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AbstractContext The Xihuang pill (XHP) is a traditional Chinese medicine formulation that has been historically used in the prevention and treatment of proliferative breast diseases. However, there is a lack of guidelines that offer recommendations for its clinical use.Objective The task force from the Chinese Guangdong Pharmaceutical Association aims to develop evidence-based guidelines for XHP to prevent and treat proliferative breast diseases.Methods We searched six Chinese and English electronic databases, including the China National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Wanfang Medical Database, PubMed, and Embase, up to November 1, 2022. Publications (case reports, clinical observation, clinical trials, reviews) on using XHP to treat proliferative breast diseases were manually searched. The search terms were Xihuang pill, hyperplasia of the mammary gland, breast lump, and mastalgia. The writing team developed recommendations based on the best available evidence.Results Treatment should be customized based on syndrome identification. We recommend using XHP for the prevention and treatment of breast hyperplasia disease when a patient presents the following syndromes: concurrent blood stasis syndrome, concurrent phlegm-stasis syndrome, and concurrent liver fire syndrome. Safety indicators, including blood analysis and liver and kidney function monitoring, should be performed regularly during treatment.Conclusions Current clinical evidence suggests that XHP can be used as a standalone treatment or in conjunction with other medications to prevent and manage breast hyperplasia diseases. More randomized controlled studies are warranted to establish high-quality evidence of its use.

During the COVID-19 epidemic, the incidence of rabies has increased in several countries, especially in remote and disadvantaged areas, due to inadequate surveillance and declining immunization coverage. Multiple vaccinations with inactivated rabies virus vaccines for pre- or post-exposure prophylaxis are considered inefficient, expensive and impractical in developing countries. Herein, three modified human recombinant adenoviruses type 5 designated Adv-RVG, Adv-E1-RVG, and Adv-RVDG, carrying rabies virus G (RVG) expression cassettes in various combinations within E1 or E3 genomic regions, were constructed to serve as rabies vaccine candidates. Adv-RVDG mediated greater RVG expression both in vitro and in vivo and induced a more robust and durable humoral immune response than the rabies vaccine strain SAD-L16, Adv-RVG, and Adv-E1-RVG by more effectively activating the dendritic cells (DCs) – follicular helper T (Tfh) cells – germinal centre (GC) / memory B cells (MBCs) – long-lived plasma cells (LLPCs) axis with 100% survival after a lethal RABV challenge in mice during the 24-week study period. Similarly, dogs and cats immunized with Adv-RVDG showed stronger and longer-lasting antibody responses than those vaccinated with a commercial inactivated rabies vaccine and showed good tolerance to Adv-RVDG. In conclusion, our study demonstrated that simultaneous insertion of protective antigens into the E1 and E3 genomic regions of adenovirus vector can significantly enhance the immunogenicity of adenoviral-vectored vaccines, providing a theoretical and practical basis for the subsequent development of multivalent and multi-conjugated vaccines using recombinant adenovirus platform. Meanwhile, our data suggest Adv-RVDG is a safe, efficient, and economical vaccine for mass-coverage immunization.

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), abnormal accumulation of α-synuclein (α-syn), and activation of microglia leading to neuroinflammation. Disturbances in circadian rhythm play a significant role in PD, with most non-motor symptoms associated with disruptions in circadian rhythm. These disturbances can be observed years before motor symptoms appear and are marked by the emergence of non-motor symptoms related to PD, such as rapid eye movement sleep behavior disorder (RBD), restless leg syndrome (RLS), excessive daytime sleepiness (EDS), depression and anxiety, changes in blood pressure, gastrointestinal dysfunction, and urinary problems. Circadian rhythm disruption precedes the onset of motor symptoms and contributes to the progression of PD. In brief, this article outlines the role of circadian rhythm disruption in triggering PD at cellular and molecular levels, as well as its clinical manifestations. It also explores how circadian rhythm research can contribute to preventing the onset and progression of PD from current and future perspectives.

Abstract Bordetella bronchiseptica (Bb) is recognized as a leading cause of respiratory diseases in dogs and cats. However, epidemiological data on Bb in dogs and cats in China are still limited, and there is no commercially available vaccine. Live vaccines containing Bb that are widely used abroad are generally effective but can establish latency and potentially reactivate to cause illness in some immunodeficient vaccinated recipients, raising safety concerns. In this study, 34 canine-derived and two feline-derived Bb strains were isolated from 1809 canine and 113 feline nasopharyngeal swab samples collected from eight provinces in China from 2021 to 2023. The PCR results showed that the percentage of positive Bb was 22.94% (441/1922), and more than 90% of the Bb isolates had four virulence factor-encoding genes (VFGs), namely, fhaB, prn, betA and dnt. All the isolated strains displayed a multidrug-resistant phenotype. The virulence of 10 Bb strains isolated from dogs with respiratory symptoms was tested in mice, and we found that eight isolates were highly virulent. Furthermore, the eight Bb isolates with high virulence were inactivated and intramuscularly injected into mice, and three Bb strains (WH1218, WH1203 and WH1224) with the best protective efficacy were selected. Dogs immunized with these three strains exhibited strong protection against challenge with the Bb field strain WH1218. Ultimately, the WH1218 strain with the greatest protection in dogs was selected as the vaccine candidate. Dogs and cats that received a vaccine containing 109 CFU of the inactivated WH1218 strain showed complete protection against challenge with the Bb field strain WH1218. This study revealed that Bb is an important pathogen that causes respiratory diseases in domestic dogs and cats in China, and all the isolates exhibited multidrug resistance. The present work contributes to the current understanding of the prevalence, antimicrobial resistance, and virulence genes of Bb in domestic dogs and cats. Additionally, our results suggest that the WH1218 strain is a promising candidate safe and efficacious inactivated Bb vaccine.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that affects the central nervous system (CNS). Neuroinflammation is a crucial factor in the pathological advancement of PD. PD is characterized by the presence of activated microglia and increased levels of proinflammatory factors, which play a crucial role in its pathology. During the immune response of PD, microglia regulation is significantly influenced by microRNA (miRNA). The excessive activation of microglia, persistent neuroinflammation, and abnormal polarization of macrophages in the brain can be attributed to the dysregulation of certain miRNAs. Additionally, there are miRNAs that possess the ability to inhibit neuroinflammation. miRNAs, which are small non-coding epigenetic regulators, have the ability to modulate microglial activity in both normal and abnormal conditions. They also have a significant impact on promoting communication between neurons and microglia.

A soft robot is composed of soft materials, which exhibit continuous deformation and driving structure integration and can arbitrarily change shapes and sizes over wide ranges. It shows strong adaptability to unstructured environments and has broad application prospects in military reconnaissance, medical rescues, agricultural production, etc. Soft robots based on ionic electroactive polymers (EAPs) have low-driving voltages, large-actuation displacements, fast responses, light weights, and low powers and have become a hot research field of bionic robots. Ionic liquid gels (ILGs) are new ionic EAPs. In this study, a new soft actuator was designed based on an ILG, and the electromechanical coupling model of an ILG soft actuator was studied in detail. Based on the system transfer function method, a mechatronic coupling model for the soft actuator was developed. According to the material characteristics and current response law of the ILG-containing EAP, an equivalent circuit model was used to describe transfer of the output current and input voltage. Based on the equivalent transformer model for ionic polymer–metal composite (IPMC) actuators proposed by Claudia Bonomo, the electromechanical coupling equation and a driving equation of the ILG soft actuator were established. The least-squares method was used with the coupling model of an ILG soft actuator to identify the system parameters for the model, and the effects of the structural parameters on the end displacement and driving force of the soft actuator were analyzed.

ABSTRACTSeveral recent attempts to improve the stability and immunogenicity of messenger RNA (mRNA) vaccines include the use of circular RNA (circRNA), targeted delivery, and lyophilization. However, these research directions have often been pursued independently, ignoring the impact of the modification of lipid nanoparticle-encapsulated mRNA vaccines on their targeted delivery after lyophilization and on their subsequent immunogenicity. Here, we develop a circRNA vaccine targeting lymph nodes that expresses rabies virus glycoprotein (G), termed circRNA-G. Mannose modification is introduced directly into the process of synthesizing PEG lipids, and the resulting PEG-mannose can be used in the preparation of mannose-LNPs (mLNPs) that target dendritic cells, thereby promoting the specific distribution of circRNA-G to lymph nodes (mLNP-circRNA-G). We demonstrated that mLNP-circRNA-G has continuous antigen availability that promotes the generation of T follicular helper cells, germinal center B cells, long-lived plasma cells, and memory B cells in mice. Importantly, the vaccine with this targeting modification remained stable for at least 24 weeks of storage at 4℃ after lyophilization, and its immunogenicity was also maintained. Notably, this strategy also enhances the antibody production of the SARS-CoV-2 trimeric receptor-binding domain circRNA vaccine and the stability of immunogenicity after lyophilization. In summary, this study provides a general platform for the design of lyophilized vaccines with targeted stability, demonstrating the potential of lymph node-targeting circRNAs as next-generation vaccines.IMPORTANCEmessenger RNA (mRNA) vaccines are a key technology in combating existing and emerging infectious diseases. However, the inherent instability of mRNA and the nonspecificity of lipid nanoparticle-encapsulated (LNP) delivery systems result in the need for cold storage and a relatively short-duration immune response to mRNA vaccines. Herein, we develop a novel vaccine in the form of circRNAs encapsulated in LNPs, and the circular structure of the circRNAs enhances their stability. Lyophilization is considered the most effective method for the long-term preservation of RNA vaccines. However, this process may result in irreversible damage to the nanoparticles, particularly the potential disruption of targeting modifications on LNPs. During the selection of lymph node-targeting ligands, we found that LNPs modified with mannose maintained their physical properties almost unchanged after lyophilization. Additionally, the targeting specificity and immunogenicity remained unaffected. In contrast, even with the addition of cryoprotectants such as sucrose, the physical properties of LNPs were impaired, leading to an obvious decrease in immunogenicity. This may be attributed to the protective role of mannose on the surface of LNPs during lyophilization. Freshly prepared and lyophilized mLNP-circRNA vaccines elicited comparable immune responses in both the rabies virus model and the SARS-CoV-2 model. Our data demonstrated that mLNP-circRNA vaccines elicit robust immune responses while improving stability after lyophilization, with no compromise in tissue targeting specificity. Therefore, mannose-modified LNP-circRNA vaccines represent a promising vaccine design strategy.

Horizontal wells are extensively utilized in the development of unconventional reservoirs. However, the logging responses and formation evaluation in horizontal wells can be impacted by factors like anisotropy and tool eccentricity. To investigate the influence of tool eccentricity on acoustic logging response, physical simulation experiments of array acoustic logging were conducted in a scaled borehole formation model under different tool eccentricity conditions. The experimental data were analyzed, and the findings revealed that when the receiver array is parallel to the borehole axis, the P-wave slowness and S-wave slowness remain unaffected by tool eccentricity. However, the amplitudes of the P-wave and S-wave decrease significantly with increasing tool eccentricity, following an approximate negative exponential pattern. Additionally, when the transmitter is centered and the receiver array intersects the borehole axis at an angle, the wave velocities increase significantly with tool eccentricity, with the P-wave velocity showing a faster increase. Conversely, when the transmitter is eccentric and the receiver array intersects the borehole axis at an angle, the wave velocity decreases notably with tool eccentricity, and the P-wave velocity decreases even faster. These findings contribute to a better understanding of the impact of tool eccentricity on array acoustic logging response in horizontal wells and offer guidance for developing correction schemes to address this effect.

Unconventional reservoirs, such as shale and tight formations, have become increasingly vital contributors to oil and gas production. In these reservoirs, fractures serve as crucial spaces for fluid migration and storage, making their precise assessment essential. Array acoustic logging stands out as a pivotal method for evaluating fractures. To investigate the impact of fracture width, fracture-filling conditions, and acoustic frequency on compressional and shear waves, a three-dimensional variable mesh finite difference program was employed for acoustic logging numerical simulation. Firstly, numerical models representing fractured formations with varying fracture widths and distinct fluid-filling conditions were established, and array acoustic logging numerical simulations were conducted at different frequencies. Subsequently, the waveform data were processed to extract acoustic characteristic parameters, such as velocities and amplitude attenuations of compressional and shear waves. Finally, a quantitative analysis was conducted to examine the variation patterns of characteristic parameters of refracted compressional and shear waves in relation to fracture properties. The research results indicate that amplitude attenuation information derived from borehole wave modes is particularly sensitive to the changes in fracture properties. As fracture width increased, we observed a significant amplitude attenuation in both compressional and shear waves, proportional to the logarithm of the attenuation coefficients. Furthermore, when the fracture width was constant, gas-filled fractures exhibited more prominent amplitude attenuation than water-filled fractures, with shear wave attenuation being more sensitive to the filling material. Moreover, from a quantitative perspective, the analysis revealed that the attenuation coefficients of refracted compressional and shear waves exhibited an exponential variation with gas saturation. Notably, once fracture width and filling conditions were established, the amplitudes of compressional and shear waves at the dominant frequency of 40 kHz were significantly reduced compared to those at 8 kHz, accompanied by increased attenuation. Subsequent quantitative analysis revealed that, when the product of fracture width and dominant frequency remains constant, the corresponding attenuation coefficient ratios approach 1. This indicates that the attenuation process of acoustic propagation in fractured media follows the principle of acoustic similarity. The findings of this study provide reference for further research on fracture property evaluation methods based on array acoustic logging data.

The persistence and clinical consequences of rabies virus (RABV) infection have prompted global efforts to develop a safe and effective vaccines against rabies. mRNA vaccines represent a promising option against emerging and re-emerging infectious diseases, gaining particular interest since the outbreak of COVID-19. Herein, we report the development of a highly efficacious rabies mRNA vaccine composed of sequence-modified mRNA encoding RABV glycoprotein (RABV-G) packaged in core–shell structured lipopolyplex (LPP) nanoparticles, named LPP-mRNA-G. The bilayer structure of LPP improves protection and delivery of RABV-G mRNA and allows gradual release of mRNA molecules as the polymer degrades. The unique core–shell structured nanoparticle of LPP-mRNA-G facilitates vaccine uptake and demonstrates a desirable biodistribution pattern with low liver targeting upon intramuscular immunization. Single administration of low-dose LPP-mRNA-G in mice elicited potent humoral immune response and provided complete protection against intracerebral challenge with lethal RABV. Similarly, single immunization of low-dose LPP-mRNA-G induced high levels of virus-neutralizing antibody titers in dogs. Collectively, our data demonstrate the potential of LPP-mRNA-G as a promising next-generation rabies vaccine used in human and companion animals.

Highlights 1. Circ_0003074 expression was upregulated in OS tissues and cells. 2. Rg3 treatment significantly decreased circ_0003074 expression in OS cells. 3. Circ_0003074 overexpression rescued Rg3-induced inhibition in OS progression. 4. Circ_0003074 induced KPNA4 production through miR-516b-5p under Rg3 treatment.

Unconventional oil and gas reservoirs have broad exploration and development prospects. Fracture parameters and effectiveness evaluation are two of the key tasks for the evaluation of these types of reservoirs. Array acoustic logging can be used for fracture evaluation to compensate for the deficiencies of the image logging fracture evaluation method. Therefore, to develop acoustic logging evaluation methods as well as nondestructive testing methods for fractures, experiments were conducted to study the shear wave transmission in fractured media. Experiment data demonstrate a good correlation between the shear wave attenuation coefficient and fracture width, and the shear wave attenuation coefficients rise logarithmically with the increase in the fracture width for all models with different porosities and distinct dip angles of fractures. The shear wave attenuation coefficient changes relatively faster with the fracture width when the fracture width is within 250 μm. In addition, the shear wave attenuation is affected by the core porosity and fracture dip angle. When the fracture width is constant, the shear wave attenuation caused by the 0° fracture is relatively larger and is obviously greater than that of the fractures at other angles, which is consistent with the existing experimental results. The results of this study can be used to guide further research on amplitude compensation methods for sonic signal transmission in fractured media and fracture evaluation methods.

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expressions of pattern recognition receptors (PRRs) also cause diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not yet been revealed. Based on TLR4-deficient (TLR42/2) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type 2 dendritic cells (CD8α- CD11b+ cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of follicular helper T (Tfh) cells promotes the proliferation of germinal center (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. [ABSTRACT FROM AUTHOR]

Lyssaviruses cause rabies, which is an acute neurological disease responsible for more than 59,000 human deaths annually and has no available effective treatments. The phosphoprotein (P) of lyssaviruses (lyssavirus-P) plays multiple roles in virus replication and immune evasion. Lyssavirus-P has been identified as the major type I interferon (IFN-I) antagonist, while the precise site and precise molecular mechanism remain unclear. Herein, we found that substitution of site 179 of lyssavirus-P from serine (Ser) to proline (Pro) impairs its antagonism function of IFN-I by sequence alignment and site mutations. Subsequent studies demonstrated that lyssavirus-P containing S179 specifically interacted with I-kappa B kinase ε (IKKε). Specifically, lyssavirus-P containing S179 interacted simultaneously with the kinase domain (KD) and scaffold dimerization domain (SDD) of IKK ε, competing with TNF receptor-associated factor 3 (TRAF3) and IFN regulatory factor 3 (IRF3) for binding with IKKε, leading to the inhibition of IFN production. Furthermore, S179 was involved in the viral pathogenicity of the typical lyssavirus rabies virus in a mouse model. Interestingly, we found that S179 is conserved among most lyssavirus-P and functional for IFN antagonism. Collectively, we identified S179 of lyssavirus-P is essential for IFN-I inhibition, which provides deep insight into the immune evasion strategies of lyssaviruses. [ABSTRACT FROM AUTHOR]

Rabies, caused by rabies virus (RABV), remains a serious threat to public health in most countries worldwide. At present, the administration of rabies vaccines has been the most effective strategy to control rabies. Herein, we evaluate the effect of colloidal manganese salt (Mn jelly [MnJ]) as an adjuvant of rabies vaccine in mice, cats, and dogs. The results showed that MnJ promoted type I interferon (IFN-I) and cytokine production in vitro and the maturation of dendritic cells (DCs) in vitro and in vivo. Besides, MnJ serving as an adjuvant for rabies vaccines could significantly facilitate the generation of T follicular helper (Tfh) cells, germinal center (GC) B cells, plasma cells (PCs), and RABV-specific antibody-secreting cells (ASCs), consequently improve the immunogenicity of rabies vaccines, and provide better protection against virulent RABV challenge. Similarly, MnJ enhanced the humoral immune response in cats and dogs as well. Collectively, our results suggest that MnJ can facilitate the maturation of DCs during rabies vaccination, which can be a promising adjuvant candidate for rabies vaccines. IMPORTANCE Extending the humoral immune response by using adjuvants is an important strategy for vaccine development. In this study, a novel adjuvant, MnJ, supplemented in rabies vaccines was evaluated in mice, cats, and dogs. Our results in the mouse model revealed that MnJ increased the numbers of mature DCs, Tfh cells, GC B cells, PCs, and RABV-specific ASCs, resulting in enhanced immunogenicity and protection rate of rabies vaccines. We further found that MnJ had the same stimulative effect in cats and dogs. Our study provides the first evidence that MnJ serving as a novel adjuvant of rabies vaccines can boost the immune response in both a mouse and pet model. [ABSTRACT FROM AUTHOR]