Inhibition of circDGKZ ameliorates myocardial ischemia/reperfusion injury by targeting miR-345-5p/TLR4.

AIMS: This study aims to explore the molecular mechanism of circular RNAs' (circRNAs) potential involvement in myocardial ischaemia-reperfusion injury (MIRI). METHODS AND RESULTS: Differently expressed genes in myocardial infarction (MI) were identified by screening the GEO database. Serum was collected from MI patients and healthy volunteers (n = 5 for each group). AC16 cells were cultured and exposed to hypoxia/reperfusion (H/R) treatment for the cell experiments. Then candidate genes were validated in human serum and the H/R model. Quantitative real-time PCR and western blot were used to detect expression of key molecules such as circDGKZ, miR-345-5p, and Toll-like receptor 4 (TLR4), as well as pyroptosis markers such as NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), ASC, C-caspase1, interleukin (IL)-1ß, and IL-18. CircDGKZ was positively correlated in human serum (P < 0.05) and in AC16 cells (P < 0.01). Knockdown of circDGKZ inhibited cardiomyocyte pyroptosis and the TLR4/nuclear factor kappa B (NF-κB) signalling pathway (all P < 0.05). A luciferase assay was used to detect the molecule interaction. MiR-345-5p was regulated by circDGKZ and regulated TLR4 in cardiomyocytes both through direct interaction (P < 0.01). The stability and distribution of circRNA or linear RNA were examined by subcellular localization and RNA decay assays. CircDGKZ was stably expressed in cardiomyocytes and mainly distributed in the cytoplasm (P < 0.01). Knockdown of circDGKZ also promoted the degradation of NLRP3 by inducing autophagy (P < 0.05). MIRI rat models were constructed (n = 5 for each group), and the cellular results were further confirmed in rat models (P < 0.05). CONCLUSIONS: Knockdown of circDGKZ interrupted pyroptosis and induced autophagy of cardiomyocytes via regulating miR-345-5p/TLR4/NF-κB.

Discovery of a novel SHP2 allosteric inhibitor using virtual screening, FMO calculation, and molecular dynamic simulation.

CONTEXT: SHP2 is a non-receptor protein tyrosine phosphatase to remove tyrosine phosphorylation. Functionally, SHP2 is an essential bridge to connect numerous oncogenic cell-signaling cascades including RAS-ERK, PI3K-AKT, JAK-STAT, and PD-1/PD-L1 pathways. This study aims to discover novel and potent SHP2 inhibitors using a hierarchical structure-based virtual screening strategy that combines molecular docking and the fragment molecular orbital method (FMO) for calculating binding affinity (referred to as the Dock-FMO protocol). For the SHP2 target, the FMO method prediction has a high correlation between the binding affinity of the protein-ligand interaction and experimental values (R2 = 0.55), demonstrating a significant advantage over the MM/PBSA (R2 = 0.02) and MM/GBSA (R2 = 0.15) methods. Therefore, we employed Dock-FMO virtual screening of ChemDiv database of ∼2,990,000 compounds to identify a novel SHP2 allosteric inhibitor bearing hydroxyimino acetamide scaffold. Experimental validation demonstrated that the new compound (E)-2-(hydroxyimino)-2-phenyl-N-(piperidin-4-ylmethyl)acetamide (7188-0011) effectively inhibited SHP2 in a dose-dependent manner. Molecular dynamics (MD) simulation analysis revealed the binding stability of compound 7188-0011 and the SHP2 protein, along with the key interacting residues in the allosteric binding site. Overall, our work has identified a novel and promising allosteric inhibitor that targets SHP2, providing a new starting point for further optimization to develop more potent inhibitors. METHODS: All the molecular docking studies were employed to identify potential leads with Maestro v10.1. The protein-ligand binding affinities of potential leads were further predicted by FMO calculations at MP2/6-31G* level using GAMESS v2020 system. MD simulations were carried out with AmberTools18 by applying the FF14SB force field. MD trajectories were analyzed using VMD v1.9.3. MM/GB(PB)SA binding free energy analysis was carried out with the mmpbsa.py tool of AmberTools18. The docking and MD simulation results were visualized through PyMOL v2.5.0.

Research progress on venous thrombosis development in patients with malignant tumors.

The coexistence of venous thromboembolism (VTE) within patients with cancer, known as cancer-associated thrombosis (CAT), stands as a prominent cause of mortality in this population. Over recent years, the incidence of VTE has demonstrated a steady increase across diverse tumor types, influenced by several factors such as patient management, tumor-specific risks, and treatment-related aspects. Furthermore, mutations in specific genes have been identified as potential contributors to increased CAT occurrence in particular cancer subtypes. We conducted an extensive review encompassing pivotal historical and ongoing studies on CAT. This review elucidates the risks, mechanisms, reliable markers, and risk assessment methodologies that can significantly guide effective interventions in clinical practice.

Percutaneous endoscopic suprapedicular decompression in the treatment of down-migrated lumbar disc herniation.

[OBJECTIVE]: This study aimed to investigate the clinical efficacy of percutaneous endoscopic suprapedicular decompression in treatment of down-migrated lumbar disc herniation. [METHODS]: The clinical data of 43 patients with down-migrated lumbar disc herniation treated with endoscopic surgery at our hospital between January 2022 and January 2023 were retrospectively analysed. Twenty-two and 21 patients underwent percutaneous endoscopic decompression using the suprapedicular and TESSYS approaches, respectively. The perioperative, follow-up, and imaging data of the groups were compared. [RESULTS]: Surgery was uneventful in both groups. The number of intraoperative fluoroscopies and duration of surgery were significantly lower in the suprapedicular group (p<0.05). The patients in both groups were followed up for at least 12 months. At the last follow-up, lumbar pain and leg pain visual analogue scale (VAS), Oswestry Disability Index (ODI), and 36-Item Short Form Health Survey (SF-36) scores were significantly improved in both groups compared with preoperative values (p<0.05); the differences in these indexes between the two groups were not significant preoperatively (p>0.05). However, at the last postoperative follow-up, lumbar pain VAS scores were significantly better in the suprapedicular group (0.83±0.85 vs. 2.54±1.32, p<0.05). There was no significant change in intervertebral space height or lumbar lordotic angle compared with preoperative values in either group at the last follow-up (p>0.05). However, the spinal canal cross-sectional area significantly increased (p<0.05). [CONCLUSION]: The treatment of down-migrated lumbar disc herniation via a suprapedicular approach enabled the incision of the superior margin of the pedicle as needed under direct vision, involved less fluoroscopy while preserving facet joint stability, and enabled targeted removal of the herniated nucleus pulposus, thus greatly reducing residual nucleus pulposus. This surgical procedure was safe, rapid, and showed satisfactory therapeutic efficacy.

The Impact of Valve Surgery on the Safety and Cardiac Function of Patients with Valvular Heart Disease Complicated by Pulmonary Arterial Hypertension.

Objective: This study evaluates the effects of valve surgery on safety and cardiac function in patients with valvular heart disease complicated by pulmonary arterial hypertension (PAH), focusing on postoperative outcomes influenced by age, heart function grade, and PAH severity. Methods: A retrospective analysis was conducted on 307 valve surgery patients from April 2017 to April 2022. The cohort had a mean age of 57.6 years, with 56.9% males, and was stratified by NYHA functional class II-IV. Outcomes assessed included mortality, complication rates, left ventricular ejection fraction (LVEF), and pulmonary artery systolic pressure (PASP), with statistical analysis performed using t-tests and chi-square tests for continuous and categorical data, respectively. Results: Postoperative outcomes varied significantly with age, NYHA class, and PASP grade. Patients aged ≤60 exhibited an average PASP reduction of 44.46% in the male group and 44.44% in the female group and an LVEF improvement of 5.28% in the male group and 5.80% in the female group. However, these patients showed a higher risk of postoperative complications, such as renal failure, arrhythmia, low cardiac output syndrome, respiratory insufficiency, (23.31%), and a higher mortality rate (13.53%)(P < .05). Higher NYHA classes correlated with increased postoperative risks of complications and mortality rates, and elevated PASP grades were associated with larger improvements in PASP and LVEF but also higher postoperative risks. Conclusion: Valve surgery in valvular heart disease with PAH is influenced by patient age, functional status, and PAH severity. Despite advances in surgical techniques, there remains a notable gap in understanding the nuanced interplay between these conditions and the variable outcomes of valve surgery. This study addresses this research gap, offering comprehensive insights into how age, heart function, and PAH severity influence postoperative outcomes. These findings are crucial for clinicians, providing a more informed basis for tailored treatment strategies, and ultimately enhancing patient care in this complex clinical scenario.Healthcare providers should consider the age-specific benefits and risks of valve surgery in patients with valvular heart disease and pulmonary arterial hypertension. Tailored decision-making, particularly for those aged ≤60, higher NYHA classes, or severe PAH, is essential for optimizing individual outcomes.

Clinical study of reoperation for acute type A aortic dissection.

Objective: The initial operation for type A aortic dissection has limitations, and there may be a need for reoperation in cases such as giant pseudoaneurysm formation and reduced blood supply to the distal vessels. In this study, we collected case data of patients who underwent cardiac major vascular surgery at our hospital to analyze the effectiveness of reoperation treatment options for type A aortic dissection and to summarize our treatment experience. Method: Between June 2018 and December 2022, 62 patients with type A aortic dissection (TAAD) underwent reoperation after previous surgical treatment. Of these, 49 patients (45 males) underwent endovascular aortic repair (EVAR) with a mean age of (49.69 ± 10.21) years (30-75 years), and 13 patients (11 males) underwent thoracoabdominal aortic replacement (TAAR) with a mean age of (41.00 ± 11.18) years (23-66 years). In this study, we retrospectively analyzed the recorded data of 62 patients. In addition, we summarized and analyzed their Computed Tomographic Angiography (CTA) results and perioperative complications. Outcome: In the EVAR group, 47 patients (95.92%) were successfully implanted with overlapping stents, and 2 patients died in the perioperative period. Postoperative complications included cerebral infarction (4.08%), acute renal insufficiency (30.61%), pulmonary insufficiency and need for ventilator (6.12%), poor wound healing (2.04%), postoperative reoperation (16.33%), and lower limb ischemia (2.04%). In the TAAR group, 12 patients (92.31%) were successfully revascularized and 1 patient died in the perioperative period. Postoperative complications included cerebral infarction (7.69%), acute kidney injury (46.15%), pulmonary insufficiency and need for ventilator (15.38%), poor wound healing (30.77%) and postoperative reoperation (15.38%). Conclusion: According to the results of the study, compared with TAAR, EVAR was less invasive, faster recovery, and offered a better choice for some high-risk and high-age patients with comorbid underlying diseases. However, the rate of revascularization was higher after EVAR than TAAR due to vascular lesions. Compared with the use of ascending aortic replacement + hemi-aortic arch replacement for acute type A aortic dissection in many countries and regions, the use of ascending aortic replacement + aortic arch replacement + elephant trunk stent is more traumatic in China, but facilitates reoperation. For young patients, the choice of treatment should be individualized combining vascular lesions and long-term quality of life.

Exceptional Magnetocaloric Responses in a Gadolinium Silicate with Strongly Correlated Spin Disorder for Sub-Kelvin Magnetic Cooling.

The development of magnetocaloric materials with a significantly enhanced volumetric cooling capability is highly desirable for the application of adiabatic demagnetization refrigerators in confined spatial environments. Here, the thermodynamic characteristics of a magnetically frustrated spin-7/2 Gd9.33[SiO4]6O2 is presented, which exhibits strongly correlated spin disorder below ≈1.5 K. A quantitative model is proposed to describe the magnetization results by incorporating nearest-neighbor Heisenberg antiferromagnetic and dipolar interactions. Remarkably, the recorded magnetocaloric responses are unprecedentedly large and applicable below 1.0 K. It is proposed that the S = 7/2 spin liquids serve as versatile platforms for investigating high-performance magnetocaloric materials in the sub-kelvin regime, particularly those exhibiting a superior cooling power per unit volume.

Discovery of novel covalent inhibitors of DJ-1 through hybrid virtual screening.

Background: DJ-1 is a ubiquitously expressed protein with multiple functions. Its overexpression has been associated with the occurrence of several cancers, positioning DJ-1 as a promising therapeutic target for cancer treatment. Methods: To find novel inhibitors of DJ-1, we employed a hybrid virtual screening strategy that combines structure-based and ligand-based virtual screening on a comprehensive compound library. Results: In silico study identified six hit compounds as potential DJ-1 inhibitors that were assessed in vitro at the cellular level. Compound 797780-71-3 exhibited antiproliferation activity in ACHN cells with an IC50 value of 12.18 µM and was able to inhibit the Wnt signaling pathway. This study discovers a novel covalent inhibitor for DJ-1 and paves the way for further optimization.

Binding Free Energy Calculation Based on the Fragment Molecular Orbital Method and Its Application in Designing Novel SHP-2 Allosteric Inhibitors.

The accurate prediction of binding free energy is a major challenge in structure-based drug design. Quantum mechanics (QM)-based approaches show promising potential in predicting ligand-protein binding affinity by accurately describing the behavior and structure of electrons. However, traditional QM calculations face computational limitations, hindering their practical application in drug design. Nevertheless, the fragment molecular orbital (FMO) method has gained widespread application in drug design due to its ability to reduce computational costs and achieve efficient ab initio QM calculations. Although the FMO method has demonstrated its reliability in calculating the gas phase potential energy, the binding of proteins and ligands also involves other contributing energy terms, such as solvent effects, the 'deformation energy' of a ligand's bioactive conformations, and entropy. Particularly in cases involving ionized fragments, the calculation of solvation free energy becomes particularly crucial. We conducted an evaluation of some previously reported implicit solvent methods on the same data set to assess their potential for improving the performance of the FMO method. Herein, we develop a new QM-based binding free energy calculation method called FMOScore, which enhances the performance of the FMO method. The FMOScore method incorporates linear fitting of various terms, including gas-phase potential energy, deformation energy, and solvation free energy. Compared to other widely used traditional prediction methods such as FEP+, MM/PBSA, MM/GBSA, and Autodock vina, FMOScore showed good performance in prediction accuracies. By constructing a retrospective case study, it was observed that incorporating calculations for solvation free energy and deformation energy can further enhance the precision of FMO predictions for binding affinity. Furthermore, using FMOScore-guided lead optimization against Src homology-2-containing protein tyrosine phosphatase 2 (SHP-2), we discovered a novel and potent allosteric SHP-2 inhibitor (compound 8).

Possible quantum-spin-liquid state in van der Waals cluster magnet Nb3Cl8.

The cluster magnet Nb3Cl8consists of Nb3trimmers that form an emergentS= 1/2 two-dimensional triangular layers, which are bonded by weak van der Waals interactions. Recent studies show that its room-temperature electronic state can be well described as a single-band Mott insulator. However, the magnetic ground state is non-magnetic due to a structural transition below about 100 K. Here we show that there exists a thickness threshold below which the structural transition will not happen. For a bulk crystal, a small fraction of the sample maintains the high-temperature structure at low temperatures and such remnant gives rise to linear-temperature dependence of the specific heat at very low temperatures. This is further confirmed by the measurements on ground powder sample orc-axis pressed single crystals, which prohibits the formation of the non-magnetic state. Moreover, the intrinsic magnetic susceptibility also tends to be constant with decreasing temperature. Our results suggest that Nb3Cl8with the high-temperature structure may host a quantum-spin-liquid ground state with spinon Fermi surfaces, which can be achieved by making the thickness of a sample smaller than a certain threshold.

Hybrid Organic-Inorganic Additive for Robust Al Anode in Alkaline Aluminum-Air Battery.

Aluminum-air batteries (AABs), known for their high energy density, environmental friendliness, and cost-effectiveness, show immense promise in the realm of energy conversion applications. Nonetheless, their commercialization has encountered inherent challenges of Al anode corrosion and material degradation. In this study, economical hybrid electrolyte additives to inhibit the Al corrosion are developed, safeguarding the integrity of the Al anode. Due to the synergistic interplay between the organic compound dithiothreitol, and inorganic compounds zinc chloride, a robust zinc film is formed on the Al surface This Zn film plays a pivotal role in quelling parasitic hydrogen evolution reactions that typically can plague the Al electrode. Consequently, the as-prepared hybrid additive culminates in a remarkable enhancement to AABs, delivering exceptional discharge capacity of 1793.37 mAh g-1 , high energy density of 2047 Wh kg-1 , and excellent battery longevity (over 20 h in on/off cycling tests). This study, therefore, introduces a novel approach in utilizing hybrid electrolyte additives to effectively counteract corrosion-related challenges and boost the stability and performance of AABs.

Carotid-subclavian bypass and endovascular aortic repair of Kommerell's diverticulum with aberrant left subclavian artery: A case report.

BACKGROUND: Kommerell's diverticulum (KD) with aberrant left subclavian artery is a rare congenital deformity and also has very little research literature about it (35% of case study). There are three types of aortic arch diverticulum. Even literature concerning the treatment options are limited. CASE SUMMARY: We present a case report of a 50-year-old male with KD in the right aortic arch with aberrant left subclavian artery. We conducted a total endovascular repair procedure, which is innovative and will spread more light in the medical world. Our patient has no past medical history and is a non-smoker and non-alcoholic. Patient presented with shortness of breath, chest pain and dizziness for six months. Blood tests were done and computerized tomography (CT) angiogram of the chest confirmed the diagnosis, illustrating showed a 3.9 cm KD. On Day 1, the CT angiogram showed mild dilatation of the thoracic aorta, adjacent esophagus, trachea was compressed and displaced. Surgery was planned as the treatment modality. Carotid-Subclavian artery bypass and endovascular aortic repair was conducted. We used prolene 5-0 C1 sutures to precisely anastomose a 6-mm Dacron graft to the left subclavian artery. Haemostasis was secured and wounds were closed. Protamine was administered and patient was shifted to intensive care unit. Post-operative, patient responded favorably and was discharged. Regular follow-up is done. CONCLUSION: The procedure we performed is novel. This will help the cardio-thoracic surgeons a better insight about the full procedures we conducted, thereby bringing more light and better treatment options in managing KD with aberrant subclavian artery.

Targeting DHODH reveals therapeutic opportunities in ATRA-resistant acute promyelocytic leukemia.

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice. Excitingly, 416 effectively overcame ATRA resistance in vitro and in vivo by inducing apoptosis and differentiation. Further mechanistic studies showed that PML/RARα lost the regulation of Bcl-2 and c-Myc in NB4-R1 cells, which probably contributed to ATRA resistance. Notably, 416 maintained its Bcl-2 and c-Myc down-regulation effect in NB4-R1 cells and overcome ATRA resistance by inhibiting DHODH. In conclusion, our study highlights the potential of 416 for APL therapy and overcoming ATRA resistance, supporting the further development of DHODH inhibitors for clinical use in refractory and relapsed APL.

First-in-Human Transapical Beating-Heart Septal Myectomy in Patients With Hypertrophic Obstructive Cardiomyopathy.

BACKGROUND: To simplify surgical septal reduction therapy for hypertrophic obstructive cardiomyopathy (HOCM), we developed a novel transapical beating-heart septal myectomy (TA-BSM) procedure. OBJECTIVES: In this study, we sought to evaluate the clinical utility of TA-BSM in a first-in-human trial. METHODS: Patients with HOCM were enrolled if they presented with drug-refractory disabling symptoms. TA-BSM was performed via minithoracotomy with the use of our beating-heart myectomy device under echocardiographic guidance, without the use of cardiopulmonary bypass. Repeated resections were performed to tailor the extent of the septal myectomy for sufficient abolishment of left ventricular outflow tract (LVOT) obstruction and mitral regurgitation (MR). The primary outcome measure was procedural success, defined by resting/provoked LVOT gradient <30/50 mm Hg and residual MR grade ≤1+ (of 4+) at 3-month follow-up. RESULTS: A total of 47 patients aged 12 to 77 years were enrolled. Of the 46 patients who were followed for 3 months, 42 achieved procedural success. The maximal LVOT gradient decreased from 86 mm Hg (IQR: 67-114 mm Hg) at baseline to 19 mm Hg (IQR: 14-28 mm Hg) at 3 months. MR grade was ≤1+ in 3 patients at baseline and in 45 patients at 3 months. One patient died on postoperative day 10 owing to device-unrelated reasons. Other major adverse events included 1 delayed ventricular septal perforation and 1 intraoperative left ventricular apical tear. CONCLUSIONS: TA-BSM is a safe and efficient minimally invasive procedure for septal reduction of heterogeneous HOCM. Compared with conventional septal myectomy, TA-BSM provides real-time evaluation to guide resection while reducing surgical trauma. (Transapical Beating-Heart Septal Myectomy in Patients With Hypertrophic Obstructive Cardiomyopathy; NCT05332691).

Debranching abdominal aortic hybrid surgery for aortic diseases involving the visceral arteries.

Objective: Aortic diseases involving branches of the visceral arteries mainly include thoracoabdominal aortic aneurysm (TAAA), aortic dissection (AD) and abdominal aortic aneurysm (AAA). The focus of treatment is to reconstruct the splanchnic arteries and restore blood supply to the organs. Commonly used methods include thoracoabdominal aortic replacement, thoracic endovascular aortic repair and hybrid approaches. Hybrid surgery for aortic disease involving the visceral arteries, consisting of visceral aortic debranching with retrograde revascularization of the celiac trunk and renal arteries and using stent grafts, has been previously described and may be considered particularly appealing in high-risk patients. This study retrospectively analyzed recorded data of patients and contrasted the outcomes with those of a similar group of patients who underwent conventional open repair surgery. Methods: Between 2019 and 2022, 72 patients (52 men) with an average age of 61.57 ± 8.66 years (range, 36-79 years) underwent one-stage debranching abdominal aortic hybrid surgery. These patients, the hybrid group, underwent preoperative Computed Tomographic Angiography (CTA) and had been diagnosed with aortic disease (aneurysm or dissection) involving the visceral arteries and were at high risk for open repair. The criteria used to define these patients as high-risk group who are in the need of hybrid treatment were American Society of Anesthesiologists (ASA) class 3 or 4. In all cases, we accomplished total visceral aortic debranching through a previous visceral artery retrograde revascularization with synthetic grafts (customized Y or four-bifurcated grafts), and aortic endovascular repair with one of two different commercially produced stent grafts (Medtronic® and Lifetech®). In some cases, we chose to connect the renal artery to the artificial vessel with a stent graft (Viabahn) and partly or totally anastomosed. We analyzed the results and compared the outcomes of the hybrid group with those of a similar group of 46 patients (36 men) with an average age 54.15 ± 12.12 years (range, 32-76). These 46 patients, the conventional open group, were selected for having had thoracoabdominal aortic replacement between 2019 and 2022. Results: In the hybrid group, 72 visceral bypasses were completed, and endovascular repair was successful in all cases. No intraoperative deaths occurred. Perioperative mortality was 2.78%, and perioperative morbidity was 9.72% (renal insufficiency in 1, unilateral renal infarction in 5, Intestinal ischemia in 1). At 1-month postoperative CTA showed 2 endoleaks, one of which was intervened. At follow-up, there were unplanned reoperation rate of 4.29% and 5 (7.14%) deaths. The remaining patients' grafts were patent at postoperative CTA and no endoleak or stent graft migration had occurred. In the conventional open group, 1 died intraoperatively, 4 died perioperatively, perioperative mortality was 10.87% and complications were respiratory failure in 5, intestinal paralysis/necrosis in 4, renal insufficiency in 17, and paraplegia in 2. At follow-up, 5 (12.20%) patients presented with synthetic grafts hematoma 4 (9.76%) patient died, and 6 (14.63%) patients required unplanned reoperation intervention. Conclusion: Hybrid surgery is technically feasible in selected cases. For aortic diseases involving the visceral arteries, the application of hybrid abdominal aorta debranching can simplify the operation process, decrease the risks of mortality and morbidity in high-risk and high-age populations and decrease the incidence of various complications while achieving ideal early clinical efficacy. However, a larger series is required for valid statistical comparisons, and longer follow-ups are necessary to evaluate the long-term efficacy of hybrid surgery.

Proximate deconfined quantum critical point in SrCu2(BO3)2.

The deconfined quantum critical point (DQCP) represents a paradigm shift in quantum matter studies, presenting a "beyond Landau" scenario for order-order transitions. Its experimental realization, however, has remained elusive. Using high-pressure 11B nuclear magnetic resonance measurements on the quantum magnet SrCu2(BO3)2, we here demonstrate a magnetic field-induced plaquette singlet to antiferromagnetic transition above 1.8 gigapascals at a notably low temperature, Tc ≃ 0.07 kelvin. First-order signatures of the transition weaken with increasing pressure, and we observe quantum critical scaling at the highest pressure, 2.4 gigapascals. Supported by model calculations, we suggest that these observations can be explained by a proximate DQCP inducing critical quantum fluctuations and emergent O(3) symmetry of the order parameters. Our findings offer a concrete experimental platform for investigation of the DQCP.

Upregulation of P2Y14 receptor in neutrophils promotes inflammation after myocardial ischemia/reperfusion injury.

BACKGROUND: P2Y14 receptor is expressed in neutrophils and is involved in activation of inflammatory signaling. However, the expression and function of P2Y14 receptor in neutrophils after myocardial infarction/reperfusion (MIR) injury remain to be elucidated. METHODS: In this research, rodent and cellular models of MIR were used to detect the involvement and function of P2Y14 receptor, as well as the regulation of inflammatory signaling via P2Y14 receptor in neutrophils post-MIR. RESULTS: In the early stage post MIR, the expression of P2Y14 receptor was upregulated in CD4+Ly-6G+ neutrophils. Additionally, the expression of P2Y14 receptor was highly induced in neutrophils subjected to uridine 5'-diphosphoglucose (UDP-Glu), which is proven to be secreted by cardiomyocytes during ischemia and reperfusion. Our results also showed the beneficial role of P2Y14 receptor antagonist PPTN in counteracting inflammation via promoting polarization of neutrophils to N2 phenotype in the infarct area of the heart tissue after MIR. CONCLUSION: These findings prove that the P2Y14 receptor is involved in the regulation of inflammation in the infarct area after MIR, and establish a novel signaling pathway concerning the interplay between cardiomyocytes and neutrophils in the heart tissue.

G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders.

Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.