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.

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.

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.

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.

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.

Modelling and analysing the dynamics of disease progression from cross-sectional studies.

Clinical trials are typically conducted over a population within a defined time period in order to illuminate certain characteristics of a health issue or disease process. These cross-sectional studies give us a 'snapshot' of this disease process over a large number of people but do not allow us to model the temporal nature of disease, thereby allowing for modelling detailed prognostic predictions. The aim of this paper is to explore an extension of the temporal bootstrap to identify intermediate stages in a disease process and sub-categories of the disease exhibiting subtly different symptoms. Our approach is compared to a strawman method and investigated in its ability to explain the dynamics of progression on biomedical data from three diseases: Glaucoma, Breast Cancer and Parkinson's disease. We focus on creating reliable time-series models from large amounts of historical cross-sectional data using the temporal bootstrap technique. Two issues are explored: how to build time-series models from cross-sectional data, and how to automatically identify different disease states along these trajectories, as well as the transitions between them. Our approach of relabeling trajectories allows us to explore the temporal nature of how diseases progress even when time-series data is not available (if the cross-sectional study is large enough). We intend to expand this research to deal with multiple studies where we can combine both cross-sectional and longitudinal datasets and to focus on the junctions of the trajectories as key stages in the progression of disease.

[Role of AT2 receptors on angiotensin II-induced tumor necrosis factor alpha and interleukin 1 beta secretion in adult rat cardiac fibroblasts].

OBJECTIVE: To investigate the role of AT2 receptors in the secretion of tumor necrosis factor alpha (alpha-TNF) and interleukin 1 beta (IL1 beta) in adult rat cardiac fibroblasts. METHODS: Adult rat cardiac fibroblasts in in vitro culture were divided into control, Ang II, AngII + Losartan, and AngII + PD123319 groups with corresponding treatments. Radioimmunoassay was used to determine alpha-TNF and IL1 beta levels in the supernatant of the treated cardiac fibroblasts. RESULTS: Ang II treatment resulted in significantly increased alpha-TNF and IL1 beta levels. Compared with AngII group, IL1 beta level was decreased by 69.1% and 78.7% and alpha-TNF by 58.7% and 65.9% after blocking AT1 and AT2 receptors, respectively. CONCLUSION: AT2 receptors are involved in alpha-TNF and IL1 beta secretions in cardiac fibroblasts.