Immune features revealed by single-cell RNA and single-cell TCR/BCR sequencing in patients with rheumatoid arthritis receiving COVID-19 booster vaccination.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, have profoundly affected human health. Booster COVID-19 vaccines have demonstrated significant efficacy in reducing infection and severe cases. However, the effects of booster COVID-19 vaccines on key immune cell subsets and their responses in rheumatoid arthritis (RA) are not well understood. By using single-cell RNA sequencing (scRNA-seq) combined with scTCR/BCR-seq analysis, a total of 8 major and 27 minor cell clusters were identified from paired peripheral blood mononuclear cells (PBMCs) which were collected 1 week before and 4 weeks after booster vaccination in stable RA patients. Booster vaccination only had limited impact on the composition and proportions of PBMCs cell clusters. CD8+ cytotoxic T cells (CD8+T_CTL) showed a trend toward an increase after vaccination, while naive B cells and conventional dendritic cells (cDCs) showed a trend toward a decrease. Transcriptomic changes were observed after booster vaccination, primarily involving T/B cell receptor signaling pathways, phagosome, antigen processing and presenting, and viral myocarditis pathways. Interferon (IFN) and pro-inflammatory response gene sets were slightly upregulated across most major cell subpopulations in COVID-19 booster-vaccinated RA individuals. Plasma neutralizing antibody titers significantly increased after booster COVID-19 vaccination (p = 0.037). Single-cell TCR/BCR analysis revealed increased B cell clone expansion and repertoire diversity postvaccination, with no consistent alterations in T cells. Several clonotypes of BCRs and TCRs were identified to be significantly over-represented after vaccination, such as IGHV3-15 and TRBV28. Our study provided a comprehensive single-cell atlas of the peripheral immune response and TCR/BCR immune repertoire profiles to inactivated SARS-CoV-2 booster vaccination in RA patients, which helps us to understand vaccine-induced immune responses better.

Systemic Type 2 Inflammation-Associated Atopic Dermatitis Exacerbates Periodontitis.

INTRODUCTION: Atopic dermatitis (AD) is a prevalent and chronic inflammatory skin disease characterized by Th2 cell-mediated type 2 inflammation. Emerging evidence indicated that AD patients exhibit an increased incidence of oral disorders. In the present study, we sought mechanistic insights into how AD affects periodontitis. METHODS: Onset of AD was induced by 2,4-dinitrochlorobenzene (DNCB). Furthermore, we induced periodontitis (P) in AD mice. The effect of AD in promoting inflammation and bone resorption in gingiva was evaluated. Hematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, immunofluorescence assay, and flow cytometry were used to investigate histomorphology and cytology analysis, respectively. RNA sequencing of oral mucosa is used tissues to further understand the dynamic transcriptome changes. 16S rRNA microbial analysis is used to profile oral microbial composition. RESULTS: Compared to control group, mice in AD group showed inflammatory signatures and infiltration of a proallergic Th2 (Th2A)-like subset in oral mucosa but not periodontitis, as identified by not substantial changes in mucosa swelling, alveolar bone loss, and TRAP+ osteoclasts infiltration. Similarly, more Th2A-like cell infiltration and interleukin-4 levels were significantly elevated in the oral mucosa of DNCB-P mice compared to P mice. More importantly, AD exacerbates periodontitis when periodontitis has occurred and the severity of periodontitis increased with aggravation of dermatitis. Transcriptional analysis revealed that aggravated periodontitis was positively correlated with more macrophage infiltration and abundant CCL3 secreted. AD also altered oral microbiota, indicating the re-organization of extracellular matrix. CONCLUSIONS: These data provide solid evidence about exacerbation of periodontitis caused by type 2 dermatitis, advancing our understanding in cellular and microbial changes during AD-periodontitis progression.

Synthesis of Chiral Diarylmethylamides via Catalytic Asymmetric Aza-Michael Addition of Amides to ortho-Quinomethanes.

Chiral diarylmethylamides are a privileged skeleton in many bioactive molecules. However, the enantioselective synthesis of such molecules remains a long-standing challenge in organic synthesis. Herein, we report a chiral bifunctional squaramide catalyzed asymmetric aza-Michael addition of amides to in situ generated ortho-quinomethanes, affording enantioenriched diarylmethylamides in good yields with excellent enantioselectivities. This work not only provides a new strategy for the construction of the diarylmethylamides but also represents the practicability of amides as nitrogen-nucleophiles in asymmetric organocatalysis.

Diastereo- and Enantioselective Synthesis of Eight-Membered N-Heterocycles from Benzofuran-Derived Azadienes and Ynones.

Enantioselective synthesis of eight-membered N-heterocycles represents a long-standing challenge in organic synthesis. Here, by combining the squaramide and DBU catalysis, a sequential asymmetric conjugate addition/cyclization reaction between benzofuran-derived azadienes and ynones has been well-developed, providing straightforward access to chiral eight-membered N-heterocycles in high yields with stereoselectivities. This protocol features the use of a bifunctional squaramide catalyst for controlling the enantioselectivity of products, while the DBU is utilized to achieve intramolecular cyclization and improve the diastereoselectivity of products.

Non B Cell-Derived Immunoglobulin, A Brighter Horizon for the Future.

The canonical theory of immunology stating that "Immunoglobulin (Ig) is produced by B lymphocytes and exerts antibody activity" has been established since the 1970s. However, the discovery of non B cell-derived Igs (non B-Igs), which can exert multiple biological activities in addition to their antibody activities, necessitates a reevaluation of the classic concept of Ig. This has been documented with a number of characteristics related to their structure, modification, genetic regulation as well as the functions associated with clinical conditions, particularly multiple cancers. The discovery of non B-Ig provides us with a new perspective to better understand not only basic immunology, but also various Ig-related clinical manifestations including autoimmune diseases, chronic inflammation, and anaphylaxis. Notably, non B-Ig can directly promote the occurrence of malignant tumours.

Conventional and multi-omics assessments of subacute inhalation toxicity due to propylene glycol and vegetable glycerin aerosol produced by electronic cigarettes.

Propylene glycol (PG) and vegetable glycerin (VG) are the most common solvents used in electronic cigarette liquids. No long-term inhalation toxicity assessments have been performed combining conventional and multi-omics approaches on the potential respiratory effects of the solvents in vivo. In this study, the systemic toxicity of aerosol generated from a ceramic heating coil-based e-cigarette was evaluated. First, the aerosol properties were characterized, including carbonyl emissions, the particle size distribution, and aerosol temperatures. To determine toxicological effects, rats were exposed, through their nose only, to filtered air or a propylene glycol (PG)/ glycerin (VG) (50:50, %W/W) aerosol mixture at the target concentration of 3 mg/L for six hours daily over a continuous 28-day period. Compared with the air group, female rats in the PG/VG group exhibited significantly lower body weights during both the exposure period and recovery period, and this was linked to a reduced food intake. Male rats in the PG/VG group also experienced a significant decline in body weight during the exposure period. Importantly, rats exposed to the PG/VG aerosol showed only minimal biological effects compared to those with only air exposure, with no signs of toxicity. Moreover, the transcriptomic, proteomic, and metabolomic analyses of the rat lung tissues following aerosol exposure revealed a series of candidate pathways linking aerosol inhalation to altered lung functions, especially the inflammatory response and disease. Dysregulated pathways of arachidonic acids, the neuroactive ligand-receptor interaction, and the hematopoietic cell lineage were revealed through integrated multi-omics analysis. Therefore, our integrated multi-omics approach offers novel systemic insights and early evidence of environmental-related health hazards associated with an e-cigarette aerosol using two carrier solvents in a rat model.

Insights on the stem elongation of spur-type bud sport mutant of 'Red Delicious' apple.

MAIN CONCLUSION: The decreased capacity of auxin-, CTK-, and BR-mediated cell division and cell enlargement pathways, combined with the enhanced capacity of GA and ETH-, JA-, ABA-, SA-mediated stress-resistant pathways were presumed to be the crucial reasons for the formation of spur-type 'Red Delicious' mutants. Vallee Spur', which exhibit short internodes and compact tree shape, is the fourth generation of the spur-type bud sport mutant of 'Red Delicious'. However, the underlying molecular mechanism of these properties remains unclear. Here, comparative phenotypic, full-length transcriptome and phytohormone analyses were performed between 'Red Delicious' (NSP) and 'Vallee Spur' (SP). The new shoot internode length of NSP was ˃ 1.53-fold higher than that of the SP mutant. Cytological analysis showed that the stem cells of the SP mutant were smaller and more tightly arranged relative to the NSP. By Iso-Seq, a total of 1426 differentially expressed genes (DEGs) were detected, including 808 upregulated and 618 downregulated genes in new shoot apex with 2 leaves of the SP mutant. Gene expressions involved in auxin, cytokinin (CTK), and brassinosteroid (BR) signal transduction were mostly downregulated in the SP mutant, whereas those involved in gibberellin (GA), ethylene (ETH), jasmonate (JA), ABA, and salicylic acid (SA) signal transduction were mostly upregulated. The overall thermogram analysis of hormone levels in the shoot apex carrying two leaves detected by LC-MS/MS absolute quantification showed that the levels of IAA-Asp, IAA, iP7G, OPDA, and 6-deoxyCS were significantly upregulated in the SP mutant, while the remaining 28 hormones were significantly downregulated. It is speculated that the decreased capacity of auxin, CTK, and BR-mediated cell division and cell enlargement pathways is crucial for the formation of the SP mutant. GA and stress-resistant pathways of ETH, JA, ABA, and SA also play vital roles in stem elongation. These results highlight the involvement of phytohormones in the formation of stem elongation occurring in 'Red Delicious' spur-type bud sport mutants and provide information for exploring its biological mechanism.

Biology and Roles in Diseases of Selenoprotein I Characterized by Ethanolamine Phosphotransferase Activity and Antioxidant Potential.

Selenoprotein I (SELENOI) has been demonstrated to be an ethanolamine phosphotransferase (EPT) characterized by a nonselenoenzymatic domain and to be involved in the main synthetic branch of phosphatidylethanolamine (PE) in the endoplasmic reticulum. Therefore, defects of SELENOI may affect the health status through the multiple functions of PE. On the other hand, selenium (Se) is covalently incorporated into SELENOI as selenocysteine (Sec) in its peptide, which forms a Sec-centered domain as in the other members of the selenoprotein family. Unlike other selenoproteins, Sec-containing SELENOI was formed at a later stage of animal evolution, and the high conservation of the structural domain for PE synthesis across a wide range of species suggests the importance of EPT activity in supporting the survival and evolution of organisms. A variety of factors, such as species characteristics (age and sex), diet and nutrition (dietary Se and fat intakes), SELENOI-specific properties (tissue distribution and rank in the selenoproteome), etc., synergistically regulate the expression of SELENOI in a tentatively unclear interaction. The N- and C-terminal domains confer 2 distinct biochemical functions to SELENOI, namely PE regulation and antioxidant potential, which may allow it to be involved in numerous physiological processes, including neurological diseases (especially hereditary spastic paraplegia), T cell activation, tumorigenesis, and adipocyte differentiation. In this review, we summarize advances in the biology and roles of SELENOI, shedding light on the precise regulation of SELENOI expression and PE homeostasis by dietary Se intake and pharmaceutical or transgenic approaches to modulate the corresponding pathological status.

Effect of melatonin on ATG2B-mediated autophagy regulation in sheep granulosa cells with different FecB genotypes.

Melatonin (MLT) protects cells by reducing reactive oxygen species (ROS) levels, which are key for inducing cellular autophagy. The aim of this study was to investigate the molecular mechanisms underlying MLT regulation of autophagy in granulosa cells (GCs) with BMPR-1B homozygous (FecB BB) and wild type (FecB ++) mutations. GCs collected from small-tailed Han sheep with different FecB genotypes were typed using a TaqMan probe assay, and autophagy levels were found to be significantly higher in GCs with FecB BB than the levels in those with FecB ++. Autophagy-related 2 homolog B (ATG2B) was associated with cell autophagy and was highly expressed in GCs with the FecB BB genotype in small-tailed Han sheep. Overexpression of ATG2B in the GCs of sheep with both FecB genotypes promoted GC autophagy, and the contrary was observed after the inhibition of ATG2B expression. Subsequently, treatment of GCs with different genotypes of FecB and MLT revealed a significant decrease in cellular autophagy and an increase in ATG2B expression. Addition of MLT to GCs with inhibited ATG2B expression revealed that MLT could protect GCs by decreasing ROS levels, especially in GCs with FecB ++ genotype. In conclusion, this study determined that autophagy levels were significantly higher in sheep GCs with FecB BB genotype than the levels in those with FecB ++ genotype, which may have contributed to the difference in lambing numbers between the two FecB genotypes. Autophagy was regulated by ATG2B and was able to protect GCs by reducing the high levels of ROS produced following inhibition of ATG2B through the addition of MLT in vitro.

Nicotine transport across calu-3 cell monolayer: effect of nicotine salts and flavored e-liquids.

OBJECTIVE: This study aimed to investigate the transport capability of nicotine across Calu-3 cell monolayer in various nicotine forms, including nicotine freebase, nicotine salts, and flavored e-liquids with nicotine benzoate. SIGNIFICANCE: Nicotine is rapidly absorbed from the respiratory system into systemic circulation during e-cigarettes use. However, the mechanism of nicotine transport in the lung has not been well understood yet. This study may offer critical biological evidence and have implications for the use and regulation of e-cigarettes. METHODS: The viability of Calu-3 cells after administration of nicotine freebase, nicotine salts and representative e-liquid were evaluated using the MTT assay, and the integrity of the Calu-3 cell monolayer was evaluated by transepithelial electrical resistance measurement and morphological analysis. Further, the nicotine transport capacity across the Calu-3 cell monolayer in various formulations of nicotine was investigated by analysis of nicotine transport amount. RESULTS: The findings indicated that nicotine transport occurred passively and was time-dependent across the Calu-3cell monolayer. In addition, the nicotine transport was influenced by the type of nicotine salts and their respective pH value. The nicotine benzoate exhibited the highest apparent permeability coefficient (Papp), and higher nicotine-to-benzoic acid ratios led to higher Papp values. The addition of flavors to e-liquid resulted in increased Papp values, with the most significant increment being observed in tobacco-flavored e-liquid. CONCLUSIONS: In summary, the transport capability of nicotine across the Calu-3 cell monolayer was influenced by the pH values of nicotine salts and flavor additives in e-liquids.

The mechanism of circadian clock and its influence on animal circannual rhythm.

The circadian clock exists in almost all life forms, and is an internal activity generated by organisms adapting to the daily periodic changes of the external environment. The circadian clock is regulated by the transcription-translation-negative feedback loop in the body, which can regulate the activities of tissues and organs. Its normal maintenance is important for the health, growth, and reproduction of organisms. In contrast, due to the season changes of the environment, organisms have also formed annual cycle physiological changes in their bodies, such as seasonal estrus, etc. The annual rhythm of living things is mainly affected by environmental factors such as photoperiod, and is related to gene expression, hormone content, morphological changes of cell and tissues in vivo. Melatonin is an important signal to recognize the changes of photoperiod, and the circadian clock plays an important role in the pituitary to interpret the signal of melatonin and regulate the changes of downstream signals, which plays an important guiding role in the recognition of annual changes in the environment and the generation of the body's annual rhythm. In this review, we summarize the progress of research on the mechanism of action of circadian clocks in influencing annual rhythms, by introducing the mechanisms of circadian and annual rhythms generation in insects and mammals, and in the context of annual rhythms in birds, with the aim of providing a broader range of ideas for future research on the mechanism of annual rhythms influence.

Progress on the effect of FecB mutation on BMPR1B activity and BMP/SMAD pathway in sheep.

BMPR1B is the first major gene of litter size identified in sheep. However, the molecular mechanism of the FecB mutation that increases the ovulation rate in sheep is still unclear. In recent years, it has been demonstrated that BMPR1B activity is regulated by the small molecule repressor protein FKBP1A, which acts as a key activity switch of the BMPR1B in the BMP/SMAD pathway. The FecB mutation is located close to the binding site of FKBP1A and BMPR1B. In this review, we summarize the structure of BMPR1B and FKBP1A proteins, and clarify the spatial interactive domains of the two proteins with respect to the location of the FecB mutation. Then the relationship between the FecB mutation and the degree of affinity of the two proteins are predicted. Finally, the hypothesis that FecB mutation causes change of activity in BMP/SMAD pathway by affecting the intensity of the interactions between BMPR1B and FKBP1A is proposed. This hypothesis provides a new clue to investigate the molecular mechanism of FecB mutation affecting ovulation rate and litter size in sheep.

Kinetically stabilized ferroelectricity in bulk single-crystalline HfO2:Y.

HfO2, a simple binary oxide, exhibits ultra-scalable ferroelectricity integrable into silicon technology. This material has a polymorphic nature, with the polar orthorhombic (Pbc21) form in ultrathin films regarded as the plausible cause of ferroelectricity but thought not to be attainable in bulk crystals. Here, using a state-of-the-art laser-diode-heated floating zone technique, we report the Pbc21 phase and ferroelectricity in bulk single-crystalline HfO2:Y as well as the presence of the antipolar Pbca phase at different Y concentrations. Neutron diffraction and atomic imaging demonstrate (anti)polar crystallographic signatures and abundant 90°/180° ferroelectric domains in addition to switchable polarization with negligible wake-up effects. Density-functional-theory calculations indicate that the yttrium doping and rapid cooling are the key factors for stabilization of the desired phase in bulk. Our observations provide insights into the polymorphic nature and phase control of HfO2, remove the upper size limit for ferroelectricity and suggest directions towards next-generation ferroelectric devices.

Generational synaptic functions of GABAA receptor ß3 subunit deteriorations in an animal model of social deficit.

BACKGROUND: Disruption of normal brain development is implicated in numerous psychiatric disorders with neurodevelopmental origins, including autism spectrum disorder (ASD). Widespread abnormalities in brain structure and functions caused by dysregulations of neurodevelopmental processes has been recently shown to exert adverse effects across generations. An imbalance between excitatory/inhibitory (E/I) transmission is the putative hypothesis of ASD pathogenesis, supporting by the specific implications of inhibitory γ-aminobutyric acid (GABA)ergic system in autistic individuals and animal models of ASD. However, the contribution of GABAergic system in the neuropathophysiology across generations of ASD is still unknown. Here, we uncover profound alterations in the expression and function of GABAA receptors (GABAARs) in the amygdala across generations of the VPA-induced animal model of ASD. METHODS: The F2 generation was produced by mating an F1 VPA-induced male offspring with naïve females after a single injection of VPA on embryonic day (E12.5) in F0. Autism-like behaviors were assessed by animal behavior tests. Expression and functional properties of GABAARs and related proteins were examined by using western blotting and electrophysiological techniques. RESULTS: Social deficit, repetitive behavior, and emotional comorbidities were demonstrated across two generations of the VPA-induced offspring. Decreased synaptic GABAAR and gephyrin levels, and inhibitory transmission were found in the amygdala from two generations of the VPA-induced offspring with greater reductions in the F2 generation. Weaker association of gephyrin with GABAAR was shown in the F2 generation than the F1 generation. Moreover, dysregulated NMDA-induced enhancements of gephyrin and GABAAR at the synapse in the VPA-induced offspring was worsened in the F2 generation than the F1 generation. Elevated glutamatergic modifications were additionally shown across generations of the VPA-induced offspring without generation difference. CONCLUSIONS: Taken together, these findings revealed the E/I synaptic abnormalities in the amygdala from two generations of the VPA-induced offspring with GABAergic deteriorations in the F2 generation, suggesting a potential therapeutic role of the GABAergic system to generational pathophysiology of ASD.

Mechanism of Intermittent Theta-Burst Stimulation in Synaptic Pathology in the Prefrontal Cortex in an Antidepressant-Resistant Depression Rat Model.

Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is considered a potential therapy for treatment-resistant depression. The synaptic mechanism of iTBS has long been known to be an effective method to induce long-term potentiation (LTP)-like plasticity in humans. However, there is limited evidence as to whether the antidepressant effect of iTBS is associated with change in synaptic function in the prefrontal cortex (PFC) in preclinical study. Hence, we applied an antidepressant (i.e., fluoxetine)-resistant depression rat model induced by severe foot-shocks to investigate the antidepressant efficacy of iTBS in the synaptic pathology. The results showed that iTBS treatment improved not only the impaired LTP, but also the aberrant long-term depression in the PFC of antidepressant-resistant depression model rats. Moreover, the mechanism of LTP improvement by iTBS involved downstream molecules of brain-derived neurotrophic factor, while the mechanism of long-term depression improvement by iTBS involved downstream molecules of proBDNF. The aberrant spine morphology was also improved by iTBS treatment. This study demonstrated that the mechanism of the iTBS paradigm is complex and may regulate not only excitatory but also inhibitory synaptic effects in the PFC.

Evaluation of the inhalation toxicity of arecoline benzoate aerosol in rats.

Arecoline is a pharmacologically active alkaloid isolated from Areca catechu. There are no published data available regarding the inhalation toxicity of arecoline in animals. This study aimed to evaluate the inhalation toxicity of arecoline in vitro and in vivo. For this purpose, arecoline benzoate (ABA) salt was prepared to stabilize arecoline in an aerosol. The MTT assay determined the half-maximal inhibitory concentration values of ABA and arecoline in A549 cell proliferation to be 832 and 412 µg/ml, respectively. The toxicity of acute and subacute inhalation in Sprague-Dawley rats was evaluated using the guidelines of the Organization for Economic Cooperation and Development. For acute inhalation, the median lethal concentration value of ABA solvent was >5175 mg/m3 . After the exposure and during the recovery period, no treatment-related clinical signs were observed. In the 28-Day inhalation toxicity test, daily nose-only exposure to 2510 mg/m3 aerosol of the ABA solvent contained 75 mg/m3 ABA for male rats and 375 mg/m3 ABA for female rats, which caused no observed adverse effects, except for the decreased body weight gain in male rats exposed to 375 mg/m3 ABA. In this study, the no observed adverse effect level (NOAEL) for the 28-day repeated dose inhalation of ABA aerosol was calculated to be around 13 mg/kg/day for male rats and 68.8 mg/kg/day for female rats, respectively.

Leishmania Regulated MTDH Expression to Suppress Dendritic Cells.

This study aimed to investigate the correlation between Leishmania infection and dendritic cell infiltration and explore the underlying molecular mechanism how Leishmania infection regulates dendritic cell infiltration. Three datasets, GSE63931, GSE80008 and GSE77528 were combined and their batch effects were removed by Combat function in sva R package. Immune cell infiltrations were estimated using the Microenvironment Cell Populations-counter (MCP-counter) R package. Statistical results were verified by Student's t test. The differential expression of metadherin (MTDH) was identified by Limma R package. The correlation between MTDH expression and dendritic cell infiltration was estimated by Pearson's product moment correlation coefficient. GDS5086 was used to explore MTDH expression pattern in dendritic cells infected with Leishmania. Compared with normal samples, 5 types of immune cells showed differential infiltration in leishmaniasis samples, including T cells, CD8+ T cells, dendritic cells, cytotoxic lymphocytes and B lineage cells. Among these, only DCs were significantly suppressed in leishmaniasis samples. Notably, MTDH expression was differential between leishmaniasis and normal samples. There was a significant correlation between MTDH expression and dendritic cell infiltration. In conclusion, these results demonstrate that Leishmania infection leads to the downregulation of MTDH expression and the suppression of dendritic cell infiltration.

Protective Effects of Hippophae rhamnoides L. Phenylpropanoids on Doxorubicin-Induced Cardiotoxicity in Zebrafish.

Hippophae rhamnoides L. is a deciduous shrub that contains many unique bioactive substances. This sea buckthorn possesses anticancer, antioxidant, anti-inflammatory, and cardiovascular protective properties. Herein, the effects of phenylpropyl compounds extracted from H. rhamnoides L. on doxorubicin (Dox)-induced cardiotoxicity were evaluated in zebrafish. Cardiac injury in zebrafish was induced using 35 µM Dox for 96 h, and 30 µM phenylpropanoid compounds were used as the protective treatment. The cardioprotective effects and mechanisms of the four phenylpropanoids were investigated using microscopy, behavioral analysis, acridine orange staining, western blotting, flow cytometry, and real-time quantitative polymerase chain reaction. The extracted phenylpropanoids could significantly relieve Dox-induced cardiac injury in zebrafish and inhibit cardiomyocyte apoptosis. The mechanisms of action were mainly related to the stability of mitochondrial biogenesis and function maintained by phenylpropanoids in zebrafish. To our knowledge, this is the first report on the protective effect of sea buckthorn against myocardial injury in zebrafish. Our findings provide support for the further research and development of sea buckthorn and its components.

[Relationship between Oral Microbiota and Alzheimer's Disease].

Alzheimer's disease (AD) is a common neurodegenerative disease. In an aging society, the high prevalence of AD and the low quality of life of AD patients create serious problems for individuals, families and the society. However, the etiology and pathogenesis of AD are still not fully understood. Age, genetics, environment and other factors are all relevant to AD, and treatment has not achieved satisfactory results. Recent studies have found that oral dysbiosis is closely related to the pathogenesis of AD, and that oral bacterial infection may be one of the causes of AD. Oral cavity is the largest microbial ecosystem of human body, and its homeostasis is critical to health. Bacterial infections caused by oral dysbiosis can directly and indirectly induce the metabolic imbalance of amyloid ß-protein (Aß) in the brain and the hyperphosphorylation of Tau protein. Then, the precipitation forms senile plaques and neurofibrillary tangles (NFTs) that damage neurons. Based on the latest research findings, we herein discussed the correlation between oral microbiota and the pathogenesis of AD and the mechanisms involved, as well as the pathogenic mechanism of main oral bacteria. In addition, we explored the potential application prospects of oral microbiota-targeted therapy.

Expression characteristics of pineal miRNAs at ovine different reproductive stages and the identification of miRNAs targeting the AANAT gene.

BACKGROUND: Many recent studies have shown that miRNAs play important roles in the regulation of animal reproduction, including seasonal reproduction. The pineal gland is a crucial hub in the regulation of seasonal reproduction. However, little is known about the expression characteristics of pineal miRNAs in different reproductive seasons (anestrus and breeding season). Therefore, the expression profiles and regulatory roles of ovine pineal miRNAs were investigated during different reproductive stages using Solexa sequencing technology and dual luciferase reporter assays. RESULTS: A total of 427 miRNAs were identified in the sheep pineal gland. Significant differences in miRNA expression were demonstrated between anestrus and the breeding season in terms of the frequency distributions of miRNA lengths, number of expressed miRNAs, and specifically and highly expressed miRNAs in each reproductive stage. KEGG analysis of the differentially expressed (DE) miRNAs between anestrus and the breeding season indicated that they are significantly enriched in pathways related to protein synthesis, secretion and uptake. Furthermore, transcriptome analysis revealed that many target genes of DE miRNAs in the ribosome pathway showed relatively low expression in the breeding season. On the other hand, analyses combining miRNA-gene expression data with target relationship validation in vitro implied that miR-89 may participate in the negative regulation of aralkylamine N-acetyltransferase (AANAT) mRNA expression by targeting its 3'UTR at a unique binding site. CONCLUSIONS: Our results provide new insights into the expression characteristics of sheep pineal miRNAs at different reproductive stages and into the negative regulatory effects of pineal miRNAs on AANAT mRNA expression.