An autoantibody profile identified by human genome-wide protein arrays in rheumatoid arthritis.

Precise diagnostic biomarkers of anticitrullination protein antibody (ACPA)-negative and early-stage RA are still to be improved. We aimed to screen autoantibodies in ACPA-negative patients and evaluated their diagnostic performance. The human genome-wide protein arrays (HuProt arrays) were used to define specific autoantibodies from the sera of 182 RA patients and 261 disease and healthy controls. Statistical analysis was performed with SPSS 17.0. In Phase I study, 51 out of 19,275 recombinant proteins covering the whole human genome were selected. In Phase II validation study, anti-ANAPC15 (anaphase promoting complex subunit 15) exhibited 41.8% sensitivity and 91.5% specificity among total RA patients. There were five autoantibodies increased in ACPA-negative RA, including anti-ANAPC15, anti-LSP1, anti-APBB1, anti-parathymosin, and anti-UBL7. Anti-parathymosin showed the highest prevalence of 46.2% (p = 0.016) in ACPA-negative early stage (<2 years) RA. To further improve the diagnostic efficacy, a prediction model was constructed with 44 autoantibodies. With increased threshold for RA calling, the specificity of the model is 90.8%, while the sensitivity is 66.1% (87.8% in ACPA-positive RA and 23.8% in ACPA-negative RA) in independent testing patients. Therefore, HuProt arrays identified RA-associated autoantibodies that might become possible diagnostic markers, especially in early stage ACPA-negative RA.

Advancing quantitative PCR with color cycle multiplex amplification.

Quantitative PCR (qPCR) is the gold standard for detection and quantitation of known DNA targets, but the scarcity of spectrally distinct fluorophores and filter sets limits the number of detectable targets. Here, we introduce color cycle multiplex amplification (CCMA) to significantly increase the number of detectable DNA targets in a single qPCR reaction using standard instrumentation. In CCMA, presence of one DNA target species results in a pre-programmed pattern of fluorescence increases. This pattern is distinguished by cycle thresholds (Cts) through rationally designed delays in amplification. For example, we design an assay wherein Staphylococcus aureus sequentially induces FAM, then Cy5.5, then ROX fluorescence increases with more than 3 cycles between each signal. CCMA offers notably higher potential for multiplexing because it uses fluorescence permutation rather than combination. With 4 distinct fluorescence colors, CCMA theoretically allows the detection of up to 136 distinct DNA target sequences using fluorescence permutation. Experimentally, we demonstrated a single-tube qPCR assay screening 21 sepsis-related bacterial DNA targets in samples of blood, sputum, pleural effusion and bronchoalveolar lavage fluid, with 89% clinical sensitivity and 100% clinical specificity, showing its potential as a powerful tool for advanced quantitative screening in molecular diagnostics.

Efficient Fabrication of Disordered Graphene with Improved Ion Accessibility, Ion Conductivity, and Density for High-Performance Compact Capacitive Energy Storage.

High-performance compact capacitive energy storage is vital for many modern application fields, including grid power buffers, electric vehicles, and portable electronics. However, achieving exceptional volumetric performance in supercapacitors is still challenging and requires effective fabrication of electrode films with high ion-accessible surface area and fast ion diffusion capability while simultaneously maintaining high density. Herein, a facile, efficient, and scalable method is developed for the fabrication of dense, porous, and disordered graphene through spark-induced disorderly opening of graphene stacks combined with mechanical compression. The obtained disordered graphene achieves a high density of 1.18 g cm-3, sixfold enhanced ion conductivity compared to common laminar graphene, and an ultrahigh volumetric capacitance of 297 F cm-3 in ionic liquid electrolyte. The fabricated stack cells deliver a volumetric energy density of 94.2 Wh L-1 and a power density of 13.7 kW L-1, representing a critical breakthrough in capacitive energy storage. Moreover, the proposed disordered graphene electrodes are assembled into ionogel-based all-solid-state pouch cells with high mechanical stability and multiple optional outputs, demonstrating great potential for flexible energy storage in practical applications.

RT-RPA-PfAgo detection platform for one-tube simultaneous typing diagnosis of human respiratory syncytial virus.

Human respiratory syncytial virus (HRSV) is the most prevalent pathogen contributing to acute respiratory tract infections (ARTI) in infants and young children and can lead to significant financial and medical costs. Here, we developed a simultaneous, dual-gene and ultrasensitive detection system for typing HRSV within 60 minutes that needs only minimum laboratory support. Briefly, multiplex integrating reverse transcription-recombinase polymerase amplification (RT-RPA) was performed with viral RNA extracted from nasopharyngeal swabs as a template for the amplification of the specific regions of subtypes A (HRSVA) and B (HRSVB) of HRSV. Next, the Pyrococcus furiosus Argonaute (PfAgo) protein utilizes small 5'-phosphorylated DNA guides to cleave target sequences and produce fluorophore signals (FAM and ROX). Compared with the traditional gold standard (RT-qPCR) and direct immunofluorescence assay (DFA), this method has the additional advantages of easy operation, efficiency and sensitivity, with a limit of detection (LOD) of 1 copy/µL. In terms of clinical sample validation, the diagnostic accuracy of the method for determining the HRSVA and HRSVB infection was greater than 95%. This technique provides a reliable point-of-care (POC) testing for the diagnosis of HRSV-induced ARTI in children and for outbreak management, especially in resource-limited settings.

Short-term and long-term outcomes of laparoscopic surgery for locally recurrent rectal cancer: a propensity score-matched cohort study.

BACKGROUND: Radical surgery remains the primary option for locally recurrent rectal cancer (LRRC) as it has the potential to considerably extend the patient's lifespan. At present, the effectiveness of laparoscopic surgery for LRRC remains unclear. METHODS: The clinical data of patients with LRRC who were admitted to the Cancer Hospital of the Chinese Academy of Medical Sciences between 2015 and 2021 were retrospectively analyzed in this study. Patients were categorized into two groups, namely the open group and the laparoscopic group, based on the surgical method used. Propensity score matching was used to reduce baseline differences. The short-term outcomes and long-term survival between the two groups were compared. RESULTS: Curative surgery was performed on 111 patients who were diagnosed with LRRC. After propensity score matching, a total of 80 patients were included and divided into the laparoscopic group (40 patients) and the open group (40 patients). The laparoscopic group had less intraoperative bleeding (100 vs. 300, P = 0.011), a lower postoperative complication rate (20.0% vs. 42.5%, P = 0.030), a lower incidence of wound infection (0 vs. 15.0%, P = 0.026), and a shorter time to first flatus (2 vs. 3, P = 0.005). The laparoscopic group had higher 3-year overall survival (85.4% vs. 57.5%, P = 0.016) and 3-year disease-free survival (63.9% vs 36.5%, P = 0.029). CONCLUSIONS: In comparison to open surgery, laparoscopic surgery is linked to less bleeding during the operation, quicker recovery after the surgery, and a lower incidence of infections at the surgical site. Moreover, laparoscopic surgery for LRRC might yield superior long-term survival outcomes.

Risk factors for mid- and long-term mortality in lung transplant recipients aged 70 years and older.

OBJECTIVES: With increased lung transplantation in those aged 70 and older, limited literature addresses risk factors affecting their survival. Our study aims to identify independent factors impacting mid- and long-term mortality in this elderly population. METHODS: This study analyzed lung transplant patients over 70 from May 2005 to December 2022 using United Network for Organ Sharing data. The 3- or 5-year cohort excluded multi-organ, secondary transplantation and loss to follow-up. Univariable Cox analysis was conducted to assess recipient, donor and transplant factors. Factors with a significance level of P < 0.2 were subsequently included in a multivariable Cox model to identify correlations with 3- and 5-year mortality in patients aged over 70. RESULTS: Multivariable analysis has identified key factors affecting 3- and 5-year mortality in elderly lung transplant patients over 70. Common notable factors include recipient total bilirubin, intensive care unit status at the time of transplantation, donor diabetes, Cytomegalovirus (CMV) mismatch and single lung transplantation. Additionally, Hispanic/Latino patients and ischaemia time of the transplant significantly impact the 3-year mortality, while recipient age, diabetes, nitric oxide use before transplantation and creatinine were identified as unique independent risk factors affecting the 5-year morality. CONCLUSIONS: The study identified several independent risk factors that impact the mid- and long-term survival of lung transplantation for individuals over 70 years. These findings can contribute to the optimization of lung transplant treatment strategies and perioperative management in elderly patients, thereby enhancing the survival rate of this age group.

Carbonate Ester-Based Sodium Metal Battery with High-Capacity Retention at -50°C Enabled by Weak Solvents and Electrodeposited Anode.

Sodium metal batteries (SMBs) have received increasing attention due to the abundant sodium resources and high energy density, but suffered from the sluggish interfacial kinetic and unstable plating/stripping of sodium anode at low temperature, especially when matched with ester electrolytes. Here, we develop a stable ultra-low-temperature SMBs with high-capacity retention at -50°C in a weak solvated carbonate ester-based electrolyte, combined with an electrodeposited Na (Cu/Na) anode. The Cu/Na anode with electrochemically activated "deposited sodium" and stable inorganic-rich solid electrolyte interphase (SEI) was favor for the fast Na+ migration, therefore accelerating the interfacial kinetic process. As a result, the Cu/Na || NaCrO2 battery exhibited the highest capacity retention (compared to room-temperature capacity) in carbonate ester-based SMBs (98.05% at -25°C, 91.3% at -40°C, 87.9% at -50°C, respectively). The cyclic stability of 350 cycles at -25°C with a high energy efficiency of 96.15% and 70 cycles at -50°C can be achieved. Even in chill atmospheric environment with the fluctuant temperature, the battery can still operate over one month. This work provides a new opportunity for the development of low-temperature carbonate ester-based SMBs.

Development of a large animal orthotopic intestinal transplantation model with long-term survival for study of immunologic outcomes.

Introduction: Intestinal transplantation (ITx) is the last remaining therapy for patients with intestinal failure once parenteral nutrition is no longer an option, however its use is limited by immunological complications, including high rates of rejection and morbidity associated with immunosuppression, such as infection and malignancy. We aimed to develop a large animal model of ITx with which to study the immune response to ITx and to design and test tolerance induction regimens. Methods: Learning from prior complications, we developed and progressively improved both surgical methods for the donor and recipient as well as postoperative management strategies. Methods of stoma generation, bowel positioning, vessel preparation, and fluid management were optimized. The immunosuppression strategy mirrored our clinical regimen. Results: As a result of our modifications, results improved from survival less than 1 month to consistent long-term survival with good graft function. We review several techniques that were developed to avoid pitfalls that were encountered, which can be used to optimize outcomes in this model. Discussion: Achieving long-term survival after swine orthotopic ITx permits immunological analysis and pre-clinical trials in a large animal model of ITx.

A Novel Gelatin Binder with Helical Crosslinked Network for High-Performance Si Anodes in Lithium-Ion Batteries.

Silicon (Si) is a promising anode material for lithium-ion batteries, but its large volume expansion during cycling poses a challenge for the binder design. In this study, a novel gelatin binder is designed and prepared with a helical crosslinked network structure. This gelatin binder is prepared by enzymatic crosslinking and immersion in Hofmeister salt solution, which induces the formation of network and helical secondary structures. The helical crosslinked network structure can be analogous to a spring group system to effectively dissipate the stress and strain caused by the Si expansion. The gelatin binder is further partially carbonized by low-temperature pyrolysis, which improves its conductivity and stability. The Si anode with the optimized gelatin binder exhibits high initial coulombic efficiency, excellent rate performance, and long-term cycling stability. This study provides an innovative approach for the preparation of high-performance Si anodes, namely by controlling the molecular configuration of the binder to significantly improve the cycle stability, which can also be applied to other high-capacity anode materials that suffer from large volume changes during cycling.

Nutrient removal efficacy and microbial dynamics in constructed wetlands using Fe(III)-mineral substrates for low carbon-nitrogen ratio sewage treatment.

This study evaluated the roles of two common sources of Fe(III)-minerals-volcanic rock (VR) and synthetic banded iron formations from waste iron tailings (BIF-W)-in vertical flow-constructed wetlands (VFCWs). The evaluation was conducted in the absence of critical environmental factors, including Fe(II), Fe(III), and soil organic matter (SOM), using metagenomic analysis and integrated correlation networks to predict nitrogen removal pathways. Our findings revealed that Fe(III)-minerals enhanced metabolic activities and cellular processes related to carbohydrate decomposition, thereby increasing the average COD removal rates by 10.7% for VR and 5.90% for BIF-W. Notably, VR improved nitrogen removal by 1.70% and 5.40% compared to BIF-W and the control, respectively. Fe(III)-mineral amendment in bioreactors also improved the retention of denitrification and nitrification bacteria (phylum Proteobacteria) and anammox bacteria (phylum Planctomycetes), with increases of 3.60% and 3.20% using VR compared to BIF-W. Metagenomic functional prediction indicated that the nitrogen removal mechanisms in VFCWs with low C/N ratios involve simultaneous partial nitrification, ANAMMOX, and denitrification (SNAD). Network-based analyses and correlation pathways further suggest that the advantages of Fe(III)-minerals are manifested in the enhancement of denitrification microorganisms. Microbial communities may be activated by the functional dissolution of Fe(III)-minerals, which improves the stability of SOM or the conversion of Fe(III)/Fe(II). This study provides new insights into the functional roles of Fe(III)-minerals in VFCWs at the microbial community level, and provides a foundation for developing Fe-based SNAD enhancement technologies.

Transition Layer Assisted Synthesis of Defect Free Amine-Phosphine Based InP QDs.

Environmentally friendly InP-based quantum dots (QDs) are promising for light-emitting diodes (LEDs) and display applications. So far, the synthesis of highly emitting InP-based QDs via safe and economically viable amine-phosphine remains a challenge. Herein, we report the synthesis of amine-phosphine based InP/ZnSe/ZnS QDs by introducing an alloyed oxidation-free In-ZnSe transition layer (TL) at the core-shell interface. The TL not only has the essential function of preventing oxidation of the core and relieving interfacial strain but also results in oriented epitaxial growth of shell. The alloyed TL significantly mitigates the nonradiative recombination at core-shell interfacial trap states, thereby boosting the photoluminescence (PL) efficiency of the QDs up to 98%. Also, the Auger recombination is suppressed, extending the biexciton lifetime from 60 to 100 ps. The electroluminescence device based on the InP-based QDs shows a high external quantum efficiency over 10%, further demonstrating high quality QDs synthesized by this process.

[Identification of chemical components in Qinggu San reference sample of classial prescription based on UHPLC-Q/Orbitrap HRMS combined with molecular network technology].

The method of ultra-high performance liquid chromatography-quadrupole-electrostatic field orbitrap high-resolution mass spectrometry(UHPLC-Q/Orbitrap HRMS)combined with molecular network was developed in this study for rapidly analyzing the chemical components of the Qinggu San reference sample of classical prescription. Firstly, an ACQUITY UPLC BEH Shield RP_(18) column(2.1 mm×100 mm, 1.7 µm)was used, and acetonitrile and 0.1% formic acid were taken as the mobile phases for gradient elution. The flow rate was 0.4 mL·min~(-1), and the column temperature was 30 ℃. Under these conditions, the mass spectrum data were collected in both positive and negative ion modes of the heated electrospray ionization source. Subsequently, the mass spectrum data of the Qinggu San reference sample were uploaded to the Global Natural Products Social Molecular Network(GNPS)platform for calculation and analysis, and a visual molecular network was built with Cytoscape 3.8.2 software. On this basis, the chemical components of the Qinggu San reference sample were identified by fragmentation regularity of standard compounds, retention time, accurate relative molecular weight of HR-MS, characteristic fragment ions information, literature, and databases. Finally, a total of 105 chemical components were identified and speculated in the Qinggu San reference sample, including 19 iridoid glycosides, 23 flavonoids, 15 phenylpropanoids, 11 triterpene saponins, and 37 other components. Meanwhile, two of these components are potential new compounds. The method used in this study not only achieved rapid and accurate identification of chemical components in the Qinggu San reference sample and provided a scie-ntific basis for the study of pharmacological substances and quality control of Qinggu San compound preparations but also provided a refe-rence for the rapid identification of chemical components in traditional Chinese medicine compound preparations.

Association of resection margin distance with anastomotic recurrence in stage I-III colon cancer: data from the National Colorectal Cancer Cohort (NCRCC) study in China.

PURPOSE: Few studies have focused on anastomotic recurrence (AR) in colon cancer. This study aimed to clarify the association of resection margin distance with AR and compare the prognosis with nonanastomotic local recurrence (NAR). METHODS: This retrospective cohort study included the clinical data of patients who underwent radical colon cancer surgery between January 1, 2009, and December 31, 2019. RESULTS: A total of 1958 colon cancer patients were included in the study. 34 of whom (1.7%) had AR and 105 of whom (5.4%) had NAR. Multivariate analysis revealed that the lower distal resection margin distance, advanced N stage, and number of lymph nodes dissected were risk factors for AR. In the proximal resection margin, the risk of AR was lowest at a distance of 6 cm or greater, with a 3-year rate of 1.3%. In the distal resection margin, the 3-year AR risk increased rapidly if the distance was less than 3 cm. The prognosis of patients in the AR group was similar to that of patients in the NAR group, regardless of synchronous distant metastases. Furthermore, the radical surgery rate for AR was significantly higher than that for NAR, but the prognosis of AR was comparable to that of NAR. CONCLUSIONS: The distal resection margin distance, advanced N stage, and less number of lymph nodes dissected are associated with AR of colon cancer. The prognosis of patients with AR was similar to that of patients with NAR. TRIAL REGISTRATION: Clinical Trial Numbers NCT04074538 ( clinicaltrials.gov ), August 26, 2019, registered, retrospectively registered.

Comprehensive bioinformatics analysis and cell line experiments revealed the important role of CDCA3 in sarcoma.

Background: Sarcoma mainly originate from bone and soft tissue and are highly aggressive malignant tumors. Cell division cycle-related protein 3 (CDCA3) is a protein involved in the regulation of the cell cycle, which is highly expressed in a variety of malignant tumors. However, its role in sarcoma remains unclear. This study aims to investigate the function and potential mechanism of CDCA3 in sarcoma and to elucidate its importance in sarcoma. Methods: We first studied the expression and prognosis of CDCA family members in sarcoma by Oncomine and the Gene Expression Profiling Interactive Analysis (GEPIA). The role of CDCA3 protein in sarcoma was further analyzed by the Cancer Genome Atlas Program (TCGA), the Cancer Cell Lineage Encyclopedia (CCLE), and Linke-dOmics. In addition, immunohistochemistry and Western blot were used to verify the expression of CDCA3 protein in clinical samples as well as sarcoma cell lines (U2OS, SAOS2, MG63, and HOS). Subsequently, in vitro experiments (cloning and scratching experiments) were performed using sh-NC as well as sh-CDCA3 group cells to reveal the biological functions of CDCA3. Results: We found that the CDCA family (CDCA3, CDCA4, and CDCA8) is highly expressed in sarcoma, and the expression level of CDCA3, CDCA4, and CDCA8 negatively correlates with the prognosis of sarcoma patients. CDCA3 mRNA was highly expressed in pan-cancer by CCLE and TCGA database analysis. KEGG analysis showed that CDCA3 was mainly enriched in the cell cycle signaling pathway (It promoted the transition of the cell cycle from the G0/G1 phase to the S phase). In the level of immune infiltration, CDCA3 was negatively correlated with pDC cells, CD8+T cells, and cytotoxic cells. Finally, patients with high CDCA3 expression in sarcoma were analyzed for resistance to NU7441 and others, while sensitive to Fulvestrant and Dihydrorotenone. Furthermore, we demonstrated high expression of CDCA3 protein in sarcoma tissues and cell lines by immunohistochemistry and Western blot experiments. Cloning, EDU, scratching, and migration experiments showed that the knockdown of CDCA3 inhibited the Proliferation and progression of sarcoma cells. Conclusion: These results suggest for the first time that knockdown of CDCA3 may inhibit sarcoma progression. CDCA3 may be an effective target for the treatment of sarcoma.

Ferric citrate enhanced bioreduction of Cr(VI) by Bacillus cereus RCr in aqueous solutions: reduction performance and mechanisms.

The bioreduction characteristics and mechanisms of Cr(VI) onto Bacillus cereus RCr enhanced by ferric citrate were investigated. The optimum conditions were initial pH 9, temperature 40 °C, inoculation amount 4%, and glucose 3 g/L, respectively. The addition of 1.5 g/L ferric citrate increased the average reduction rate from 120.43 to 220.61 mg/(L∙h) compared with the control (without ferric citrate). The binding capacity of Cr(III) on the cell surface increased to 21%, in which the precipitates were mainly CrO(OH), Cr2O3, and FeCr2O4. Cell membrane was the main site of reduction, related important functional groups: - COOH, C-H, - NH2, C = C, and P-O. Fe(III) increased the yield of NADH and cytochrome c by approximately 48.51% and 68.63%, which significantly facilitated the electron generation and electron transfer, thus increasing the amount of electrons in the bioreduction of heavy metals by an average of 110%. Among the electrons obtained by Cr(VI), the proportion of indirect reduction mediated by Fe(III)/Fe(II) shuttle was 62% on average, whereas direct reduction mediated by reductase was 38%. These results may provide insights into the bioreduction process by bacteria enhanced by Fe(III) for detoxification of heavy metals with multiple valences, as an important step towards improving microbial remediation.

Rapidly-manufactured CD276 CAR-T cells exhibit enhanced persistence and efficacy in pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer. METHODS: In the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T. RESULTS: We found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48-72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal. CONCLUSIONS: In this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.

m6A-dependent mature miR-151-5p accelerates the malignant process of HNSCC by targeting LYPD3.

miRNA has emerged as a crucial regulator in various of pathological and physiological processes, yet its precise mechanism of action the detailed mechanism of their action in Head and neck squamous cell carcinoma (HNSCC) remains incompletely understood. This study sheds light on the role of mi-151-5p, revealing its significantly elevated expression in tumor cells, which notably enhances the invasion and migration of HNSCC cells. This effect is achieved through directly targeting LY6/PLAUR Domain Containing 3 (LYPD3) by miR-151-5p, involving complementary binding to the 3'-untranslated regions (3'-UTR) in the mRNA of LYPD3. Consequently, this interaction accelerates the metastasis of HNSCC. Notably, clinical observations indicate a correlation between high expression of miR-151-5p and low levels of LYPD3 in clinical settings are correlated with poor prognosis of HNSCC patients. Furthermore, our investigation demonstrates that glycosylation of LYPD3 modulates its subcellular localization and reinforces its role in suppressing HNSCC metastasis. Additionally, we uncover a potential regulatory mechanism involving the facilitation of miR-151-5p maturation and accumulation through N6-methyladenosine (m6A) modification. This process is orchestrated by methyltransferase-like 3 (METTL3) and mediated by a newly identified reader, heterogeneous nuclear ribonucleoprotein U (hnRNP U). These findings collectively underscore the significance of the METTL3/miR-151-5p/LYPD3 axis serves as a prominent driver in the malignant progression of HNSCC.

The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells.

BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.

Magnetic Stimulation of Gigantocellular Reticular Nucleus with Iron Oxide Nanoparticles Combined Treadmill Training Enhanced Locomotor Recovery by Reorganizing Cortico-Reticulo-Spinal Circuit.

Background: Gigantocellular reticular nucleus (GRNs) executes a vital role in locomotor recovery after spinal cord injury. However, due to its unique anatomical location deep within the brainstem, intervening in GRNs for spinal cord injury research is challenging. To address this problem, this study adopted an extracorporeal magnetic stimulation system to observe the effects of selective magnetic stimulation of GRNs with iron oxide nanoparticles combined treadmill training on locomotor recovery after spinal cord injury, and explored the possible mechanisms. Methods: Superparamagnetic iron oxide (SPIO) nanoparticles were stereotactically injected into bilateral GRNs of mice with moderate T10 spinal cord contusion. Eight-week selective magnetic stimulation produced by extracorporeal magnetic stimulation system (MSS) combined with treadmill training was adopted for the animals from one week after surgery. Locomotor function of mice was evaluated by the Basso Mouse Scale, Grid-walking test and Treadscan analysis. Brain MRI, anterograde virus tracer and immunofluorescence staining were applied to observe the tissue compatibility of SPIO in GRNs, trace GRNs' projections and evaluate neurotransmitters' expression in spinal cord respectively. Motor-evoked potentials and H reflex were collected for assessing the integrity of cortical spinal tract and the excitation of motor neurons in anterior horn. Results: (1) SPIO persisted in GRNs for a minimum of 24 weeks without inducing apoptosis of GRN cells, and degraded slowly over time. (2) MSS-enabled treadmill training dramatically improved locomotor performances of injured mice, and promoted cortico-reticulo-spinal circuit reorganization. (3) MSS-enabled treadmill training took superimposed roles through both activating GRNs to drive more projections of GRNs across lesion site and rebalancing neurotransmitters' expression in anterior horn of lumbar spinal cord. Conclusion: These results indicate that selective MSS intervention of GRNs potentially serves as an innovative strategy to promote more spared fibers of GRNs across lesion site and rebalance neurotransmitters' expression after spinal cord injury, paving the way for the structural remodeling of neural systems collaborating with exercise training, thus ultimately contributing to the reconstruction of cortico-reticulo-spinal circuit.