Visualizing electrostatic gating effects in two-dimensional heterostructures.

The ability to directly monitor the states of electrons in modern field-effect devices-for example, imaging local changes in the electrical potential, Fermi level and band structure as a gate voltage is applied-could transform our understanding of the physics and function of a device. Here we show that micrometre-scale, angle-resolved photoemission spectroscopy1-3 (microARPES) applied to two-dimensional van der Waals heterostructures4 affords this ability. In two-terminal graphene devices, we observe a shift of the Fermi level across the Dirac point, with no detectable change in the dispersion, as a gate voltage is applied. In two-dimensional semiconductor devices, we see the conduction-band edge appear as electrons accumulate, thereby firmly establishing the energy and momentum of the edge. In the case of monolayer tungsten diselenide, we observe that the bandgap is renormalized downwards by several hundreds of millielectronvolts-approaching the exciton energy-as the electrostatic doping increases. Both optical spectroscopy and microARPES can be carried out on a single device, allowing definitive studies of the relationship between gate-controlled electronic and optical properties. The technique provides a powerful way to study not only fundamental semiconductor physics, but also intriguing phenomena such as topological transitions5 and many-body spectral reconstructions under electrical control.

Effects of the motor cortical theta-burst transcranial-focused ultrasound stimulation on the contralateral motor cortex.

Theta-burst transcranial ultrasound stimulation (tbTUS) increases primary motor cortex (M1) excitability for at least 30 min. However, the remote effects of focal M1 tbTUS on the excitability of other cortical areas are unknown. Here, we examined the effects of left M1 tbTUS on right M1 excitability. An 80 s train of active or sham tbTUS was delivered to the left M1 in 20 healthy subjects. Before and after the tbTUS, we measured: (1) corticospinal excitability using motor-evoked potential (MEP) amplitudes from single-pulse transcranial magnetic stimulation (TMS) of left and right M1; (2) interhemispheric inhibition (IHI) from left to right M1 and from right to left M1 using a dual-site paired-pulse TMS paradigm; and (3) intracortical circuits of the right M1 with short-interval intracortical inhibition and intracortical facilitation (ICF) using paired-pulse TMS. Left M1 tbTUS decreased right M1 excitability as shown by decreased MEP amplitudes, increased right M1 ICF and decreased short-interval IHI from left to right hemisphere at interstimulus interval (ISI) of 10 ms but not long-interval IHI at interstimulus interval of 40 ms. The study showed that left M1 tbTUS can change the excitability of remote cortical areas with decreased right M1 excitability and interhemispheric inhibition. The remote effects of tbTUS should be considered when it is used in neuroscience research and as a potential neuromodulation treatment for brain disorders. KEY POINTS: Transcranial ultrasound stimulation (TUS) is a novel non-invasive brain stimulation technique for neuromodulation with the advantages of being able to achieve high spatial resolution and target deep brain structures. A repetitive TUS protocol, with an 80 s train of theta burst patterned TUS (tbTUS), has been shown to increase primary motor cortex (M1) excitability, as well as increase alpha and beta movement-related spectral power in distinct brain regions. In this study, we examined on the effects of the motor cortical tbTUS on the excitability of contralateral M1 measured with MEPs elicited by transcranial magnetic stimulation. We showed that left M1 tbTUS decreased right M1 excitability and left-to-right M1 interhemispheric inhibition, and increased intracortical facilitation of right M1. These results lead to better understand the effects of tbTUS and can help the development of tbTUS for the treatment of neurological and psychiatric disorders and in neuroscience research.

Chemotactic Micro/Nanomotors for Biomedical Applications.

In nature, many organisms respond chemotactically to external chemical stimuli in order to extract nutrients or avoid danger. Inspired by this natural chemotaxis, micro/nanomotors with chemotactic properties have been developed and applied to study a variety of disease models. This chemotactic strategy has shown promising results and has attracted the attention of an increasing number of researchers. This paper mainly reviews the construction methods of different types of chemotactic micro/nanomotors, the mechanism of chemotaxis, and the potential applications in biomedicine. First, based on the classification of materials, the construction methods and therapeutic effects of chemotactic micro/nanomotors based on natural cells and synthetic materials in cellular and animal experiments will be elaborated in detail. Second, the mechanism of chemotaxis of micro/nanomotors is elaborated in detail: chemical reaction induced chemotaxis and physical process driven chemotaxis. In particular, the main differences and significant advantages between chemotactic micro/nanomotors and magnetic, electrical and optical micro/nanomotors are described. The applications of chemotactic micro/nanomotors in the biomedical fields in recent years are then summarized, focusing on the mechanism of action and therapeutic effects in cancer and cardiovascular disease. Finally, the authors are looking forward to the future development of chemotactic micro/nanomotors in the biomedical fields.

Anisotropic Te/PdSe2 Van Der Waals Heterojunction for Self-Powered Broadband and Polarization-Sensitive Photodetection.

Polarization-sensitive broadband optoelectronic detection is crucial for future sensing, imaging, and communication technologies. Narrow bandgap 2D materials, such as Te and PdSe2, show promise for these applications, yet their polarization performance is limited by inherent structural anisotropies. In this work, a self-powered, broadband photodetector utilizing a Te/PdSe2 van der Waals (vdWs) heterojunction, with orientations meticulously tailored is introduced through polarized Raman optical spectra and tensor calculations to enhance linear polarization sensitivity. The device exhibits anisotropy ratios of 1.48 at 405 nm, 3.56 at 1550 nm, and 1.62 at 4 µm, surpassing previously-reported photodetectors based on pristine Te and PdSe2. Additionally, it exhibits high responsivity (617 mA W-1 at 1550 nm), specific detectivity (5.27 × 1010 Jones), fast response (≈4.5 µs), and an extended spectral range beyond 4 µm. The findings highlight the significance of orientation-engineered heterostructures in enhancing polarization-sensitive photodetectors and advancing optoelectronic technology.

Association between BMI-based metabolic phenotypes and prevalence of intracranial atherosclerotic stenosis: a cross-sectional study.

BACKGROUND: Obesity and metabolic syndrome (MetS) have been acknowledged to commonly co-exist and lead to increased risks of stroke, whereas the association between various BMI-based metabolic phenotypes and development of intracranial atherosclerotic stenosis (ICAS) remained controversial. METHODS: A total of 5355 participants were included from the Asymptomatic Polyvascular Abnormalities Community (APAC) study. Participants were categorized into six groups according to their body mass index (BMI) and MetS status. ICAS was assessed using transcranial Doppler (TCD) Ultrasonography. Logistic regression was employed to evaluate the association between BMI-based metabolic phenotypes and ICAS. RESULTS: 704 participants were diagnosed with ICAS. Compared to the metabolic healthy normal weight (MH-NW) group, the metabolic unhealthy normal weight (MUH-NW) group demonstrated a higher risk of ICAS (full-adjusted odds ratio [OR], 1.91; 95% confidence interval [CI], 1.42-2.57), while no significant association was observed in the metabolic unhealthy obesity (MUO) group (full-adjusted OR, 1.07; 95% CI, 0.70-1.65) and other metabolic healthy groups regardless of BMI. The results were consistent across gender, age, smoking, alcohol intake, and physical activity subgroups. CONCLUSION: The present study suggested that MUH-NW individuals had a significant association with increased risk of ICAS compared with MH-NW individuals.

Association of triglyceride-glucose index and its related parameters with atherosclerotic cardiovascular disease: evidence from a 15-year follow-up of Kailuan cohort.

BACKGROUND: Triglyceride glucose (TyG) index and its related parameters have been introduced as cost-effective surrogate indicators of insulin resistance, while prospective evidence of their effects on atherosclerotic cardiovascular disease (ASCVD) remained scattered and inconsistent. We aimed to evaluate the association of TyG and its related parameters with new-onset ASCVD, and the predictive capacity were further compared. METHOD: A total of 95,342 ASCVD-free participants were enrolled from the Kailuan study. TyG and its related parameters were defined by fasting blood glucose, triglyceride, body mass index (BMI), waist circumstance (WC) and waist-to-height ratio (WHtR). The primary outcome was incident ASCVD, comprising myocardial infarction (MI) and ischemic stroke (IS). Cox proportional hazard models and restricted cubic spline (RCS) analyses were adopted to investigate the association between each index and ASCVD. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were used for comparison of their predictive value for ASCVD. RESULTS: During a median follow-up of 15.0 years, 8,031 new cases of ASCVD were identified. The incidence rate of ASCVD increased along with elevated levels of each index, and the relationships were found to be nonlinear in the RCS analyses. The hazard ratio (HR) and 95% confidence interval (95% CI) for ASCVD was 1.39 (1.35, 1.43), 1.46 (1.41, 1.50), 1.50 (1.46, 1.55), and 1.52 (1.48, 1.57) per 1 IQR increase of baseline TyG, TyG-BMI, TyG-WC, and TyG-WHtR, respectively, and the association were more pronounced for females and younger individuals aged < 60 years (Pfor interaction<0.05). Using the updated mean or time-varying measurements instead of baseline indicators did not significantly alter the primary findings. Additionally, TyG-WC and TyG-WHtR showed better performance in predicting risk of ASCVD than TyG, with the IDI (95% CI) of 0.004 (0.001, 0.004) and 0.004 (0.001, 0.004) and the category-free NRI (95% CI) of 0.120 (0.025, 0.138) and 0.143 (0.032, 0.166), respectively. Similar findings were observed for MI and IS. CONCLUSIONS: Both the TyG index and its related parameters were significantly and positively associated with ASCVD. TyG-WC and TyG-WHtR had better performance in predicting incident ASCVD than TyG, which might be more suitable indices for risk stratification and enhance the primary prevention of ASCVD.

Constitutively expressed small heat shock protein LsHsp21.5 not only enhances heat tolerance but also helps to maintain reproduction in female Laodelphax striatellus.

Coping with stressful conditions and maintaining reproduction are two key biological processes that affect insect population dynamics. Small heat shock proteins (sHSPs) are involved in the stress response and the development of insects. The sHsp gene Laodelphax striatellus (Hemiptera: Delphacidae) sHsp 21.5 (LsHsp21.5) showed constitutive, stage- and organ-specific expression in L. striatellus, a pest that damages cultivated rice in east Asia. The expression of LsHsp21.5 was highest in the ovary, with 43.60, 12.99 and 1.45 time higher expression here than in the head, gut and female fat bodies, respectively. The expression of this gene was weakly affected by heat or cold shock. The gene provided in vitro protection against heat damage to malate dehydrogenase and in vivo protection against heat stress in Escherichia coli (Enterobacteriales: Enterobacteriaceae) BL21(DE3) and L. striatellus. Moreover, L. striatellus reproduction decreased by 1.85 times when the expression of LsHsp21.5 was inhibited by RNA interference. The expression of some genes related to reproduction, such as the homologous gene of chorion protein, also declined. These results suggest that LsHsp21.5 expression not only protects other proteins against stress but also helps maintain the stable expression of some reproduction-related genes under non-stressful conditions, with impacts on L. striatellus fecundity.

Longitudinal cardiovascular health measured by life's essential 8 metrics with incident diabetes: A 13-year prospective cohort study.

AIMS: To investigate the associations of baseline and longitudinal cardiovascular health (CVH) measured by 'Life's Essential 8' (LE8) metrics with the risk of diabetes in Chinese people with normoglycaemia or prediabetes. MATERIALS AND METHODS: A total 86,149 participants without diabetes were enroled from the Kailuan study and were stratified by baseline glycaemic status (normoglycaemia or prediabetes). Cardiovascular health score ranged from 0 to 100 points was categorised into low (0-49), middle (50-79), and high (80-100) CVH status. Cox regressions were used to assess the associations of baseline and time-updated CVH status with incident diabetes in the overall cohort and across baseline glycaemic statuses. RESULTS: During a median follow-up of 12.94 (interquartile rage: 12.48-13.16) years, we identified 13,097 (15.20%) cases of incident diabetes. Baseline and time-updated high CVH status was associated with a lower risk of diabetes, the corresponding hazard ratio (HR) versus low CVH status was 0.27 (95% confidence interval [CI], 0.23-0.31) and 0.26 (95% CI, 0.23-0.30) in the overall cohort, respectively. Additionally, the effect of high CVH on diabetes was more prominent in participants with normoglycaemia than those with prediabetes (P < 0.0001), with an HR of 0.26 (95% CI, 0.22-0.31) versus 0.50 (95% CI, 0.41-0.62) for baseline CVH, and 0.25 (95% CI, 0.21-0.30) versus 0.39 (95% CI, 0.32-0.48) for time-updated CVH. CONCLUSIONS: Elevated baseline and longitudinal CVH score assessed by LE8 metrics is associated with a lower risk of subsequent diabetes, especially in normoglycaemic adults.

Tannic Acid Modulation of Substrate Utilization, Microbial Community, and Metabolic Traits in Sludge Anaerobic Fermentation for Volatile Fatty Acid Promotion.

Anaerobic fermentation is a crucial route to realize effective waste activated sludge (WAS) resource recovery and utilization, while the overall efficiency is commonly restrained by undesirable disruptors (i.e., chemical dewatering agents). This work unveiled the unexpectedly positive effects of biodewatering tannic acid (TA) on the volatile fatty acids (VFAs) biosynthesis during WAS anaerobic fermentation. The total VFAs yield was remarkably increased by 15.6 folds with enriched acetate and butyrate in TA-occurred systems. TA was capable to disintegrate extracellular polymeric substances to promote the overall organics release. However, TA further modulated the soluble proteins structure by hydrogen bonding and hydrophobic interactions, resulting in the decrease of proteins bioavailability and consequential alteration of metabolic substrate feature. These changes reshaped the microbial community and stimulated adaptive regulatory systems in hydrolytic-acidogenic bacteria. The keystone species for carbohydrate metabolism (i.e., Solobacterium and Erysipelotrichaceae) were preferentially enriched. Also, the typical quorum sensing (i.e., enhancing substrate transport) and two-component systems (i.e., sustaining high metabolic activity) were activated to promote the microbial networks connectivity and ecological cooperative behaviors in response to TA stress. Additionally, the metabolic functions responsible for carbohydrate hydrolysis, transmembrane transport, and intracellular metabolism as well as VFA biosynthesis showed increased relative abundance, which maintained high microbial activities for VFAs biosynthesis. This study underscored the advantages of biodewatering TA for WAS treatment in the context of resource recovery and deciphered the interactive mechanisms.

Chemokine CCL2 promotes cardiac regeneration and repair in myocardial infarction mice via activation of the JNK/STAT3 axis.

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 µg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 µM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 µM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

Bidirectional extracellular electron transfer pathways of Geobacter sulfurreducens biofilms: Molecular insights into extracellular polymeric substances.

The basis for bioelectrochemical technology is the capability of electroactive bacteria (EAB) to perform bidirectional extracellular electron transfer (EET) with electrodes, i.e. outward- and inward-EET. Extracellular polymeric substances (EPS) surrounding EAB are the necessary media for EET, but the biochemical and molecular analysis of EPS of Geobacter biofilms on electrode surface is largely lacked. This study constructed Geobacter sulfurreducens-biofilms performing bidirectional EET to explore the bidirectional EET mechanisms through EPS characterization using electrochemical, spectroscopic fingerprinting and proteomic techniques. Results showed that the inward-EET required extracellular redox proteins with lower formal potentials relative to outward-EET. Comparing to the EPS extracted from anodic biofilm (A-EPS), the EPS extracted from cathodic biofilm (C-EPS) exhibited a lower redox activity, mainly due to a decrease of protein/polysaccharide ratio and α-helix content of proteins. Furthermore, less cytochromes and more tyrosine- and tryptophan-protein like substances were detected in C-EPS than in A-EPS, indicating a diminished role of cytochromes and a possible role of other redox proteins in inward-EET. Proteomic analysis identified a variety of redox proteins including cytochrome, iron-sulfur clusters-containing protein, flavoprotein and hydrogenase in EPS, which might serve as an extracellular redox network for bidirectional EET. Those redox proteins that were significantly stimulated in A-EPS and C-EPS might be essential for outward- and inward-EET and warranted further research. This work sheds light on the mechanism of bidirectional EET of G. sulfurreducens biofilms and has implications in improving the performance of bioelectrochemical technology.

Environmental exposure to per- and polyfluoroalkyl substances mixture and asthma in adolescents.

BACKGROUND: Previous epidemiological studies about the relationship between per- and polyfluoroalkyl substances (PFAS) concentrations and adolescent asthma have typically examined single PFAS, without considering the mixtures effects of PFAS. METHODS: Using data from the 2013-2018 National Health and Nutrition Examination Survey (NHANES), 886 adolescents aged 12-19 years were included in this study. We explored the association between PFAS mixture concentrations and adolescent asthma using weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models, respectively. RESULTS: After adjusting for confounders, the results of the WQS regression and BKMR models were consistent, with mixed exposure to the five PFAS not significantly associated with asthma in all adolescents. The association remained nonsignificant in the subgroup analysis by sex. CONCLUSIONS: Our study demonstrated no significant association between mixed exposure to PFAS and adolescent asthma, and more large cohort studies are needed to confirm this in the future.

Systemic Immune-Inflammation Response is Associated with Futile Recanalization After Endovascular Treatment.

BACKGROUND: Frequent incidence of futile recanalization decreases the benefit of endovascular treatment (EVT) in acute ischemic stroke. We hypothesized that the inflammation and immune response after ischemic are associated with futile recanalization. We aimed to investigate the correlation of admission systemic immune-inflammation index (SII) with futile recanalization post EVT. METHODS: Patients with successful recanalization (modified Thrombolysis in Cerebral Ischemia angiographic score 2b-3) and maintained artery recanalized after 24 h of EVT were chosen from a prospective nationwide registry study. Futile recanalization was defined as a poor functional outcome (modified Rankin Scale score 3-6) at 90 days, irrespective of a successful recanalization. At admission, SII was calculated as (platelet count × neutrophil count)/lymphocyte count/100. Logistic regression analysis helped to test the relationship of SII with futile recanalization. RESULTS: Among the 1,002 patients included, futile recanalization occurred in 508 (50.70%). No matter whether tested as quartiles or continuous variables, SII was significantly associated with futile recanalization (P < 0.05), and for every one standard deviation increase of SII, the risk of futile recanalization elevated by 22.3% (odds ratio 1.223, 95% confidence interval 1.053-1.444, P = 0.0093). Moreover, no significant interactions could be observed between SII or SII quartiles and age, baseline National Institutes of Health Stroke Scale scores, onset-to-recanalization time, and modified Thrombolysis in Cerebral Ischemia angiographic scores (all P for interaction > 0.05). CONCLUSIONS: Early SII elevation was associated with an increased risk of futile recanalization among patients with EVT. Our results indicated that therapeutic drug targeting hyperreactive immune-inflammation response might be helpful for reducing the incidence of futile recanalization.

A gene cluster encoding a nonribosomal peptide synthetase-like enzyme catalyzes γ-aromatic butenolides.

Sea cucumber-derived fungi have attracted much attention due to their capacity to produce an incredible variety of secondary metabolites. Genome-wide information on Aspergillus micronesiensis H39 obtained using third-generation sequencing technology (PacBio-SMRT) showed that the strain contains nonribosomal peptide synthetase (NRPS)-like gene clusters, which aroused our interest in mining its secondary metabolites. 11 known compounds (1-11), including two γ-aromatic butenolides (γ-AB) and five cytochalasans, were isolated from A. micronesiensis H39. The structures of the compounds were determined by NMR and ESIMS, and comparison with those reported in the literature. From the perspective of biogenetic origins, the γ-butyrolactone core of compounds 1 and 2 was assembled by NRPS-like enzyme. All of the obtained compounds showed no inhibitory activity against drug-resistant bacteria and fungi, as well as compounds 1 and 2 had no anti-angiogenic activity against zebrafish.

Evolution of Wolbachia reproductive and nutritional mutualism: insights from the genomes of two novel strains that double infect the pollinator of dioecious Ficus hirta.

Wolbachia is a genus of maternally inherited endosymbionts that can affect reproduction of their hosts and influence metabolic processes. The pollinator, Valisia javana, is common in the male syconium of the dioecious fig Ficus hirta. Based on a high-quality chromosome-level V. javana genome with PacBio long-read and Illumina short-read sequencing, we discovered a sizeable proportion of Wolbachia sequences and used these to assemble two novel Wolbachia strains belonging to supergroup A. We explored its phylogenetic relationship with described Wolbachia strains based on MLST sequences and the possibility of induction of CI (cytoplasmic incompatibility) in this strain by examining the presence of cif genes known to be responsible for CI in other insects. We also identified mobile genetic elements including prophages and insertion sequences, genes related to biotin synthesis and metabolism. A total of two prophages and 256 insertion sequences were found. The prophage WOjav1 is cryptic (structure incomplete) and WOjav2 is relatively intact. IS5 is the dominant transposon family. At least three pairs of type I cif genes with three copies were found which may cause strong CI although this needs experimental verification; we also considered possible nutritional effects of the Wolbachia by identifying genes related to biotin production, absorption and metabolism. This study provides a resource for further studies of Wolbachia-pollinator-host plant interactions.

Impacts of DNA methylases and demethylases on the methylation and expression of Arabidopsis ethylene signal pathway genes.

Arabidopsis ethylene (ET) signal pathway plays important roles in various aspects. Cytosine DNA methylation is significant in controlling gene expression in plants. Here, we analyzed the bisulfite sequencing and mRNA sequencing data from Arabidopsis (de)methylase mutants met1, cmt3, drm1/2, ddm1, ros1-4, and rdd to investigate how DNA (de)methylases influence the DNA methylation and expression of Arabidopsis ET pathway genes. At least 32 genes are found to involved in Arabidopsis ET pathway by text mining. Among them, 14 genes are unmethylated or methylated with very low levels. ACS6 and ACS9 are conspicuously methylated within their upstream regions. The other 16 genes are predominantly methylated at the CG sites within gene body regions in wild-type plants, and mutation of MET1 resulted in almost entire elimination of the CG methylations. In addition, CG methylations within some genes are jointly maintained by MET1 and other (de)methylases. Analyses of mRNA-seq data indicated that some ET pathway genes were differentially expressed between wild-type and diverse mutants. PDF1.2, the marker gene of ET signal pathway, was found being regulated indirectly by the methylases. Eighty-two transposable elements (TEs) were identified to be associated to 15 ET pathway genes. ACS11 is found located in a heterochromatin region that contains 57 TEs, indicating its specific expression and regulation. Together, our results suggest that DNA (de)methylases are implicated in the regulation of CG methylation within gene body regions and transcriptional activity of some ET pathway genes and that maintenance of normal CG methylation is essential for ET pathway in Arabidopsis.

Rosmarinic Acid-Crosslinked Supramolecular Nanoassembly with Self-Regulated Photodynamic and Anti-Metastasis Properties for Synergistic Photoimmunotherapy.

A primary concern about photodynamic therapy (PDT) is its inability to regulate the generation levels of reactive oxidative species (ROS) based on the complex microenvironment, resulting in the impairment toward normal tissues and immunosuppression. Besides, tumor metastasis also compromises PDT's efficacy and drives mortality. However, it is very challenging to achieve such two goals within one nanosystem. Here, the nanoassembly (CPR) with self-regulated photodynamic and antimetastasis properties comprises three parts: chlorin e6-conjugated ß-cyclodextrin (CD-Ce6) acts as the main PDT agent and ferrocene (Fc)-terminated phenylboronic acid-containing conjugates entering into the cavity of CD-Ce6, as well as rosmarinic acid (RA)-boronic acid crosslinked shell. Compared with non-crosslinked counterpart, CPR displays better stability and enhanced tumor accumulation. Under laser irradiation, CPR generates plenty of ROS to damage tumor cells and induce immunogenic cell death. Mildly acidic TME partly cleaves the crosslinkers to dissociate antioxidant RAs from micelles, which together with Fc in CPR scavenge PDT-induced ROS in the TME. By contrast, under acidic lysosomal conditions, Fc catalyzes abundant H2 O2 in tumor cells to produce highly cytotoxic •OH, while RA continuously reduces ferroptosis-generated Fc+ into Fc, both to augment the PDT efficacy in tumor cells. CPR also remarkably hinders the epithelial-mesenchymal transition to prevent the lung metastasis.

In Situ Tumor Vaccine for Lymph Nodes Delivery and Cancer Therapy Based on Small Size Nanoadjuvant.

Tumor vaccine is a promising cancer treatment modality, however, the convenient antigens loading in vivo and efficient delivery of vaccines to lymph nodes (LNs) still remain a formidable challenge. Herein, an in situ nanovaccine strategy targeting LNs to induce powerful antitumor immune responses by converting the primary tumor into whole-cell antigens and then delivering these antigens and nanoadjuvants simultaneously to LNs is proposed. The in situ nanovaccine is based on a hydrogel system, which loaded with doxorubicin (DOX) and nanoadjuvant CpG-P-ss-M. The gel system exhibits ROS-responsive release of DOX and CpG-P-ss-M, generating abundant in situ storage of whole-cell tumor antigens. CpG-P-ss-M adsorbs tumor antigens through the positive surface charge and achieves charge reversal, forming small-sized and negatively charged tumor vaccines in situ, which are then primed to LNs. Eventually, the tumor vaccine promotes antigens uptake by dendritic cells (DCs), maturation of DCs, and proliferation of T cells. Moreover, the vaccine combined with anti-CTLA4 antibody and losartan inhibits tumor growth by 50%, significantly increasing the percentage of splenic cytotoxic T cells (CTLs), and generating tumor-specific immune responses. Overall, the treatment effectively inhibits primary tumor growth and induces tumor-specific immune response. This study provides a scalable strategy for in situ tumor vaccination.

Induction of Human Motor Cortex Plasticity by Theta Burst Transcranial Ultrasound Stimulation.

OBJECTIVE: Transcranial ultrasound stimulation (TUS) is a promising noninvasive brain stimulation technique with advantages of high spatial precision and ability to target deep brain regions. This study aimed to develop a TUS protocol to effectively induce brain plasticity in human subjects. METHODS: An 80-second train of theta burst patterned TUS (tbTUS), regularly patterned TUS (rTUS) with the same sonication duration, and sham tbTUS was delivered to the motor cortex in healthy subjects. Transcranial magnetic stimulation (TMS) was used to examine changes in corticospinal excitability, intracortical inhibition and facilitation, and the site of plasticity induction. The effects of motor cortical tbTUS on a visuomotor task and the effects of occipital cortex tbTUS on motor cortical excitability were also tested. RESULTS: The tbTUS produced consistent increase in corticospinal excitability for at least 30 minutes, whereas rTUS and sham tbTUS produced no significant change. tbTUS decreased short-interval intracortical inhibition and increased intracortical facilitation. The effects of TMS in different current directions suggested that the site of the plastic changes was within the motor cortex. tbTUS to the occipital cortex did not change motor cortical excitability. Motor cortical tbTUS shortened movement time in a visuomotor task. INTERPRETATION: tbTUS is a novel and efficient paradigm to induce cortical plasticity in humans. It has the potential to be developed for neuromodulation treatment for neurological and psychiatric disorders, and to advance neuroscience research. ANN NEUROL 2022;91:238-252.

Magnitude and time course of insulin resistance accumulation with the risk of cardiovascular disease: an 11-years cohort study.

BACKGROUND: The risk of cardiovascular disease (CVD) depended on the magnitude and exposure duration of insulin resistance (IR). This study aimed to investigate the associations of cumulative metabolic score for IR (cumMETS-IR) with incident CVD, and to further explore the modulated effects of time course of METS-IR accumulation. METHODS: We enrolled 47,270 participants without CVD and underwent three examinations during 2006-2010 from the Kailuan study. CumMETS-IR from 2006 to 2010 were calculated as the mean values of METS-IR between consecutive examinations multiplying by time intervals between visits. Time course of METS-IR accumulation was calculated as the slope of METS-IR versus time. Hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD risk were calculated with multivariable-adjusted Cox regressions. RESULTS: During a median follow-up of 10.99 years, we identified 3184 cases of incident CVD. The risk of incident CVD increased with increasing cumMETS-IR (HR, 1.77; 95% CI 1.58-1.98 for the Q4 versus Q1 group), exposure duration (HR, 1.60; 95% CI 1.45-1.77 for 6 years versus 0 years), and cumulative burden (HR, 1.49; 95% CI 1.37-1.61 for burden ≥ 0 versus < 0). A positive slope was associated with 14% higher risk of CVD (HR, 1.14; 95% CI 1.07-1.22). When combining cumMETS-IR and slope, those with cumMETS-IR ≥ median (142.78) and slope ≥ 0 had the highest risk of CVD (HR,1.38; 95% CI 1.25-1.53). CONCLUSIONS: The risk of CVD increased with elevated cumMETS-IR and an increasing trend over time, emphasizing the importance of maintaining optimal METS-IR levels across life span.