Exploring Integrin α5ß1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies.

Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Although several drugs are approved for the treatment of PAH, mortality remains high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored. We found that the arginine-glycine-aspartate (RGD)-binding integrin α5ß1 is upregulated in PA endothelial cells (PAEC) and PA smooth muscle cells (PASMC) from PAH patients and remodeled PAs from animal models. Blockade of the integrin α5ß1 or depletion of the α5 subunit resulted in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. Using a novel small molecule integrin inhibitor and neutralizing antibodies, we demonstrated that α5ß1 integrin blockade attenuates pulmonary vascular remodeling and improves hemodynamics and RV function in multiple preclinical models. Our results provide converging evidence to consider α5ß1 integrin inhibition as a promising therapy for pulmonary hypertension. One sentence summary: The α5ß1 integrin plays a crucial role in pulmonary vascular remodeling.

ß-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers.

NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in most solid cancers, emerging as a promising target for tumor-selective killing. ß-Lapachone (ß-Lap), an NQO1 bioactivatable drug, exhibits significant antitumor effects on NQO1-positive cancer cells by inducing immunogenic cell death (ICD) and enhancing tumor immunogenicity. However, the interaction between ß-Lap-mediated antitumor immune responses and neutrophils, novel antigen-presenting cells (APCs), remains unknown. This study demonstrates that ß-Lap selectively kills NQO1-positive murine tumor cells by significantly increasing intracellular ROS formation and inducing DNA double strand breaks (DSBs), resulting in DNA damage. Treatment with ß-Lap efficiently eradicates immunocompetent murine tumors and significantly increases the infiltration of tumor-associated neutrophils (TANs) into the tumor microenvironment (TME), which plays a crucial role in the drug's therapeutic efficacy. Further, the presence of ß-Lap-induced antigen medium leads bone marrow-derived neutrophils (BMNs) to directly kill murine tumor cells, aiding in dendritic cells (DCs) recruitment and significantly enhancing CD8+ T cell proliferation. ß-Lap treatment also drives the polarization of TANs toward an antitumor N1 phenotype, characterized by elevated IFN-ß expression and reduced TGF-ß cytokine expression, along with increased CD95 and CD54 surface markers. ß-Lap treatment also induces N1 TAN-mediated T cell cross-priming. The HMGB1/TLR4/MyD88 signaling cascade influences neutrophil infiltration into ß-Lap-treated tumors. Blocking this cascade or depleting neutrophil infiltration abolishes the antigen-specific T cell response induced by ß-Lap treatment. Overall, this study provides comprehensive insights into the role of tumor-infiltrating neutrophils in the ß-Lap-induced antitumor activity against NQO1-positive murine tumors.

Effect of oxidized starch on the storage stability of frozen raw noodles: Water distribution, protein structure, and quality attributes.

Freezing is a popular method of food preservation with multiple advantages. However, it may change the internal composition and quality of food. This study aimed to investigate the effect of modified starch on the storage stability of frozen raw noodles (FRNs) under refrigerated storage conditions. Oxidized starch (OS), a modified starch, is widely used in the food industry. In the present study, texture and cooking loss rate analyses showed that the hardness and chewiness of FRNs with added OS increased and the cooking loss rate decreased during the frozen storage process. Low-field nuclear magnetic resonance characterization confirmed that the water-holding capacity of FRNs with OS was enhanced. When 6% OS was added, the maximum freezable water content of FRNs was lower than the minimum freezable water content (51%) of FRNs without OS during freezing. Fourier-transform infrared spectroscopy showed that after the addition of OS, the secondary structures beneficial for structural maintenance were increased, forming a denser protein network and improving the microstructure of FRNs. In summary, the water state, protein structure, and quality characteristics of FRNs were improved by the addition of OS within an appropriate range.

ACE2 mediates tryptophan alleviation on diarrhea by repairing intestine barrier involved mTOR pathway.

The membrane-delimited receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), angiotensin-converting enzyme 2 (ACE2), which is expressed in the intestine, collaborates with broad neutral amino acid transporter 1 (B0AT1). Tryptophan (Trp) is transported into intestinal epithelial cells by ACE2 and B0AT1. However, whether ACE2 and its binding protein B0AT1 are involved in Trp-mediated alleviation of intestinal injury is largely unknown. Here, we used weaned piglets and IPEC-J2 cells as models and found that ACE2/B0AT1 alleviated lipopolysaccharide (LPS)-induced diarrhea and promoted intestinal barrier recovery via transport of Trp. The levels of the aryl hydrocarbon receptor (AhR) and mechanistic target of rapamycin (mTOR) pathways were altered by ACE2. Dietary Trp supplementation in LPS-treated weaned piglets revealed that Trp alleviated diarrhea by promoting ACE2/B0AT1 expression, and examination of intestinal morphology revealed that the damage to the intestinal barrier was repaired. Our study demonstrated that ACE2 accompanied by B0AT1 mediated the alleviation of diarrhea by Trp through intestinal barrier repair via the mTOR pathway.

Anti-PD-1 cis-delivery of low-affinity IL-12 activates intratumoral CD8+T cells for systemic antitumor responses.

Immune checkpoint blockade (ICB) therapies function by alleviating immunosuppression on tumor-infiltrating lymphocytes (TILs) but are often insufficient to fully reactivate these dysfunctional TILs. Although interleukin 12 (IL-12) has been used in combination with ICB to improve efficacy, this remains limited by severe toxicity associated with systemic administration of this cytokine. Here, we engineer a fusion protein composed of an anti-PD-1 antibody and a mouse low-affinity IL-12 mutant-2 (αPD1-mIL12mut2). Systemic administration of αPD1-mIL12mut2 displays robust antitumor activities with undetectable toxicity. Mechanistically, αPD1-mIL12mut2 preferentially activates tumor-infiltrating PD-1+CD8+T cells via high-affinity αPD-1 mediated cis-binding of low-affinity IL-12. Additionally, αPD1-mIL12mut2 treatment exerts an abscopal effect to suppress distal tumors, as well as metastasis. Collectively, αPD1-mIL12mut2 treatment induces robust systemic antitumor responses with reduced side effects.

Macroscopic tunneling probe of Moiré spin textures in twisted CrI3.

Various noncollinear spin textures and magnetic phases have been predicted in twisted two-dimensional CrI3 due to competing ferromagnetic (FM) and antiferromagnetic (AFM) interlayer exchange from moiré stacking-with potential spintronic applications even when the underlying material possesses a negligible Dzyaloshinskii-Moriya or dipole-dipole interaction. Recent measurements have shown evidence of coexisting FM and AFM layer order in small-twist-angle CrI3 bilayers and double bilayers. Yet, the nature of the magnetic textures remains unresolved and possibilities for their manipulation and electrical readout are unexplored. Here, we use tunneling magnetoresistance to investigate the collective spin states of twisted double-bilayer CrI3 under both out-of-plane and in-plane magnetic fields together with detailed micromagnetic simulations of domain dynamics based on magnetic circular dichroism. Our results capture hysteretic and anisotropic field evolutions of the magnetic states and we further uncover two distinct non-volatile spin textures (out-of-plane and in-plane domains) at ≈1° twist angle, with a different global tunneling resistance that can be switched by magnetic field.

Conformal frequency selective rasorber in S, C, X-band with low backward-scattering.

In this paper, a polarization-insensitive high transmittance bandpass filter with low radar cross section (RCS) in both S- and X-band is proposed. This is the first study to use the partition layout loading approach for conformal structures with transmissive windows, reducing the operating band RCS. Curved structures have stronger radiation at a smaller angle to the incident wave, and that is how their scattering differs from uniform scattering from flat structures. The structure is divided by analyzing the radiative contribution of different regions. The surface was discussed in regions according to surface angles, and a new partition layout loading method was used to suppress the side currents and decreased backward scattering, achieving a backward RCS reduction of more than 10 dB at 4-8 GHz (66.7%). The bandpass layer operating at 6.9 GHz is designed through equivalent circuit theory. In combination with the lossy layer, absorption above 0.8 at 3.7-5.6 GHz and 9.1-12.5 GHz was achieved. Further, the structure was fashioned into a curved surface with varying curvature, demonstrating its effective absorption and transmission properties across different curvatures. A 15 × 15 cell structure was designed and fabricated, and there was good agreement between the test results and simulation results. The proposed structure has important applications in radomes, conformal structures, and electromagnetic shielding.

Promising Cytokine Adjuvants for Enhancing Tuberculosis Vaccine Immunity.

Tuberculosis, caused by Mycobacterium tuberculosis (M. tuberculosis), remains a formidable global health challenge, affecting a substantial portion of the world's population. The current tuberculosis vaccine, bacille Calmette-Guérin (BCG), offers limited protection against pulmonary tuberculosis in adults, underscoring the critical need for innovative vaccination strategies. Cytokines are pivotal in modulating immune responses and have been explored as potential adjuvants to enhance vaccine efficacy. The strategic inclusion of cytokines as adjuvants in tuberculosis vaccines holds significant promise for augmenting vaccine-induced immune responses and strengthening protection against M. tuberculosis. This review delves into promising cytokines, such as Type I interferons (IFNs), Type II IFN, interleukins such as IL-2, IL-7, IL-15, IL-12, and IL-21, alongside the use of a granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant, which has shown effectiveness in boosting immune responses and enhancing vaccine efficacy in tuberculosis models.

Sophocarpine attenuates doxorubicin-induced heart injury through inhibition of fibrosis.

BACKGROUND: Doxorubicin (DOX) is a potent anti-cancer medication that is associated with numerous adverse effects, particularly concerning damage to the heart. METHODS: This study aimed to investigate the impact of sophocarpine (SOP) on DOX-induced heart injury through both in vivo and in vitro experiments. The experimental techniques employed encompassed echocardiography, hematoxylin/eosin (H&E) staining, Masson staining, immunohistochemical staining, western blotting, and so on. RESULTS: Echocardiography showed that SOP alleviated DOX-induced cardiac dysfunction, as evidenced by the improvements in both left ventricle ejection fraction and left ventricle fractional shortening. DOX caused upregulations of creatine kinase-MB and lactate dehydrogenase, while SOP decreased these indices. Staining methods such as H&E and Masson showed that SOP reversed the pathological changes induced by DOX. DOX elevated the expression levels of fibrosis-associated proteins such as Collagen I, Collagen III, α-SMA, Fibronectin, MMP-2, and MMP-9. However, SOP reversed these changes. Moreover, the study further revealed that SOP inhibited the TGF-ß1/Smad3 signaling pathway. CONCLUSIONS: These findings imply that SOP has the potential to mitigate DOX-induced heart injury by suppressing fibrosis. The underlying molecular mechanism may involve the inhibition of the TGF-ß1/Smad3 signaling pathway.

Prognostic Factors of Pediatric Acute Myeloid Leukemia Patients with t(8;21) (q22;q22): A Single-Center Retrospective Study.

This retrospective study aimed to analyze the treatment effect and prognostic factors of pediatric acute myeloid leukemia (AML) patients with t(8;21). A total of 268 newly diagnosed pediatric AML (pAML) enrolled from 1 January 2005 to 31 December 2022 were retrospectively reviewed, and 50 (18.7%) patients harbored t(8;21) translocation. CR rate, OS, EFS, and RFS were assessed by multivariate Logistic and Cox regression models in these patients. Of the 50 patients, 2 patients abandoned treatment during the first induction course. Of the remaining 48 patients who received double-induction therapy and were included in the final analyses, CR1 and CR2 were 75.0% (36/48) and 95.8% (46/48), respectively. The overall three-year OS, EFS, and RFS were 68.4% (95% CI, 55.0-85.1), 64.2% (95% CI, 50.7-81.4), and 65.5% (95% CI, 51.9-82.8), respectively. The presence of loss of sex chromosome (LOS) at diagnosis (n = 21) was associated with a better 3-year OS [87.5% (95% CI, 72.7-100) vs. 52.7% (95% CI, 35.1-79.3), p = 0.0089], 3-year EFS [81.6% (95% CI, 64.7-100) vs. 49.7% (95% CI, 32.4-76.4), p = 0.023], and 3-year RFS [81.6% (95% CI, 64.7-100) vs. 51.7% (95% CI, 33.9-78.9), p = 0.036] than those without LOS (n = 27), and it was also an independent good prognostic factor of OS (HR, 0.08 [95% CI, 0.01-0.48], p = 0.005), EFS (HR, 0.22 [95% CI, 0.05-0.85], p = 0.029), and RFS (HR, 0.21 [95% CI, 0.05-0.90], p = 0.035). However, extramedullary leukemia (EML) featured the independent risk factors of inferior OS (HR, 10.99 [95% CI, 2.08-58.12], p = 0.005), EFS (HR, 4.75 [95% CI, 1.10-20.61], p = 0.037), and RFS (HR, 6.55 [95% CI, 1.40-30.63], p = 0.017) in pediatric individuals with t(8;21) AML. Further analysis of combining LOS with EML indicated that the EML+LOS- subgroup had significantly inferior OS (92.9%, [95% CI, 80.3-100]), EFS (86.2%, [95% CI, 70.0-100]), and RFS (86.2%, [95% CI, 80.3-100]) compared to the other three subgroups (all p < 0.001). LOS and EML are independent prognostic factors of OS, EFS, and RFS with t(8;21) pAML patients. LOS combined with EML may help improve risk stratification.

Negation and social avoidance in language recruits the right inferior frontal gyrus: a tDCS study.

Introduction: In the process of comprehension, linguistic negation induces inhibition of negated scenarios. Numerous studies have highlighted the role of the right Inferior Frontal Gyrus (rIFG) - a key component of the inhibitory network - in negation processing. Social avoidance can be linguistically portrayed using attitudinal verbs such as "exclude" vs. "include", which inherently carry negative connotations. Consequently, we hypothesize that the interplay between explicit negation and the implicit negativity of avoidance verbs can be modulated via transcranial direct current stimulation (tDCS) targeting the rIFG. Methods: In our study, sixty-four participants read approach/avoidance sentences, which were either affirmative or negative, such as "Anne included (did not include) meat in her diet" vs. "Anne excluded (did not exclude) meat in her diet". This reading task followed a 20-minute tDCS session. The sentences were sequentially displayed, and at 1500 ms post-sentence, a verb was shown - either the one previously mentioned or its semantic alternative counterpart (e.g., included vs. excluded). Results: Findings revealed that anodal stimulation intensifies the inhibitory impact of negation during sentence comprehension. Under anodal conditions, negative sentences led to extended reading times for the mentioned verbs compared to their affirmative counterparts, suggesting an increased inhibitory effect on the verb. Furthermore, in avoidance sentences, anodal stimulation resulted in reduced reading times for alternative verbs (e.g. "included") in negative sentences compared to alternative verbs (e.g. "excluded") in negated approach sentences. Discussion: As "avoidance" is semantically equivalent to "non-approach", the inhibitory effect of negation is primarily applied to the implicit negation: NOT EXCLUDED = NOT→NOT (INCLUDED), which consequently activates the representation of the alternative verb making it more available. We further discuss these findings in light of the rIFG's pivotal role in processing attitudinal verbs and linguistic negation. This discussion is framed within the overarching context of the two-step model of negation processing, highlighting its significance in the realm of social communication.

Another Perspective of Over-Smoothing: Alleviating Semantic Over-Smoothing in Deep GNNs.

Graph neural networks (GNNs) are widely used for analyzing graph-structural data and solving graph-related tasks due to their powerful expressiveness. However, existing off-the-shelf GNN-based models usually consist of no more than three layers. Deeper GNNs usually suffer from severe performance degradation due to several issues including the infamous "over-smoothing" issue, which restricts the further development of GNNs. In this article, we investigate the over-smoothing issue in deep GNNs. We discover that over-smoothing not only results in indistinguishable embeddings of graph nodes, but also alters and even corrupts their semantic structures, dubbed semantic over-smoothing. Existing techniques, e.g., graph normalization, aim at handling the former concern, but neglect the importance of preserving the semantic structures in the spatial domain, which hinders the further improvement of model performance. To alleviate the concern, we propose a cluster-keeping sparse aggregation strategy to preserve the semantic structure of embeddings in deep GNNs (especially for spatial GNNs). Particularly, our strategy heuristically redistributes the extent of aggregations for all the nodes from layers, instead of aggregating them equally, so that it enables aggregate concise yet meaningful information for deep layers. Without any bells and whistles, it can be easily implemented as a plug-and-play structure of GNNs via weighted residual connections. Last, we analyze the over-smoothing issue on the GNNs with weighted residual structures and conduct experiments to demonstrate the performance comparable to the state-of-the-arts.

Emerging trends in CDs@hydrogels composites: from materials to applications.

Carbon dots (CDs) are nanoscale carbon materials with unique optical properties and biocompatibility. Their applications are limited by their tendency to aggregate or oxidize in aqueous environments. Turning weakness to strengths, CDs can be incorporated with hydrogels, which are three-dimensional networks of crosslinked polymers that can retain large amounts of water. Hydrogels can provide a stable and tunable matrix for CDs, enhancing their fluorescence, stability, and functionality. CDs@hydrogels, known for their ease of synthesis, strong binding capabilities, and rich surface functional groups, have emerged as promising composite materials. In this review, recent advances in the synthesis and characterization of CDs@hydrogels, composite materials composed of CDs and various types of natural or synthetic hydrogels, are summarized. The potential applications of CDs@hydrogels in fluorescence sensing, adsorption, drug delivery, antibacterial activity, flexible electronics, and energy storage are also highlighted. The current challenges and future prospects of CDs@hydrogels systems for the novel functional materials are discussed.

Syringeable Near-Infrared Light-Activated In Situ Immunogenic Hydrogel Boosts the Cancer-Immunity Cycle to Enhance Anticancer Immunity.

Effective anticancer immunity depends on properly activating multiple stepwise events in the cancer-immunity cycle. An immunologically "cold" tumor microenvironment (TME) engenders immune evasion and refractoriness to conventional checkpoint blockade immunotherapy. Here, we combine nanoparticle formulations and an in situ formed hydrogel scaffold to treat accessible tumors locally and to stimulate systemic immunity against metastatic tumor lesions. The nanoparticles encapsulate poly(ε-caprolactone)-derived cytotoxic chemotherapy and adjuvant of Toll-like receptor 7/8 through a reactive oxygen species (ROS)-cleavable linker that can be self-activated by the coassembled neighboring photosensitizer following near-infrared (NIR) laser irradiation. Further development results in syringeable, NIR light-responsive, and immunogenic hydrogel (iGEL) that can be implanted peritumorally and deposited into the tumor surgical bed. Upon NIR laser irradiation, the generated ROS induces iGEL degradation and bond cleavage in the polymer-drug conjugates, triggering the immunogenic cell death cascade in cancer cells and spontaneously releasing encapsulated agents to rewire the cancer-immunity cycle. Notably, upon application in multiple preclinical models of melanoma and triple-negative breast cancer, which are aggressive and refractory to conventional immunotherapy, iGEL induces durable remission of established tumors, extends postsurgical tumor-free survival, and inhibits metastatic burden. The result of this study is a locally administrable immunogenic hydrogel for triggering host systemic immunity to improve immunotherapeutic efficacy with minimal off-target side effects.

Electrochemical cytosensor utilizing tetrahedral DNA/bimetallic AuPd holothurian-shaped nanoparticles for ultrasensitive non-destructive detection of circulating tumor cells.

As a real-time fluid biopsy method, the detection of circulating tumor cells (CTCs) provides important information for the early diagnosis, precise treatment, and prognosis of cancer. However, the low density of CTCs in the peripheral blood hampers their capture and detection with high sensitivity and selectivity using currently available methods. Hence, we designed a sandwich-type electrochemical aptasensor that utilizes holothurian-shaped AuPd nanoparticles (AuPd HSs), tetrahedral DNA nanostructures (TDNs), and CuPdPt nanowire networks (NWs) interwoven with a graphdiyne (GDY) sheet for ultrasensitive non-destructive detection of MCF-7 breast cancer cells. CuPdPt NW-GDY effectively enhanced the electron transfer rate and coupled with the loaded TDNs. The TDNs could capture MCF-7 cells with precision and firmness, and the resulting composite complex was combined with AuPd HSs to form a sandwich-type structure. This novel aptasensor showed a linear range between 10 and 106 cells mL-1 and an ultralow detection limit of 7 cells mL-1. The specificity, stability, and repeatability of the measurements were successfully verified. Moreover, we used benzonase nuclease to achieve non-destructive recovery of cells for further clinical studies. According to the results, our aptasensor was more sensitive measuring the number of CTCs than other approaches because of the employment of TDNs, CuPdPt NW-GDY, and AuPd HSs. We designed a reliable sensor system for the detection of CTCs in the peripheral blood, which could serve as a new approach for cancer diagnosis at an early stage.

Targeting the dendritic cell-secreted immunoregulatory cytokine CCL22 alleviates radioresistance.

PURPOSE: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that dendritic cells (cDC) maintain Treg we sought to identify and target cDC signaling to block Treg infiltration after radiation. EXPERIMENTAL DESIGN: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT, but associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. RESULTS: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. CONCLUSIONS: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration, and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy.

Visible-light-induced three-component reactions of α-diazoesters, quinazolinones and cyclic ethers toward quinazoline-based hybrids.

An effective approach for the construction of 4-short-chain ether attached carbonyl group-substituted quinazolines was developed. Visible-light-induced three-component reactions of α-diazoesters, quinazolinones, and cyclic ethers, with a broad substrate scope and excellent functional group tolerance, under extremely mild conditions without the need for any additional additives and catalysts, selectively led to quinazoline-based hybrids in good to excellent yields. The synthesized hybrids, which are a conglomeration of a quinazoline, a short-chain ether, and a carbonyl group in one molecular skeleton, have potential for application in the development of new drugs or drug candidates.

Dihydroquercetin regulates HIF-1α/AKT/NR2B signalling to improve impaired brain function in rats with metabolic syndrome.

Dihydroquercetin (DHQ) is commonly used as a dietary additive, but its activity in improving brain injury with metabolic syndrome (MS) remains known. In present study, the MS rat model was induced using 10 % fructose water. The apoptosis rate of primary brain cells was detected. The HIF-1α/AKT/NR2B signalling pathway, levels of KEAP1/NRF2, HO-1 and NQO-1 were detected. In vitro experiments were performed using H2O2-stimulated PC-12 cells. The effect of DHQ on rates of cell survival and apoptosis were detected. After silencing HIF-1α, we further elucidate the mechanism of action of DHQ. The results indicated that DHQ reduced the hyperactivity and inhibited oxidative stress via increasing the levels of HIF-1α/AKT/NR2B signalling pathway, whereas regulated KEAP1/NRF2 pathway. In vitro experiments showed that the HIF-1α plays an important role in this process. Overall, DHQ may improve impaired brain function in rats with metabolic syndrome by regulating the HIF-1α/AKT/NR2B signalling pathway.

Neural correlates of emotion-label vs. emotion-laden word processing in late bilinguals: evidence from an ERP study.

The brain processes underlying the distinction between emotion-label words (e.g. happy, sad) and emotion-laden words (e.g. successful, failed) remain inconclusive in bilingualism research. The present study aims to directly compare the processing of these two types of emotion words in both the first language (L1) and second language (L2) by recording event-related potentials (ERP) from late Chinese-English bilinguals during a lexical decision task. The results revealed that in the early word processing stages, the N170 emotion effect emerged only for L1 negative emotion-laden words and L2 negative emotion-label words. In addition, larger early posterior negativity (EPN) was elicited by emotion-laden words than emotion-label words in both L1 and L2. In the later processing stages, the N400 emotion effect was evident for L1 emotion words, excluding positive emotion-laden words, while it was absent in L2. Notably, L1 emotion words elicited enhanced N400 and attenuated late positive complex (LPC) compared to those in L2. Taken together, these findings confirmed the engagement of emotion, and highlighted the modulation of emotion word type and valence on word processing in both early and late processing stages. Different neural mechanisms between L1 and L2 in processing written emotion words were elucidated.

Cryo-EM structure of human HCN3 channel and its regulation by cAMP.

HCN channels are important for regulating heart rhythm and nerve activity and have been studied as potential drug targets for treating depression, arrhythmia, nerve pain, and epilepsy. Despite possessing unique pharmacological properties, HCN channels share common characteristics in that they are activated by hyperpolarization and modulated by cAMP and other membrane lipids. However, the mechanisms of how these ligands bind and modulate HCN channels are unclear. In this study, we solved structures of full-length human HCN3 using cryo-EM and captured two different states, including a state without any ligand bound and a state with cAMP bound. Our structures reveal the novel binding sites for cholesteryl hemisuccinate in apo state and show how cholesteryl hemisuccinate and cAMP binding cause conformational changes in different states. These findings explain how these small modulators are sensed in mammals at the molecular level. The results of our study could help to design more potent and specific compounds to influence HCN channel activity and offer new therapeutic possibilities for diseases that lack effective treatment.