Plasticity in single-crystalline Mg3Bi2 thermoelectric material.

Most of the state-of-the-art thermoelectric materials are inorganic semiconductors. Owing to the directional covalent bonding, they usually show limited plasticity at room temperature1,2, for example, with a tensile strain of less than five per cent. Here we discover that single-crystalline Mg3Bi2 shows a room-temperature tensile strain of up to 100 per cent when the tension is applied along the (0001) plane (that is, the ab plane). Such a value is at least one order of magnitude higher than that of traditional thermoelectric materials and outperforms many metals that crystallize in a similar structure. Experimentally, slip bands and dislocations are identified in the deformed Mg3Bi2, indicating the gliding of dislocations as the microscopic mechanism of plastic deformation. Analysis of chemical bonding reveals multiple planes with low slipping barrier energy, suggesting the existence of several slip systems in Mg3Bi2. In addition, continuous dynamic bonding during the slipping process prevents the cleavage of the atomic plane, thus sustaining a large plastic deformation. Importantly, the tellurium-doped single-crystalline Mg3Bi2 shows a power factor of about 55 microwatts per centimetre per kelvin squared and a figure of merit of about 0.65 at room temperature along the ab plane, which outperforms the existing ductile thermoelectric materials3,4.

AVCAPIR: A Novel Procalcific PIWI-Interacting RNA in Calcific Aortic Valve Disease.

BACKGROUND: Calcification of the aortic valve leads to increased leaflet stiffness and consequently results in the development of calcific aortic valve disease (CAVD). However, the underlying molecular and cellular mechanisms of calcification remain unclear. Here, we identified a novel aortic valve calcification-associated PIWI-interacting RNA (piRNA; AVCAPIR) that increases valvular calcification and promotes CAVD progression. METHODS: Using piRNA sequencing, we identified piRNAs contributing to the pathogenesis of CAVD that we termed AVCAPIRs. High-cholesterol diet-fed ApoE-/- mice with AVCAPIR knockout were used to examine the role of AVCAPIR in aortic valve calcification (AVC). Gain- and loss-of-function assays were conducted to determine the role of AVCAPIR in the induced osteogenic differentiation of human valvular interstitial cells. To dissect the mechanisms underlying AVCAPIR-elicited procalcific effects, we performed various analyses, including an RNA pulldown assay followed by liquid chromatography-tandem mass spectrometry, methylated RNA immunoprecipitation sequencing, and RNA sequencing. RNA pulldown and RNA immunoprecipitation assays were used to study piRNA interactions with proteins. RESULTS: We found that AVCAPIR was significantly upregulated during AVC and exhibited potential diagnostic value for CAVD. AVCAPIR deletion markedly ameliorated AVC in high-cholesterol diet-fed ApoE-/- mice, as shown by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased peak transvalvular jet velocity and mean transvalvular pressure gradient, as well as increased aortic valve area), and diminished levels of osteogenic markers (Runx2 and Osterix) in aortic valves. These results were confirmed in osteogenic medium-induced human valvular interstitial cells. Using unbiased protein-RNA screening and molecular validation, we found that AVCAPIR directly interacts with FTO (fat mass and obesity-associated protein), subsequently blocking its N6-methyladenosine demethylase activity. Further transcriptomic and N6-methyladenosine modification epitranscriptomic screening followed by molecular validation confirmed that AVCAPIR hindered FTO-mediated demethylation of CD36 mRNA transcripts, thus enhancing CD36 mRNA stability through the N6-methyladenosine reader IGF2BP1 (insulin-like growth factor 2 mRNA binding protein 1). In turn, the AVCAPIR-dependent increase in CD36 stabilizes its binding partner PCSK9 (proprotein convertase subtilisin/kexin type 9), a procalcific gene, at the protein level, which accelerates the progression of AVC. CONCLUSIONS: We identified a novel piRNA that induced AVC through an RNA epigenetic mechanism and provide novel insights into piRNA-directed theranostics in CAVD.

Realizing a Superior Conversion Efficiency of ≈11.3% in the Group IV-VI Thermoelectric Module.

GeTe-based materials exhibit superior thermoelectric performance, while the development of power generation devices has mainly been limited by the challenge of designing the interface due to the phase transition in GeTe. In this work, via utilizing the low-temperature nano-Ag sintering technique and screening suitable Ti-Al alloys, a reliable interface with excellent connection performance has been realized. The Ti-Al intermetallic compounds effectively inhibit the diffusion process at Ti-34Al/Ge0.9Sb0.1Te interface. Thus, the thickness of the interfacial reaction layer only increases by ≈2.08 µm, and the interfacial electrical contact resistivity remains as low as ≈15.2 µΩ cm2 even after 30 days of isothermal aging at 773 K. A high conversion efficiency of ≈11.3% has been achieved in the GeTe/PbTe module at a hot-side temperature of 773 K and a cold-side temperature of 300 K. More importantly, the module's performance and the reliability of the interface remain consistently stable throughout 50 thermal cycles and long-term aging. This work promotes the application of high-performance GeTe materials for thermoelectric power generation.

Hyphae Carbon Coupled with Gel Composite Assembly for Construction of Advanced Carbon/Sulfur Cathodes for Lithium-Sulfur Batteries.

The design and fabrication of novel carbon hosts with high conductivity, accelerated electrochemical catalytic activities, and superior physical/chemical confinement on sulfur and its reaction intermediates polysulfides are essential for the construction of high-performance C/S cathodes for lithium-sulfur batteries (LSBs). In this work, a novel biofermentation coupled gel composite assembly technology is developed to prepare cross-linked carbon composite hosts consisting of conductive Rhizopus hyphae carbon fiber (RHCF) skeleton and lamellar sodium alginate carbon (SAC) uniformly implanted with polarized nanoparticles (V2O3, Ag, Co, etc.) with diameters of several nanometers. Impressively, the RHCF/SAC/V2O3 composites exhibit enhanced physical/chemical adsorption of polysulfides due to the synergistic effect between hierarchical pore structures, heteroatoms (N, P) doping, and polar V2O3 generation. Additionally, the catalytic conversion kinetics of cathodes are effectively improved by regulating the 3D carbon structure and optimizing the V2O3 catalyst. Consequently, the LSBs assembled with RHCF/SAC/V2O3-S cathode show exceptional cycle stability (capacity retention rate of 94.0% after 200 cycles at 0.1 C) and excellent rate performance (specific capacity of 578 mA h g-1 at 5 C). This work opens a new door for the fabrication of hyphae carbon composites via fermentation for electrochemical energy storage.

An Advanced Gel Polymer Electrolyte for Solid-State Lithium Metal Batteries.

All-solid-state lithium metal batteries (LMBs) are regarded as one of the most viable energy storage devices and their comprehensive properties are mainly controlled by solid electrolytes and interface compatibility. This work proposes an advanced poly(vinylidene fluoride-hexafluoropropylene) based gel polymer electrolyte (AP-GPEs) via functional superposition strategy, which involves incorporating butyl acrylate and polyethylene glycol diacrylate as elastic optimization framework, triethyl phosphate and fluoroethylene carbonate as flameproof liquid plasticizers, and Li7La3Zr2O12 nanowires (LLZO-w) as ion-conductive fillers, endowing the designed AP-GPEs/LLZO-w membrane with high mechanical strength, excellent flexibility, low flammability, low activation energy (0.137 eV), and improved ionic conductivity (0.42 × 10-3 S cm-1 at 20 °C) due to continuous ionic transport pathways. Additionally, the AP-GPEs/LLZO-w membrane shows good safety and chemical/electrochemical compatibility with the lithium anode, owing to the synergistic effect of LLZO-w filler, flexible frameworks, and flame retardants. Consequently, the LiFePO4/Li batteries assembled with AP-GPEs/LLZO-w electrolyte exhibit enhanced cycling performance (87.3% capacity retention after 600 cycles at 1 C) and notable high-rate capacity (93.3 mAh g-1 at 5 C). This work proposes a novel functional superposition strategy for the synthesis of high-performance comprehensive GPEs for LMBs.

Association between Human Blood Proteome and the Risk of Myocardial Infarction.

Background: The objective of this study is to estimate the causal relationship between plasma proteins and myocardial infarction (MI) through Mendelian randomization (MR), predict potential target-mediated side effects associated with protein interventions, and ensure a comprehensive assessment of clinical safety. Methods: From 3 proteome genome-wide association studies (GWASs) involving 9775 European participants, 331 unique blood proteins were screened and chosed. The summary data related to MI were derived from a GWAS meta-analysis, incorporating approximately 61,000 cases and 577,000 controls. The assessment of associations between blood proteins and MI was conducted through MR analyses. A phenome-wide MR (Phe-MR) analysis was subsequently employed to determine the potential on-target side effects of protein interventions. Results: Causal mediators for MI were identified, encompassing cardiotrophin-1 (CT-1) (odds ratio [OR] per SD increase: 1.16; 95% confidence interval [CI]: 1.13-1.18; p = 1.29 × 10 - 31 ), Selenoprotein S (SELENOS) (OR: 1.16; 95% CI: 1.13-1.20; p = 4.73 × 10 - 24 ), killer cell immunoglobulin-like receptor 2DS2 (KIR2DS2) (OR: 0.93; 95% CI: 0.90-0.96; p = 1.08 × 10 - 5 ), vacuolar protein sorting-associated protein 29 (VPS29) (OR: 0.92; 95% CI: 0.90-0.94; p = 8.05 × 10 - 13 ), and histo-blood group ABO system transferase (NAGAT) (OR: 1.05; 95% CI: 1.03-1.07; p = 1.41 × 10 - 5 ). In the Phe-MR analysis, memory loss risk was mediated by CT-1, VPS29 exhibited favorable effects on the risk of 5 diseases, and KIR2DS2 showed no predicted detrimental side effects. Conclusions: Elevated genetic predictions of KIR2DS2 and VPS29 appear to be linked to a reduced risk of MI, whereas an increased risk is associated with CT-1, SELENOS, and NAGAT. The characterization of side effect profiles aids in the prioritization of drug targets. Notably, KIR2DS2 emerges as a potentially promising target for preventing and treating MI, devoid of predicted detrimental side effects.

Plasma Technology for Advanced Electrochemical Energy Storage.

"Carbon Peak and Carbon Neutrality" is an important strategic goal for the sustainable development of human society. Typically, a key means to achieve these goals is through electrochemical energy storage technologies and materials. In this context, the rational synthesis and modification of battery materials through new technologies play critical roles. Plasma technology, based on the principles of free radical chemistry, is considered a promising alternative for the construction of advanced battery materials due to its inherent advantages such as superior versatility, high reactivity, excellent conformal properties, low consumption and environmental friendliness. In this perspective paper, we discuss the working principle of plasma and its applied research on battery materials based on plasma conversion, deposition, etching, doping, etc. Furthermore, the new application directions of multiphase plasma associated with solid, liquid and gas sources are proposed and their application examples for batteries (e. g. lithium-ion batteries, lithium-sulfur batteries, zinc-air batteries) are given. Finally, the current challenges and future development trends of plasma technology are briefly summarized to provide guidance for the next generation of energy technologies.

Deletion of myeloid-specific Orai1 calcium channel does not affect pancreatic tissue damage in experimental acute pancreatitis.

BACKGROUND: Store-operated Ca2+ entry (SOCE) mediated by ORAI1 channel plays a crucial role in acute pancreatitis (AP). Macrophage is an important regulator in amplifying pancreatic tissue damage, but little is known about the role of ORAI1 in macrophages. In this study, we examined the effects of macrophage-specific ORAI1 on pancreatic tissue damage in AP. METHOD: Myeloid-specific Orai1 deficient mice was generated by crossing a LysM-Cre mouse line with Orai1f/f mice. Bone marrow-derived macrophages (BMDMs) were isolated, cultured, and stimulated to induce M1 or M2 macrophage polarization. Intracellular Ca2+ signals were measured by time-lapse confocal microscope imaging, with a Ca2+ indicator (Fluo 4). Experimental AP was induced by hourly intraperitoneal injections of caerulein or retrograde biliopancreatic infusion of sodium taurocholate. Pancreatic tissue damage was assessed by histopathological scoring and immunostaining. Sepsis was induced by intraperitoneal injection of lipopolysaccharide; organ damage and serum pro-inflammatory cytokines were measured. RESULT: Myeloid-specific Orai1 deletion exhibited minimal effect on SOCE in M0 macrophages and promoted M2 macrophage polarization ex vivo. Myeloid-specific Orai1 deletion did not affect pancreatic tissue damage, nor neutrophil or macrophage infiltration in two models of AP. Similarly, myeloid-specific Orai1 deletion did not influence overall survival rate in a model of sepsis, nor lung, kidney, and liver damage; while serum pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1ß were higher in Orai1ΔLysM mice, but were largely reduced in mice with Orai1 inhibitor. CONCLUSION: Our data suggest that ORAI1 may not be a predominant SOCE channel in macrophages and play a limited role in mediating pancreatic tissue damage in AP.

Exosomal miR-15a-5p from cardiomyocytes promotes myocardial fibrosis.

The emergence of myofibroblasts is a key step in myocardial fibrosis, but the trigger for the transformation of cardiac fibroblasts into myofibroblasts remains not entirely clear. Exosomes play a key role between cardiomyocytes and cardiac fibroblasts. Here, we not only investigated the relationship between exosomes derived from angiotensin (Ang)-II-treated cardiomyocytes and cardiac fibroblasts, the underlying mechanisms were also explored. Ang-II-treated C57 male mice and mouse cardiac fibroblasts were employed for in vivo and in vitro experiments, respectively. Transmission electron microscopy nanoparticle tracking analysis, and western blot of CD9, CD63, CD81 were performed to identify exosomes; QRT-PCR was performed to detect miR-15a-5p expression; luciferase reporter assay was employed to determine the interaction between miR-15a-5p and dyrk2; western blot was performed to examine the protein levels of fibrosis markers; Counting Kit-8 was performed to determine cell viability; HE and Masson staining were performed to assess the pathological changes of myocardial tissues. MiR-15a-5p expression was found up-regulated in serum of myocardial fibrosis patients, serum and myocardial tissues of Ang-II-treated mice, and Ang-II-treated cardiomyocytes. Mechanically, exosomes from Ang-II-treated cardiomyocytes shuttled miR-15a-5p to cardiac fibroblasts, where miR-15a-5p dephosphorylated NFAT by targeting dyrk2 to promote cell viability and elevated the protein levels of α-smooth muscle actin, collagen type 1 α1 and collagen type 3 α1, thus promoting myocardial fibrosis. This study identified a novel molecular target for anti-fibrotic therapeutic interventions.

Cyclopeptide RA-V from Rubia yunnanensis restores activity of Adagrasib against colorectal cancer by reducing the expression of Nrf2.

Adagrasib (MRTX849), an approved and promising KRAS G12C inhibitor, has shown the promising results for treating patients with advanced non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) harboring KRAS-activating mutations. However, emergence of the acquired resistance limits its long-term efficacy and clinical application. Further understanding of the mechanism of the acquired resistance is crucial for developing more new effective therapeutic strategies. Herein, we firstly found a new connection between the acquired resistance to MRTX849 and nuclear factor erythroid 2-related factor 2 (Nrf2). The expression levels of Nrf2 and GLS1 proteins were substantially elevated in different CRC cell lines with the acquired resistance to MRTX849 in comparison with their corresponding parental cell lines. Next, we discovered that RA-V, one of natural cyclopeptides isolated from the roots of Rubia yunnanensis, could restore the response of resistant CRC cells to MRTX849. The results of molecular mechanisms showed that RA-V suppressed Nrf2 protein through the ubiquitin-proteasome-dependent degradation, leading to the induction of oxidative and ER stress, and DNA damage in CRC cell lines. Consequently, RA-V reverses the resistance to MRTX849 by inhibiting the Nrf2/GLS1 axis, which shows the potential for further developing into one of novel adjuvant therapies of MRTX849.

Development and validation of a nomogram based on Lasso-Logistic regression for predicting splenomegaly secondary to acute pancreatitis.

PURPOSE: Investigate the clinical characteristics of splenomegaly secondary to acute pancreatitis (SSAP) and construct a nomogram prediction model based on Lasso-Logistic regression. METHODS: A retrospective case-control study was conducted to analyze the laboratory parameters and computed tomography (CT) imaging of acute pancreatitis (AP) patients recruited at Xuanwu Hospital from December 2014 to December 2021. Lasso regression was used to identify risk factors, and a novel nomogram was developed. The performance of the nomogram in discrimination, calibration, and clinical usefulness was evaluated through internal validation. RESULTS: The prevalence of SSAP was 9.2% (88/950), with the first detection occurring 65(30, 125) days after AP onset. Compared with the control group, the SSAP group exhibited a higher frequency of persistent respiratory failure, persistent renal failure, infected pancreatic necrosis, and severe AP, along with an increased need for surgery and longer hospital stay (P < 0.05 for all). There were 185 and 79 patients in the training and internal validation cohorts, respectively. Variables screened by Lasso regression, including platelet count, white blood cell (WBC) count, local complications, and modified CT severity index (mCTSI), were incorporated into the Logistic model. Multivariate analysis showed that WBC count ≦9.71 × 109/L, platelet count ≦140 × 109/L, mCTSI ≧8, and the presence of local complications were independently associated with the occurrence of SSAP. The area under the receiver operating characteristic curve was 0.790. The Hosmer-Lemeshow test showed that the model had good fitness (P = 0.954). Additionally, the nomogram performed well in the internal validation cohorts. CONCLUSIONS: SSAP is relatively common, and patients with this condition often have a worse clinical prognosis. Patients with low WBC and platelet counts, high mCTSI, and local complications in the early stages of the illness are at a higher risk for SSAP. A simple nomogram tool can be helpful for early prediction of SSAP.

Immunogenicity and safety of a recombinant COVID-19 vaccine (ZF2001) as heterologous booster after priming with inactivated vaccine in healthy children and adolescents aged 3-17 years: an open-labeled, single-arm clinical trial.

Considering that neutralizing antibody levels induced by two doses of the inactivated vaccine decreased over time and had fallen to low levels by 6 months, and homologous and heterologous booster immunization programs have been implemented in adults in China. The booster immunization of recombinant COVID-19 vaccine (ZF2001) after priming with inactivated vaccine in healthy children and adolescents has not been reported. We performed an open-labeled, single-arm clinical trial to evaluate the safety and immunogenicity of heterologous booster immunization with ZF2001 after priming with inactivated vaccine among 240 population aged 3-17 years in China. The primary outcome was immunogenicity, including geometric mean titers (GMTs), geometric mean ratios (GMRs) and seroconversion rates of SARS-CoV-2 neutralizing antibodies against prototype SARS-CoV-2 and Omicron BA.2 variant at 14 days after vaccination booster. On day 14 post-booster, a third dose booster of the ZF2001 provided a substantial increase in antibody responses in minors, and the overall occurrence rate of adverse reactions after heterologous vaccination was low and all adverse reactions were mild or moderate. The results showed that the ZF2001 heterologous booster had high immunogenicity and good safety profile in children and adolescents, and can elicit a certain level of neutralizing antibodies against Omicron.Trial registration NCT05895110 (Retrospectively registered, First posted in ClinicalTrials.gov date: 08/06/2023).

Chronic diseases spectrum and multimorbidity in elderly inpatients based on a 12-year epidemiological survey in China.

BACKGROUND: The number and proportion of the elderly population have been continuously increasing in China, leading to the elevated prevalence of chronic diseases and multimorbidity, which ultimately brings heavy burden to society and families. Meanwhile, the status of multimorbidity tends to be more complex in elderly inpatients than community population. In view of the above concerns, this study was designed to investigate the health status of elderly inpatients by analyzing clinical data in Chinese People's Liberation Army (PLA) General Hospital from 2008 to 2019, including the constitution of common diseases, comorbidities, the status of multimorbidity, in-hospital death and polypharmacy among elderly inpatients, so as to better understand the diseases spectrum and multimorbidity of elderly inpatients and also to provide supporting evidence for targeted management of chronic diseases in the elderly. METHODS: A clinical inpatients database was set up by collecting medical records of elderly inpatients from 2008 to 2019 in Chinese PLA General Hospital, focusing on diseases spectrum and characteristics of elderly inpatients. In this study, we collected data of inpatients aged ≥ 65 years old, and further analyzed the constitution of diseases, multimorbidity rates and mortality causes in the past decade. In addition, the prescriptions were also analyzed to investigate the status of polypharmacy in elderly inpatients. RESULTS: A total of 210,169 elderly patients were hospitalized from January 1st, 2008 to December 31st, 2019. The corresponding number of hospitalizations was 290,833. The average age of the study population was 72.67 years old. Of the total population, 73,493 elderly patients were re-admitted within one year, with the re-hospitalization rate of 25.27%. Malignant tumor, hypertension, ischemic heart disease, diabetes mellitus and cerebrovascular disease were the top 5 diseases. Among the study population, the number of patients with two or more long-term health conditions was 267,259, accounting for 91.89%, with an average of 4.68 diseases. In addition, the average number of medications taken by the study population was 5.4, among which, the proportion of patients taking more than 5 types of medications accounted for 55.42%. CONCLUSIONS: By analyzing the constitution of diseases and multimorbidity, we found that multimorbidity has turned out to be a prominent problem in elderly inpatients, greatly affecting the process of healthy aging and increasing the burden on families and society. Therefore, multidisciplinary treatment should be strengthened to make reasonable preventive and therapeutic strategies to improve the life quality of the elderly. Meanwhile, more attention should be paid to reasonable medications for elderly patients with multimorbidity to avoid preventable side effects caused by irrational medication therapy.

A Retrospective Cohort Study of vNOTES Extraperitoneal Versus Laparoscopic Sacral Hysteropexy With Uterine Preserving Regarding Surgical Outcomes and Two-Year Follow-Up Results.

STUDY OBJECTIVE: To explore the effectiveness of transvaginal natural orifice transluminal endoscopic surgery extraperitoneal sacral hysteropexy (vNOTES-ESH) in women with symptomatic uterine prolapse over a 2 year follow-up. DESIGN: Retrospective cohort study. SETTING: Gynecological minimally invasive center. PATIENTS: Women undergoing sacral hysteropexy either by vNOTES (n = 25) or laparoscopic (n = 74) between November 2016 and December 2020. INTERVENTIONS: Both vNOTES-ESH and laparoscopic sacral hysteropexy (LAP-SH) were used for uterine prolapse. Demographic data, operative characteristics, perioperative outcomes, and follow-up information 2 years postsurgery in the 2 groups were retrospectively evaluated. RESULTS: Both procedures showed similar operation time, estimated blood loss, hospital stays, and pain scores (p >0.05). During a median follow-up of 59 (24-72) months, the surgical success rate was 96% for vNOTES-ESH and 97.3% for LAP-SH (p >0.05), with no differences in anatomical position or pelvic organ function after the operation. Women in the LAP-SH group experienced more bothersome symptoms of constipation compared to those in the vNOTES-ESH group (5.41% vs 0, p <0.05). Lastly, 1 case in the vNOTES-ESH group had a mesh exposed area of less than 1 cm2, and 1 patient in the LAP-SH group experienced stress incontinence. CONCLUSIONS: In this retrospective study, vNOTES-ESH met our patients' preference for uterine preservation and was a successful and effective treatment for uterine prolapse, providing good functional improvement in our follow-up. This procedure should be considered as an option for patients with pelvic organ prolapse.

Ultrasound and computed tomography angiography diagnosis of fetal right atrial isomerism with cardiac total anomalous pulmonary venous connection and intestinal malrotation: a case report and literature review.

Right atrial isomerism is a rare and severe isomerism. It is frequently associated with complex congenital heart disease and various extracardiac anomalies. Imaging diagnosis of right atrial isomerism is a challenge. Multisystem and complex anomalies in a 24-week-old fetus were diagnosed with prenatal ultrasound, postnatal computed tomography angiography (CTA), and autopsy. The ultrasound detected most major cardiovascular anomalies including right atrial isomerism and total anomalous pulmonary venous connection. The CTA further detected thoracic and abdominal malformations such as bilateral morphologically right bronchus, diaphragmatic hernia, asplenia, midline liver, and intestinal malrotation. The autopsy confirmed both ultrasound and CTA findings with additional findings, namely, bilateral trilobed lungs and bilateral morphological right auricles. Prenatal ultrasound and postnatal CTA can be complementary to each other in detecting multi-system complex anomalies. Their combined use can be useful for prenatal counseling and postpartum management.

Unveiling adcyap1 as a protective factor linking pain and nerve regeneration through single-cell RNA sequencing of rat dorsal root ganglion neurons.

BACKGROUND: Severe peripheral nerve injury (PNI) often leads to significant movement disorders and intractable pain. Therefore, promoting nerve regeneration while avoiding neuropathic pain is crucial for the clinical treatment of PNI patients. However, established animal models for peripheral neuropathy fail to accurately recapitulate the clinical features of PNI. Additionally, researchers usually investigate neuropathic pain and axonal regeneration separately, leaving the intrinsic relationship between the development of neuropathic pain and nerve regeneration after PNI unclear. To explore the underlying connections between pain and regeneration after PNI and provide potential molecular targets, we performed single-cell RNA sequencing and functional verification in an established rat model, allowing simultaneous study of the neuropathic pain and axonal regeneration after PNI. RESULTS: First, a novel rat model named spared nerve crush (SNC) was created. In this model, two branches of the sciatic nerve were crushed, but the epineurium remained unsevered. This model successfully recapitulated both neuropathic pain and axonal regeneration after PNI, allowing for the study of the intrinsic link between these two crucial biological processes. Dorsal root ganglions (DRGs) from SNC and naïve rats at various time points after SNC were collected for single-cell RNA sequencing (scRNA-seq). After matching all scRNA-seq data to the 7 known DRG types, we discovered that the PEP1 and PEP3 DRG neuron subtypes increased in crushed and uncrushed DRG separately after SNC. Using experimental design scRNA-seq processing (EDSSP), we identified Adcyap1 as a potential gene contributing to both pain and nerve regeneration. Indeed, repeated intrathecal administration of PACAP38 mitigated pain and facilitated axonal regeneration, while Adcyap1 siRNA or PACAP6-38, an antagonist of PAC1R (a receptor of PACAP38) led to both mechanical hyperalgesia and delayed DRG axon regeneration in SNC rats. Moreover, these effects can be reversed by repeated intrathecal administration of PACAP38 in the acute phase but not the late phase after PNI, resulting in alleviated pain and promoted axonal regeneration. CONCLUSIONS: Our study reveals that Adcyap1 is an intrinsic protective factor linking neuropathic pain and axonal regeneration following PNI. This finding provides new potential targets and strategies for early therapeutic intervention of PNI.

Development of Pure Certified Reference Material of Cannabidiol.

Cannabidiol (CBD) is the major functional component in hemp and has a broad range of pharmacological applications, such as analgesic, anti-epileptic, anti-anxiety, etc. Currently, CBD is widely used in pharmaceuticals, cosmetics, and food. To ensure the quality and safety of the products containing CBD, more and more related sample testing is being conducted, and the demand for CBD-certified reference material (CRM) has also sharply increased. However, there is currently a lack of relevant reference materials. In this paper, a simple method for preparing CBD CRM was established based on preparative liquid chromatography using crude hemp extract as a raw material. A qualitative analysis of CBD was performed using techniques such as ultraviolet absorption spectroscopy (UV), infrared spectroscopy (IR), mass spectrometry (MS), nuclear magnetic resonance spectroscopy (NMR), and differential scanning calorimetry (DSC). High-performance liquid chromatography (HPLC) was used for the homogeneity and stability tests, and the data were analyzed using an F-test and a T-test, respectively. Then, eight qualified laboratories were chosen for the determination of a certified value using HPLC. The results show that the CBD CRM had excellent homogeneity and good stability for 18 months. The certified value was 99.57%, with an expanded uncertainty of 0.24% (p = 0.95, k = 2). The developed CBD CRM can be used for the detection and quality control of cannabidiol products.

[FeIIICl(TMPPH2)][FeIIICl4]2: A Stand-Alone Molecular Nanomedicine That Induces High Cytotoxicity by Ferroptosis.

Developing clinically meaningful nanomedicines for cancer therapy requires the drugs to be effective, safe, simple, cheap, and easy to store. In the present work, we report that a simple cationic Fe(III)-rich salt of [FeIIICl(TMPPH2)][FeIIICl4]2 (Fe-TMPP) exhibits a superior anticancer performance on a broad spectrum of cancer cell lines, including breast, colorectal cancer, liver, pancreatic, prostate, and gastric cancers, with half maximal inhibitory concentration (IC50) values in the range of 0.098-3.97 µM (0.066-2.68 µg mL-1), comparable to the best-reported medicines. Fe-TMPP can form stand-alone nanoparticles in water without the need for extra surface modification or organic-solvent-assisted antisolvent precipitation. Critically, Fe-TMPP is TME-responsive (TME = tumor microenvironment), and can only elicit its function in the TME with overexpressed H2O2, converting H2O2 to the cytotoxic •OH to oxidize the phospholipid of the cancer cell membrane, causing ferroptosis, a programmed cell death process of cancer cells.

Tacrolimus-binding protein FKBP8 directs myosin light chain kinase-dependent barrier regulation and is a potential therapeutic target in Crohn's disease.

OBJECTIVE: Intestinal barrier loss is a Crohn's disease (CD) risk factor. This may be related to increased expression and enzymatic activation of myosin light chain kinase 1 (MLCK1), which increases intestinal paracellular permeability and correlates with CD severity. Moreover, preclinical studies have shown that MLCK1 recruitment to cell junctions is required for tumour necrosis factor (TNF)-induced barrier loss as well as experimental inflammatory bowel disease progression. We sought to define mechanisms of MLCK1 recruitment and to target this process pharmacologically. DESIGN: Protein interactions between FK506 binding protein 8 (FKBP8) and MLCK1 were assessed in vitro. Transgenic and knockout intestinal epithelial cell lines, human intestinal organoids, and mice were used as preclinical models. Discoveries were validated in biopsies from patients with CD and control subjects. RESULTS: MLCK1 interacted specifically with the tacrolimus-binding FKBP8 PPI domain. Knockout or dominant negative FKBP8 expression prevented TNF-induced MLCK1 recruitment and barrier loss in vitro. MLCK1-FKBP8 binding was blocked by tacrolimus, which reversed TNF-induced MLCK1-FKBP8 interactions, MLCK1 recruitment and barrier loss in vitro and in vivo. Biopsies of patient with CD demonstrated increased numbers of MLCK1-FKBP8 interactions at intercellular junctions relative to control subjects. CONCLUSION: Binding to FKBP8, which can be blocked by tacrolimus, is required for MLCK1 recruitment to intercellular junctions and downstream events leading to immune-mediated barrier loss. The observed increases in MLCK1 activity, MLCK1 localisation at cell junctions and perijunctional MLCK1-FKBP8 interactions in CD suggest that targeting this process may be therapeutic in human disease. These new insights into mechanisms of disease-associated barrier loss provide a critical foundation for therapeutic exploitation of FKBP8-MLCK1 interactions.

Noninvasive detection of brain gliomas using plasma cell-free DNA 5-hydroxymethylcytosine sequencing.

Liquid biopsy techniques based on deep sequencing of plasma cell-free DNA (cfDNA) could detect the low-frequency somatic mutations and provide an accurate diagnosis for many cancers. However, for brain gliomas, reliable performance of these techniques currently requires obtaining cfDNA from patients' cerebral spinal fluid, which is cumbersome and risky. Here we report a liquid biopsy method based on sequencing of plasma cfDNA fragments carrying 5-hydroxymethylcytosine (5hmC) using selective chemical labeling (hMe-Seal). We first constructed a dataset including 180 glioma patients and 229 non-glioma controls. We found marked concordance between cfDNA hydroxymethylome and the aberrant transcriptome of the underlying gliomas. Functional analysis also revealed overrepresentation of the differentially hydroxymethylated genes (DhmGs) in oncogenic and neural pathways. After splitting our dataset into training and test cohort, we showed that a penalized logistic model constructed with training set DhmGs could distinguish glioma patients from healthy controls in both our test set (AUC = 0.962) and an independent dataset (AUC = 0.930) consisting of 111 gliomas and 111 controls. Additionally, the DhmGs between gliomas with mutant and wild-type isocitrate dehydrogenase (IDH) could be used to train a cfDNA predictor of the IDH mutation status of the underlying tumor (AUC = 0.816), and patients with predicted IDH mutant gliomas had significantly better outcome (P = .01). These results indicate that our plasma cfDNA 5hmC sequencing method could obtain glioma-specific signals, which may be used to noninvasively detect these patients and predict the aggressiveness of their tumors.