), and fecal microbiota transplantation (FMT) experiment, we evaluated the role of gut microbiota in affecting the memory and seed-hoarding behavior of rodents. According to their scatter-hoarding intensity, South China field mice (Apodemus draco) were divided into scatter-hoarding group (SG) and non-scatter-hoarding group (NG). Results: We found that the SG performed better than the NG in the NORT. FMT from SG donor mice altered the NG recipient mice's gut microbiota structure. Further tests demonstrated FMT from SG donor mice increased memory of NG recipient mice in laboratory tests and seed larder hoarding intensity of NG recipient mice in enclosures. Conclusion: Our results suggest gut microbiota could modulate the memory and seed-hoarding behavior of animals.

Nanobodies with cross-neutralizing activity provide prominent therapeutic efficacy in mild and severe COVID-19 rodent models.

The weakened protective efficacy of COVID-19 vaccines and antibodies caused by SARS-CoV-2 variants presents a global health emergency, which underscores the urgent need for universal therapeutic antibody intervention for clinical patients. Here, we screened three alpacas-derived nanobodies (Nbs) with neutralizing activity from twenty RBD-specific Nbs. The three Nbs were fused with the Fc domain of human IgG, namely aVHH-11-Fc, aVHH-13-Fc and aVHH-14-Fc, which could specifically bind RBD protein and competitively inhibit the binding of ACE2 receptor to RBD. They effectively neutralized SARS-CoV-2 pseudoviruses D614G, Alpha, Beta, Gamma, Delta, and Omicron sub-lineages BA.1, BA.2, BA.4, and BA.5 and authentic SARS-CoV-2 prototype, Delta, and Omicron BA.1, BA.2 strains. In mice-adapted COVID-19 severe model, intranasal administration of aVHH-11-Fc, aVHH-13-Fc and aVHH-14-Fc effectively protected mice from lethal challenges and reduced viral loads in both the upper and lower respiratory tracts. In the COVID-19 mild model, aVHH-13-Fc, which represents the optimal neutralizing activity among the above three Nbs, effectively protected hamsters from the challenge of SARS-CoV-2 prototype, Delta, Omicron BA.1 and BA.2 by significantly reducing viral replication and pathological alterations in the lungs. In structural modeling of aVHH-13 and RBD, aVHH-13 binds to the receptor-binding motif region of RBD and interacts with some highly conserved epitopes. Taken together, our study illustrated that alpaca-derived Nbs offered a therapeutic countermeasure against SARS-CoV-2, including those Delta and Omicron variants which have evolved into global pandemic strains.

The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia.

Although primary cilia are found on neurons throughout the brain, their physiological function remains elusive. Human ciliopathies are associated with cognition defects, and transgenic mice lacking proteins expressed in primary cilia exhibit defects in learning and memory. Recently, it was reported that mice lacking the G-protein-coupling receptor somatostatin receptor-3 (SSTR3), a protein expressed predominately in the primary cilia of neurons, have defective memory for novel object recognition and lower cAMP levels in the brain. Since SSTR3 is coupled to regulation of adenylyl cyclase, this suggests that adenylyl cyclase activity in primary cilia of CNS neurons may be critical for some forms of learning and memory. Because the type 3 adenylyl cyclase (AC3) is expressed in primary cilia of hippocampal neurons, we examined AC3(-/-) mice for several forms of learning and memory. Here, we report that AC3(-/-) mice show no short-term memory for novel objects and fail to exhibit extinction of contextual fear conditioning. They also show impaired learning and memory for temporally dissociative passive avoidance. Since AC3 is exclusively expressed in primary cilia, we conclude that cAMP signals generated within primary cilia contribute to some forms of learning and memory, including extinction of contextual fear conditioning.

Study on the Nonlinear Behavior and Factors Influencing the Axial Compression of High-Durability Fibrous Concrete Wrapped Steel Tube Composite Members.

Thin-walled steel pipe concrete has better economic performance, but the problem of local buckling is more prominent with a thin-walled steel pipe; meanwhile, thin-walled steel pipe is more sensitive to the environment and the influence of rusting is more prominent. To solve the above problems, this paper proposes new spiral stiffened rib thin-walled steel pipe concrete laminated members to obtain better force and economic performance. Based on axial compression tests on five forms of composite members, this paper studies the nonlinear behavior of the axial compression of this new type of laminated member and the factors influencing it. The following conclusions are obtained. Under the constraint of the spiral ribs, the new composite member has good integrity and each part can ensure cooperative stress; the buckling of the steel pipe is well limited and the mechanical performance is significantly improved. Compared with ordinary thin-walled concrete-filled steel tubular members, the bearing capacity is increased by about 20% and the deformation ability is increased by more than 30%. The nonlinear behavior of the member in compression can be better achieved through finite element analysis. The parametric analysis shows that the pitch and the steel tube width-to-thickness ratio greatly influence the force behavior of the member. In contrast, the spiral rib width-to-thickness ratio and the external reinforcement only need to meet the structural requirements. Finally, based on the superposition theory, the proposed method of calculating the member's axial compressive load-bearing capacity is given and design suggestions are made. The results of this paper can provide some basis for the engineering application of this new combination member.