Genome-wide association study provided insights into the polled phenotype and polled intersex syndrome (PIS) in goats.

BACKGROUND: Breeding polled goats is a welfare-friendly approach for horn removal in comparison to invasive methods. To gain a comprehensive understanding of the genetic basis underlying polledness in goats, we conducted whole-genome sequencing of 106 Xinong Saanen dairy goats, including 33 horned individuals, 70 polled individuals, and 3 polled intersexuality syndrome (PIS) individuals. METHODS: The present study employed a genome-wide association study (GWAS) and linkage disequilibrium (LD) analysis to precisely map the genetic locus underlying the polled phenotype in goats. RESULTS: The analysis conducted in our study revealed a total of 320 genome-wide significant single nucleotide polymorphisms (SNPs) associated with the horned/polled phenotype in goats. These SNPs exhibited two distinct peaks on chromosome 1, spanning from 128,817,052 to 133,005,441 bp and from 150,336,143 to 150,808,639 bp. The present study identified three genome-wide significant SNPs, namely Chr1:129789816, Chr1:129791507, and Chr1:129791577, as potential markers of PIS-affected goats. The results of our LD analysis suggested a potential association between MRPS22 and infertile intersex individuals, as well as a potential association between ERG and the polled trait in goats. CONCLUSION: We have successfully identified three marker SNPs closely linked to PIS, as well as several candidate genes associated with the polled trait in goats. These results may contribute to the development of SNP chips for early prediction of PIS in goats, thereby facilitating breeding programs aimed at producing fertile herds with polled traits.

Acetylated tau exacerbates apoptosis by disturbing mitochondrial dynamics in HEK293 cells.

An increase in tau acetylation at K274 and K281 and abnormal mitochondrial dynamics have been observed in the brains of Alzheimer's disease (AD) patients. Here, we constructed three types of tau plasmids, TauKQ (acetylated tau mutant, by mutating its K274/K281 into glutamine to mimic disease-associated lysine acetylation), TauKR (non-acetylated tau mutant, by mutating its K274/K281 into arginine), and TauWT (wild-type human full-length tau). By transfecting these tau plasmids in HEK293 cells, we found that TauWT and TauKR induced mitochondrial fusion by increasing the level of mitochondrial fusion proteins. Conversely, TauKQ induced mitochondrial fission by reducing mitochondrial fusion proteins, exacerbating mitochondrial dysfunction and apoptosis. BGP-15 ameliorated TauKQ-induced mitochondrial dysfunction and apoptosis by improving mitochondrial dynamics. Our findings suggest that acetylation of K274/281 represents an important post-translational modification site regulating mitochondrial dynamics, and that BGP-15 holds potential as a therapeutic agent for mitochondria-associated diseases such as AD.

The influence of radiation-induced bystander effect in osteoblasts mediated by plasma-derived extracellular vesicles (EVs).

OBJECTIVES: Head and neck tumor patients may develop post-radiotherapy diseases after radiotherapy treatment. And radiotherapy can elicit radiation-induced bystander effect, wherein extracellular vesicles (EVs) play a crucial role. For normal parts of the body that have not been directly irradiated, the effect of EVs on them needs to be further explored. This study aims to investigate the functions of plasma-derived EVs in regulating normal osteoblasts during radiation-induced bystander effects. METHODS AND MATERIALS: Rat plasma-derived EVs were isolated and identified firstly, followed by an evaluation of their intracellular biological effects on normal osteoblasts in vitro. Transcriptome sequencing analysis and confirmations were performed to identify potential mechanisms. RESULTS: Irradiated plasma-derived EVs were found to enhance osteoblast proliferation, migration, and cell cycle progression, concurrently suppressing the expression of osteogenesis-related genes and proteins. Furthermore, these EVs attenuated the expression of osteogenesis and oxidative stress resistance related genes, while upregulating the PI3K-AKT pathway and intracellular reactive oxygen species in osteoblasts. CONCLUSIONS: Irradiated plasma-derived EVs could alter the biological effects in osteoblasts, which is closely associated with the levels of GPX1 and the PI3K-AKT signaling pathway. This suggests that plasma-derived EVs serve as a crucial factor contributing to radiation-induced bystander effect in osteoblasts.

BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy.

The high prevalence of major depressive disorder (MDD) frequently imposes severe constraints on psychosocial functioning and detrimentally impacts overall well-being. Despite the growing interest in the hypothesis of mitochondrial dysfunction, the precise mechanistic underpinnings and therapeutic strategies remain unclear and require further investigation. In this study, an MDD model was established in mice using lipopolysaccharide (LPS). Our research findings demonstrated that LPS exposure induced depressive-like behaviors and disrupted mitophagy by diminishing the mitochondrial levels of PINK1/Parkin in the brains of mice. Furthermore, LPS exposure evoked the activation of the NLRP3 inflammasome, accompanied by a notable elevation in the concentrations of pro-inflammatory factors (TNF-α, IL-1ß, and IL-6). Additionally, neuronal apoptosis was stimulated through the JNK/p38 pathway. The administration of BGP-15 effectively nullified the impact of LPS, corresponding to the amelioration of depressive-like phenotypes and restoration of mitophagy, prevention of neuronal injury and inflammation, and suppression of reactive oxygen species (ROS)-mediated NLRP3 inflammasome activation. Furthermore, we elucidated the involvement of mitophagy in BGP-15-attenuated depressive-like behaviors using the inhibitors targeting autophagy (3-MA) and mitophagy (Mdivi-1). Notably, these inhibitors notably counteracted the antidepressant and anti-inflammatory effects exerted by BGP-15. Based on the research findings, it can be inferred that the antidepressant properties of BGP-15 in LPS-induced depressive-like behaviors could potentially be attributed to the involvement of the mitophagy pathway. These findings offer a potential novel therapeutic strategy for managing MDD.

Artificial intelligence model system for bone age assessment of preschool children.

BACKGROUD: Our study aimed to assess the impact of inter- and intra-observer variations when utilizing an artificial intelligence (AI) system for bone age assessment (BAA) of preschool children. METHODS: A retrospective study was conducted involving a total sample of 53 female individuals and 41 male individuals aged 3-6 years in China. Radiographs were assessed by four mid-level radiology reviewers using the TW3 and RUS-CHN methods. Bone age (BA) was analyzed in two separate situations, with/without the assistance of AI. Following a 4-week wash-out period, radiographs were reevaluated in the same manner. Accuracy metrics, the correlation coefficient (ICC)and Bland-Altman plots were employed. RESULTS: The accuracy of BAA by the reviewers was significantly improved with AI. The results of RMSE and MAE decreased in both methods (p < 0.001). When comparing inter-observer agreement in both methods and intra-observer reproducibility in two interpretations, the ICC results were improved with AI. The ICC values increased in both two interpretations for both methods and exceeded 0.99 with AI. CONCLUSION: In the assessment of BA for preschool children, AI was found to be capable of reducing inter-observer variability and enhancing intra-observer reproducibility, which can be considered an important tool for clinical work by radiologists. IMPACT: The RUS-CHN method is a special bone age method devised to be suitable for Chinese children. The preschool stage is a critical phase for children, marked by a high degree of variability that renders BA prediction challenging. The accuracy of BAA by the reviewers can be significantly improved with the aid of an AI model system. This study is the first to assess the impact of inter- and intra-observer variations when utilizing an AI model system for BAA of preschool children using both the TW3 and RUS-CHN methods.

Preparation of near-infrared photoacoustic imaging and photothermal treatment agent for cancer using a modifiable acid-triggered molecular platform.

Ratiometric near-infrared fluorescent pH probes with various pKa values were innovatively designed and synthesized based on cyanine with a diamine moiety. The photochemical properties of these probes were thoroughly evaluated. Among the series, IR-PHA exhibited an optimal pKa value of approximately 6.40, closely matching the pH of cancerous tissues. This feature is particularly valuable for real-time pH monitoring in both living cells and living mice. Moreover, when administered intravenously to tumor-bearing mice, IR-PHA demonstrated rapid and significant enhancement of near-infrared fluorescence and photoacoustic signals within the tumor region. This outcome underscores the probe's exceptional capability for dual-modal cancer imaging utilizing near-infrared fluorescence (NIRF) and photoacoustic (PA) modalities. Concurrently, the application of a continuous-wave near-infrared laser efficiently ablated cancer cells in vivo, attributed to the photothermal effect induced by IR-PHA. The results strongly indicate that IR-PHA is well-suited for NIRF/PA dual-modality imaging and photothermal therapy of tumors. This makes it a promising candidate for theranostic applications involving small molecules.

Discovery of novel pyridone-benzamide derivatives possessing a 1-methyl-2-benzimidazolinone moiety as potent EZH2 inhibitors for the treatment of B-cell lymphomas.

Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50 = 0.32 nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50 = 1.20 nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC50 = 0.03 nM; EZH2 Y641N, IC50 = 0.08 nM), which were approximately 10-fold more active than those of 1 (EZH2 Y641F, IC50 = 0.37 nM; EZH2 Y641N, IC50 = 0.85 nM). Furthermore, compound N40 (IC50 = 3.52 ±â€¯1.23 nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than 1 (IC50 = 35.01 ±â€¯1.28 nM). Further cellular experiments showed that N40 arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, N40 inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.

Discovery and optimization of dihydropteridone derivatives as novel PLK1 and BRD4 dual inhibitor for the treatment of cancer.

In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50 = 17.3 nM, MDA-MB-361 IC50 = 8.4 nM, and MV4-11 IC50 = 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 µL·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-t = 657 ng·h·mL-1, oral bioavailability of 21.4 %) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.

Thermal Reactions of NiAl3O6+ and Al4O6+ with Methane: Reactivity Enhancement by Doping.

Investigation of the reactivity of heteronuclear metal oxide clusters is an important way to uncover the molecular-level mechanisms of the doping effect. Herein, we performed a comparative study on the reactions of CH4 with NiAl3O6+ and Al4O6+ cluster cations at room temperature to understand the role of Ni during the activation and transformation of methane. Mass spectrometric experiments identify that both NiAl3O6+ and Al4O6+ could bring about hydrogen atom abstraction reaction to generate CH3• radical; however, only NiAl3O6+ has the potential to stabilize [CH3] moiety and then transform [CH3] to CH2O. Density functional theory calculations demonstrate that the terminal oxygen radicals (Ot-•) bound to Al act as the reactive sites for the two clusters to activate the first C-H bond. Although the Ni atom cannot directly participate in methane activation, it can manipulate the electronic environment of the surrounding bridging oxygen atoms (Ob) and enable such Ob to function as an electron reservoir to help Ot-• oxidize CH4 to [H-O-CH3]. The facile reduction of Ni3+ to Ni+ also facilitates the subsequent step of activating the second C-H bond by the bridging "lattice oxygen" (Ob2-), finally enabling the oxidation of methane into formaldehyde. The important role of the dopant Ni played in improving the product selectivity of CH2O for methane conversion discovered in this study allows us to have a possible molecule-level understanding of the excellent performance of the catalysts doping with nickel.

Experimental Reactivity of (MoO3)NO- (N = 1-21) Cluster Anions with C1-C4 Alkanes: A Simple Model to Predict the Reactivity with Methane.

Metal oxide clusters with atomic oxygen radical anions are important model systems to study the mechanisms of activating and transforming very stable alkane molecules under ambient conditions. It is extremely challenging to characterize the activation and conversion of methane, the most stable alkane molecule, by metal oxide cluster anions due to the low reactivity of the anionic species. In this study, using a ship-lock type reactor that could be run at relatively high pressure conditions to provide a high number of collisions in ion-molecule reactions, the rate constants of the reactions between (MoO3)NO- (N = 1-21) cluster anions and the light alkanes (C1-C4) were measured under thermal collision conditions. The relationships among the reaction rates of different alkanes were obtained to establish a model to predict the low rate constants with methane from the high rate constants with C2-C4 alkanes. The model was tested by using available experimental results in literature. This study provides a new method to estimate the relatively low reactivity of atomic oxygen radical anions with methane on metal oxide clusters.

Spatial profiles of the bacterial microbiota throughout the gastrointestinal tract of dairy goats.

The gastrointestinal tract (GIT) is stationed by a dynamic and complex microbial community with functions in digestion, metabolism, immunomodulation, and reproduction. However, there is relatively little research on the composition and function of microorganisms in different GIT segments in dairy goats. Herein, 80 chyme samples were taken from ten GIT sites of eight Xinong Saanen dairy goats and then analyzed and identified the microbial composition via 16S rRNA V1-V9 amplicon sequencing. A total of 6669 different operational taxonomic units (OTUs) were clustered, and 187 OTUs were shared by ten GIT segments. We observed 264 species belonging to 23 different phyla scattered across ten GITs, with Firmicutes (52.42%) and Bacteroidetes (22.88%) predominating. The results revealed obvious location differences in the composition, diversity, and function of the GIT microbiota. In LEfSe analysis, unidentified_Lachnospiraceae and unidentified_Succinniclassicum were significantly enriched in the four chambers of stomach, with functions in carbohydrate fermentation to compose short-chain fatty acids. Aeriscardovia, Candidatus_Saccharimonas, and Romboutsia were significantly higher in the foregut, playing an important role in synthesizing enzymes, amino acids, and vitamins and immunomodulation. Akkermansia, Bacteroides, and Alistipes were significantly abundant in the hindgut to degrade polysaccharides and oligosaccharides, etc. From rumen to rectum, α-diversity decreased first and then increased, while ß-diversity showed the opposite trend. Metabolism was the major function of the GIT microbiome predicted by PICRUSt2, but with variation in target substrates along the regions. In summary, GIT segments play a decisive role in the composition and functions of microorganisms. KEY POINTS: • The jejunum and ileum were harsh for microorganisms to colonize due to the presence of bile acids, enzymes, faster chyme circulation, etc., exhibiting the lowest α-diversity and the highest ß-diversity. • Variability in microbial profiles between the three foregut segments was greater than four chambers of stomach and hindgut, with a higher abundance of Firmicutes dominating than others. • Dairy goats dominated a higher abundance of Kiritimatiellaeota than cows, which was reported to be associated with fatty acid synthesis.

The role of exosomal circular RNA ZNF292 in intermittent hypoxia-induced AC16 cardiomyocytes injury.

BACKGROUND: Exosomes are involved in cell-to-cell communication in numerous diseases including cardiovascular diseases, neurological diseases. Little attention has been dedicated to exosomal circular RNAs in obstructive sleep apnea (OSA)-related cardiovascular diseases. The aim of this study was to explore the role of exosomal circular RNA ZNF292 (circZNF292) on AC16 cells exposure to intermittent hypoxia (IH). METHODS: Exosome release inhibitor GW4869 was used to examine the effect of exosomes on IH-induced AC16 cells apoptosis. The expression of exosomal circZNF292 was detected by qRT-PCR in AC16 cells exposure to IH, and a luciferase reporter assay was conducted to confirm the connection between circZNF292 and miR-146a-5p. Exosomal circZNF292 was stably transfected with short hairpin RNAs (shRNAs) against circZNF292 and co-cultured with AC16 cells. The expression of miR-146a-5p and apoptosis-related protein was then measured to evaluate the effect of exosomal circZNF292. RESULTS: We found that IH contributed to the AC16 cells apoptosis, and the administration of GW4869 increased the apoptosis of cardiomyocytes when exposed to IH. The expression of exosomal circZNF292 decreased and miR-146a-5p increased significantly in AC16 cells exposed to IH compared to normoxic conditions. Bioinformatics analysis predicted a circZNF292/miR-146a-5p axis in IH-induced cardiomyocytes apoptosis. The dual-luciferase reporter system validated the direct interaction of circZNF292 and miR-146a-5p. Knockdown of circZNF292 increased the expressions of miR-146a-5p and accelerated the AC16 cardiomyocytes apoptosis. CONCLUSIONS: The findings of this study suggested a novel mechanism by which exosomes transmit intrinsic regulatory signals to the myocardium through the exosomal circZNF292/miR-146a-5p axis. This finding highlights the potential of targeting this pathway as a therapeutic approach for treating cardiovascular diseases associated with OSA.

Identification of the FGB gene polymorphism and analysis of its association with fat deposition traits in Hu sheep.

As a crucial economic trait, fat deposition is directly related to carcass quality and feed efficiency in sheep. The purpose of this study was to investigate the polymorphisms of the FGB gene related to fat deposition and detect the expression features of the FGB gene in different adipose tissues of sheep by using Sanger sequencing, MassARRAY® SNP technique, and quantitative real-time PCR (qRT-PCR). Results showed that in the intron region of the FGB gene, a SNP g. 3378953 A > T has been identified, and significant association was found between perirenal fat weight, perirenal fat relative weight, mesenteric fat weight, and mesenteric fat relative weight (P < 0.05). Moreover, qRT-PCR analysis showed that FGB was expressed in all three adipose tissues, and FGB gene expression level in the AA genotype was significantly lower than that in the AT or TT genotypes (P < 0.05). Therefore, the FGB gene can be used as a candidate gene to reduce fat deposition in Hu sheep breeding, and the selection of the AA genotype in Hu sheep in production practice is more conducive to improving production efficiency.

Prognostic value of systemic immune-inflammation index and monocyte-to-HDL-cholesterol ratio in early cardio-cerebral complications in elderly patients with acute severe carbon monoxide poisoning.

To investigate how effectively systemic immune-inflammation index (SII) and Monocyte-to-HDL-cholesterol ratio (MHR) predict the development of early cardio-cerebral complications in elderly patients who have experienced acute severe carbon monoxide poisoning (ASCMP). A retrospective analysis was conducted on 77 elderly patients with ASCMP admitted to the emergency department of Harrison International Peace Hospital from November 2020 to March 2022. The prevalence of early-onset complications among the 77 individuals was 38.96%. Binary Logistics regression analysis showed that SII and MHR were independent influencing factors of early cardio-cerebral complications in elderly patients with ASCMP. The complication group had a longer length of stay, a greater mortality rate, and a higher incidence of delayed encephalopathy after acute carbon monoxide poisoning (p < .05) than the non-complication group. The area under the curve (AUC) of SII and MHR in predicting early cardio-cerebral complications in elderly patients with ASCMP were 0.724 and 0.796, respectively, with 80.0% and 63.3% sensitivity, and 61.7% and 87.2% specificity. The incidence of early cardio-cerebral complications in elderly patients who had ASCMP is high and the prognosis is poor. SII and MHR can be utilized as independent predictors of early cardio-cerebral complications in elderly patients with ASCMP, allowing doctors to diagnose and treat cardio-cerebral complications earlier and improve prognosis.

Analytical quality by design based on knowledge organization: A case study of developing an ultrahigh-performance liquid chromatography method for the detection of phenolic compounds.

INTRODUCTION: Despite numerous successful cases, there are still some challenges in using analytical quality by design (AQbD) for the development of analytical methods. Knowledge organization helps to enhance the objectivity of risk assessment, reduce the number of preliminary exploratory experiments, identify potential critical method parameters (CMPs) and their scope. OBJECTIVE: In the present study, we aimed to develop a simple, rapid, and robust analytical method for detecting phenolic compounds in Xiaochaihu capsule intermediates utilizing knowledge organization. METHODS: Knowledge organization and AQbD were combined to obtain the initial analytical conditions through knowledge collection, extraction, reorganization, and analysis. The quantitative relationship between critical method attributes (CMAs) and CMPs was then established by a definitive screening design. The method operable design region was calculated using an exhaustive Monte Carlo approach based on the probability of reaching the standard. Robustness investigation and methodological validation were finally performed. RESULTS: Analytical target profiles, CMAs, potential CMPs, and initial analytical conditions were initially identified, and the optimized ranges of operating parameters were obtained. A UHPLC method was successfully established for the analysis of phenolic compounds in ginger-ginger pinellia percolate, and the method validation outcomes were also satisfactory. CONCLUSION: The developed method can be a reliable means to detect the phenolic compounds of Xiaochaihu capsule intermediates. Knowledge organization provides a new approach for making better use of prior knowledge, significantly enhancing the efficiency of analytical method development. The approach is versatile and can be similarly applied to the development of other methods.

Rechargeable Afterglow Nanotorches for In Vivo Tracing of Cell-Based Microrobots.

As one of the self-luminescence imaging approaches that require pre-illumination instead of real-time light excitation, afterglow luminescence imaging has attracted increasing enthusiasm to circumvent tissue autofluorescence. In this work, we developed organic afterglow luminescent nanoprobe (nanotorch), which could emit persistent luminescence more than 10 days upon single light excitation. More importantly, the nanotorch could be remote charged by 660 nm light in a non-invasive manner, which showed great potential for real-time tracing the location of macrophage cell-based microrobots.

Clinical Forms of Japanese Spotted Fever from Case-Series Study, Zigui County, Hubei Province, China, 2021.

We report a case-series study of 5 patients with Japanese spotted fever from the Three Gorges Area in China, including 1 fatal case. Seroprevalence of Rickettsia japonica was ≈21% among the local population. Our report highlights the emerging potential threat to human health of Japanese spotted fever in the area.

Anisotropic Black Phosphorene Structural Modulation for Thermal Storage and Solar-Thermal Conversion.

Exploiting novel strategies for simultaneously harvesting ubiquitous, renewable, and easily accessible solar energy based on the photothermal effect, and efficiently storing the acquired thermal energy plays a vital role in revolutionizing the current fossil fuel-dominating energy structure. Developing black phosphorene-based phase-change composites with optimized photothermal conversion efficiencyand high latent heat is the most promising way to achieve efficient solar energy harvesting and rapid thermal energy storage. However, exfoliating high-quality black phosphorene nanosheets  remains challenging, Furthermore, an efficient strategy that can construct the aligned black phosphorene frameworks to maximize thermal conductivity enhancement is still lacking. Herein, high-quality black phosphorene nanosheets are prepared by an optimized exfoliating strategy. Meanwhile, by regulating the temperature gradient during freeze-casting, the framework consisting of shipshape aligned black phosphorene at long-range is successfully fabricated, improving the thermal conductivity of the poly(ethylene glycol) matrix up to 1.81 W m-1  K-1 at 20 vol% black phosphorene loading. The framework also endows the composite with excellent phase-change material encapsulation capacity and  high latent heat of 103.91 J g-1 . It is envisioned that the work advances the paradigm of contrasting frameworks with nanosheets toward controllable structure thermal enhancement of the composites.

Reduced cerebral cortex thickness is related to overexpression of exosomal miR-146a-5p in medication-free patients with major depressive disorder.

BACKGROUND: Previous studies have confirmed that miR-146a-5p overexpression suppresses neurogenesis, thereby enhancing depression-like behaviors. However, it remains unclear how miR-146a-5p dysregulation produces in vivo brain structural abnormalities in patients with major depressive disorder (MDD). METHODS: In this case-control study, we combined cortical morphology analysis of magnetic resonance imaging (MRI) and miR-146a-5p quantification to investigate the neuropathological effect of miR-146a-5p on cortical thickness in MDD patients. Serum-derived exosomes that were considered to readily cross the blood-brain barrier and contain miR-146a-5p were isolated for miRNA quantification. Moreover, follow-up MRI scans were performed in the MDD patients after 6 weeks of antidepressant treatment to further validate the clinical relevance of the relationship between miR-146a-5p and brain structural abnormalities. RESULTS: In total, 113 medication-free MDD patients and 107 matched healthy controls were included. Vertex-vise general linear model revealed miR-146a-5p-dependent cortical thinning in MDD patients compared with healthy individuals, i.e., overexpression of miR-146a-5p was associated with reduced cortical thickness in the left orbitofrontal cortex (OFC), anterior cingulate cortex, bilateral lateral occipital cortices (LOCs), etc. Moreover, this relationship between baseline miR-146a-5p and cortical thinning was nonsignificant for all regions in the patients who had received antidepressant treatment, and higher baseline miR-146a-5p expression was found to be related to greater longitudinal cortical thickening in the left OFC and right LOC. CONCLUSIONS: The findings of this study reveal a relationship between miR-146a-5p overexpression and cortical atrophy and thus may help specify the in vivo mediating effect of miR-146a-5p dysregulation on brain structural abnormalities in patients with MDD.

Mild Hypothermia Alleviates Complement C5a-Induced Neuronal Autophagy During Brain Ischemia-Reperfusion Injury After Cardiac Arrest.

After restoration of spontaneous circulation (ROSC) following cardiac arrest, complements can be activated and excessive autophagy can contribute to the brain ischemia-reperfusion (I/R) injury. Mild hypothermia (HT) protects against brain I/R injury after ROSC, but the mechanisms have not been fully elucidated. Here, we found that HT significantly inhibited the increases in serum NSE, S100ß, and C5a, as well as neurologic deficit scores, TUNEL-positive cells, and autophagic vacuoles in the pig brain cortex after ROSC. The C5a receptor 1 (C5aR1) mRNA and the C5a, C5aR1, Beclin 1, LC3-II, and cleaved caspase-3 proteins were significantly increased, but the P62 protein and the PI3K/Akt/mTOR pathway-related proteins were significantly reduced in pigs after ROSC or neuronal oxygen-glucose deprivation/reoxygenation. HT could significantly attenuate the above changes in NT-treated neurons. Furthermore, C5a treatment induced autophagy and apoptosis and reduced the PI3K/Akt/mTOR pathway-related proteins in cultured neurons, which could be reversed by C5aR1 antagonist PMX205. Our findings demonstrated that C5a could bind to C5aR1 to induce neuronal autophagy during the brain I/R injury, which was associated with the inhibited PI3K/Akt/mTOR pathway. HT could inhibit C5a-induced neuronal autophagy by regulating the C5a-C5aR1 interaction and the PI3K/Akt/mTOR pathway, which might be one of the neuroprotective mechanisms underlying I/R injury. The C5a receptor 1 (C5aR1) mRNA and the C5a, C5aR1, Beclin 1, LC3-II, and cleaved caspase-3 proteins were significantly increased, but the P62 protein and the PI3K/Akt/mTOR pathway-related proteins were significantly reduced in pigs after ROSC or neuronal oxygen-glucose deprivation/reoxygenation. Mild hypothermia (HT) could significantly attenuate the above changes in NT-treated neurons. Furthermore, C5a treatment induced autophagy and apoptosis and reduced the PI3K/Akt/mTOR pathway-related proteins in cultured neurons, which could be reversed by C5aR1 antagonist PMX205. Proposed mechanism by which HT protects against brain I/R injury by repressing C5a-C5aR1-induced excessive autophagy. Complement activation in response to brain I/R injury generates C5a that can interact with C5aR1 to inactivate mTOR, probably through the PI3K-AKT pathway, which can finally lead to autophagy activation. The excessively activated autophagy ultimately contributes to cell apoptosis and brain injury. HT may alleviate complement activation and then reduce C5a-induced autophagy to protect against brain I/R injury. HT, mild hypothermia; I/R, ischemia reperfusion.