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Abstract Background Olfactory dysfunction is among the earliest non-motor symptoms of Parkinson’s disease (PD). As the foremost pathological hallmark, α-synuclein initiates the pathology in the olfactory pathway at the early stage of PD, particularly in the olfactory epithelium (OE) and olfactory bulb (OB). However, the local neural microcircuit mechanisms underlying olfactory dysfunction between OE and OB in early PD remain unknown. Results We observed that odor detection and discrimination were impaired in 6-month-old SNCA-A53T mice, while their motor ability remained unaffected. It was confirmed that α-synuclein increased and accumulated in OB but not in OE. Notably, the hyperactivity of mitral/tufted cells and the excitation/inhibition imbalance in OB were found in 6-month-old SNCA-A53T mice, which was attributed to the impaired GABAergic transmission and aberrant expression of GABA transporter 1 and vesicular GABA transporter in OB. We further showed that tiagabine, a potent and selective GABA reuptake inhibitor, could reverse the impaired olfactory function and GABAergic signaling in OB of SNCA-A53T mice. Conclusions Taken together, our findings demonstrate potential synaptic mechanisms of local neural microcircuit underlying olfactory dysfunction at the early stage of PD. These results highlight the critical role of aberrant GABAergic signaling of OB in early diagnosis and provide a potential therapeutic strategy for early-stage PD.

The damage characteristics of fused silica were investigated under low-temporal coherence light (LTCL). It was found that the laser-induced damage threshold (LIDT) of fused silica for the LTCL was lower than that of the single longitudinal mode pulse laser, and for the LTCLs, the LIDTs decrease with the increasing of laser bandwidth, which is not consistent with the temporal spike intensity. This is due to the nonlinear self-focusing effect and multi-pulse accumulation effect. The specific reasons were analyzed based on theoretical simulation and experimental study. This research work is helpful and of great significance for the construction of high-power LTCL devices.

Background: Ketosis is one of the most frequent and costly metabolic disorders in high-producing dairy cows, and negatively associated with the health and reproductive performance of bovine. Ketosis is mainly caused by the accumulation of ketone body β-hydroxybutyric acid and its diagnosis is based on β-hydroxybutyrate (βHB) concentration in blood.Methods: In this study, we investigated the effects of βHB on bovine oocyte maturation in the concentration of subclinical (1.2 mM) βHB and clinical (3.6 mM).Results: The results showed βHB disrupted bovine oocyte maturation and development capacity. Further analysis showed that βHB induced oxidative stress and mitochondrial dysfunction, as indicated by the increased level of reactive oxygen species (ROS), disrupted mitochondrial structure and distribution, and depolarized membrane potential. Furthermore, oxidative stress triggered early apoptosis, as shown by the enhanced levels of Caspase-3 and Annexin-V. Moreover, 3.6 mM βHB induced the disruption of the pyruvate dehydrogenase (PDH) activity, showing with the decrease of the global acetylation modification and the increase of the abnormal spindle rate.Conclusion: Our study showed that βHB in subclinical/clinical concentration had toxic effects on mitochondrial function and PDH activity, which might affect energy metabolism and epigenetic modification of bovine oocytes and embryos.

Autophagy is a highly conserved process that utilizes lysosomes to selectively degrade a variety of intracellular cargo, thus providing quality control over cellular components and maintaining cellular regulatory functions. Autophagy is triggered by multiple stimuli ranging from nutrient starvation to microbial infection. Autophagy extensively shapes and modulates the inflammatory response, the concerted action of immune cells, and secreted mediators aimed to eradicate a microbial infection or to heal sterile tissue damage. Here, we first review how autophagy affects innate immune signaling, cell-autonomous immune defense, and adaptive immunity. Then, we discuss the role of non-canonical autophagy in context of microbial infections and inflammation. Finally, we review how crosstalk between autophagy and inflammation influences infectious diseases as well as metabolic and autoimmune disorders.

Ligand-engaged chemokine receptors trigger nucleotide exchange in heterotrimeric Gαi proteins, which stimulates cytoskeletal reorganization and cell polarity changes. To better understand the signaling events responsible for these cellular changes, we focused on early changes in F-actin dynamics after engagement of the chemokine receptor CXCR5 in murine splenic B cells. Within 10 seconds of exposure to the CXCR5 ligand CXCL13, three-dimensional lamellar-like pseudopods and F-actin–rich ridges appeared. The transient F-actin increase depended on Gαi2/3 signaling, the PI3K/AKT pathway, ERK activation, phospholipase C activity, and Rac1/2 activation mediated by Dock2 (dedicator of cytokinesis 2). Immunoblot analyses identified the kinase WNK1 (with no lysine kinase 1) as a potential early AKT effector. Treating B cells with specific WNK inhibitors disrupted F-actin dynamics and impaired B cell polarity, motility, and chemotaxis. These changes were mimicked in a murine B cell line by CRISPR-Cas9 gene editing of Wnk1, which also suggested that WNK1 contributed to B cell proliferation. Administration of a single dose of a WNK inhibitor transiently reduced B cell motility and polarity in the lymph nodes of live mice. These results indicate that WNK1 signaling maintains B cell responsiveness to CXCL13 and suggest that pharmacological inhibition of WNK1, which is involved in cancer progression and blood pressure regulation, may affect humoral immunity. Editor's summary: The chemokine CXCL13 induces cytoskeletal changes that enable B cells to migrate to sites of inflammation. Hwang et al. identified the activation of the kinase WNK1 as an early signaling event triggered by CXCL13 in B cells. Pharmacological inhibition or genetic deletion of WNK1 prevented CXCL13-induced cytoskeletal changes and migration in primary mouse B cells and B cell lines. Pharmacological inhibition of WNK1 also reduced B cell motility in mouse lymph nodes. Thus, suppressing B cell responses to CXCL13 could be a side effect of inhibiting WNK1, which is a potential therapeutic target in cancer and hypertension. —Wei Wong [ABSTRACT FROM AUTHOR]

The control rod assembly is an important part of the fast reactor control system and safety protection system. The accurate solution of the fast reactor control rod worth is very important. The direct volume homogenization method is used in the calculation of the fast reactor few�group homogenization constants based on the PASC�5 code, which will lead to a serious overestimation of the control rod worth, and the heterogeneous effects of the control rod assembly must be corrected. Based on the idea of group constant correction, the applications of three methods including volume�flux weight, reaction rate ratio preservation, and reactivity preservation were studied in the correction of heterogeneous effects of fast reactor control rod assembly in the paper. Based on the two�dimensional characteristic line code, the calculation code named FRHP for the group constant correction was developed. Tested and verified by the China Experimental Fast Reactor case, the corrected control rod worth calculation results are in good agreement with the MCNP calculation reference results, indicating that the three methods can effectively correct the heterogeneous effects of the control rod assembly, among which the reactivity preservation method has the best correction effect.

The use of low-coherence light is expected to be one of the effective ways to suppress or even eliminate the laser–plasma instabilities that arise in attempts to achieve inertial confinement fusion. In this paper, a review of low-coherence high-power laser drivers and related key techniques is first presented. Work at typical low-coherence laser facilities, including Gekko XII, PHEBUS, Pharos III, and Kanal-2 is described. The many key techniques that are used in the research and development of low-coherence laser drivers are described and analyzed, including low-coherence source generation, amplification, harmonic conversion, and beam smoothing of low-coherence light. Then, recent progress achieved by our group in research on a broadband low-coherence laser driver is presented. During the development of our low-coherence high-power laser facility, we have proposed and implemented many key techniques for working with low-coherence light, including source generation, efficient amplification and propagation, harmonic conversion, beam smoothing, and precise beam control. Based on a series of technological breakthroughs, a kilojoule low-coherence laser driver named Kunwu with a coherence time of only 300 fs has been built, and the first round of physical experiments has been completed. This high-power laser facility provides not only a demonstration and verification platform for key techniques and system integration of a low-coherence laser driver, but also a new type of experimental platform for research into, for example, high-energy-density physics and, in particular, laser–plasma interactions.

In this Letter, we study the second-harmonic (SH) generation of temporally low-coherence light using the statistical optics method. By introducing the statistical characteristics of low-coherence light into the nonlinear coupled wave equation, we predict the self-convolution relationship between the power spectral density of the second-harmonic and that of the fundamental wave and demonstrate it in experiments. The effects of phase matching and group velocity matching on the second-harmonic bandwidth and conversion efficiency are analyzed, which is beneficial to improve the efficiency of low-coherent SH light. Combining the statistics optics and nonlinear optics, our research provides a suitable mathematical model for the study of nonlinear frequency conversion processes of temporally low-coherence light. Due to its statistical characteristics and temporal incoherence, low-coherence SH light would have further applications in uniform illumination, quantum optics, metrology, and so on.

Objective To know the influencing factors of dental caries in first permanent molars among children aged 10⁃12 years old in Guangzhou, and to give references for dental caries prevention. Methods The samples were selected by stratified random sampling method. Oral health examination and questionnaires were applied to all the 18 656 children who were 5 or 6⁃grade in 149 primary schools. Results The prevalence of dental caries in first perma⁃ nent molars was 18.19%. Girls accouted for 19.96%, which was significantly higher than that of boys (16.71%) (c2 = 32.817, P < 0.001). Multiple regression analyses were used to investigate the influencing factors of dental caries in first permanent molars. After controlling school cluster and other factors, household register, gender, pit and fissure sealant, consumption of sweets and chocolates, consumption of sweet milk were influencing factors of permanent teeth caries. And household register, gender, pit and fissure sealant, consumption of sweets and chocolates were associated with mean DMFT. Conclusion school oral health education should focus on the consumption of sugars and cares should be put into the differences between urban and rural area. In addition, strengthening publicity of the sealant retention proj⁃ ect,raising public awareness, and improving sealant retention quality are necessary to ensure the anti⁃caries effect.

Conjugative transfer of antibiotic resistance genes (ARGs) by plasmids is an important route for ARG dissemination. An increasing number of antibiotic and nonantibiotic compounds have been reported to aid the spread of ARGs, highlighting potential challenges for controlling this type of horizontal transfer. Development of conjugation inhibitors that block or delay the transfer of ARG-bearing plasmids is a promising strategy to control the propagation of antibiotic resistance. Although such inhibitors are rare, they typically exhibit relatively high toxicity and low efficacy in vivo and their mechanisms of action are inadequately understood. Here, we studied the effects of dihydroartemisinin (DHA), an artemisinin derivative used to treat malaria, on conjugation. DHA inhibited the conjugation of the IncI2 and IncX4 plasmids carrying the mobile colistin resistance gene (mcr-1) by more than 160- fold in vitro in Escherichia coli, and more than two-fold (IncI2 plasmid) in vivo in a mouse model. It also suppressed the transfer of the IncX3 plasmid carrying the carbapenem resistance gene blaNDM-5 by more than twofold in vitro. Detection of intracellular adenosine triphosphate (ATP) and proton motive force (PMF), in combination with transcriptomic and metabolomic analyses, revealed that DHA impaired the function of the electron transport chain (ETC) by inhibiting the tricarboxylic acid (TCA) cycle pathway, thereby disrupting PMF and limiting the availability of intracellular ATP for plasmid conjugative transfer. Furthermore, expression levels of genes related to conjugation and pilus generation were significantly down-regulated during DHA exposure, indicating that the transfer apparatus for conjugation may be inhibited. Our findings provide new insights into the control of antibiotic resistance and the potential use of DHA. [ABSTRACT FROM AUTHOR]