Sevoflurane acts as an antidepressant by suppression of GluN2D-containing NMDA receptors on interneurons.

BACKGROUND AND PURPOSE: Sevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects. EXPERIMENTAL APPROACH: To assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole-cell patch-clamp recordings, to examine the effects on GluN1-GluN2 incorporated N-methyl-d-aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple-channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (grin2d-/-) mice were used to confirm the requirement of GluN2D for the antidepressant effects. KEY RESULTS: Repeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C- and GluN2D-containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in grin2d-/- mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect. CONCLUSION AND IMPLICATIONS: Sevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression.

Knockdown of vitellogenin receptor based on minute insect RNA interference methods affects the initial mature egg load in the pest natural enemy Trichogramma dendrolimi.

Vitellogenin receptor (VgR) plays a crucial role in oogenesis by mediating endocytosis of vitellogenin and a portion of the yolk proteins in many insect species. However, the function of VgR in minute parasitoid wasps is largely unknown. Here, we applied Trichogramma dendrolimi, a minute egg parasitoid, as a study model to investigate the function of VgR in parasitoids. We developed RNA interference (RNAi) methods based on microinjection of prepupae in T. dendrolimi. RNAi employs nanomaterial branched amphipathic peptide capsules (BAPC) as a carrier for double-stranded RNA (dsRNA), significantly enhancing delivery efficiency. Also, artificial hosts without medium were used to culture the injected prepupae in vitro. Utilizing these methods, we found that ovarian growth was disrupted after knockdown of TdVgR, as manifested by the suppressed development of the ovariole and the inhibition of nurse cell internalization by oocytes. Also, the initial mature egg load in the ovary was significantly reduced. Notably, the parasitic capacity of the female adult with ovarian dysplasia was significantly decreased, possibly resulting from the low availability of mature eggs. Moreover, ovarian dysplasia in T. dendrolimi caused by VgR deficiency are conserved despite feeding on different hosts. The results confirmed a critical role of TdVgR in the reproductive ability of T. dendrolimi and provided a reference for gene functional studies in minute insects.

Younger patients with colorectal cancer may have better long-term survival after surgery: a retrospective study based on propensity score matching analysis.

BACKGROUND: The relationship between postoperative long-term prognosis and age in colorectal cancer patients remains controversial. The purpose of this study based on a Chinese CRC cohort is to determine the disparity in long-term survival outcomes between younger and older colorectal cancer (CRC) patients after surgery using a propensity score matching (PSM). METHODS: Data for this study was derived from the CRC cohort of the Database from Colorectal Cancer (DACCA) at West China Hospital of Sichuan University from January 2007 to September 2022. The long­term prognoses were compared between younger and older groups. RESULTS: A total of 2374 CRC patients were evaluated in this study, including 1039 older patients and 1335 younger ones. After 1:1 ratio PSM, each group contained 784 CRC patients. There was no significant difference in baseline information after PSM (p < 0.05). Multivariate analysis showed that younger age was an independent predictor of better overall survival (OS) (p < 0.001, HR = 1.750, 95% CI = 1.407-2.177) and disease-specific survival (DSS) (p < 0.001, HR = 1.718, 95% CI = 1.369-2.157). In terms of different tumor pathological stages after PSM, in comparison to older group, younger group had better OS in stage II (p < 0.001), stage III (p = 0.0085), and stage IV (p = 0.0014) and better DSS in stage II (p = 0.0035), stage III (p = 0.0081), and stage IV (p < 0.001). CONCLUSION: Younger CRC patients have better prognosis than older CRC patients after surgery, especially, and have better OS and DSS in stages II, III, and IV CRC. Younger CRC patient may gain greater benefit from CRC resection and combined therapy. As for the cut-off age, it may be determined by a specific model suitable for local patients.

Relationship between parasitism and morphology of Trichogramma (Hymenoptera: Trichogrammatidae) on Spodoptera frugiperda (Lepidoptera: Noctuidae).

In this study, 5 species of Trichogramma Westwood were evaluated for the biological control of Spodoptera frugiperda (JE Smith), concerning the physical characteristics of female Trichogramma. The results showed that Trichogramma chilonis Ishii, Trichogramma dendrolimi Matsumura, and Trichogramma ostriniae Pang et Chen exhibited high parasitism rates, emergence rates, and offspring numbers, with the highest values observed for T. ostriniae. The ovipositor length of Trichogramma japonicum Ashmead and T. dendrolimi were longer than those of other species, and the hind tibia length was the shortest in Trichogramma cacoeciae Marchal. We further evaluated relationships between the parasitism ability of Trichogramma and various morphological indexes based on Spearman's rank correlation coefficients. A positive correlation was found between the parasitism rate and hind tibia length of T. cacoeciae. In T. dendrolimi, the parasitism rate was negatively correlated with ovipositor width and positively correlated with the length-width ratio of the ovipositor. A significant positive correlation was observed between the proportion of female offspring and the mother's ovipositor length in T. japonicum. However, there were no significant correlations between morphological indexes and indexes of parasitism in T. ostriniae. Overall, the parasitic abilities of T. chilonis on S. frugiperda eggs were significantly correlated with the morphology of the female ovipositors.

Neural energy computations based on Hodgkin-Huxley models bridge abnormal neuronal activities and energy consumption patterns of major depressive disorder.

Limited by the current experimental techniques and neurodynamical models, the dysregulation mechanisms of decision-making related neural circuits in major depressive disorder (MDD) are still not clear. In this paper, we proposed a neural coding methodology using energy to further investigate it, which has been proven to strongly complement the neurodynamical methodology. We augmented the previous neural energy calculation method, and applied it to our VTA-NAc-mPFC neurodynamical H-H models. We particularly focused on the peak power and energy consumption of abnormal ion channel (ionic) currents under different concentrations of dopamine input, and investigated the abnormal energy consumption patterns for the MDD group. The results revealed that the energy consumption of medium spiny neurons (MSNs) in the NAc region were lower in the MDD group than that of the normal control group despite having the same firing frequencies, peak action potentials, and average membrane potentials in both groups. Dopamine concentration was also positively correlated with the energy consumption of the pyramidal neurons, but the patterns of different interneuron types were distinct. Additionally, the ratio of mPFC's energy consumption to total energy consumption of the whole network in MDD group was lower than that in normal control group, revealing that the mPFC region in MDD group encoded less neural information, which matched the energy consumption patterns of BOLD-fMRI results. It was also in line with the behavioral characteristics that MDD patients demonstrated in the form of reward insensitivity during decision-making tasks. In conclusion, the model in this paper was the first neural network energy computational model for MDD, which showed success in explaining its dynamical mechanisms with an energy consumption perspective. To build on this, we demonstrated that energy consumption levels can be used as a potential indicator for MDD, which also showed a promising pipeline to use an energy methodology for studying other neuropsychiatric disorders.

Extracting Venom from the Parasitoid Wasp Trichogramma dendrolimi using an Artificial Host.

Parasitoid wasps are a diverse group of hymenopteran insects that serve as invaluable resources for pest biocontrol. To ensure successful parasitism, parasitoid wasps inject venom into their hosts to suppress their hosts' immunity, modulate hosts' development, metabolism, and even behavior. With over 600,000 estimated species, the diversity of parasitoid wasps surpasses that of other venomous animals, such as snakes, cone snails, and spiders. Parasitoid wasp venom is an underexplored source of bioactive molecules with potential applications in pest control and medicine. However, collecting parasitoid venom is challenging due to the inability to use direct or electrical stimulation and the difficulty in dissection because of their small size. Trichogramma is a genus of tiny (~0.5 mm) egg parasitoid wasps that are widely used for the biological control of lepidopteran pests in both agriculture and forests. Here, we report a method for extracting venom from T. dendrolimi using artificial hosts. These artificial hosts are created with polyethylene film and amino acid solutions and then inoculated with Trichogramma wasps for parasitism. The venom was subsequently collected and concentrated. This method enables the extraction of large amounts of Trichogramma venom while avoiding contamination from other tissues caused by dissection, a common issue in venom reservoir dissection protocols. This innovative approach facilitates the study of Trichogramma venom, paving the way for new research and potential applications.

Molecular basis of ClC-6 function and its impairment in human disease.

ClC-6 is a late endosomal voltage-gated chloride-proton exchanger that is predominantly expressed in the nervous system. Mutated forms of ClC-6 are associated with severe neurological disease. However, the mechanistic role of ClC-6 in normal and pathological states remains largely unknown. Here, we present cryo-EM structures of ClC-6 that guided subsequent functional studies. Previously unrecognized ATP binding to cytosolic ClC-6 domains enhanced ion transport activity. Guided by a disease-causing mutation (p.Y553C), we identified an interaction network formed by Y553/F317/T520 as potential hotspot for disease-causing mutations. This was validated by the identification of a patient with a de novo pathogenic variant p.T520A. Extending these findings, we found contacts between intramembrane helices and connecting loops that modulate the voltage dependence of ClC-6 gating and constitute additional candidate regions for disease-associated gain-of-function mutations. Besides providing insights into the structure, function, and regulation of ClC-6, our work correctly predicts hotspots for CLCN6 mutations in neurodegenerative disorders.

Protocol for identifying immune checkpoint on circulating tumor cells of human pancreatic ductal adenocarcinoma by single-cell RNA sequencing.

Circulating tumor cells (CTCs) are regarded as the "seeds" of tumor metastasis. Identifying immune checkpoints on CTCs is essential for establishing efficient immunotherapies to prevent tumor metastasis. Here, we present a protocol for isolating CTCs and obtaining single-cell suspensions from pancreatic ductal adenocarcinoma liver metastatic patients. We describe steps for biospecimen acquisition, CTC isolation, and tissue dissociation. We then detail procedures for performing single-cell RNA-seq, annotating cell types, and identifying immune checkpoints on CTCs. For complete details on the use and execution of this protocol, please refer to Liu et al. (2023).1.

The Management and Antithrombotic Strategies of Patients with Coronary Artery Disease and High Bleeding Risk.

PURPOSE OF REVIEW: In this review, we aim to summarize the current understanding of high bleeding risk (HBR) patients in coronary artery disease (CAD) and provide a comprehensive evaluation of the available antithrombotic strategies for both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) procedures. RECENT FINDINGS: CAD is a major cause of mortality among cardiovascular diseases, resulting from insufficient blood flow in the coronary artery due to atherosclerosis. Antithrombotic therapy is a crucial component of drug therapy for CAD and multiple studies had been focusing on the optimal antithrombotic strategies of different CAD populations. However, there is no fully harmonized definition of the model of bleeding, and the optimal antithrombotic strategy for such patients at HBR is inconclusive. In this review, we summarize bleeding risk stratification models for CAD patients and discuss the de-escalation of antithrombotic strategies among HBR patients. Furthermore, we realize that for certain subgroups of CAD-HBR patients, more individualized and precise antithrombotic strategy development is needed. So, we highlight special populations, such as CAD patients combined with valvular diseases, with both high ischemia and bleeding risks, and those proceeding surgical treatment, which requires greater research attention. We note that de-escalating therapy for CAD-HBR patients is an emerging trend in managing this population, but the optimal antithrombotic strategies should be re-considered according to the patient's baseline characteristics.

Post-translational modifications of soluble α-synuclein regulate the amplification of pathological α-synuclein.

Cell-to-cell transmission and subsequent amplification of pathological proteins promote neurodegenerative disease progression. Most research on this has focused on pathological protein seeds, but how their normal counterparts, which are converted to pathological forms during transmission, regulate transmission is less understood. Here we show in cultured cells that phosphorylation of soluble, nonpathological α-synuclein (α-Syn) at previously identified sites dramatically affects the amplification of pathological α-Syn, which underlies Parkinson's disease and other α-synucleinopathies, in a conformation- and phosphorylation site-specific manner. We performed LC-MS/MS analyses on soluble α-Syn purified from Parkinson's disease and other α-synucleinopathies, identifying many new α-Syn post-translational modifications (PTMs). In addition to phosphorylation, acetylation of soluble α-Syn also modified pathological α-Syn transmission in a site- and conformation-specific manner. Moreover, phosphorylation of soluble α-Syn could modulate the seeding properties of pathological α-Syn. Our study represents the first systematic analysis how of soluble α-Syn PTMs affect the spreading and amplification of pathological α-Syn, which may affect disease progression.

Direct and indirect effects of banker plants on population establishment of Harmonia axyridis and aphid control on pepper crop.

Banker plant systems increase biological pest control by supporting populations of natural enemies, i.e., using non-pest arthropod species as alternative prey. However, the presence of alternative prey does not always result in improved control of the target pest species owing to the complexity of biotic interactions. To increase the effectiveness of banker plants in IPM programs, a fine understanding of the indirect interactions between target aphid and alternative prey mediated by biocontrol agents is necessary. In this study, we first established a banker plant system, banker plant (Vicia faba)-alternative prey (Megoura japonica)-predator (Harmonia axyridis), to control the target pest (Myzus persicae) on pepper. We found that M. japonica strongly preferred faba bean as a host plant and posed no risk to Solanaceous crops. Harmonia axyridis adults had no significant predation preference for the alternative prey. In the short term, the interaction direction of the two aphid species depended on the relative initial density and the timescale. Harmonia axyridis showed a stronger negative effect on M. persicae than that on M. japonica. In the long term, the presence of alternative prey, M. japonica, enhanced the control effect of H. axyridis to M. persicae with initial density of 100-500 aphids per plant. The presence of the alternative prey could proliferate the population of H. axyridis, with from 0.2- to 2.1-fold increase of H. axyridis eggs. Overall, we put forward a strategy for setting the initial density of alternative prey of the banker plant system to target the high and low density of aphids, which highlighted the importance of indirect interactions in designing a proper banker plant system.

Development of a quadruple PCR-based gene microarray for detection of vaccine and wild-type classical swine fever virus, African swine fever virus and atypical porcine pestivirus.

BACKGROUND: Classical swine fever (CSF), African swine fever (ASF), and atypical porcine pestivirus (APPV) are acute, virulent, and contagious viral diseases currently hampering the pig industry in China, which result in mummification or stillbirths in piglets and mortality in pigs. Diagnostic assays for the differentiation of infection and vaccination of CSFV, in addition to the detection of ASFV and APPV, are urgently required for better prevention, control, and elimination of these viral diseases in China. METHODS: A quadruple PCR-based gene microarray assay was developed in this study to simultaneously detect wild-type and vaccine CSFV strains, ASFV and APPV according to their conserved regions. Forty-two laboratory-confirmed samples, including positive samples of 10 other swine viral diseases, were tested using this assay to confirm its high specificity. RESULTS: This assay's limit of detections (LODs) for the wild-type and vaccine CSFV were 6.98 and 6.92 copies/µL. LODs for ASFV and APPV were 2.56 × 10 and 1.80 × 10 copies/µL, respectively. When compared with standard RT-PCR or qPCR for CSFV (GB/T 26875-2018), ASFV (MARR issue No.172), or APPV (CN108611442A) using 219 clinical samples, the coincidence was 100%. The results showed that this assay with high sensitivity could specifically distinguish ASFV, APPV, and CSFV, including CSFV infection and immunization. CONCLUSION: This assay provides a practical, simple, economic, and reliable test for the rapid detection and accurate diagnosis of the three viruses and may have good prospects for application in an epidemiological investigation, prevention, and control and elimination of these three diseases.

Dopamine-Mediated Major Depressive Disorder in the Neural Circuit of Ventral Tegmental Area-Nucleus Accumbens-Medial Prefrontal Cortex: From Biological Evidence to Computational Models.

Major depressive disorder (MDD) is a serious psychiatric disorder, with an increasing incidence in recent years. The abnormal dopaminergic pathways of the midbrain cortical and limbic system are the key pathological regions of MDD, particularly the ventral tegmental area- nucleus accumbens- medial prefrontal cortex (VTA-NAc-mPFC) neural circuit. MDD usually occurs with the dysfunction of dopaminergic neurons in VTA, which decreases the dopamine concentration and metabolic rate in NAc/mPFC brain regions. However, it has not been fully explained how abnormal dopamine concentration levels affect this neural circuit dynamically through the modulations of ion channels and synaptic activities. We used Hodgkin-Huxley and dynamical receptor binding model to establish this network, which can quantitatively explain neural activity patterns observed in MDD with different dopamine concentrations by changing the kinetics of some ion channels. The simulation replicated some important pathological patterns of MDD at the level of neurons and circuits with low dopamine concentration, such as the decreased action potential frequency in pyramidal neurons of mPFC with significantly reduced burst firing frequency. The calculation results also revealed that NaP and KS channels of mPFC pyramidal neurons played key roles in the functional regulation of this neural circuit. In addition, we analyzed the synaptic currents and local field potentials to explain the mechanism of MDD from the perspective of dysfunction of excitation-inhibition balance, especially the disinhibition effect in the network. The significance of this article is that we built the first computational model to illuminate the effect of dopamine concentrations for the NAc-mPFC-VTA circuit between MDD and normal groups, which can be used to quantitatively explain the results of existing physiological experiments, predict the results for unperformed experiments and screen possible drug targets.

Early Detection and Identification of Parasitoid Wasps Trichogramma Westwood (Hymenoptera: Trichogrammatidae) in Their Host Eggs Using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism.

Parasitoid wasps are invaluable agents in pest biological control. Early detection and identification of parasitoid immatures are vital in characterizing parasitoid-host interactions and for evaluating parasitism rates accurately in the field. Trichogramma is the most widely used parasitoid wasp, and several studies have been performed for its molecular identification. However, those studies were mainly focused on Trichogramma adults and rarely on immatures. Here, we report a method to detect and identify Trichogramma larvae in their host eggs. We designed a pair of Trichogramma-specific primers that amplified Trichogramma mtCOI sequences from Corcyra cephalonica (Stainton) eggs parasitized by any of eight Trichogramma species tested but not from nonparasitized eggs of four lepidopteran hosts. This PCR method reliably detected Trichogramma immatures in parasitized eggs as early as 1 h after parasitism. We further developed an RFLP (restriction fragment length polymorphism) assay using restriction enzymes SspI and VspI to differentiate eight Trichogramma species at their immature stage. Overall, we developed a sensitive and reliable PCR-RFLP method to detect and identify immature-stage Trichogramma in their lepidopteran hosts. This method shows promise for conveniently identifying Trichogramma in insectaries and accurately evaluating parasitism rates in the field.

Mitochondrial Genomes of Two Asexual Trichogramma (Hymenoptera: Trichogrammatidae) Strains and Comparison with Their Sexual Relatives.

Despite its substantial costs, sexual reproduction dominates in animals. One popular explanation for the paradox of sex is that asexual reproduction is more likely to accumulate deleterious mutations than sexual reproduction. To test this hypothesis, we compared the mitogenomes of two asexual wasp strains, Trichogramma cacoeciae and T. pretiosum, to their sexual relatives. These two asexual strains represent two different transition mechanisms in Trichogramma from sexual to asexual reproduction. Asexual T. pretiosum is induced by Wolbachia, while T. cacoeciae presumably originated from interspecific hybridization. We sequenced and assembled complete mitochondrial genomes of asexual T. cacoeciae and T. pretiosum. Compared to four sexual relatives, we found no evidence of higher mutation accumulation in asexual Trichogramma mitogenomes than in their sexual relatives. We also did not detect any relaxed selection in asexual Trichogramma mitogenomes. In contrast, the intensified selection was detected in Nad1 and Nad4 of the asexual T. pretiosum mitogenome, suggesting more purifying selection. In summary, no higher mitochondrial mutation accumulation was detected in these two asexual Trichogramma strains. This study provides a basis for further investigating mitochondrial evolution and asexual reproduction in Trichogramma.

Application of artificial intelligence to the public health education.

With the global outbreak of coronavirus disease 2019 (COVID-19), public health has received unprecedented attention. The cultivation of emergency and compound professionals is the general trend through public health education. However, current public health education is limited to traditional teaching models that struggle to balance theory and practice. Fortunately, the development of artificial intelligence (AI) has entered the stage of intelligent cognition. The introduction of AI in education has opened a new era of computer-assisted education, which brought new possibilities for teaching and learning in public health education. AI-based on big data not only provides abundant resources for public health research and management but also brings convenience for students to obtain public health data and information, which is conducive to the construction of introductory professional courses for students. In this review, we elaborated on the current status and limitations of public health education, summarized the application of AI in public health practice, and further proposed a framework for how to integrate AI into public health education curriculum. With the rapid technological advancements, we believe that AI will revolutionize the education paradigm of public health and help respond to public health emergencies.

Chinese Patent Medicine as Adjuvant for Mild-to-Moderate Active Ulcerative Colitis: A Network Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To evaluate the effectiveness and safety of Chinese patent medicine for mild-to-moderate active ulcerative colitis (UC) using network meta-analysis (NMA). METHODS: We systematically searched PubMed, Cochrane library, Embase, Sino-Med, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Scientific Journal Database (VIP) databases to October, 2020. We included randomized controlled trials (RCTs) on Chinese patent medicine for mild-to-moderate active UC. The main analysis was complemented by network subanalyses and standard pairwise comparisons. Statistical heterogeneity, inconsistencies, and ranking probability were also evaluated. RESULTS: The databases search identified 3222 citations, of which 33 RCTs involving 2971 patients met the inclusion criteria. A total of 15 Chinese patent medicines were analyzed. The overall quality of the included studies was low. Pairwise meta-analysis showed that Chinese patent medicine was superior to Mesalazine in improving disappearances of clinical symptoms, recurrence rate, and Mayo score. Based on decreases in adverse events, results from NMA showed that Xilei powder plus Mesalazine was more effective than other drugs. Other NMA results indicated that Danshen freeze-dried powder plus Mesalazine (RR: 0.13; 95% CI, 0.02-0.78) and Kangfuxin lotion plus Mesalazine (RR: 0.24; 95% CI, 0.07-0.57) were superior to Mesalazine in decreasing recurrence rate. Another NMA result indicated that Kangfuxin lotion plus Mesalazine (RR: 0.00; 95% CI, 0.00-0.02) and Zhi Kang capsule plus Mesalazine (RR: 0.00; 95% CI, 0.00-0.02) were superior to Mesalazine in increasing the disappearance of tenesmus. CONCLUSION: In the probability sorting, Xilei powder combined with Mesalazine ranked first for having the fewest adverse events, Maintaining Intestines Antidiarrheal Pills combined with Mesalazine ranked first for having the lowest recurrence rate, Xilei powder combined with Mesalazine ranked first for improving disappearance rate of mucopurulent bloody stool/abdominal pain, and Kangfuxin lotion combined with Mesalazine ranked first for improving the disappearance rate of diarrhea/tenesmus. However, there is a lack of direct comparisons among Chinese patent medicines for UC. More multiarm RCTs are needed in the future to provide direct comparative evidence.

ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation.

Inducible regulatory T (iTreg) cells play a central role in immune suppression. As iTreg cells are differentiated from activated T (Th0) cells, cell metabolism undergoes dramatic changes, including a shift from fatty acid synthesis (FAS) to fatty acid oxidation (FAO). Although the reprogramming in fatty acid metabolism is critical, the mechanism regulating this process during iTreg differentiation is still unclear. Here we have revealed that the enzymatic activity of ATP-citrate lyase (ACLY) declined significantly during iTreg differentiation upon transforming growth factor ß1 (TGFß1) stimulation. This reduction was due to CUL3-KLHL25-mediated ACLY ubiquitination and degradation. As a consequence, malonyl-CoA, a metabolic intermediate in FAS that is capable of inhibiting the rate-limiting enzyme in FAO, carnitine palmitoyltransferase 1 (CPT1), was decreased. Therefore, ACLY ubiquitination and degradation facilitate FAO and thereby iTreg differentiation. Together, we suggest TGFß1-CUL3-KLHL25-ACLY axis as an important means regulating iTreg differentiation and bring insights into the maintenance of immune homeostasis for the prevention of immune diseases.

Computer-assisted ultrasound assessment of plaque characteristics in radiation-induced and non-radiation-induced carotid atherosclerosis.

BACKGROUND: This study investigated the feasibility of using a computer-assisted method to evaluate and differentiate the carotid plaque characteristics in radiation-induced and non-radiation-induced carotid atherosclerosis. METHODS: This study included 107 post-radiotherapy (post-RT) nasopharyngeal carcinoma (NPC) patients and 110 subjects with cardiovascular risk factors (CVRFs). Each participant had a carotid ultrasound examination, and carotid plaques and carotid intima-media thickness (CIMT) were evaluated with grey scale ultrasound. The carotid plaque characteristics were evaluated for grey-scale median (GSM) and detailed plaque texture analysis (DPTA) using specific computer software. In DPTA, five different intra-plaque components were colour-coded according to different grey scale ranges. A multivariate linear regression model was used to evaluate the correlation of risk factors and carotid plaque characteristics. RESULTS: Post-RT NPC patients have significantly higher CIMT (748±15.1 µm, P=0.001), more patients had a plaque formation (80.4%, P<0.001) and more plaque locations (2.3±0.2, P<0.001) than CVRF subjects (680.4±10.0 µm, 38.2% and 0.5±0.1 respectively). Among the five intra-plaque components, radiation-induced carotid plaques had significantly larger area of calcification (4.8%±7.7%, P=0.012), but lesser area of lipid (42.1%±16.9%, P=0.034) when compared to non-radiation-induced carotid plaques (3.0%±5.7% and 46.3%±17.9% respectively). Age, radiation and number of CVRF were significantly associated with the carotid atherosclerosis burden (P<0.001). Besides, age was significantly associated with the amount of lipid and calcification within carotid plaques (P<0.001). CONCLUSIONS: Radiation caused more severe carotid artery disease than CVRF with larger CIMT and more prevalent of carotid plaque. Radiation-induced carotid plaques tended to have more intra-plaque calcifications, whereas non-radiation-induced carotid plaques had more lipids. Ultrasound aided by computer-assisted image analysis has potential for more accurate assessment of carotid atherosclerosis.