LLM-Twin: mini-giant model-driven beyond 5G digital twin networking framework with semantic secure communication and computation.

Beyond 5G networks provide solutions for next-generation communications, especially digital twins networks (DTNs) have gained increasing popularity for bridging physical and digital space. However, current DTNs pose some challenges, especially when applied to scenarios that require efficient and multimodal data processing. Firstly, current DTNs are limited in communication and computational efficiency, since they require to transmit large amounts of raw data collected from physical sensors, as well as to ensure model synchronization through high-frequency computation. Second, current models of DTNs are domain-specific (e.g. E-health), making it difficult to handle DT scenarios with multimodal data processing requirements. Finally, current security schemes for DTNs introduce additional overheads that impair the efficiency. Against the above challenges, we propose a large language model (LLM) empowered DTNs framework, LLM-Twin. First, based on LLM, we propose digital twin semantic networks (DTSNs), which enable more efficient communication and computation. Second, we design a mini-giant model collaboration scheme, which enables efficient deployment of LLM in DTNs and is adapted to handle multimodal data. Then, we designed a native security policy for LLM-twin without compromising efficiency. Numerical experiments and case studies demonstrate the feasibility of LLM-Twin. To our knowledge, this is the first to propose an LLM-based semantic-level DTNs.

PI4P-mediated solid-like Merlin condensates orchestrate Hippo pathway regulation.

Despite recent studies implicating liquid-like biomolecular condensates in diverse cellular processes, many biomolecular condensates exist in a solid-like state, and their function and regulation are less understood. We show that the tumor suppressor Merlin, an upstream regulator of the Hippo pathway, localizes to both cell junctions and medial apical cortex in Drosophila epithelia, with the latter forming solid-like condensates that activate Hippo signaling. Merlin condensation required phosphatidylinositol-4-phosphate (PI4P)-mediated plasma membrane targeting and was antagonistically controlled by Pez and cytoskeletal tension through plasma membrane PI4P regulation. The solid-like material properties of Merlin condensates are essential for physiological function and protect the condensates against external perturbations. Collectively, these findings uncover an essential role for solid-like condensates in normal physiology and reveal regulatory mechanisms for their formation and disassembly.

Spatial multiomics reveals a subpopulation of fibroblasts associated with cancer stemness in human hepatocellular carcinoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are the prominent cell type in the tumor microenvironment (TME), and CAF subsets have been identified in various tumors. However, how CAFs spatially coordinate other cell populations within the liver TME to promote cancer progression remains unclear. METHODS: We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays. RESULTS: We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells. CONCLUSIONS: We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells.

Association between dietary fiber intake and kidney stones: results from the National Health and Nutrition Examination Survey (2011-2018).

BACKGROUND/OBJECTIVES: Studies on the impact of dietary fiber intake on kidney stones are few, and their results were controversial. This study aimed to explore the association between dietary fiber intake and kidney stones in the nationally representative population of the USA. SUBJECTS/METHODS: This cross-sectional research included 8,588 participants from the National Health and Nutrition Examination Survey, 2011 to 2018. Information regarding dietary fiber intake was obtained from a 24-h recall survey. Participants were categorized into different dietary fiber intake tertiles according to the average of 2 days of dietary recall data. The outcome was self-reported kidney stones. After adjusting for the traditional risk factors, a multivariate logistic regression model was used to examine the association between dietary fiber intake and kidney stones. RESULTS: Eight hundred seventy-two participants had kidney stones. The weighted prevalence (SE) of kidney stones in the lowest tertile, medium tertile, and highest tertile of dietary fiber intake was 11.8% (0.8%), 10.3% (0.8%), and 9.1% (0.8%), respectively. After adjusting for age, sex, race and ethnicity, education level, smoking status, alcohol consumption, physical activity, body mass index, hypertension, diabetes, dyslipidemia, daily water intake, chronic kidney disease stage 3-5, and total energy intake, participants with the highest tertile of fiber intake had a significantly lower risk of kidney stones (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.48-0.95) compared to those in the lowest tertile. Every 5 g/day increment in dietary fiber intake was associated with a significant decrease in risk of kidney stones (OR, 0.90; 95% CI, 0.83-0.98). CONCLUSION: An increase in dietary fiber intake was associated with a lower risk of kidney stones, suggesting adults should be encouraged to maintain an adequate dietary fiber intake to prevent the development of kidney stones. Our results provide evidence to formulate nutrition management strategies for the prevention of kidney stones.

Development of novel humanized CD19/BAFFR bicistronic chimeric antigen receptor T cells with potent antitumor activity against B-cell lineage neoplasms.

Chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable efficacy in treating advanced B-cell malignancies by targeting CD19, but antigen-negative relapses and immune responses triggered by murine-derived antibodies remain significant challenges, necessitating the development of novel humanized multitarget CAR-T therapies. Here, we engineered a second-generation 4-1BB-CD3ζ-based CAR construct incorporating humanized CD19 single-chain variable fragments (scFvs) and BAFFR single-variable domains on heavy chains (VHHs), also known as nanobodies. The resultant CAR-T cells, with different constructs, were functionally compared both in vitro and in vivo. We found that the optimal tandem and bicistronic (BI) structures retained respective antigen-binding abilities, and both demonstrated specific activation when stimulated with target cells. At the same time, BI CAR-T cells (BI CARs) exhibited stronger tumour-killing ability and better secretion of interleukin-2 and tumour necrosis factor-alpha than single-target CAR-T cells. Additionally, BI CARs showed less exhaustion phenotype upon repeated antigen stimulation and demonstrated more potent and persistent antitumor effects in mouse xenograft models. Overall, we developed a novel humanized CD19/BAFFR bicistronic CAR (BI CAR) based on a combination of scFv and VHH, which showed potent and sustained antitumor ability both in vitro and in vivo, including against tumours with CD19 or BAFFR deficiencies.

Regulatory T cells inhibit FoxP3 to increase the population of tumor initiating cells in hepatocellular carcinoma.

PURPOSE: Tumor initiating cells (TICs) or cancer stem cells (CSCs) are considered to be the main culprit of hepatocellular carcinoma (HCC) initiation and progression, nevertheless the mechanism by which tumor microenvironment maintains the HCC 'stemness' is not fully understood. This study aims to investigate the effect of regulatory T cells (Tregs) on the TICs characteristics of HCC. METHODS: Immunocytochemistry, flow cytometry, real-time PCR, western blot, in vitro sphere-formation, and in vivo tumorigenesis assay were used to detect HCC 'stemness'. Additionally, after forced expression or inhibition of FoxP3, ß-catenin expression and HCC 'stemness' were investigated. RESULTS: Tregs enhanced the 'stemness' of HCC cells by upregulating TIC-related markers CD133, Oct3/4, Sox2, c-Myc, Klf4, Nanog, CD13, EpCAM, and inducting epithelial to mesenchymal transition (EMT), increasing TICs ratio, as well as promoting tumorigenic ability. Moreover, ß-catenin and c-Myc were upregulated in HCC cells after co-cultured with Tregs. HCC 'stemness' was inhibited after treatment with Wnt/ß-catenin pathway inhibitor. Furthermore, forced expression of FoxP3 resulted in increased GSK3ß, decreased ß-catenin and TIC ratio in HCC. In contrast, FoxP3 interference reduced GSK3ß, enhanced ß-catenin and TIC ratio of HCC. CONCLUSION: This study, for the first time, demonstrated that Tregs increased the population of TICs in HCC by inhibiting FoxP3 as well as promoting ß-catenin expression.

[Research progress on biological characteristics and propagation technology of Atractylodes lancea].

Atractylodes lancea is a perennial herb of the Asteraceae family and is one of the well-known traditional Chinese medicine(TCM). Several studies have documented polyene alkyne and sesquiterpenoid compounds as the main bioactive compounds of A. lancea, especially atractylodin, atractylon, ß-eudesmol, and hinesol in its rhizomes, which possess anti-virus, anti-inflammation, hypoglycemic, anti-hypoxia, liver protection, and diuresis activities. In parallel with the recent advancements in biotechnology, important achievements have been made in the study of biological characteristics and propagation technology of A. lancea. This study reviews the research progress on morphological features, cytogenetics, ecological planting, effective ingredients, and tissue culture techniques of A. lancea from the biology perspective, so as to provide a theoretical basis for reasonable development of A. lancea resources.

Diosgenin alleviates arsenic trioxide induced cardiac fibrosis by inhibiting endothelial mesenchymal transition.

BACKGROUD: Arsenic trioxide (ATO), the first-line drug in treating acute premyelogenous leukemia, has the profound side effect of inducing endothelial mesenchymal transition (EndMT) and causing cardiac fibrosis. Diosgenin (DIO), a pharmaceutical compound found in Paris polyphylla, exhibits promising potential in safeguarding cardiovascular health by mitigating EndMT. PURPOSE: This study aims to explore the role and mechanism of DIO in ATO-induced myocardial fibrosis to provide a novel therapeutic agent for ATO-induced cardiac fibrosis. METHODS: Wistar rats were given DIO by gavage and ATO by tail vein. Cardiac function and fibrosis were evaluated by echocardiography and Masson's trichrome staining in rats. Human aortic endothelial cells (HAECs) were utilized to analyze ATO-induced EndMT in vitro. The cytoskeleton of HAECs was visualized using F-actin staining to observe cell morphology, while Dil-Ac-LDL staining was employed to assess cell functionality. EndMT-related factors (CD31 and α-SMA), glucocorticoid receptor (GR) and interleukin-6 (IL-6) were detected by immunofluorescence and Western blot in vivo and in vitro. Furthermore, GR was knocked down by si-GR, and IL-6 was blocked by IL-6 neutralizing antibody to verify their role in the effect of DIO on ATO-induced EndMT in HAECs. RESULTS: DIO exhibited significant efficacy in ATO-induced damage to both cardiac diastolic and systolic function, along with mitigating cardiac fibrosis. Additionally, DIO alleviated the loss of cytoskeletal anisotropy and enhanced the uptake of Dil-Ac-LDL in HAECs. Furthermore, it reversed the ATO-induced downregulation of endothelial-specific markers CD31 and GR, while suppressing the upregulation of mesenchymal markers α-SMA and IL-6, both in vivo and in vitro. Notably, the protective effect of DIO was compromised upon knockdown of GR, which also led to a reversal of DIO-induced IL-6 downregulation. Furthermore, the neutralization of IL-6 with specific antibodies abolished the ATO-induced changes related to EndMT. CONCLUSION: In this study, we clarified the protective effect of DIO on ATO-induced myocardial fibrosis against EndMT via the GR/IL-6 axis for the first time and provided a potential therapeutic agent for preventing heart damage caused by ATO.

Platelet indices and inflammatory bowel disease: a Mendelian randomization study.

Background: Platelets play a significant role in the innate and adaptive processes of immunity and inflammation. Inflammatory bowel disease (IBD) is an autoimmune disease that is widely understood to be caused by a combination of genetic predisposition, aberrant immune responses, etc. Methods: To examine the relationships between genetically determined platelet indices and IBD, we conducted a Mendelian randomization (MR) study. Data associated with platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT) were used from the UK Biobank. The outcome data, including IBD, Crohn's disease (CD), ulcerative colitis (UC), were from the FinnGen database. The inverse variance-weighted (IVW), MR-Egger, weighted median methods were used for MR analyses. Results: The MR estimations from the IVW approach show a significant connection between PLT and IBD. Similarly, PCT and IBD have a relationship following the IVW and MR-Egger approaches. While PLT and PCT have strong relationships with CD, according to the findings of all three approaches respectively. Nevertheless, PDW was the only relevant indicator of UC. The only significant result was IVW's. Conclusion: Our findings suggest that the fluctuation of platelet indicators is of great significance in the development of IBD. PLT and PCT have a close association with IBD and CD, respectively; PDW only has a connection with UC. Platelets play an important role in the progression of IBD (UC, CD).

Escitalopram moderately outperforms citalopram towards anti-neuroinflammation and neuroprotection in 6-hydroxydopamine-induced mouse model of Parkinson's disease.

Citalopram and escitalopram are structurally close-related antidepressants and both forms are widely used in the world. We aimed to comparatively evaluate the anti-neuroinflammatory and neuroprotective effects of escitalopram and citalopram in Parkinson's disease (PD) mouse model. Mice were randomly divided into six groups and received 6-hydroxydopamine (6-OHDA) or vehicle administration. The mice were then treated with escitalopram, citalopram or saline for consecutive 7 days. Behaviors, neuroinflammation, neurotransmitters, and neurotoxicity were assessed. Results showed that citalopram but not escitalopram worsened body weight loss and increased freezing time in the PD mice. Both drugs had no impact on the anxiety-like behaviors but ameliorated the depressive-like behaviors as in elevated plus maze and sucrose splash tests. Escitalopram but not citalopram ameliorated motor discoordination in the PD mice as in rotarod test. In accordance, escitalopram but not citalopram attenuated the 6-OHDA-induced nigrostriatal dopaminergic loss. Further mechanistic investigations showed that both drugs mitigated activations of microglia and astrocytes and/or levels of pro-inflammatory cytokines in the PD mice, but escitalopram showed appreciably better effects in the substantia nigra. Neurotransmitter examination in the prefrontal cortex suggested that the two drugs had comparable effects on the disturbed neurotransmitters in the PD mice, but citalopram was prone to disrupt certain normal homeostasis. In conclusion, escitalopram is moderately superior than citalopram to suppress neuroinflammation and to protect against dopaminergic neuronal death and motor discoordination in the 6-OHDA-induced PD mice. Our findings imply that escitalopram shall be prescribed with priority over citalopram to treat PD patients with depression as escitalopram may meanwhile provide greater additional benefits to the patients.

Enhanced cadmium removal by a magnetic potassium ferrocyanide framework: Performance and mechanism study.

Polluted environments often contain large amounts of toxic metals, such as cadmium, which pose a major threat to ecosystems and public health. Contamination by cadmium and its compounds is often observed in areas surrounding zinc mining sites and electroplating factories, and the control of cadmium pollution is essential for environmental safety and health. In this study, a highly efficient and straightforward separation strategy for K4Fe(CN)6@Fe3O4 nanocomposites is successfully developed to capture the Cd ions in the water environment. Batch adsorption experiments revealed that K4Fe(CN)6@Fe3O4 exhibited a high cadmium removal rate (greater than 98 %) at a pH level of 6.0 and solid-liquid ratio of 1.0 g/L at room temperature (298 K). Kinetic analysis revealed that the adsorption process followed a pseudo-second-order model and cadmium was rapidly removed in the first 10 min, with chemisorption dominating the capture of Cd2+ by K4Fe(CN)6@Fe3O4. Adsorption isotherms revealed a heterogeneous adsorption behavior, with a maximum adsorption capacity of 40.78 mg/g. The intrinsic adsorption of Cd2+ by K4Fe(CN)6@Fe3O4 occurring primarily through electrostatic interaction and ion exchange. In addition, K4Fe(CN)6@Fe3O4 exhibited an excellent regeneration capacity. Therefore, integrating Fe3O4 into the metal cyanide not only provided the composite material with excellent chemical stability and selective adsorption sites for Cd2+, but also facilitated subsequent sorbent collection and recovery. Overall, this study presents a simple and feasible approach for integrating Fe3O4 into potassium ferrocyanide frameworks for efficient cadmium removal from contaminated water.

Exosomes derived from human urine-derived stem cells ameliorate IL-1ß-induced intervertebral disk degeneration.

BACKGROUND: Human intervertebral disk degeneration (IVDD) is a sophisticated degenerative pathological process. A key cause of IVDD progression is nucleus pulposus cell (NPC) degeneration, which contributes to excessive endoplasmic reticulum stress in the intervertebral disk. However, the mechanisms underlying IVDD and NPC degeneration remain unclear. METHODS: We used interleukin (IL)-1ß stimulation to establish an NPC-degenerated IVDD model and investigated whether human urine-derived stem cell (USC) exosomes could prevent IL-1ß-induced NPC degeneration using western blotting, quantitative real-time polymerase chain reaction, flow cytometry, and transcriptome sequencing techniques. RESULTS: We successfully extracted and identified USCs and exosomes from human urine. IL-1ß substantially downregulated NPC viability and induced NPC degeneration while modulating the expression of SOX-9, collagen II, and aggrecan. Exosomes from USCs could rescue IL-1ß-induced NPC degeneration and restore the expression levels of SOX-9, collagen II, and aggrecan. CONCLUSIONS: USC-derived exosomes can prevent NPCs from degeneration following IL-1ß stimulation. This finding can aid the development of a potential treatment strategy for IVDD.

Berberine as a novel ACSL4 inhibitor to suppress endothelial ferroptosis and atherosclerosis.

The discovery of an inhibitor for acyl-CoA synthetase long-chain family member 4 (ACSL4), a protein involved in the process of cell injury through ferroptosis, has the potential to ameliorate cell damage. In this study, we aimed to investigate the potential of berberine (BBR) as an inhibitor of ACSL4 in order to suppress endothelial ferroptosis and provide protection against atherosclerosis. An atherosclerosis model was created in ApoE-/- mice by feeding a high fat diet for 16 weeks. Additionally, a mouse model with endothelium-specific overexpression of ACSL4 was established. BBR was administered orally to assess its potential therapeutic effects on atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low density lipoprotein (ox-LDL) to simulate atherosclerotic endothelial damage in vitro. The interaction between ACSL4 and BBR has been confirmed, with BBR playing a role in inhibiting erastin-induced ferroptosis by regulating ACSL4. Additionally, BBR has been found to inhibit lipid deposition, plaque formation, and collagen deposition in the aorta, thereby delaying the progression of atherosclerosis. It also restored the abnormal expression of ferroptosis-related proteins in atherosclerotic vascular endothelial cells both in vivo and in vitro. In conclusion, BBR, acting as an ACSL4 inhibitor, can improve atherosclerosis by inhibiting ferroptosis in endothelial cells. This highlights the potential of targeted inhibition of vascular endothelial ACSL4 as a strategy for treating atherosclerosis, with BBR being a candidate for this purpose.

Evaluation of pancreatic iodine uptake and related influential factors in multiphase dual-energy CT.

OBJECTIVES: To establish normative values and identify potential factors influencing pancreatic iodine uptake using dual-energy CT (DECT). MATERIALS AND METHODS: This retrospective study included participants without pancreatic diseases undergoing DECT at two institutions with different platforms. Their protocols both included arterial phase (AP), portal venous phase (PP), and equilibrium phase (EP), defined as 35 s-40 s, 60 s-70 s, and 150 s-180 s after injection of contrast agent, respectively. Both iodine concentration (IC) and normalised IC (NIC) were measured. Demographic features, local measurements of the pancreas and visceral fat area (VFA) were considered as potential factors influencing iodine uptake using multivariate linear regression analyses. RESULTS: A total of 562 participants (median age 58 years [interquartile range: 47-67], with 282 men) were evaluated. The mean IC differed significantly between two institutions (all p < 0.001) across three contrast-enhanced phases, while the mean NIC showed no significant differences (all p > 0.05). The mean values of NIC were 0.22 at AP, 0.43 at PP and 0.45 at EP. NICAP was independently affected by VFA (ß = 0.362, p < 0.001), smoking (ß = -0.240, p = 0.001), and type-II diabetes (ß = -0.449, p < 0.001); NICPP by VFA (ß = -0.301, p = 0.017) and smoking (ß = -0.291, p < 0.001); and NICEP by smoking (ß = -0.154, p = 0.10) and alcohol consumption (ß = -0.350, p < 0.001) with statistical power values over 0.81. CONCLUSION: NIC values were consistent across institutions. Abdominal obesity, smoking, alcohol consumption, and diabetes are independent factors influencing pancreatic iodine uptake. CLINICAL RELEVANCE STATEMENT: This study has provided reference normative values, influential factors and effective normalisation methods of pancreatic iodine uptake in multiphase dual-energy CT for future studies in this area as a new biological marker. KEY POINTS: Evaluation of pancreatic iodine uptake measured by dual-energy CT is a promising method for future studies. Abdominal obesity, smoking, alcohol consumption, diabetes, and sex are independent factors influencing pancreatic iodine uptake. Utility of normalised iodine concentration is necessary to ensure the consistency across different institutions.

Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction.

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.

Coherent O-band WDM transmission of DP-16QAM over a 50-km BDFA-amplified link.

We present wavelength-division multiplexed coherent transmission in an O-band amplified link enabled by bismuth-doped fiber amplifiers (BDFAs). Transmission of 4 × 25 GBd DP-16QAM (4 × 200 Gb/s) is demonstrated over a single span of 50-km length, occupying a bandwidth of 4.7 THz across the wavelengths 1323 nm to 1351 nm.

A predictive study of the efficacy of transcutaneous auricular vagus nerve stimulation in the treatment of major depressive disorder: An fMRI-based machine learning analysis.

BACKGROUND: In order to improve taVNS efficacy, the usage of fMRI to explore the predictive neuroimaging markers would be beneficial for screening the appropriate MDD population before treatment. METHODS: A total of 86 MDD patients were recruited in this study, and all subjects were conducted with the clinical scales and resting-state functional magnetic resonance imaging (fMRI) scan before and after 8 weeks' taVNS treatment. A two-stage feature selection strategy combining Machine Learning and Statistical was used to screen out the critical brain functional connections (FC) that were significantly associated with efficacy prediction, then the efficacy prediction model was constructed for taVNS treating MDD. Finally, the model was validated by separated the responding and non-responding patients. RESULTS: This study showed that taVNS produced promising clinical efficacy in the treatment of mild and moderate MDD. Eleven FCs were selected out and were found to be associated with the cortico-striatal-pallidum-thalamic loop, the hippocampus and cerebellum and the HAMD-17 scores. The prediction model was created based on these FCs for the efficacy prediction of taVNS treatment. The R-square of the conducted regression model for predicting HAMD-17 reduction rate is 0.44, and the AUC for classifying the responding and non-responding patients is 0.856. CONCLUSION: The study demonstrates the validity and feasibility of combining neuroimaging and machine learning techniques to predict the efficacy of taVNS on MDD, and provides an effective solution for personalized and precise treatment for MDD.

Bortezomib in previously treated phosphatase and tension homology-deficient patients with advanced intrahepatic cholangiocarcinoma: An open-label, prospective and single-centre phase II trial.

INTRODUCTION: Intrahepatic cholangiocarcinoma (ICC) is characterized by a dismal prognosis with limited therapeutic alternatives. To explore phosphatase and tension homolog (PTEN) as a biomarker for proteasome inhibition in ICC, we conducted a phase II trial to assess the second-line efficacy of bortezomib in PTEN-deficient advanced ICC patients. METHODS: A total of 130 patients with advanced ICC in our centre were screened by PTEN immunohistochemical staining between 1 July 2017, and 31 December 2021, and 16 patients were ultimately enrolled and treated with single-agent bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle. The primary endpoint was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors v1.1. RESULTS: The median follow-up was 6.55 months (95% confidence interval [CI]: 0.7-19.9 months). Among the 16 enrolled patients, the ORR was 18.75% (3/16) and the disease control rate was 43.75% (7/16). The median progress-free survival was 2.95 months (95% CI: 2.1-5.1 months) and the median overall survival (mOS) was 7.2 months (95% CI: 0.7-21.6 months) in the intent-to-treat-patients. Treatment-related adverse events of any grade were reported in 16 patients, with thrombopenia being the most common toxicity. Patients with PTEN staining scores of 0 were more likely to benefit from bortezomib than those with staining scores > 0. CONCLUSIONS: Bortezomib yielded an encouraging objective response and a favourable OS as a second-line agent in PTEN-deficient ICC patients. Our findings suggest bortezomib as a promising therapeutic option for patients with PTEN-deficient ICC. HIGHLIGHTS: There is a limited strategy for the second-line option of intrahepatic cholangiocarcinoma (ICC). This investigator-initiated phase 2 study evaluated bortezomib in ICC patients with phosphatase and tension homology deficiency. The overall response rate was 18.75% and the overall survival was 7.2 months in the intent-to-treat cohort. These results justify further developing bortezomib in ICC patients with PTEN deficiency.

Effects of Connectivity Isomerization on Electron Transport Through Thiophene Heterocyclic Molecular Junction.

Connectivity isomerization of the same aromatic molecular core with different substitution positions profoundly affects electron transport pathways and single-molecule conductance. Herein, we designed and synthesized all connectivity isomers of a thiophene (TP) aromatic ring substituted by two dihydrobenzo[b]thiophene (BT) groups with ethynyl spacers (m,n-TP-BT, (m,n = 2,3; 2,4; 2,5; 3,4)), to systematically probe how connectivity contributes to single-molecule conductance. Single-molecule conductance measurements using a scanning tunneling microscopy break junction (STM-BJ) technique show ∼12-fold change in conductance values, which follow an order of 10-4.83 G0 (2,4-TP-BT) < 10-4.78 G0 (3,4-TP-BT) < 10-4.06 G0 (2,3-TP-BT) < 10-3.75 G0 (2,5-TP-BT). Electronic structure analysis and theoretical simulations show that the connectivity isomerization significantly changes electron delocalization and HOMO-LUMO energy gaps. Moreover, the connectivity-dependent molecular structures lead to different quantum interference (QI) effects in electron transport, e.g., a strong destructive QI near E = EF leads the smallest conductance value for 2,4-TP-BT. This work proves a clear relationship between the connectivity isomerization and single-molecule conductance of thiophene heterocyclic molecular junctions for the future design of molecular devices.