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In this study, we investigated the surface-confined coupling reactions of 1,8-dibromobiphenylene (BPBr2) on Cu(111) to elucidate the details of the organometallic intermediates via Ullmann reactions. We used scanning tunneling microscopy (STM) to characterize the resulting organometallic intermediates. Moreover, submolecular resolution of the non-contact atomic force microscopy (nc-AFM) qPlus technique enables the bond-resolving within the organometallic dimer product. Our findings reveal the debromination of BPBr2 on Cu(111), leading to the formation of an organometallic dimer intermediate at room temperature. Through nc-AFM measurements, we confirm and visualize the formation of the C-Cu-C bond. These insights enhance our understanding of Ullmann reaction and hold potential implications for the design of novel two-dimensional electronic devices.

Abstract Two-dimensional materials possessing intrinsic multiferroic properties have long been sought to harness the magnetoelectric coupling in nanoelectronic devices. Here, we report the achievement of robust type I multiferroic order in single-layer chromium trihalides by decorating transition metal atoms. The out-of-plane ferroelectric polarization exhibits strong atomic selectivity, where 12 of 84 single-layer transition metal-based multiferroic materials possess out-of-plane ferroelectric or antiferroelectric polarization. Group theory reveals that this phenomenon is strongly dependent on p–d coupling and crystal field splitting. Cu decoration enhances the intrinsic ferromagnetism of trihalides and increases the ferromagnetic transition temperature. Moreover, both ferroelectric and antiferroelectric phases are obtained, providing opportunities for electrical control of magnetism and energy storage and conversion applications. Furthermore, the transport properties of Cu(CrBr3)2 devices are calculated based on the non-equilibrium Green’s function, and the results demonstrate outstanding spin-filtering properties and a low-bias negative differential resistance (NDR) effect for low power consumption.

Abstract Quantum spin liquids (QSLs) are in a quantum disordered state that is highly entangled and has fractional excitations. As a highly sought-after state of matter, QSLs were predicted to host spinon excitations and to arise in frustrated spin systems with large quantum fluctuations. Here we report on the experimental observation and theoretical modeling of QSL signatures in monolayer 1T-NbSe2, which is a newly emerging two-dimensional material that exhibits both charge-density-wave (CDW) and correlated insulating behaviors. By using scanning tunneling microscopy and spectroscopy (STM/STS), we confirm the presence of spin fluctuations in monolayer 1T-NbSe2 by observing the Kondo resonance as monolayer 1T-NbSe2 interacts with metallic monolayer 1H-NbSe2. Subsequent STM/STS imaging of monolayer 1T-NbSe2 at the Hubbard band energy further reveals a long-wavelength charge modulation, in agreement with the spinon modulation expected for QSLs. By depositing manganese-phthalocyanine (MnPc) molecules with spin S = 3/2 onto monolayer 1T-NbSe2, new STS resonance peaks emerge at the Hubbard band edges of monolayer 1T-NbSe2. This observation is consistent with the spinon Kondo effect induced by a S = 3/2 magnetic impurity embedded in a QSL. Taken together, these experimental observations indicate that monolayer 1T-NbSe2 is a new promising QSL material.

Abstract Advanced atomic tracking techniques play a critical role in characterizing structural evolution, elucidating fundamental mechanisms of exotic phenomena and tailoring delicate properties. Thermally driven structural modulation in 2D crystals, such as the charge density wave (CDW), often leads to intriguing quantum properties, making them a valuable platform for exploring fundamental physics and potential device applications. However, despite their significance, experimental studies addressing atomic tracking of thermally‐driven structural evolution in 2D crystals have been limited. Herein, we utilize high‐accuracy variable‐temperature atomic tracking measurements with scanning tunneling microscopy (STM) to directly observe a series of structural transitions in a model 2D crystal, namely NbSe2. With the atomic tracking technique, we confirm the existence of the universal thermally‐driven CDW transition hysteresis between the heating and cooling cycles. This transition hysteresis, characterized by a constant temperature offset, represents a new phenomenon of structural evolution. Our findings provide a feasible method to track CDW transitions at the atomic scale in 2D crystals, significantly contributing to a better understanding and the potential modulation of these materials' functions in nanodevices.

ABSTRACT: Background: Cardiovascular surgery is usually associated with higher degree of postoperative pain that influences a patient's physical recovery. Multiple clinical measures have been taken to avoid overuse of opioid agents for postoperative pain management, which led to the development of clinical pathways for analgesic drug treatment using a multimodal approach. Objective: To evaluate the effectiveness and safety of a multimodal postoperative analgesic drug pathway (ADP) for pain management following cardiovascular surgery. Methods: This retrospective, controlled, nonrandomized study evaluated a postoperative ADP in patients undergoing cardiovascular surgery in a tertiary general hospital in Qingdao, China. Effectiveness and safety outcomes were compared before and after the implementation of the ADP. Outcome indicators included postoperative pain scores, consumption of opioids in analgesic pumps, and incidence of adverse events. Results: Patients who underwent cardiovascular surgery from September to November 2021 before the implementation of the ADP (n = 193) and from September to November 2022 after the implementation of the ADP (n = 218) were enrolled. Pain scores were reduced on day 1, 3, and 5 after surgery and the reduction was most significant in mild pain (P < .001). Opioids in analgesic pumps consumption was also significantly reduced and there was decreased incidence of adverse events such as nausea and vomiting (P = .026), respiratory inhibition (P = .027), and dizziness and headache (P = .028) in cardiovascular surgery patients after implementation of the ADP. Conclusions: Improved effectiveness and safety were observed following the implementation of the ADP. Multimodal analgesic ADP methodology can be effectively used for postoperative pain management in patients undergoing cardiovascular surgery.

Abstract The lattice geometry induced second-order topological corner states in breathing Kagome lattice have attracted enormous research interests, while the realistic breathing Kagome materials identified as second-order topological insulators are still lacking. Here, we report by first-principles calculations the second-order topological states emerging in two-dimensional d-orbital breathing Kagome crystals, i.e., monolayer niobium/tantalum chalcogenide halides M3QX7 (M = Nb, Ta; Q = S, Se, Te; X = Cl, Br, I). We find that the orbital degree of freedom of d orbitals can give rise to multiple sets of corner states. Combining fraction corner anomaly, orbital components and real space distribution of the corner states, we can also identify the topology of these corner states. Our work not only extends the lattice geometry induced second-order topological states to realistic materials, but also builds a clear and complete picture on their multiple sets of second-order topological states.

Abstract Background CMV gastroenteritis is common in patients receiving allogeneic hematopoietic stem cell transplantation and it is difficult to distinguish from acute graft-versus-host disease (aGvHD), which has very similar symptoms but needs quite different treatment. CMV gastroenteritis is caused by local infection or reactivation of CMV in the gastrointestinal tract while aGvHD is due to immune rejection. The gold standard of diagnosis of CMV gastroenteritis and aGvHD is gastrointestinal biopsy under endoscopy, which is invasive and can potentially lead to severe side effects. Stool samples testing with quantitative polymerase chain reaction (qPCR) may be an alternative, while the application in trace level measurements and precision are not all satisfactory enough in reported research. Methods In this study, we designed a novel method that extracted the cell free DNA (cfDNA) from the fecal supernatant to perform digital PCR (dPCR) for the detection of CMV, analyzed the performance and compared it with the total DNA extracted by the current procedure. Results Twenty-two paired stool samples using two DNA extraction methods proved that the cfDNA extraction method had markedly higher DNA concentrations and control gene copy number, suggesting that cfDNA may be more informative and more useful for the detection of CMV DNA segment. The dPCR approach in detecting CMV DNA segment also exhibit good linearity (R2 = 0.997) and higher sensitivity (limit of detection at 50% was 3.534 copies/μL). Eighty-two stool samples from 44 immunocompromised patients were analyzed, CMV-positive rate was 28%, indicating that more than one-quarter of the gastrointestinal symptoms within these patients may be caused by CMV infection or reactivation. Conclusion The combined results suggest that detection of CMV by dPCR in cfDNA of stool supernatant is a powerful method to identify CMV gastroenteritis and helps in clinical treatment decision making.

Abstract Monolayer transition metal dichalcogenides (TMDs) can host exotic phenomena such as correlated insulating and charge‐density‐wave (CDW) phases. Such properties are strongly dependent on the precise atomic arrangements. Strain, as an effective tuning parameter in atomic arrangements, has been widely used for tailoring material's structures and related properties, yet to date, a convincing demonstration of strain‐induced dedicate phase transition at nanometer scale in monolayer TMDs has been lacking. Here, a strain engineering technique is developed to controllably introduce out‐of‐plane atomic deformations in monolayer CDW material 1T‐NbSe2. The scanning tunneling microscopy and spectroscopy (STM and STS) measurements, accompanied by first‐principles calculations, demonstrate that the CDW phase of 1T‐NbSe2 can survive under both tensile and compressive strains even up to 5%. Moreover, significant strain‐induced phase transitions are observed, i.e., tensile (compressive) strains can drive 1T‐NbSe2 from an intrinsic‐correlated insulator into a band insulator (metal). Furthermore, experimental evidence of the multiple electronic phase coexistence at the nanoscale is provided. The results shed new lights on the strain engineering of correlated insulator and useful for design and development of strain‐related nanodevices.

With the success of chimeric antigen receptor-modified (CAR) T-cell therapy for relapsed/refractory (r/r) B-cell malignancies, severe complications after CAR T-cell infusion have emerged as nonnegligible prognosis-related factors. However, the prognosis of patients with CAR T-cell-related hyperferritinaemia (HFA) is unclear. We report the efficacy and safety of CAR T-cell therapy in 16 r/r B-cell malignancy patients with CAR T-cell-related HFA. The rates of serum ferritin levels above 10,000 ng/ml during CAR T-cell therapy were 6.2% and 14.3% in B-cell non-Hodgkin’s lymphoma (B-NHL) and acute B lymphocyte leukemia (B-ALL), respectively. These patients were characterized by an extremely high tumor burden and a high rate of extranodal involvement. In lymphoma, the complete remission (CR) rate was 37.5% (3/8), which was lower than that in the control group with the lowest value of ferritin (CR was 87.5% (7/8), P=0.0406), and it could also be seen that the OS of the control group (1-year OS rate 100%) had a better trend than HFA group (1-year OS rate 50%). In the B-ALL patients, the OS of the control group (1-year OS rate 100%) was higher than HFA group (1-year OS rate 45%, P=0.0189), although there was no significant difference in CR rate. High-grade CRS (≥3) occurred in 56.25% of the patients, and the mortality rate was 56.25%, which was significantly higher than control group (12.5% and 12.5%, P=0.009). The peak serum ferritin level in the patients who died of CRS was significantly higher than others (P=0.0168). Regardless of whether the CAR T-related MAS diagnostic criteria were met, there was no significant difference in ORR and OS in HFA group, however patients with MAS showed a higher rate of high-grade CRS. Interestingly, in our study, glucocorticoid intervention in HFA group showed little impact on expansion of CAR-T cells, whether compared with control group or compared within HFA group by dividing patients into high and low dosage subgroups based on the median dose of glucocorticoid. High mortality was observed in patients with CAR T-cell-related HFA. Early glucocorticoid intervention might be worth trying to improve the safety of CAR T therapy in these patients.

Abstract Background Hispidin (HIP) and its derivatives, a class of natural fungal metabolites, possess complex chemical structures with extensive pharmacological activities. Phellinus igniarius, the most common source of HIP, can be used as both medicine and food. However, the biosynthetic pathway of HIP in P. igniarius remains unclear and we have a limited understanding of the regulatory mechanisms related to HIP. In this work, we sought to illustrate a biosynthesis system for hispidin and its derivatives at the protein level. Results We found that tricetolatone (TL) is a key biosynthetic precursor in the biosynthetic pathway of hispidin and that its addition led to increased production of hispidin and various hispidin derivatives. Based on the changes in the concentrations of precursors and intermediates, key timepoints in the biosynthetic process were identified. We used isobaric tags for relative and absolute quantification (iTRAQ) to study dynamic changes of related proteins in vitro. The 270 differentially expressed proteins were determined by GO enrichment analysis to be primarily related to energy metabolism, oxidative phosphorylation, and environmental stress responses after TL supplementation. The differentially expressed proteins were related to ATP synthase, NAD binding protein, oxidoreductase, and other elements associated with electron transfer and dehydrogenation reactions during the biosynthesis of hispidin and its derivatives. Multiple reaction monitoring (MRM) technology was used to selectively verify the iTRAQ results, leading us to screen 11 proteins that were predicted to be related to the biosynthesis pathways. Conclution These findings help to clarify the molecular mechanism of biosynthesis of hispidin and its derivatives and may serve as a foundation for future strategies to identify new hispidin derivatives.

To meet the pressing needs concerning the optimization of the performance of powder metallurgy (P/M) superalloys for turbine disc applications, the effects of solution temperature on a novel high γ′ volume fraction P/M superalloy FGH 4107 were investigated. The results indicated that the size of the γ′ precipitates decreased dramatically as the solution temperature increased from 1160 to 1200 °C. Theoretical calculations showed that the precipitation strengthening played a dominant role in enhancing the strength of the high γ′ volume fraction P/M superalloy, and a higher solution temperature was beneficial for the modification of the γ′ phase distribution during the following cooling and aging process.

Growing evidence now suggests that circulating tumour DNA (ctDNA) has great potential as a non-invasive biomarker for disease monitoring, since ctDNA carries tumour-specific modifications. In particular, monitoring ctDNA has important implications for identifying patients with haematological malignancies at clinical risk of disease progression. We hereby describe three patients with B-cell non-Hodgkin lymphoma and investigate the clinical value of sequential ctDNA profiling for the early detection of tumour relapse. Somatic mutations in diagnostic tumour biopsy samples of these three patients were identified by applying high-throughput next-generation sequencing. Droplet digital PCR probes and primers were designed and tested for each hotspot mutation. Serial ctDNA analysis was subsequently conducted among these three patients. We found that the longitudinal monitoring of plasma ctDNA could predict for at least one month in advance compared with flow cytometry, cytology and conventional imaging modalities. Therefore, our results support liquid biopsy based on ctDNA as a non-invasive complementary modality to other detection methods for detecting early relapse and contribute to more precise management for non-Hodgkin lymphoma patients.

Context: CYP3A4 and P-gp together form a highly efficient barrier for orally absorbed drugs and always share the same substrates. Our previous work revealed that chrysosplenetin (CHR) significantly augmented the rat plasma level and anti-malarial efficacy of artemisinin (ART), partially due to the uncompetitive inhibition effect of CHR on rat CYP3A. But the impact of CHR on P-gp is still unknown. Objective: The present study investigates whether CHR interferes with P-gp-mediated efflux of ART and elucidates the underlying mechanism. Materials and methods: P-gp-over-expressing Caco-2 cells were treated with ART (10 μM) or ART-CHR (1:2, 10:20 μM) in ART bidirectional transport experiment. ART concentration was determined by UHPLC-MS/MS method. Healthy male ICR mice were randomly divided into nine groups (n = 6) including negative control (0.5% CMC-Na solution, 13 mL/kg), ART alone (40 mg/kg), verapamil (positive control, 40 mg/kg), ART-verapamil (1:1, 40:40 mg/kg), CHR alone (80 mg/kg), ART-CHR (1:0.1, 40:4 mg/kg), ART-CHR (1:1, 40:40 mg/kg), ART-CHR (1:2, 40:80 mg/kg) and ART-CHR (1:4, 40:160 mg/kg). The drugs were administrated intragastrically for seven consecutive days. MDR1 and P-gp expression levels in mice small intestine were examined by performing RT-PCR and western blot analysis. ABC coupling ATPase activity was also determined. Results: After combined with CHR (1:2), Papp (AP-BL) and Papp (BL-AP) of ART changed to 4.29 × 10 − 8 (increased 1.79-fold) and 2.85 × 10 − 8 cm/s (decreased 1.24-fold) from 2.40 × 10 − 8 and 3.54 × 10 − 8 cm/s, respectively. Efflux ratio (PBA/PAB) declined 2.21-fold (p

Ultra-short-term load demand forecasting is significant to the rapid response and real-time dispatching of the power demand side. Considering too many random factors that affect the load, this paper combines convolution, long short-term memory (LSTM), and gated recurrent unit (GRU) algorithms to propose an ultra-short-term load forecasting model based on deep learning. Firstly, more than 100,000 pieces of historical load and meteorological data from Beijing in the three years from 2016 to 2018 were collected, and the meteorological data were divided into 18 types considering the actual meteorological characteristics of Beijing. Secondly, after the standardized processing of the time-series samples, the convolution filter was used to extract the features of the high-order samples to reduce the number of training parameters. On this basis, the LSTM layer and GRU layer were used for modeling based on time series. A dropout layer was introduced after each layer to reduce the risk of overfitting. Finally, load prediction results were output as a dense layer. In the model training process, the mean square error (MSE) was used as the objective optimization function to train the deep learning model and find the optimal super parameter. In addition, based on the average training time, training error, and prediction error, this paper verifies the effectiveness and practicability of the load prediction model proposed under the deep learning structure in this paper by comparing it with four other models including GRU, LSTM, Conv-GRU, and Conv-LSTM.

Abstract Histological analysis with 2,3,5-triphenyltetrazolium chloride (TTC) staining is the most frequently used tool to detect myocardial ischemia/reperfusion injury. However, its practicality is often challenged by poor image quality in gross histology, leading to an equivocal infarct-boundary delineation and potentially compromised measurement accuracy. Here, we introduce several crucial refinements in staining protocol and sample processing, which enable TTC images to be analyzed with light microscopy. The refined protocol involves a two-step TTC staining process (perfusion and immersion) and subsequent Zamboni fixation to differentiate myocardial viability and necrosis, and use of Coomassie brilliant blue to label area-at-risk. After the duo-staining steps were completed, the heart sample was embedded and sliced transversally by a cryostat into a series of thin sections (50 µm) for microscopic analysis. The refined TTC (redTTC) assay yielded remarkably high-quality images with striking color intensity and sharply defined boundaries, permitting unambiguous and reliable delineation of the infarct and area-at-risk. In the same animals, the redTTC assay showed good agreement with the in-vivo gold standard measurements (LGE and MEMRI). Meanwhile, redTTC imaging allows tracking of viable cardiomyocytes at cellular resolution, and with this enhanced capability, we convincingly demonstrated the pro-survival action of stem cells based-therapy. Therefore, the redTTC assay represents a significant technical advance that permits precise detection of the true extent of cardiac injury and cardiomyocyte viability. This approach is cost-effective and may be adapted for use in diverse applications, making it highly appealing to many laboratories performing ischemia/reperfusion injury experiments.

Abstract. Breast cancer, a malignant tumor with a high incidence in women, lacks in vitro research models that can represent the biological functions of breast tumors in vivo. As a new biological tool, the organoid model has unique advantages over traditional methods, such as cell culture and patient-derived xenografts. Combining organoids with other emerging technologies, such as gene engineering and microfluidic chip technology, provides an effective method to compensate for the deficiencies in organoid models of breast cancer in vivo. The emergence of breast cancer organoids has provided new tools and research directions in precision medicine, and drug research. In this review, we summarized the merits and demerits of organoids compared to traditional biological models, explored the latest developments in the combination of new technologies and organoid models, and discussed the construction methods and application prospects of different breast cancer organoid models.

Abstract Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

Objectives. The aim of this study was to explore the functional consequences of two common variants, p.V37I and c.299-300delAT, in the hearing loss-associated gene GJB2. Methods. Connexin 26 expression and gap junctional permeability were studied in HEK 293T cells transfected with plasmids expressing GJB2 wild-type, p.V37I, or c.299-300delAT CX26 proteins tagged with fluorescent markers. Functional analyses of various GJB2 haplotypes were conducted to thoroughly evaluate alterations in ionic and small-molecule coupling. Results. The p.V37I protein was localized at the plasma membrane, but it failed to effectively transport intercellular propidium iodide or Ca2+ efficiently, indicating an impairment in both biochemical and ionic coupling. The presence of GJB2 p.V37I seemed to increase the cells’ sensitivity to H2O2 treatment. In contrast, the known variant c.299-300delAT protein was not transported to the cell membrane and was unable to form gap junctions, remaining confined to the cytoplasm. Both ionic and biochemical coupling were defective in cells transfected with c.299-300delAT. Conclusion. The p.V37I and c.299-300delAT GJB2 mutations resulted in deficient gap junction-mediated coupling. Additionally, environmental factors could influence the functional outcomes of the GJB2 p.V37I mutation. These findings could pave the way for the development of molecular therapies targeting GJB2 mutations to treat hearing loss.

This literature review emphasizes the innovative role of ferroptosis in cancer treatment. Ferroptosis is a kind of deliberate cell death that is characterized by the generation of lipid peroxides and needs the presence of iron. Ferroptosis is a controlled cell death process that adheres to certain rules and regulations. The inhibition of System Xc- and the involvement of GPX4 are two of the primary areas of exploration that are engaged in the process of ferroptosis. This review explores the treatments that are used to treat ferroptosis in a range of malignancies, with a particular focus on breast carcinoma. Attention is paid to certain pathways, such as the FSP1-independent regulation of glutathione, involvement of cholesterol, and the prominin 2-MVB/exosome-ferritin pathway. Ferroptosis plays a key role in resistance to tumor therapy.

Abstract Objective Proliferative nodular formation represents a characteristic pathological feature of benign prostatic hyperplasia (BPH) and serves as the primary cause for prostate volume enlargement and consequent lower urinary tract symptoms (LUTS). Its specific mechanism is largely unknown, although several cellular processes have been reported to be involved in BPH initiation and development and highlighted the crucial role of epithelial cells in proliferative nodular formation. However, the technological limitations hinder the in vivo investigation of BPH patients. Methods The robust cell type decomposition (RCTD) method was employed to integrate spatial transcriptomics and single cell RNA sequencing profiles, enabling the elucidation of epithelial cell alterations during nodular formation. Immunofluorescent and immunohistochemical staining was performed for verification. Results The alterations of epithelial cells during the formation of nodules in BPH was observed, and a distinct subgroup of basal epithelial (BE) cells, referred to as BE5, was identified to play a crucial role in driving this progression through the hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway. BE5 served as both the initiating cell during nodular formation and the transitional cell during the transformation from luminal epithelial (LE) to BE cells. A distinguishing characteristic of the BE5 cell subgroup in patients with BPH was its heightened hypoxia and upregulated expression of FOS. Histological verification results confirmed a significant association between c-Fos expression and key biological processes such as hypoxia and cell proliferation, as well as the close relationship between hypoxia and EMT in BPH tissues. Furthermore, a strong link between c-Fos expression and the progression of BPH was also been validated. Additionally, notable functional differences were observed in glandular and stromal nodules regarding BE5 cells, with BE5 in glandular nodules exhibiting enhanced capacities for EMT and cell proliferation characterized by club-like cell markers. Conclusions This study elucidated the comprehensive landscape of epithelial cells during in vivo nodular formation in patients, thereby offering novel insights into the initiation and progression of BPH.

ABSTRACT Protein acetylation and deacetylation are key epigenetic modifications that regulate the initiation and development of several diseases. In the context of infection with Mycobacterium tuberculosis (M. tb), these processes are essential for host–pathogen interactions and immune responses. However, the specific effects of acetylation and deacetylation on cellular functions during M. tb infection are not fully understood. This study employed Tandem Mass Tag (TMT) labeling for quantitative proteomic profiling to examine the acetylproteome (acetylome) profiles of noninfected and M. tb-infected macrophages. We identified 715 acetylated peptides from 1,072 proteins and quantified 544 lysine acetylation sites (Kac) in 402 proteins in noninfected and M. tb-infected macrophages. Our research revealed a link between acetylation events and metabolic changes during M. tb infection. Notably, the deacetylation of heat shock protein 60 (HSP60), a key chaperone protein, was significantly associated with this process. Specifically, the deacetylation of HSP60 at K96 by sirtuin3 (SIRT3) enhances macrophage apoptosis, leading to the elimination of intracellular M. tb. These findings underscore the pivotal role of the SIRT3–HSP60 axis in the host immune response to M. tb. This study offers a new perspective on host protein acetylation and suggests that targeting host-directed therapies could be a promising approach for tuberculosis immunotherapy.IMPORTANCEProtein acetylation is crucial for the onset, development, and outcome of tuberculosis (TB). Our study comprehensively investigated the dynamics of lysine acetylation during M. tb infection, shedding light on the intricate host–pathogen interactions that underlie the pathogenesis of tuberculosis. Using an advanced quantitative lysine proteomics approach, different profiles of acetylation sites and proteins in macrophages infected with M. tb were identified. Functional enrichment and protein–protein network analyses revealed significant associations between acetylated proteins and key cellular pathways, highlighting their critical role in the host response to M. tb infection. Furthermore, the deacetylation of HSP60 and its influence on macrophage-mediated clearance of M. tb underscore the functional significance of acetylation in tuberculosis pathogenesis. In conclusion, this study provides valuable insights into the regulatory mechanisms governing host immune responses to M. tb infection and offers promising avenues for developing novel therapeutic interventions against TB.

ObjectiveThe purpose of this study is to investigate potential associations between osteopenia, osteosarcopenia, and postoperative outcomes in patients with hepatobiliary-pancreatic cancer (HBPC).MethodsThree online databases, including Embase, PubMed, and the Cochrane Library, were thoroughly searched for literature describing the relationship between osteopenia, osteosarcopenia, and outcomes of surgical treatment of HBPC patients from the start of each database to September 29, 2023. The Newcastle-Ottawa Scale was used to rate the quality of the studies.ResultsThis analysis included a total of 16 articles with a combined patient cohort of 2,599 individuals. The results demonstrated that HBPC patients with osteopenia had significantly inferior OS (HR: 2.27, 95% CI: 1.70-3.03, p < 0.001) and RFS (HR: 1.96, 95% CI: 1.42-2.71, p < 0.001) compared to those without osteopenia. Subgroup analysis demonstrated that these findings were consistent across univariate and multivariate analyses, as well as hepatocellular carcinoma, biliary tract cancer, and pancreatic cancer. The risk of postoperative major complications was significantly higher in patients with osteopenia compared to those without osteopenia (OR: 1.66, 95% CI: 1.19-2.33, p < 0.001). Besides, we also found that the presence of osteosarcopenia in HBPC patients was significantly related to poorer OS (HR: 3.31, 95% CI: 2.00-5.48, p < 0.001) and PFS (HR: 2.50, 95% CI: 1.62-3.84, p < 0.001) in comparison to those without osteosarcopenia.ConclusionPreoperative osteopenia and osteosarcopenia can predict poorer OS and RFS with HBPC after surgery.

Abstract Background Glioblastoma multiforme (GBM) is a devastating disease that lacks effective drugs for targeted therapy. Previously, we found that the third-generation epidermal growth factor receptor (EGFR) inhibitor AZD-9291 persistently blocked the activation of the ERK pathway but had no inhibitory effect on the phosphoinositide 3-kinase (PI3K)/Akt pathway. Given that the PI3K inhibitor GDC-0084 is being evaluated in phase I/II clinical trials of GBM treatment, we hypothesized that combined inhibition of the EGFR/ERK and PI3K/Akt pathways may have a synergistic effect in the treatment of GBM. Methods The synergistic effects of cotreatment with AZD-9291 and GDC-0084 were validated using cell viability assays in GBM and primary GBM cell lines. Moreover, the underlying inhibitory mechanisms were assessed through colony formation, EdU proliferation, and cell cycle assays, as well as RNA-seq analyses and western blot. The therapeutic effects of the drug combination on tumor growth and survival were investigated in mice bearing tumors using subcutaneously or intracranially injected LN229 xenografts. Results Combined treatment with AZD-9291 and GDC-0084 synergistically inhibited the proliferation and clonogenic survival, as well as induced cell cycle arrest of GBM cells and primary GBM cells, compared to monotherapy. Moreover, AZD-9291 plus GDC-0084 combination therapy significantly inhibited the growth of subcutaneous tumors and orthotopic brain tumor xenografts, thus prolonging the survival of tumor-bearing mice. More importantly, the combination of AZD-9291 and GDC-0084 simultaneously blocked the activation of the EGFR/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby exerting significant antitumor activity. Conclusion Our findings demonstrate that the combined blockade of the EGFR/MEK/ERK and PI3K/AKT/mTOR pathways is more effective against GBM than inhibition of each pathway alone, both in vitro and in vivo. Our results suggest that AZD-9291 combined with GDC-0084 may be considered as a potential treatment strategy in future clinical trials. Video Abstract

Drought stress seriously threatens plant growth. The improvement of plant water use efficiency (WUE) and drought tolerance through stomatal regulation is an effective strategy for coping with water shortages. Epidermal patterning factor (EPF)/EPF-like (EPFL) family proteins regulate stomatal formation and development in plants and thus contribute to plant stress adaptation. Here, our analysis revealed the presence of 14 PeEPF members in the Populus euphratica genome, which exhibited a relatively conserved gene structure with 1–3 introns. Subcellular localisation prediction revealed that 9 PeEPF members were distributed in the chloroplasts of P. euphratica, and 5 were located extracellularly. Phylogenetic analysis indicated that PeEPFs can be divided into three clades, with genes within the same clade revealing a relatively conserved structure. Furthermore, we observed the evolutionary conservation of PeEPFs and AtEPF/EPFLs in certain domains, which suggests their conserved function. The analysis of cis-acting elements suggested the possible involvement of PeEPFs in plant response to multiple hormones. Transcriptomic analysis revealed considerable changes in the expression level of PeEPFs during treatment with polyethylene glycol and abscisic acid. The overexpression of PeEPF2 resulted in low stomatal density in transgenetic lines. These findings provide a basis for gaining insights into the function of PeEPFs in response to abiotic stress.