Gray matters: ViT-GAN framework for identifying schizophrenia biomarkers linking structural MRI and functional network connectivity.

Brain disorders are often associated with changes in brain structure and function, where functional changes may be due to underlying structural variations. Gray matter (GM) volume segmentation from 3D structural MRI offers vital structural information for brain disorders like schizophrenia, as it encompasses essential brain tissues such as neuronal cell bodies, dendrites, and synapses, which are crucial for neural signal processing and transmission; changes in GM volume can thus indicate alterations in these tissues, reflecting underlying pathological conditions. In addition, the use of the ICA algorithm to transform high-dimensional fMRI data into functional network connectivity (FNC) matrices serves as an effective carrier of functional information. In our study, we introduce a new generative deep learning architecture, the conditional efficient vision transformer generative adversarial network (cEViT-GAN), which adeptly generates FNC matrices conditioned on GM to facilitate the exploration of potential connections between brain structure and function. We developed a new, lightweight self-attention mechanism for our ViT-based generator, enhancing the generation of refined attention maps critical for identifying structural biomarkers based on GM. Our approach not only generates high quality FNC matrices with a Pearson correlation of 0.74 compared to real FNC data, but also uses attention map technology to identify potential biomarkers in GM structure that could lead to functional abnormalities in schizophrenia patients. Visualization experiments within our study have highlighted these structural biomarkers, including the medial prefrontal cortex (mPFC), dorsolateral prefrontal cortex (DL-PFC), and cerebellum. In addition, through cross-domain analysis comparing generated and real FNC matrices, we have identified functional connections with the highest correlations to structural information, further validating the structure-function connections. This comprehensive analysis helps to understand the intricate relationship between brain structure and its functional manifestations, providing a more refined insight into the neurobiological research of schizophrenia.

Engineered coiled-coil HIF1α protein domain mimic.

The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-inducible factor (HIF), in particular HIF1, plays a key role in tumor adaptation to hypoxia, and inhibiting its interaction with p300 has been shown to provide therapeutic potential. Using a multivalent assembled protein (MAP) approach based on the self-assembly of the cartilage oligomeric matrix protein coiled-coil (COMPcc) domain fused to the critical residues of the C-terminal transactivation domain (C-TAD) of the α subunit of HIF1 (HIF1α), we generate HIF1α-MAP (H-MAP). The resulting H-MAP demonstrates picomolar binding affinity to p300, the ability to downregulate hypoxia-inducible genes, and in vivo tumor targeting capability.

Visualization analysis of mitochondrial dynamics in heart failure based on bibliometrics: Trends, hotspots, and topics.

This study aimed to conduct a visual analysis of the relevant literature on mitochondrial dynamics in heart failure, explore the research progress, frontier topics, and development trends in this field, and provide references for the study concerning mitochondrial dynamics in the prevention and treatment of heart failure. The Web of Science was searched from inception to October 1, 2023 to identify relevant English literature on mitochondrial dynamics in heart failure. Bibliometric methods were utilized to statistically analyze the eligible literature, and CiteSpace 6.2.R5 software was employed to visualize data such as countries of publication, institutions, authors, and keywords. A total of 1755 Science Citation Index articles were included. The global publication volume showed an increasing trend year by year, with China and the United States having the most publications, and the United States displaying the highest centrality in publications. As revealed by keyword and citation analyses, the research hotspots and frontiers in this field mainly included the pathogenesis of heart failure, mitochondrial dynamics markers, mitochondrial quality control, and potential therapeutic targets for heart failure. Research on mitochondrial dynamics in heart failure is under vigorous development. It is a development trend in this research field to explore the differential gene expression and molecular mechanisms of targeted treatment in the mitochondrial dynamics in heart failure, which will contribute to the formulation of new strategies for the prevention and treatment of heart failure.

Computational Prediction of Coiled-Coil Protein Gelation Dynamics and Structure.

Protein hydrogels represent an important and growing biomaterial for a multitude of applications, including diagnostics and drug delivery. We have previously explored the ability to engineer the thermoresponsive supramolecular assembly of coiled-coil proteins into hydrogels with varying gelation properties, where we have defined important parameters in the coiled-coil hydrogel design. Using Rosetta energy scores and Poisson-Boltzmann electrostatic energies, we iterate a computational design strategy to predict the gelation of coiled-coil proteins while simultaneously exploring five new coiled-coil protein hydrogel sequences. Provided this library, we explore the impact of in silico energies on structure and gelation kinetics, where we also reveal a range of blue autofluorescence that enables hydrogel disassembly and recovery. As a result of this library, we identify the new coiled-coil hydrogel sequence, Q5, capable of gelation within 24 h at 4 °C, a more than 2-fold increase over that of our previous iteration Q2. The fast gelation time of Q5 enables the assessment of structural transition in real time using small-angle X-ray scattering (SAXS) that is correlated to coarse-grained and atomistic molecular dynamics simulations revealing the supramolecular assembling behavior of coiled-coils toward nanofiber assembly and gelation. This work represents the first system of hydrogels with predictable self-assembly, autofluorescent capability, and a molecular model of coiled-coil fiber formation.

Protein-Engineered Fibers For Drug Encapsulation Traceable via 19F Magnetic Resonance.

Theranostic materials research is experiencing rapid growth driven by the interest in integrating both therapeutic and diagnostic modalities. These materials offer the unique capability to not only provide treatment but also track the progression of a disease. However, to create an ideal theranostic biomaterial without compromising drug encapsulation, diagnostic imaging must be optimized for improved sensitivity and spatial localization. Herein, we create a protein-engineered fluorinated coiled-coil fiber, Q2TFL, capable of improved sensitivity to 19F magnetic resonance spectroscopy (MRS) detection. Leveraging residue-specific noncanonical amino acid incorporation of trifluoroleucine (TFL) into the coiled-coil, Q2, which self-assembles into nanofibers, we generate Q2TFL. We demonstrate that fluorination results in a greater increase in thermostability and 19F magnetic resonance detection compared to the nonfluorinated parent, Q2. Q2TFL also exhibits linear ratiometric 19F MRS thermoresponsiveness, allowing it to act as a temperature probe. Furthermore, we explore the ability of Q2TFL to encapsulate the anti-inflammatory small molecule, curcumin (CCM), and its impact on the coiled-coil structure. Q2TFL also provides hyposignal contrast in 1H MRI, echogenic signal with high-frequency ultrasound and sensitive detection by 19F MRS in vivo illustrating fluorination of coiled-coils for supramolecular assembly and their use with 1H MRI, 19F MRS and high frequency ultrasound as multimodal theranostic agents.

Glutathione/pH-responsive copper-based nanoplatform for amplified chemodynamic therapy through synergistic cycling regeneration of reactive oxygen species and dual glutathione depletion.

The rapid scavenging of reactive oxygen species (ROS) by glutathione (GSH) and insufficient endogenous hydrogen peroxide (H2O2) in tumor cells are the major factors greatly restricting the efficacy of chemodynamic therapy (CDT). Herein, we developed a tumor microenvironment (TME)-responsive Cu-based metal-mesoporous organosilica nanoplatform integrating vitamin k3 (VK3), which could deplete GSH and specifically regenerate H2O2 for amplified CDT of cancer. Once the CuO@MON-PEG/VK3 nanoparticles entered into the tumor cells through enhanced permeability and retention (EPR) effect, the organosilicon shell and CuO core would be successively degraded upon the triggering of GSH and endo/lysosomal acidity. Subsequently, the enriched tetrasulfide bridges and released Cu2+ could consume GSH substantially, thus triggering Fenton-like reaction for CDT. Furthermore, the released VK3 could be catalyzed by the highly expressed quinone oxidoreductase-1 (NQO1) inside tumor cells to generate sufficient H2O2 through a "reversible" redox cycle, which in turn promoted Cu+-mediated Fenton-like reaction. Both in vitro and in vivo studies demonstrated that this nanoplatform could achieve synergistic CDT against tumor through synergistic cycling regeneration of ROS and dual GSH exhaustion with excellent biosafety. Our finding highlight the promising potential of CuO@MON-PEG/VK3 nanoplatform with multiple oxidative stress amplification for highly efficient tumor therapy.

High-throughput screening identification of novel immunomodulatory combinations for the generation of tolerogenic dendritic cells.

Introduction: Tolerogenic Dendritic Cells (tolDCs) have an exceptional promise as a potential therapy for autoimmune disease and transplantation rejection. TolDCs are a unique phenotype of antigen presenting cells (APCs) that can influence naïve T cells into antigen specific T regulatory cells (Tregs), which can re-establish tolerance against auto/allo-antigens in the long term. Despite their promise, tolDCs have not found clinical success. Most strategies seek to generate tolDCs ex vivo by differentiating naïve dendritic cells (DCs) with immunosuppressive agents. Recently, we developed a tolDC generation strategy, which we call Push/Pull Immunomodulation (PPI). In PPI, DCs are treated with combinations of toll-like-receptor (TLR) agonists and immunomodulatory agents, which generate more robust, Treg-inducing tolDCs than previous strategies. Here, we seek to identify more potent and clinically viable PPI formulations using data from a high-throughput screening project. Methods: Over 40,000 combinations of pathogen-associated molecular patterns (PAMPs) and immunomodulatory small molecules were screened using a modified murine macrophage line, RAW dual cells, to observe the effect of these combinations on two major immune regulatory transcription factors, NF-κB and IRF. Combinations were further screened for inflammatory cytokine activity using a human monocyte cell line, THP-1, then on murine DCs. Leading candidates were co-cultured with T cells to assess antigen specific T cell responses. Results: From this data, we identified 355 combinations that showed low or moderate IRF activity, low NF-κB activity, low inflammatory cytokine generation and good viability: all hallmarks of tolerogenic potential. We further screened these 355 combinations using bone marrow derived DCs (BMDCs) and identified 10 combinations that demonstrated high IL-10 (tolerogenic) and low TNF-α (inflammatory) secretion. After further optimizing these combinations, we identified two combinations that generate robust tolDCs from BMDCs ex vivo. We further show that these PPI-tolDCs can also generate antigen specific Tregs but do not increase overall Treg populations. Discussion: These second-generation PPI formulations have significant potential to generate robust tolDCs and strong antigen specific Tregs.

Supramolecular Assembly and Small-Molecule Binding by Protein-Engineered Coiled-Coil Fibers.

The ability to engineer a solvent-exposed surface of self-assembling coiled coils allows one to achieve a higher-order hierarchical assembly such as nano- or microfibers. Currently, these materials are being developed for a range of biomedical applications, including drug delivery systems; however, ways to mechanistically optimize the coiled-coil structure for drug binding are yet to be explored. Our laboratory has previously leveraged the functional properties of the naturally occurring cartilage oligomeric matrix protein coiled coil (C), not only for its favorable motif but also for the presence of a hydrophobic pore to allow for small-molecule binding. This includes the development of Q, a rationally designed pentameric coiled coil derived from C. Here, we present a small library of protein microfibers derived from the parent sequences of C and Q bearing various electrostatic potentials with the aim to investigate the influence of higher-order assembly and encapsulation of candidate small molecule, curcumin. The supramolecular fiber size appears to be well-controlled by sequence-imbued electrostatic surface potential, and protein stability upon curcumin binding is well correlated to relative structure loss, which can be predicted by in silico docking.

A randomized, placebo-controlled, double-blind trial to evaluate efficacy and safety of Shen-Yuan-Dan capsules, a traditional Chinese medicine, for treatment of peri-procedure myocardial injury following percutaneous coronary intervention.

BACKGROUND: Peri-procedural myocardial injury (PMI) is a common complication of percutaneous coronary intervention (PCI), which cannot be entirely avoided using available treatments. The findings of earlier research have shown that Shen-Yuan-Dan (SYD) capsules, a traditional Chinese medicine, can potentially alleviating PMI. This study aimed to confirm further this hypothesis in a rigorous, well-designed randomized controlled study. METHODS: Our clinical trial was randomized, double-blinded, and placebo-controlled. A total of 181 patients with unstable angina (UA) undergoing elective PCI were randomized to pretreatment with SYD or a placebo under the basis of conventional treatment; 87 patients were pretreated with SYD (4 capsules, 3 times a day, with a further 4 capsules 2 h before PCI) 3 days before the procedure, and 94 patients were given a placebo. No patients received reloading statins before PCI, and SYD or placebo was maintained for 1 month after PCI. The primary endpoint was the incidence of PMI. The secondary endpoint was calculating the incidence rate of all 30-day major adverse cardiovascular events (all-cause mortality, non-fatal myocardial infarction, unplanned revascularization). The safety outcomes, including abnormalities in electrocardiogram and serum biochemical examinations caused by drug use, were also tested. RESULTS: The levels of creatine kinase-myocardial band (CK-MB) in both the SYD and placebo groups were increased at 4 h and 24 h after PCI compared with before the procedure (P < 0.05). The incidence rate of PMI in the SYD group (10.3 %) was lower than that in the placebo group (34 %) (absolute difference, 23.7 % [95 % CI, 11.7-34.8 %], P < 0.01). After taking SYD, the relative risk reduction (RRR) and absolute risk reduction (ARR) were 69.7 % and 24.3 %, respectively; further, number needed to treat (NNT) was 4.2. The 30-day major adverse cardiovascular event (MACE) rate was not statistically different between the SYD and placebo groups (6.9 % vs. 9.6 %, P = 0.352). There were no abnormal situations during the trial. CONCLUSION: These findings showed that pretreatment with SYD could safely reduce the incidence rate of PMI in patients with UA undergoing elective PCI. Further study on the effects of SYD and how it can improve adverse cardiovascular events outcomes is needed.

Synthesis of K[B3H7NH2BH2NH2B3H7] for a K-ion solid-state electrolyte.

All-solid-state K batteries are ideal energy storage devices for grid-scale applications of renewable energies. A novel electrolyte K[B3H7NH2BH2NH2B3H7] with weakly coordinating anions was synthesized. It has a high K+ conductivity of 1.01 × 10-4 S cm-1 at 75 °C, which is probably due to the increased electrostatic potential and size of the anions.

GSH-Responsive and Hypoxia-Activated Multifunctional Nanoparticles for Synergetically Enhanced Tumor Therapy.

The integration of reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and photodynamic therapy (PDT) has attracted enormous attention for synergistic antitumor therapies. However, the strategy is severely hampered by tumor hypoxia and overproduced antioxidant glutathione (GSH) in the tumor microenvironment. Inspired by the concept of metal coordination-based nanomedicines, we proposed an effective strategy for synergistic cancer treatment in response to the special tumor microenvironmental properties. Herein, we present novel metal-coordinated multifunctional nanoparticles (NPs) by the Cu2+-triggered assembly of photosensitizer indocyanine green (ICG) and hypoxia-activated anticancer prodrug tirapazamine (TPZ) (Cu-ICG/TPZ NPs). After accumulating within tumor sites via the enhanced permeability and retention (EPR) effect, the Cu-ICG/TPZ NPs were capable of triggering a cascade of combinational therapeutic reactions, including hyperthermia, GSH elimination, and Cu+-mediated •OH generation and the subsequent hypoxia-triggered chemotherapeutic effect of TPZ, thus achieving synergistic tumor therapy. Both in vitro and in vivo evaluations suggested that the multifunctional Cu-ICG/TPZ NPs could realize satisfactory therapeutic efficacy with excellent biosafety. These results thus suggested the great potential of Cu-ICG/TPZ NPs to serve as a metallodrug nanoagent for synergetically enhanced tumor treatment.

Clinical Efficacy and Safety of Shensong Yangxin Capsule-Amiodarone Combination on Heart Failure Complicated by Ventricular Arrhythmia: A Meta-Analysis of Randomized Controlled Trials.

Background: Shensong Yangxin capsule (SSYX) is a well-known traditional Chinese patent medicine for treating arrhythmia. Recently, a flurry of randomized controlled trials (RCTs) of SSYX combined with amiodarone (SSYX-amiodarone) was reported in the treatment of heart failure (HF) complicated by ventricular arrhythmia (VA) in China. However, these RCTs have not been systematically evaluated. Therefore, this study aimed to evaluate the efficacy and safety of SSYX-amiodarone in the treatment of heart failure complicated by ventricular arrhythmia (HF-VA). Methods: Seven electronic literature databases (the Cochrane Library, PubMed, EMBASE, China Biomedical database web, China National Knowledge Infrastructure Databases, Chinese Scientific Journal database and Wanfang database) were searched from their inceptions to June 1, 2020 to identify RCTs of SSYX-amiodarone in the treatment of HF-VA. The primary outcomes included the total effective rate and adverse events (ADRs). The secondary outcomes included the frequency of ventricular premature complexes, left ventricular ejection fraction, N terminal pro Btype natriuretic peptide (NT-proBNP), and QT dispersion (QTd). The quality of the included RCTs was assessed using the Cochrane risk-of-bias tool. All data was analyzed using RevMan 5.3 software. The registration number of this protocol is PROSPERO CRD42020196689. Results: There are Eighteen trials involving 1,697 patients were included in this study. Meta-analysis showed that SSYX-amiodarone group was superior to the amiodarone group in improving the total effective rate [RR = 1.21; 95%CI (1.16, 1.27); p < 0.01], meanwhile reducing the ADRs [RR = 0.65; 95%CI (0.45, 0.95); p = 0.03], VPCs [MD = 170.96; 95%CI (159.88, 182.04); p < 0.01] and QTd [MD = 8.39; 95%CI (6.91, 9.87); p < 0.01]. No significant difference of enhancing LVEF [MD = 4.32; 95%CI (-0.56, 9.20); p = 0.08] and reducing NT-proBNP [SMD = 0.17; 95%CI (-0.81, 1.14); p = 0.73] was observed between SSYX-amiodarone and amiodarone group. Conclusions: Despite the apparent positive findings reported, the evidence provided by this meta-analysis was still insufficient to support the routine use of SSYX-amiodarone for HF-VA due to the poor methodological quality of included studies. The overall effect should to be verified in further through more well-design clinical studies with reasonable sample and good methodological quality.

[Clinical trials of treatment of woman menopause insomnia due to disharmony between heart and kidney by body and auricular acupuncture].

OBJECTIVE: To observe the therapeutic effect of body acupuncture combined with auricular acupuncture in the treatment of woman menopause insomnia induced by disharmony between the heart and kidney. METHODS: A total of 111 outpatients with menopausal insomnia were randomly divided into treatment group (n＝55, body acupoints plus auricular points) and control group (n＝56, body acupoints). For control group, Shenmen (HT7), Sanyinjiao (SP6), Anmian, Zhaohai (KI6), Shenmai (BL62), Sishencong (EX-HN1), Xinshu (BL15) and Shenshu (BL21) were needled with filiform needles, and HT7, SP6, Anmian, BL15 and BL21 were also stimulated with electroacupuncture (EA) for 30 min, once every other day, 3 times a week for 3 weeks. For the treatment group, auricular points as Kidney, Shenmen, Sympathetic and Endocrine around the ear canal and the ear cavity were punctured with filiform needles in combination with the same intervention methods mentioned above in the control group. The quality and efficiency of sleep were assessed by using Pittsburgh Sleep Quality Index (PSQI) scale before and after the treatment. The symptom scores of traditional Chinese medicine (TCM) and the therapeutic effect were determined according to the "Guide Principles for Clinical Research of New Drugs of TCM" (formulated by Chinese Ministry of Health, 1997). RESULTS: After the treatment, the scores of sleep quantity and effective rate of PSQI scale, and those of insomnia and dreaminess, dysphoria with feverish sensation in chest, palms and soles, paplpitation and irritability, fatigue and forgetfulness of TCM were reduced significantly in both groups compared with their own pre-treatment (P<0.05). Of the 56 and 55 cases in the control and treatment groups, 18 (32.1%) and 30 (54.5%) experienced a marked improvement in their symptoms, 28 (50.0%) and 22 (40.0%) were effective, and 10 (17.9%) and 3 (5.5%) failed, with the effective rate being 82.1% and 94.5%, respectively. The therapeutic effect of stimulation of the body acupoints plus auricular acupoints was significantly superior to that of stimulation of simple body acupoints in lowering scores of PSQI scale, insomnia and dreaminess, dysphoria with feverish sensation in chest, palms and soles, dizziness and tinninus, paplpitation and irritability, and tital fever and night sweating of TCM, as well as the effective rate (P<0.05). CONCLUSION: Both body acupuncture and body acupuncture combined with auricular acupuncture are effective in the treatment of woman menopause insomnia due to disharmony between the heart and kidney, and the two combined treatment was evidently better.

Efficacy and safety of Shen-Yuan-Dan capsules for peri-procedural myocardial injury following percutaneous coronary intervention: study protocol for a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Peri-procedural myocardial injury (PMI) during percutaneous coronary intervention (PCI) will result in an unfavorable clinical prognosis in patients, thus urgently necessitating effective drug treatment measures. Shen-Yuan-Dan (SYD) capsules are a traditional Chinese medicine (TCM) preparation that have been found to have potential myocardial protection effects during the peri-procedural phase of PCI in previous clinical and basic research; however, there is a lack of rigorous, randomized, and controlled studies. The aim of this study is to evaluate the efficacy and safety of SYD in decreasing PMI. METHODS: This is a randomized, double-blind, placebo-controlled clinical trial. A total of 284 patients with unstable angina will be randomized into test and control groups. The two groups will be given SYD or a placebo (three times each day, four capsules each time) 3 days before PCI on the basis of conventional treatment. Twelve hours before PCI, an additional 4 capsules will be given, and drug treatment is planned to be maintained for 1 month after surgery. Dynamic changes in the myocardial enzyme in four time-points (before PCI, and 4, 24, 48 hours after PCI) in both groups of patients that will be observed. The follow-up period will be 1 month. The primary observation markers are planned to evaluate the efficacy and safety of SYD in decreasing PMI. The secondary observation markers will be to evaluate the major adverse cardiovascular events (MACEs) status at day 30 after PCI, (all-cause mortality, non-fatal myocardial infarction, repeated revascularization of target blood vessel) and Seattle Angina Questionnaire scores. GRACE scores will be used for risk stratification, and the intervention efficacy of SYD on PMI patients with different risks will be retrospectively evaluated. DISCUSSION: This study will provide a rigorous clinical evidence to evaluate the efficacy and safety of SYD in decreasing PMI and the results are worth anticipating. TRIAL REGISTRATION: The design of this trial has been registered with the Chinese Clinical Trial Registry (No. ChiCTR-IPR-17011069).

[Detection of pain thresholds of acupoints for irritable bowel syndrome].

OBJECTIVE: To compare the pain thresholds of acupoints in the meridians related to irritable bowel syndrome(IBS) between IBS patients and healthy people. METHODS: Thirty-four healthy adults were collected into a normal group,and 60 patients with IBS were arranged into an IBS group. Pain thresholds were detected on the acupoints of large intestinal,small intestinal,stomach,spleen,gallbladder meridians and some commone use acupoints for IBS by pain measuring apparatus three times. Bilateral jing-well,xing-spring,shu-stream,jing-river,he-sea,front mu-alarm,lower he-sea,yuan-primary,luo-connecting and back shu-transport points of each meridian were selected as the main acupoints. And pain thresholds of acupoints common used in clinic were compared between the two groups. RESULTS: The thresholds of five shu-transport points and luo-connecting point of the large intestinal meridian in the IBS group were apparently lower than those in the normal group(all P<0.05),with Hegu(LI 4),Tianshu(ST 25),Shangjuxu(ST 37) and Dachangshu(BL 25) more decreasing(all P<0.01). The thresholds of five shu-transport points,front mu-alarm point and yuan-primary point of the small intestinal meridian in the IBS group were obviously lower than those in the normal group(all P<0.05),with Zhizheng(SI 7),Xiajuxu(ST 39) and Xiaochangshu(BL 27) more decreasing(all P<0.01). The thresholds of Zusanli(ST 36),Weishu(BL 21),Yanglingquan(GB 34),Danshu(BL 19),Pishu(BL 20),Neiguan(PC 6),Taichong(LR 3),Taixi(KI 3),Sanyinjiao(SP 6) and Qihai(CV 6) in the IBS group were markedly lower than those in the normal group(all P<0.05). CONCLUSIONS: The pathological changes of IBS often appeared in the stomach,large intestinal,small intestinal,bladder meridians,and some acupoints in the liver,spleen and kidney meridians. When the functions of viscera are abnormal,the pain thresholds of related acupoints tend to decrease,and meridians and acupoints become sensitized from quiet state.