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Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a promising therapeutic target for cancer therapy. In this work, we presented the structure-guided design of 5,6-fused bicyclic allosteric SHP2 inhibitors, leading to the identification of pyrazolopyrazine-based TK-642 as a highly potent, selective, orally bioavailable allosteric SHP2 inhibitor (SHP2WT IC50 = 2.7 nmol/L) with favorable pharmacokinetic profiles (F = 42.5%; t1/2 = 2.47 h). Both dual inhibition biochemical assay and docking analysis indicated that TK-642 likely bound to the “tunnel” allosteric site of SHP2. TK-642 could effectively suppress cell proliferation (KYSE-520 cells IC50 = 5.73 μmol/L) and induce apoptosis in esophageal cancer cells by targeting the SHP2-mediated AKT and ERK signaling pathways. Additionally, oral administration of TK-642 also demonstrated effective anti-tumor effects in the KYSE-520 xenograft mouse model, with a T/C value of 83.69%. Collectively, TK-642 may warrant further investigation as a promising lead compound for the treatment of esophageal cancer.

Abstract Humic acid (HA) can substantially enhance plant growth and improve soil health. Currently, the impacts of HA concentrations variation on the development and soil quality of Panax notoginseng (Sanqi) from the forest understorey are still unclear. In this study, exogenous HA was administered to the roots of Sanqi at varying concentrations (2, 4, and 6 ml/L). Subsequently, the diversity and community structure of bacteria and fungi were assessed through high-throughput sequencing technology. The investigation further involved analyzing the interplay among the growth of sanqi, soil edaphic factors, and the microbial network stability. Our finding revealed that moderate concentrations (4 ml/L) of HA improved the fresh/dry weight of Sanqi and NO3 -−N levels. Compared with control, the moderate concentrations of HA had a notable impact on the bacterial and fungal communities compositions. However, there was no significant difference in the α and β diversity of bacteria and fungi. Moreover, the abundance of beneficial bacteria (Bradyrhizobium) and harmful bacteria (Xanthobacteraceae) increased and decreased at 4 ml/L HA, respectively, while the bacterial and fungal network stability were enhanced. Structural equation model (SEM) revealed that the fresh weight of Sanqi and bacterial and fungal communities were the factors that directly affected the microbial network stability at moderate concentrations of HA. In conclusion, 4 ml/L of HA is beneficial for promoting Sanqi growth and soil quality. Our study provides a reference for increasing the yield of Sanqi and sustainable development of the Sanqi-pine agroforestry system.

Abstract Introduction Radiation Therapy and IRreversible Electroporation for Intermediate Risk Prostate Cancer (RTIRE) is a phase II clinical trial testing combination of radiation therapy and irreversible electroporation for intermediate risk prostate cancer Background PCa is the most common non-cutaneous cancer in men and the second leading cause of cancer death in men. PCa treatment is associated with long term side effects including urinary, sexual, and bowel dysfunction. Management of PCa is based on risk stratification to prevent its overtreatment and associated treatment-related toxicity. There is increasing interest in novel treatment strategies, such as focal therapy, to minimize treatment associated morbidity. Focal therapy alone has yet to be included in mainstream guidelines, given ongoing concerns with potentially higher risk of recurrence. We hypothesize combining focal therapy with whole gland, reduced dose radiotherapy will provide acceptable oncologic efficacy with minimal treatment associated morbidity. RTIRE is a phase II single institution, investigator-initiated study combining a local ablative technique though local irreversible electroporation (IRE) with MR guided RT (MRgRT) to treat the entire prostate. The goal is to provide excellent oncologic outcomes and minimize treatment related side effects through leveraging benefits of locally ablative therapy with established radiation treatment techniques. Methods A total of 42 men with intermediate risk PCa per NCCN guidelines and focal grade group (GG) 2 or 3, Gleason Score (GS) 3 + 4 or GS 4 + 3, cancer in an MRI target will be enrolled. Patients with MRI visible foci of GG2/GG3 will undergo focal therapy with IRE of this lesion. Following successful focal therapy, patients will then undergo a course of reduced dose, whole gland MRgRT with either 32.5 Gy in 5 Fractions or 22 Gy in 2 fractions. The primary objective of the study is to determine safety. Secondary outcomes include evaluation of oncologic efficacy (as measured by the proportion of patients free of clinically significant cancer as defined as > Grade Group 1 at 1-year follow-up biopsy), imaging characteristics of patients pre and post RTIRE, impact on quality of life (QoL), and PSA kinetics. Discussion Combining IRE with a reduced dose radiotherapy may offer a new treatment paradigm for PCa by both reducing treatment effects of full dose radiotherapy and minimizing the risk of recurrence observed with focal therapy. Trial Registration Clinicaltrials.gov identifier: NCT05345444. Date of registration: April 25, 2022. Protocol Version: 6.0, July 7, 2023.

Amaranthus roxburghianus H.W. Kung 1935, belonging to the Amaranthaceae family, is recognized for its significant medicinal properties. However, molecular research on this species has been limited. This study represents the inaugural documentation of the sequencing and assembly of the complete plastome of A. roxburghianus. The genome spans a total length of 149,969 base pairs (bp), exhibiting a conventional quadripartite structure. This structure comprises a large single-copy (LSC) region of 83,917 bp, a small single-copy (SSC) region of 18,124 bp, and two inverted repeat (IR) regions, each extending to 23,964 bp. In its entirety, the A. roxburghianus plastome encompasses 128 genes, of which 107 are unique, encompassing 77 individual protein-coding genes, 26 unique tRNA genes, and four unique rRNA genes. Phylogenetic analysis has shown a close resemblance between A. roxburghianus and A. polygonoides, both part of the subgenus Albersia. Although the genus Amaranthus is roughly divided into three subgenera, additional plastid genomic data are required for a more accurate assignment of A. albus and A. blitoides. The sequencing of this plastome is a significant step forward, likely to expedite the development of molecular markers and significantly contribute to genetic assays involving this distinctive species.

Abstract This study addresses the challenges in large-scale unmanned aerial vehicle (UAV) clusters, specifically the scalability issues and limitations of using reactive routing protocols for inter-cluster routing. These traditional methods place an excessive burden on cluster heads and struggle to adapt to frequently changing topologies, leading to decreased network performance. To solve these problems, we propose an innovative inter-cluster routing protocol (ICRP), which is based on a hybrid ant colony algorithm. During the route establishment phase, ICRP uses this algorithm to identify the optimal relay node. This approach is inspired by the foraging behavior of Physarum polycephalum, combining factors such as the number of hops from the source node, the load condition of the node, and its weight in the pheromone calculation. In the route maintenance phase, ICRP uses a predictive repair and contraction mechanism to dynamically maintain routes, accommodating the high mobility of UAVs. Comparative simulations in OMNeT + + showed that this protocol surpasses ad-hoc on-demand distance vector (AODV), fuzzy-logic-assisted-AODV, and Enhanced-Ant-AODV routing protocols in packet delivery rate and end-to-end transmission delay. Furthermore, it showed superior adaptation to network environments with high-speed node mobility.

Abstract Background Multiple genetic and epigenetic regulatory mechanisms are crucial in the development and tumorigenesis process. Transcriptional regulation often involves intricate relationships and networks with post-transcriptional regulatory molecules, impacting the spatial and temporal expression of genes. However, the synergistic relationship between transcription factors and N6-methyladenosine (m6A) modification in regulating gene expression, as well as their influence on the mechanisms underlying the occurrence and progression of non-small cell lung cancer (NSCLC), requires further investigation. The present study aimed to investigate the synergistic relationship between transcription factors and m6A modification on NSCLC. Methods The transcription factor NFIC and its potential genes was screened by analyzing publicly available datasets (ATAC-seq, DNase-seq, and RNA-seq). The association of NFIC and its potential target genes were validated through ChIP-qPCR and dual-luciferase reporter assays. Additionally, the roles of NFIC and its potential genes in NSCLC were detected in vitro and in vivo through silencing and overexpression assays. Results Based on multi-omics data, the transcription factor NFIC was identified as a potential tumor suppressor of NSCLC. NFIC was significantly downregulated in both NSCLC tissues and cells, and when NFIC was overexpressed, the malignant phenotype and total m6A content of NSCLC cells was suppressed, while the PI3K/AKT pathway was inactivated. Additionally, we discovered that NFIC inhibits the expression of METTL3 by directly binding to its promoter region, and METTL3 regulates the expression of KAT2A, a histone acetyltransferase, by methylating the m6A site in the 3’UTR of KAT2A mRNA in NSCLC cells. Intriguingly, NFIC was also found to negatively regulate the expression of KAT2A by directly binding to its promoter region. Conclusions Our findings demonstrated that NFIC suppresses the malignant phenotype of NSCLC cells by regulating gene expression at both the transcriptional and post-transcriptional levels. A deeper comprehension of the genetic and epigenetic regulatory mechanisms in tumorigenesis would be beneficial for the development of personalized treatment strategies.

Abstract Purpose and method Necrotizing tracheobronchitis is a rare clinical entity presented as a necrotic inflammation involving the mainstem trachea and distal bronchi. We reported a case of severe necrotizing tracheobronchitis caused by influenza B and methicillin-resistant Staphylococcus aureus (MRSA) co-infection in an immunocompetent patient. Case presentation We described a 36-year-old man with initial symptoms of cough, rigors, muscle soreness and fever. His status rapidly deteriorated two days later and he was intubated. Bronchoscopy demonstrated severe necrotizing tracheobronchitis, and CT imaging demonstrated multiple patchy and cavitation formation in both lungs. Next-generation sequencing (NGS) and bronchoalveolar lavage fluid (BALF) culture supported the co-infection of influenza B and MRSA. We also found T lymphocyte and NK lymphocyte functions were extremely suppressed during illness exacerbation. The patient was treated with antivirals and antibiotics including vancomycin. Subsequent bronchoscopy and CT scans revealed significant improvement of the airway and pulmonary lesions, and the lymphocyte functions were restored. Finally, this patient was discharged successfully. Conclusion Necrotizing tracheobronchitis should be suspected in patients with rapid deterioration after influenza B infection. The timely diagnosis of co-infection and accurate antibiotics are important to effective treatment.

Abstract Background The present study aims to identify the differential miRNA expression profile in middle ear cholesteatoma and explore their potential roles in its pathogenesis. Methods Cholesteatoma and matched normal retroauricular skin tissue samples were collected from patients diagnosed with acquired middle ear cholesteatoma. The miRNA expression profiling was performed using small RNA sequencing, which further validated by quantitative real-time PCR (qRT-PCR). Target genes of differentially expressed miRNAs in cholesteatoma were predicted. The interaction network of 5 most significantly differentially expressed miRNAs was visualized using Cytoscape. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses were processed to investigate the biological functions of miRNAs in cholesteatoma. Results The miRNA expression profile revealed 121 significantly differentially expressed miRNAs in cholesteatoma compared to normal skin tissues, with 56 upregulated and 65 downregulated. GO and KEGG pathway enrichment analyses suggested their significant roles in the pathogenesis of cholesteatoma. The interaction network of the the 2 most upregulated (hsa-miR-21-5p and hsa-miR-142-5p) and 3 most downregulated (hsa-miR-508-3p, hsa-miR-509-3p and hsa-miR-211-5p) miRNAs identified TGFBR2, MBNL1, and NFAT5 as potential key target genes in middle ear cholesteatoma. Conclusions This study provides a comprehensive miRNA expression profile in middle ear cholesteatoma, which may aid in identifying therapeutic targets for its management.

Abstract Background Ovarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti–PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC. Methods and results The retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p

Magnesium oxysulfide (MOS) cement has emerged as a promising cementitious material due to the high strength and excellent durability, but research on its rust inhibition remains limited. In this study, the chloride and nitrite were introduced in the MOS cement composites, aiming to investigate the corrosion properties and reveal the rust inhibition mechanism of steel bar under different W/C ratio. Experimental results show that the corrosion area ratios reach the largest value of approximately 98% and the lowest value of approximately 3%, respectively, as the chloride and nitrite contents increase to 2%. Compared with chloride, the effect of W/C ratio on the mass loss of steel bar is gradually weakened when the nitrite content is larger than 0.5%. Based on the natural potential, the change of corrosion degree mainly occurs after 28d. In addition, the corrosion potential of steel bar decreases and corrosion rate increases with the increase of chloride content in MOS cement composites. Conversely, the presence of Mg(NO2)2 from nitrite engenders an opposite effect. Besides, the increase of W/C ratio results in higher electrochemical parameters. At this time, the rust inhibition mechanism is revealed based on the micro-structure analysis.

Abstract Background Deep brain stimulation (DBS) is a promising therapy for refractory Gilles de la Tourette syndrome (GTS). However, its long-term efficacy, safety, and recommended surgical age remain controversial, requiring evidence to compare different age categories. Methods This retrospective cohort study recruited 102 GTS patients who underwent DBS between October 2006 and April 2022 at two national centers. Patients were divided into two age categories: children (aged 0.05), and the children group received significantly higher improvement in GTS-QOL scores than adults (55.9% vs. 47.9%, p = 0.049). Conclusions DBS showed acceptable long-term efficacy and safety for both children and adults with GTS. Surgeries performed for patients younger than 18 years seemed to show acceptable long-term efficacy and safety and were not associated with increased risks of loss of benefit compared to patients older than 18 at the time of surgery. However, surgeries for children should also be performed cautiously to ensure their refractoriness and safety.

Abstract Objective Perioperative Neurocognitive Disorders (PND) is a common neurological complication after radical colorectal cancer surgery, which increases adverse outcomes. So, our objective is to explore the influence of dexmedetomidine added to ropivacaine for transversus abdominis plane block (TAPB) on perioperative neurocognitive disorders, and to provide a new way to reduce the incidence of PND. Methods One hundred and eighty patients submitted to radical laparoscopic colorectal cancer surgery were randomly divided into Control group and Dex group. Ultrasound guided TAPB was performed after anesthesia induction: 0.5% ropivacaine 20 ml was injected into each transversus abdominis plane in Control group, 0.5% ropivacaine + 1 μg/kg dexmedetomidine (amounting to 20 ml) in Dex group. We observed the incidence of PND within 30 days after surgery. Results One hundred and sixty-nine cases were finally analyzed, including 84 cases in Control group and 85 cases in Dex group. Compared with Control group, there was no significant difference in terms of the incidence of PND on the 3rd day and the 7th day (P > 0.05), but the incidence significantly decreased at the 6th hour, at the 24th hour and on the 30th day after surgery (P

Brentuximab vedotin (BV) monotherapy (BV-M) and combination (BV-C) therapies are safe and effective for classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphomas (PTCLs). Although the sample sizes have been small (12–29 patients), in clinical studies, response rates of 53–88% have been reported for BV retreatment in patients with an initial BV response. We evaluated the real-world characteristics and treatment patterns of cHL/PTCL patients who received BV and were retreated in the United States. Symphony Health Patient Claims (11/2013–1/2022) were retrospectively analyzed to identify cHL/PTCL patients treated with BV and retreated with BV-M, BV-C, or non-BV therapy. Patient characteristics were described by retreatment, and predictors of BV-M retreatment were identified. Among the cHL and PTCL patients treated with BV (n = 6442 and 2472, respectively), 13% and 12%, respectively, were retreated with BV; the median times from initial BV to BV-M retreatment were 5 and 7 months, respectively; and the numbers of BV-M retreatment doses were 4 and 5, respectively. Among cHL patients, the predictors of BV-M retreatment were age (18–39 vs. ≥60 years), sex (women vs. men), and previous stem cell transplantation (yes vs. no). Among PTCL patients, the only predictor of BV-M retreatment was systemic anaplastic large-cell lymphoma subtype (yes vs. no). Real-world data support clinical study results suggesting earlier BV treatment be considered, as BV retreatment may be an option.

Commelina benghalensis L. 1753, a member of the Commelinaceae family, holds significant medicinal and culinary value. This study represents the first documentation of the sequencing and assembly of the entire plastome of C. benghalensis. The genome spans a total length of 160,663 bp, exhibiting a conventional quadripartite architecture that comprises a large single-copy (LSC) region (87,750 bp), a small single-copy (SSC) region (18,417 bp), and two inverted repeats (IR) regions (both 27,248 bp). In its entirety, the C. benghalensis plastome encompasses 129 genes (with 108 being unique), incorporating 77 individual protein-coding genes, 37 unique tRNA genes, and four unique rRNA genes. Phylogenetic analysis revealed a close resemblance between C. benghalensis and C. communis. The sequencing of this plastome stands to expedite the development of molecular markers and significantly contribute to genetic assays involving this distinctive plant.

The utilization of vanadium titano-magnetite concentrate (VTM) for pellet preparation poses challenges in terms of low consolidation strength and high energy consumption during the thermal process. The effect and function mechanism of high-pressure grinding roll (HPGR) pretreatment on the preparation of VTM pellets were investigated. The results indicate that HPGR pretreatment increased the strength of the pellets prepared by VTM and decreased the thermal processing temperature and time. The main reason can be attributed to the reduced particle size of VTM, accompanied by an increase in specific surface area, iron-bearing mineral liberation, and improved interfacial hydrophilicity and particle ballability. Moreover, HPGR pretreatment reduced the crystallite size of VTM and increased lattice microstrain and amorphousness, leading to a 13.21 kJ/mol improvement in the mechanical energy storage of titanomagnetite. The increased specific surface area was a crucial factor in strengthening the preparation of VTM pellets, which increased the contacting points participated in interface physicochemical reactions. The enhanced hydrophilicity and ballability were beneficial to improving the strength of green pellets, while the increased strength of roasted pellets was primarily attributed to the iron-containing mineral liberation and crystal mechanical activation, which promoted the oxidation of iron-bearing minerals and the microcrystalline diffusion and connection. Compared with the untreated VTM, the compressive strength of roasted pellets increased from 2168 N P−1 (Newton per pellet) to 2813 N P−1 when the roller pressure intensity was 12 MPa, and the proper roasting temperature could be reduced by more than 50 °C.

Abstract Background Hearing loss (HL) is a worldwide public health issue for which the role of dyslipidemia has not been fully elucidated. This study aimed to use the atherogenic index of plasma (AIP), a well-established serum lipid marker, to investigate the association of dyslipidemia with HL among the general population. Methods Participants (n = 3267) from the National Health and Nutrition Examination Survey database (2005–2012, 2015–2018) were included in the present study. The AIP was calculated based on the following formula: log10 (triglycerides/high-density lipoprotein cholesterol). HL was defined as a pure-tone average of at least 20 dBHL in the better ear. Weighted multivariable logistic regression, subgroup analysis, generalized additive model, and threshold analysis were adopted to reveal the association between the AIP and HL. Results In this study of US adults, a positive association was found between the AIP and high-frequency HL. However, the association between the AIP and low-frequency HL was not as strong. In addition, a reverse L-shaped curve with an inflection point located at -0.27 was detected between the AIP and high-frequency HL, followed by a significant positive association after the inflection point. Conclusions The potential of the AIP as a bioindicator for high-frequency HL is noteworthy, and maintaining an AIP value below a certain threshold might provide beneficial outcomes in the management of high-frequency HL.

BackgroundIn the ongoing battle against breast cancer, a leading cause of cancer-related mortality among women globally, the urgent need for innovative prognostic markers and therapeutic targets is undeniable. This study pioneers an advanced methodology by integrating machine learning techniques to unveil a vascular mimicry signature, offering predictive insights into breast cancer outcomes. Vascular mimicry refers to the phenomenon where cancer cells mimic blood vessel formation absent of endothelial cells, a trait associated with heightened tumor aggression and diminished response to conventional treatments.MethodsThe study’s comprehensive analysis spanned data from over 6,000 breast cancer patients across 12 distinct datasets, incorporating both proprietary clinical data and single-cell data from 7 patients, accounting for a total of 43,095 cells. By employing an integrative strategy that utilized 10 machine learning algorithms across 108 unique combinations, the research scrutinized 100 existing breast cancer signatures. Empirical validation was sought through immunohistochemistry assays, alongside explorations into potential immunotherapeutic and chemotherapeutic avenues.ResultsThe investigation successfully identified six genes related to vascular mimicry from multi-center cohorts, laying the groundwork for a novel predictive model. This model outstripped the prognostic accuracy of traditional clinical and molecular indicators in forecasting recurrence and mortality risks. High-risk individuals identified by our model faced worse outcomes. Further validation through IHC assays in 30 patients underscored the model’s extensive applicability. Notably, the model unveiled varying therapeutic responses; low-risk patients might achieve greater benefits from immunotherapy, whereas high-risk patients demonstrated a particular sensitivity to certain chemotherapies, such as ispinesib.ConclusionsThis model marks a significant step forward in the precise evaluation of breast cancer prognosis and therapeutic responses across different patient groups. It heralds the possibility of refining patient outcomes through tailored treatment strategies, accentuating the potential of machine learning in revolutionizing cancer prognosis and management.

To explore the mechanism of the refinement and toughening of Nb-Si-based composites with different Y contents, Nb-16Si-20Ti-2ZrC-(0, 0.05, 0.1, 0.5) Y composites were prepared by arc melting. The results show that Y has a positive effect on the shift of the eutectic point and promotes it moving to the low Si side. Adding 0.1 at.% Y refines the Nbss phase from 38.7 to 11.2 μm. Y2O3 forms due to the strong affinity of Y to O. The edge-to-edge model predicted that there was no phase relationship between Y2O3 and Nbss and primary γ-(Nb,X)5Si3, which was verified by TEM. Y refines the Nbss and the Nbss/γ-(Nb,X)5Si3 cluster with compositional supercooling. As Y content increased, the fracture toughness at room temperature increased and decreased. When the Y content was 0.1 %, the KQ value reached 17.2 MPa·m1/2. The internal oxygen consumption of Y and the refinement of Nbss lead to the toughness improvement of the Nbss phase, promoting the formation of a large number of dimples. Microcracks form in the fine γ-(Nb,X)5Si3 of eutectoid cluster, which hinder the primary crack growth and enhance the ambient fracture toughness. These findings are of great significance for the further development of high-performance Nb-Si-based matrix composites.

Currently, immunotherapy is being widely used for treating cancers. However, the significant heterogeneity in patient responses is a major challenge for its successful application. CD8-positive T cells (CD8+ T cells) play a critical role in immunotherapy. Both their infiltration and functional status in tumors contribute to treatment outcomes. Therefore, accurate monitoring of CD8+ T cells, a potential biomarker, may improve therapeutic strategy. Positron emission tomography (PET) is an optimal option which can provide molecular imaging with enhanced specificity. This review summarizes the mechanism of action of CD8+ T cells in immunotherapy, and highlights the recent advancements in PET-based tracers that can visualize CD8+ T cells and discusses their clinical applications to elucidate their potential role in cancer immunotherapy.

Electroacupuncture pretreatment is considered as an optimal strategy for inducing cerebral ischaemic tolerance. However, the underlying neuroprotective mechanism of this approach has never been explored from the perspective of calcium homeostasis. Intracellular calcium overload is a key inducer of cascade neuronal injury in the early stage after cerebral ischaemia attack and the Na+/Ca2+ exchanger (NCX) is the main plasma membrane calcium extrusion pathway maintaining post-ischaemic calcium homeostasis. This study aims to investigate whether the regulation of NCX-mediated calcium transport contributes to the cerebroprotective effect of electroacupuncture pretreatment against ischaemic injury and to elucidate the underlying mechanisms involved in this process. Following five days of repeated electroacupuncture stimulation on Baihui (GV20), Neiguan (PC6), and Sanyinjiao (SP6) acupoints in rats, in vivo and in vitro models of cerebral ischaemia were induced through middle cerebral artery occlusion and oxygen/glucose deprivation (OGD), respectively. Firstly, we verified the neuroprotective effect of electroacupuncture pretreatment from the perspective of neurological score, infarct volume and neuronal apoptosis. Our findings from brain slice patch-clamp indicated that electroacupuncture pretreatment enhanced the Ca2+ efflux capacity of NCX after OGD. NCX1 expression in the ischaemic penumbra exhibited a consistent decline from 1 to 24 h in MCAO rats. Electroacupuncture pretreatment upregulated the expression of NCX1, especially at 24 h, and silencing NCX1 by short hairpin RNA (shRNA) administration reversed the protective effect of electroacupuncture pretreatment against cerebral ischaemic injury. Furthermore, we administered LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, prior to inducing ischaemia to investigate the upstream regulatory mechanism of electroacupuncture pretreatment on NCX1 expression. Electroacupuncture pretreatment activates PI3K/Akt pathway, leading to an increase in the expression of NCX1, which facilitates calcium extrusion and exerts a neuroprotective effect against cerebral ischaemia. These findings provided a novel insight into the prevention of ischemic stroke and other similar conditions characterized by brain ischaemia or hypoperfusion.

An 8-year-old castrated male teddy bear dog presented to our clinic with a persistent cough. The sick dog suffered from vehicular trauma 6 months prior to the visit and had imaging and exploratory laparotomy. Imaging and exploratory laparotomy at the time showed no significant damage. We performed contrast radiography (barium gavage) on the sick dog. Based on the results of a complete contrast radiography (barium gavage), tubular shadows in the thoracic cavity were identified as the small intestine and cecum, and delayed traumatic diaphragmatic hernia with hepatothorax and enterothorax was confirmed with radiographs. Accordingly, the sick dog underwent general anesthesia, manual ventilation and diaphragmatic herniorrhaphy by standard ventral midline abdominal approach. Postoperatively, the dog was given analgesia and antibacterial treatment, and the liver biochemical indexes were monitored to prevent endotoxin. Postoperative radiographs revealed clear contours of thoracic and abdominal organs. The dog moved, ate, and urinated normally within 10 days of the surgery. This case provides a reference for a complete barium meal imaging procedure that clearly shows the position of the organs in the thoracoabdominal cavity after the occurrence of a delayed traumatic diaphragmatic hernia. This paper provides a practical reference for the diagnosis of delayed traumatic diaphragmatic hernia with hepatothorax and enterothorax.

BackgroundParkinson’s disease (PD) is a common neurodegenerative disease with a rapid increase in incidence in recent years. Existing treatments cannot slow or stop the progression of PD. It was proposed that neuroinflammation leads to neuronal death, making targeting neuroinflammation a promising therapeutic strategy. Our previous studies have demonstrated that rhein protects neurons in vitro by inhibiting neuroinflammation, and it has been found to exhibit neuroprotective effects in Alzheimer’s disease and epilepsy, but its neuroprotective mechanisms and effects on PD are still unclear.MethodsPD animal model was induced by 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP). ELISA, RT-qPCR, western blot and Immunofluorescence were used to detect the levels of inflammatory cytokines and M1 polarization markers. The protein expression levels of signaling pathways were measured by western blot. Hematoxylin–eosin (HE) staining showed that rhein did not damage the liver and kidney. Two behavioral tests, pole test and rotarod test, were used to evaluate the improvement effect of rhein on movement disorders. The number of neurons in the substantia nigra was evaluated by Nissl staining. Immunohistochemistry and western blot were used to detect tyrosine hydroxylase (TH) and α-synuclein.ResultsRhein inhibited the activation of MAPK/IκB signaling pathway and reduced the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and M1 polarization markers of microglia in vivo. In a mouse model of PD, rhein ameliorated movement disorders, reduced dopaminergic neuron damage and α-synuclein deposition.ConclusionRhein inhibits neuroinflammation through MAPK/IκB signaling pathway, thereby reducing neurodegeneration, α-synuclein deposition, and improving movement disorders in Parkinson’s disease.

Background: Despite regional brain structural changes having been reported in patients with chronic low back pain (CLBP), the topological properties of structural covariance networks (SCNs), which refer to the organization of the SCNs, remain unclear. This study applied graph theoretical analysis to explore the alterations of the topological properties of SCNs, aiming to comprehend the integration and separation of SCNs in patients with CLBP. Methods: A total of 38 patients with CLBP and 38 healthy controls (HCs), balanced for age and sex, were scanned using three-dimensional T1-weighted magnetic resonance imaging. The cortical thickness was extracted from 68 brain regions, according to the Desikan–Killiany atlas, and used to reconstruct the SCNs. Subsequently, graph theoretical analysis was employed to evaluate the alterations of the topological properties in the SCNs of patients with CLBP. Results: In comparison to HCs, patients with CLBP had less cortical thickness in the left superior frontal cortex. Additionally, the cortical thickness of the left superior frontal cortex was negatively correlated with the Visual Analogue Scale scores of patients with CLBP. Furthermore, patients with CLBP, relative to HCs, exhibited lower global efficiency and small-worldness, as well as a longer characteristic path length. This indicates a decline in the brain's capacity to transmit and process information, potentially impacting the processing of pain signals in patients with CLBP and contributing to the development of CLBP. In contrast, there were no significant differences in the clustering coefficient, local efficiency, nodal efficiency, nodal betweenness centrality, or nodal degree between the two groups. Conclusions: From the regional cortical thickness to the complex brain network level, our study demonstrated changes in the cortical thickness and topological properties of the SCNs in patients with CLBP, thus aiding in a better understanding of the pathophysiological mechanisms of CLBP.

The study investigates the impact of incorporating multi-scale nano-zinc oxide (nano-ZnO) particles into a PG 64–22 asphalt binder, exploring changes in morphology, rheology, and physical properties. Utilizing nano-ZnO particles of varying sizes (10–30 nm, 50–70 nm, 100–200 nm) and concentrations (1–5%), the research employs Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) for morphological analysis and Dynamic Shear Rheometer (DSR) testing for rheological properties. The findings reveal substantial improvements in binder elasticity and rutting resistance, with notable enhancements in physical attributes such as lower penetration grades, higher ductility, and increased softening points. Additionally, nano-ZnO modified binders demonstrate superior aging resistance, maintaining their enhanced properties after both short-term and long-term aging tests. This comprehensive study underscores the potential of nano-ZnO as an effective modifier in asphalt binders, promising increased durability and resilience against common roadway distresses.

ABSTRACT: Excessive free fatty acid (FFA) oxidation and related metabolism are the major cause of oxidative stress and liver injury in dairy cows during the early postpartum period. In nonruminants, activation of transcription factor EB (TFEB) can improve cell damage and reduce the overproduction of mitochondrial reactive oxygen species. As a downstream target of TFEB, peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α, gene name PPARGC1A) is a critical regulator of oxidative metabolism. Nuciferine (Nuc), a major bioactive compound isolated from the lotus leaf, has been reported to possess hepatoprotective activity. Therefore, the objective of this study was to investigate whether Nuc could protect bovine hepatocytes from FFA-induced lipotoxicity and the underlying mechanisms. A mixture of FFA was diluted in RPMI-1640 basic medium containing 2% low fatty acid bovine serum albumin to treat hepatocytes. Bovine hepatocytes were isolated from newborn calves and treated with various concentrations of FFA mixture (0, 0.3, 0.6, or 1.2 mM) or Nuc (0, 25, 50, or 100 μM), as well as co-treated with 1.2 mM FFA and different concentrations of Nuc. For the experiments of gene silencing, bovine hepatocytes were transfected with small interfering RNA targeted against TFEB or PPARGC1A for 36 h followed by treatment with 1.2 mM FFA for 12 h in presence or absence of 100 μΜ Nuc. The results revealed that FFA treatment decreased protein abundance of nuclear TFEB, cytosolic TFEB, total (t)-TFEB, lysosome-associated membrane protein 1 (LAMP1) and PGC-1α and mRNA abundance of LAMP1, but increased phosphorylated (p)-TFEB. In addition, FFA treatment increased the content of malondialdehyde (MDA) and hydrogen peroxide (H2O2) and decreased the activities of catalase (CAT) and glutathione peroxidase (GSH-Px) in bovine hepatocytes. Moreover, FFA administration enhanced the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactose dehydrogenase (LDH) in the medium of FFA-treated hepatocytes, but reduced the content of urea. In FFA-treated bovine hepatocytes, Nuc administration increased TFEB nuclear localization and the protein abundance of t-TFEB, LAMP1, and PGC-1α and mRNA abundance of LAMP1, decreased the contents of MDA and H2O2 and the protein abundance of p-TFEB, and enhanced the activities of CAT and GSH-Px in a dose-dependent manner. Consistently, Nuc administration reduced the activities of ALT, AST, and LDH and increased the content of urea in the medium of FFA-treated hepatocytes. Importantly, knockdown of TFEB reduced the protein abundance of p-TFEB, t-TFEB, LAMP1, and PGC-1α and mRNA abundance of LAMP1, and impeded the beneficial effects of Nuc on FFA-induced oxidative damage in bovine hepatocytes. In addition, PPARGC1A silencing did not alter Nuc-induced nuclear translocation of TFEB, increase of the protein abundance of t-TFEB, LAMP1, and PGC-1α and mRNA abundance of LAMP1, or decrease of the protein abundance of p-TFEB, whereas it partially reduced the beneficial effects of Nuc on FFA-caused oxidative injury. Taken together, Nuc exerts protective effects against FFA-induced oxidative damage in bovine hepatocytes through activation of the TFEB/PGC-1α signaling pathway.

Abstract To investigate the relationship of the middle cerebral artery (MCA) bifurcation aneurysms with patients’ age and sex, vascular angles at the bifurcation, and diameters of the M1 and two M2 arteries, patients with and without MCA aneurysms were retrospectively enrolled. The lateral angles, MCA bifurcation angle and arterial diameter were measured and analyzed. Totally, 121 (19.0%) patients with and 517 (81.0%) without MCA aneurysms were enrolled. Most (n = 88 or 72.7%) aneurysms were present in the age range of 40–70 years, and significantly (P = 0.01) more women than men had the bifurcation aneurysms. The MCA bifurcation angle was significantly greater (149.2° ± 32.6° vs. 107.2° ± 26.3°; P

In recent years, many studies have shown that extreme climate events occur more frequently. The extreme climate led to frequent drought and inundation events, which affected the growth of both exotic and native plants. In order to discuss the strategies of exotic and native plants in adapting to temporal heterogeneity in water conditions by investigating their responses to the sequence of drought and inundation events, four native and four exotic perennial herbaceous species in western Montana, USA were used as study objects. All plants were treated with moderate water (CK), initial inundation before drought (I-D) and initial drought before inundation (D-I) conditions, and variations in a series of morphological and biomass traits were measured. The results were as follows: (1) Compared with CK, both D-I and I-D treatments significantly reduced the total biomass of exotic species (P

Abstract Aim As the second most prevalent subtype of epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) is known for its chemoresistance to conventional platinum‐based therapy. In this work, we examined the tryptophan (Trp) metabolism enzymes' differential expression in patients with OCCC to assess the potential for personalised treatment. Methods A total of 127 OCCC tissues were used to construct tissue microarrays, and immunohistochemistry (IHC) staining of the Trp enzymes IDO1, IDO2, TDO2 and IL4I1 was performed. The correlations between Trp enzyme expression and clinical characteristics were analysed. Results Positive IDO1, IDO2, TDO2 and IL4I1 staining was identified in 26.8%, 94.5%, 75.6% and 82.7% of OCCC respectively. IDO1‐positive samples were more common in the chemoresistant group than in the platinum‐sensitive group (46.7% vs. 19.8%). Moreover, positive expression of IDO1, TDO2 and IL4I1 was related to advanced stage, metastasis, bilateral tumours, endometriosis and tumour rupture (p

Abstract Background The aberrant formation of neutrophil extracellular traps (NETs) has been implicated in ulcerative colitis (UC), a chronic recurrent intestinal inflammation. Cyclosporine A (CsA) is now applied as rescue therapy for acute severe UC. In addition, it has been certained that CsA inhibits the formation of NETs in vitro and the mechanism of which was still vague. The study aimed to explore the mechanism CsA inhibits the NETs formation of colitis in vivo and in vitro. Methods NETs enrichment in clinical samples was analyzed using databases from Gene Expression Omnibus and verified in our center. Dextran sulfate sodium (DSS)-induced acute colitis mice model was used to investigate the effect of CsA on NETs of colonic tissue expression. To clarify the mechanism, intracellular energy metabolites were examined by Liquid Chromatograph Mass Spectrometer, and reactive oxygen species (ROS) levels were examined by fluorescence intensity in neutrophils treated with CsA after LPS stimulation. The transcriptional level and activity of G6PD of neutrophils were also assessed using qRT-PCR and WST-8. RNA Sequencing was used to detect differentially expressed genes of neutrophils stimulated by LPS with or without CsA. The expression levels of related proteins were detected by western blot. Results NETs enrichment was especially elevated in moderate-to-severe UC patients compared to HC. NETs expression in the colon from DSS colitis was decreased after CsA treatment. Compared with neutrophils stimulated by LPS, NETs formation and cellular ROS levels were decreased in LPS + CsA group. Cellular ribulose 5-phosphate and NADPH/NADP + related to the pentose phosphate pathway (PPP) were reduced in LPS + CsA group. In addition, CsA could decrease G6PD activity in neutrophils stimulated with LPS, and the results were further verified by inhibiting G6PD activity. At last, P53 protein was highly expressed in LPS + CsA group compared with the LPS group. Intracellular G6PD activity, ROS level and NETs formation, which were downregulated by CsA, could be reversed by a P53 inhibitor. Conclusion Our results indicated CsA could alleviate the severity of colitis by decreasing the formation of NETs in vivo. In vitro, CsA reduced ROS-dependent NETs release via downregulating PPP and cellular ROS levels by decreasing G6PD activity directly by activating the P53 protein.

Abstract Idiopathic fertility disorders are associated with mutations in various genes. Here, we report that coiled-coil glutamate-rich protein 1 (CCER1), a germline-specific and intrinsically disordered protein (IDP), mediates postmeiotic spermatid differentiation. In contrast, CCER1 deficiency results in defective sperm chromatin compaction and infertility in mice. CCER1 increases transition protein (Tnp1/2) and protamine (Prm1/2) transcription and mediates multiple histone epigenetic modifications during the histone-to-protamine (HTP) transition. Immiscible with heterochromatin in the nucleus, CCER1 self-assembles into a polymer droplet and forms a liquid-liquid phase-separated condensate in the nucleus. Notably, we identified loss-of-function (LoF) variants of human CCER1 (hCCER1) in five patients with nonobstructive azoospermia (NOA) that were absent in 2713 fertile controls. The mutants led to premature termination or frameshift in CCER1 translation, and disrupted condensates in vitro. In conclusion, we propose that nuclear CCER1 is a phase-separated condensate that links histone epigenetic modifications, HTP transitions, chromatin condensation, and male fertility.

Summary: Reliable blood-based tests for identifying early-stage breast cancer remain elusive. Employing single-cell transcriptomic sequencing analysis, we illustrate a close correlation between nucleotide metabolism in the breast cancer and activation of regulatory T cells (Tregs) in the tumor microenvironment, which shows distinctions between subtypes of patients with triple-negative breast cancer (TNBC) and non-TNBC, and is likely to impact cancer prognosis through the A2AR-Treg pathway. Combining machine learning with absolute quantitative metabolomics, we have established an effective approach to the early detection of breast cancer, utilizing a four-metabolite panel including inosine and uridine. This metabolomics study, involving 1111 participants, demonstrates high accuracy across the training, test, and independent validation cohorts. Inosine and uridine prove predictive of the response to neoadjuvant chemotherapy (NAC) in patients with TNBC. This study deepens our understanding of nucleotide metabolism in breast cancer development and introduces a promising non-invasive method for early breast cancer detection and predicting NAC response in patients with TNBC.

Alkaloids have remarkable biological and pharmacological properties and have recently garnered extensive attention. Various alkaloids, including commercially available drugs such as berberine, substantially affect ferroptosis. In addition to the three main pathways of ferroptosis, iron metabolism, phospholipid metabolism, and the glutathione peroxidase 4-regulated pathway, novel mechanisms of ferroptosis are continuously being identified. Alkaloids can modulate the progression of various diseases through ferroptosis and exhibit the ability to exert varied effects depending on dosage and tissue type underscores their versatility. Therefore, this review comprehensively summarizes primary targets and the latest advancements of alkaloids in ferroptosis, as well as the dual roles of alkaloids in inhibiting and promoting ferroptosis.

IntroductionCrohn’s disease (CD) is a chronic inflammatory disease. Approximately 50% of patients with CD progressed from inflammation to fibrosis. Currently, there are no effective drugs for treating intestinal fibrosis. Biologic therapies for CD such as ustekinumab have benefited patients; however, up to 30% of patients with CD have no response to initial treatment, and the effect of ustekinumab on intestinal fibrosis is still uncertain. Therefore, it is of great significance to explore the predictive factors of ustekinumab treatment response and the effect of ustekinumab on intestinal fibrosis.Materials and methodsPublic datasets—GSE207465 (blood samples) and GSE112366 and GSE207022 (intestinal samples)—were downloaded and analyzed individually (unmerged) based on the treatment response. Differentially expressed genes (DEGs) were identified by the “limma” R package and changes in immune cell infiltration were determined by the “CIBERSORT” R package in both blood and intestinal samples at week 0 (before treatment). To find predictive factors of ustekinumab treatment response, the weighted gene co-expression network analysis (WGCNA) R package was used to identify hub genes in GSE112366. Hub genes were then verified in GSE207022, and a prediction model was built by random forest algorithm. Furthermore, fibrosis-related gene changes were analyzed in ileal samples before and after treatment with ustekinumab.Results(1) Our analysis found that MUC1, DUOX2, LCN2, and PDZK1IP1 were hub genes in GSE112366. GSE207022 revealed that MUC1 (AUC:0.761), LCN2 (AUC:0.79), and PDZK1IP1 (AUC:0.731) were also lower in the response group. Moreover, the random forest model was shown to have strong predictive capabilities in identifying responders (AUC = 0.875). To explore the relationship between intestinal tissue and blood, we found that ITGA4 had lower expression in the intestinal and blood samples of responders. The expression of IL18R1 is also lower in responders’ intestines. IL18, the ligand of IL18R1, was also found to have lower expression in the blood samples from responders vs. non-responders. (2) GSE112366 revealed a significant decrease in fibrosis-related module genes (COL4A1, TUBB6, IFITM2, SERPING1, DRAM1, NAMPT, MMP1, ZEB2, ICAM1, PFKFB3, and ACTA2) and fibrosis-related pathways (ECM–receptor interaction and PI3K-AKT pathways) after ustekinumab treatment.ConclusionMUC1, LCN2, and PDZK1IP1 were identified as hub genes in intestinal samples, with lower expression indicating a positive prediction of ustekinumab treatment response. Moreover, ITGA4 and IL18/IL18R1 may be involved in the treatment response in blood and intestinal samples. Finally, ustekinumab treatment was shown to significantly alter fibrotic genes and pathways.

IntroductionThe incorporation of Staphylococcus xylosus in sausage production is hypothesized to affect various physicochemical properties and flavor profiles of sausages. This study aimed to evaluate the simulation of these features in a sausage model and establish its applicability for in vitro studies.MethodsBoth a control and an experimental model, inclusive of Staphylococcus xylosus, were assessed for changes in physicochemical indexes (pH and water activity, Aw) and the concentration of flavoring components (esters and aldehydes). Thiobarbituric acid reactive substances (TBARS) values were also measured to evaluate lipid oxidation.ResultsThe introduction of Staphylococcus xylosus resulted in no significant changes in pH and Aw between the sausage and the model. However, there was a considerable increase in the content of volatile flavor compounds, specifically esters and aldehydes, in the experimental groups compared to the control. Additionally, the TBARS values in experimental groups were significantly lower than those in the control group at the end of the testing period.DiscussionThe findings indicate that Staphylococcus xylosus plays a critical role in enhancing the flavor profile of sausages through the increased synthesis of volatile compounds and inhibiting fat oxidation. The sausage model effectively simulated the physicochemical and flavor index responses, demonstrating its potential utility for further in vitro research on sausage fermentation and preservation techniques.

Gynostemma pentaphyllum (Thunb.) Makino is an important producer of dammarene-type triterpenoid saponins. These saponins (gypenosides) exhibit diverse pharmacological benefits such as anticancer, antidiabetic, and immunomodulatory effects, and have major potential in the pharmaceutical and health care industries. Here, we employed single-cell RNA sequencing (scRNA-seq) to profile the transcriptomes of more than 50,000 cells derived from G. pentaphyllum shoot apexes and leaves. Following cell clustering and annotation, we identified five major cell types in shoot apexes and four in leaves. Each cell type displayed substantial transcriptomic heterogeneity both within and between tissues. Examining gene expression patterns across various cell types revealed that gypenoside biosynthesis predominantly occurred in mesophyll cells, with heightened activity observed in shoot apexes compared to leaves. Furthermore, we explored the impact of transposable elements (TEs) on G. pentaphyllum transcriptomic landscapes. Our findings the highlighted the unbalanced expression of certain TE families across different cell types in shoot apexes and leaves, marking the first investigation of TE expression at the single-cell level in plants. Additionally, we observed dynamic expression of genes involved in gypenoside biosynthesis and specific TE families during epidermal and vascular cell development. The involvement of TE expression in regulating cell differentiation and gypenoside biosynthesis warrant further exploration. Overall, this study not only provides new insights into the spatiotemporal organization of gypenoside biosynthesis and TE activity in G. pentaphyllum shoot apexes and leaves but also offers valuable cellular and genetic resources for a deeper understanding of developmental and physiological processes at single-cell resolution in this species.

BackgroundThis study aims to identify precise biomarkers for breast cancer to improve patient outcomes, addressing the limitations of traditional staging in predicting treatment responses.MethodsOur analysis encompassed data from over 7,000 breast cancer patients across 14 datasets, which included in-house clinical data and single-cell data from 8 patients (totaling 43,766 cells). We utilized an integrative approach, applying 10 machine learning algorithms in 54 unique combinations to analyze 100 existing breast cancer signatures. Immunohistochemistry assays were performed for empirical validation. The study also investigated potential immunotherapies and chemotherapies.ResultsOur research identified five consistent glutamine metabolic reprogramming (GMR)-related genes from multi-center cohorts, forming the foundation of a novel GMR-model. This model demonstrated superior accuracy in predicting recurrence and mortality risks compared to existing clinical and molecular features. Patients classified as high-risk by the model exhibited poorer outcomes. IHC validation in 30 patients reinforced these findings, suggesting the model’s broad applicability. Intriguingly, the model indicates a differential therapeutic response: low-risk patients may benefit more from immunotherapy, whereas high-risk patients showed sensitivity to specific chemotherapies like BI-2536 and ispinesib.ConclusionsThe GMR-model marks a significant leap forward in breast cancer prognosis and the personalization of treatment strategies, offering vital insights for the effective management of diverse breast cancer patient populations.

Objective: Ramucirumab is a VEGFR2 antagonist. The aim of this trial is to evaluate the efficacy and safety of ramucirumab combined with nab-paclitaxel, lobaplatin and S-1 in neoadjuvant and conversion therapy for advanced gastric cancer. Methods: and analysis: This study is a prospective single-center, randomized controlled and open label clinical study, enrolling a total of 140 patients with advanced gastric cancer distributed across two distinct cohorts (Cohort A n = 70; Cohort B n = 70). The central focus of the study lies in evaluating the pathological complete response (pCR) of the cancer post-neoadjuvant or conversion therapy. Secondary endpoints encompass the assessment of the R0 resection rate subsequent to the aforementioned therapies, the occurrence of adverse events (AE), progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the total response rate and its duration, the disease control rate (DCR), and the duration of overall response (DOR). Ethics: Ethics approval has been obtained from the Ethics Committee at the First Affiliated Hospital (Xijing Hospital) of Air force Military Medical University (KY20232220–F-1). Trial registration: This trial has been registered at the ClinicalTrials.gov: NCT06169410 (registration date: December 5, 2023).

BackgroundNeuroimaging studies have suggested a pivotal role for the amygdala involvement in chronic low back pain (CLBP). However, the relationship between the amygdala subregions and CLBP has not yet been delineated. This study aimed to analyze whether the amygdala subregions were linked to the development of CLBP.MethodsA total of 45 patients with CLBP and 45 healthy controls (HCs) were included in this study. All subjects were asked to complete a three-dimensional T1-weighted magnetic resonance imaging (3D-T1 MRI) scan. FreeSurfer 7.3.2 was applied to preprocess the structural MRI images and segment the amygdala into nine subregions. Afterwards, comparisons were made between the two groups in terms of the volumes of the amygdala subregions. Correlation analysis is utilized to examine the relationship between the amygdala subregion and the scale scores, as well as the pain duration in patients with CLBP. Additionally, logistic regression was used to explore the risk of the amygdala and its subregions for CLBP.ResultsIn comparison to HCs, patients with CLBP exhibited a significant enlargement of the left central nucleus (Ce) and left cortical nucleus (Co). Furthermore, the increased volume of the left Ce was associated with a higher risk of CLBP.ConclusionOur study suggests that the left Ce and left Co may be involved in the pathophysiological processes of CLBP. Moreover, the volume of the left Ce may be a biomarker for detecting the risk of CLBP.

BackgroundDespite advancements, breast cancer outcomes remain stagnant, highlighting the need for precise biomarkers in precision medicine. Traditional TNM staging is insufficient for identifying patients who will respond well to treatment.MethodsOur study involved over 6,900 breast cancer patients from 14 datasets, including in-house clinical data and single-cell data from 8 patients (37,451 cells). We integrated 10 machine learning algorithms in 55 combinations and analyzed 100 existing breast cancer signatures. IHC assays were conducted for validation, and potential immunotherapies and chemotherapies were explored.ResultsWe pinpointed six stable Panoptosis-related genes from multi-center cohorts, leading to a robust Panoptosis-model. This model outperformed existing clinical and molecular features in predicting recurrence and mortality risks, with high-risk patients showing worse outcomes. IHC validation from 30 patients confirmed our findings, indicating the model’s broader applicability. Additionally, the model suggested that low-risk patients benefit more from immunotherapy, while high-risk patients are sensitive to specific chemotherapies like BI-2536 and ispinesib.ConclusionThe Panoptosis-model represents a major advancement in breast cancer prognosis and treatment personalization, offering significant insights for effectively managing a wide range of breast cancer patients.

Abstract Background Guideline adaptation is an emerging field to provide more appropriate recommendations for local clinical practice quality and to promote global health equity. However, its utilization status, adaptation procedures, and related materials remain to be studied. Methods This study developed a quality improvement protocol for a study as the Development, Evaluation, and impLemenTation for guideline Adaptation (DELTA) study. Current adapted clinical practice guidelines (CPGs) will be systematically searched. Their characteristics, utilization status, and adaptation procedures will be extracted, compared, and analyzed. Whether these adapted CPGs rigorously followed the instruments and steps of adaptation frameworks will also be appraised. In addition, the advantages and limitations of current adaptation methods and their suitable application situations will be analyzed. In addition, future perspectives as DELTA series and DELTA system, aiming for comprehensively evaluating current needs for guideline adaptation and developing a unified framework and related materials were proposed to improve the acceptability, applicability, and implementation of guideline adaptation in clinical practice. The DELTA series are divided into four phases: phase I in analyzing status, characteristics, and procedures and completeness of adapted CPGs; phase II in analyzing differences, heterogeneity, and implementation between adapted and original CPGs; and phase III in collecting, analyzing, and comparing all available adaptation materials. With these research bases, an international working group will be established in phase IV and will develop unified guideline adaptation materials after Delphi consensus, including adaptation frameworks, appraisal tools and checklists, registries, and databases. Discussion Guideline adaptation has been advanced as an efficient way to guide local clinical practice. However, it still faces several major challenges. The proposed DELTA study, series, and system will further contribute to this emerging topic. Trial registration: This study has been registered by the PROSPERO international database. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=400170 .

Abstract Background The protein tyrosine phosphatase H receptor (PTPRH) is known to regulate the occurrence and development of pancreatic and colorectal cancer. However, its association with glycolysis in non-small cell lung cancer (NSCLC) is still unclear. In this study, we aimed to investigate the relationship between PTPRH expression and glucose metabolism and the underlying mechanism of action. Methods The expression of PTPRH in NSCLC cells was evaluated by IHC staining, qRT‒PCR and Western blotting. The effect of PTPRH on cell biological behavior was evaluated by colony assays, EdU experiments, Transwell assays, wound healing assays and flow cytometry. Changes in F-18-fluorodeoxyglucose (18F‐FDG) uptake and glucose metabolite levels after altering PTPRH expression were detected via a gamma counter and lactic acid tests. The expression of glycolysis-related proteins in NSCLC cells was detected by Western blotting after altering PTPRH expression. Results The results showed that PTPRH was highly expressed in clinical patient tissue samples and closely related to tumor diameter and clinical stage. In addition, PTPRH expression was associated with glycometabolism indexes on 18F-FDG positron emission tomography/computed tomography (PET/CT) imaging, the expression level of Ki67 and the expression levels of glycolysis-related proteins. PTPRH altered cell behavior, inhibited apoptosis, and promoted 18F-FDG uptake, lactate production, and the expression of glycolysis-related proteins. In addition, PTPRH modulated the glycometabolism of NSCLC cells via the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, as assessed using LY294002 and 740Y-P (an inhibitor and agonist of PI3K, respectively). The same results were validated in vivo using a xenograft tumor model in nude mice. Protein expression levels of PTPRH, glycolysis-related proteins, p-PI3K/PI3K and p-AKT/AKT were measured by IHC staining using a subcutaneous xenograft model in nude mice. Conclusions In summary, we report that PTPRH promotes glycolysis, proliferation, migration, and invasion via the PI3K/AKT/mTOR signaling pathway in NSCLC and ultimately promotes tumor progression, which can be regulated by LY294002 and 740Y-P. These results suggest that PTPRH is a potential therapeutic target for NSCLC. Graphical Abstract

Abstract Introduction Serum neurofilament light chain (sNfL) is an emerging biomarker of neuronal damage in several neurological disorders. Its association with cognitive function in the general US population aged 60 years and above is unknown. The aim of this study was to investigate the correlation between sNfL and cognitive function in the general US population aged 60 and above. Methods The data were obtained from the 2013–2014 National Health and Nutrition Examination Survey (NHANES), which include 506 individuals aged 60 or older who met our search criteria. In our study, sNfL levels were divided into two groups based on dichotomization (19.0 pg/mL). After adjusting for multiple covariates, it was found that the high sNfL group (≥ 19.0 pg/mL) had lower cognitive performance than the low sNfL group (

Shrub species Caragana korshinskii Kom. dominates slope protection and soil and water conservation in the loess area of the northeastern Qinghai–Tibet Plateau. However, the root anchoring mechanism and the effects of soil consolidation and slope protection of this shrub species remain unclear. This study aimed to elucidate the anchoring mechanism of roots of the C. korshinskii roots and establish a calculation model to evaluate their contribution to the stability of shallow loess slopes. C. korshinskii plants with an 11-year growth period were selected as the study subject. The anchoring force of C. korshinskii roots was determined through in-situ excavation tests, in-situ root pullout tests, and theoretical analysis, along with their impact on the stability of shallow loess soil slopes. The results showed that, due to the absence of a “bolt head” structure on the root surface, it was reasonable to consider the anchoring force provided by the roots as the minimum value between the maximum pullout resistance of the roots below the sliding surface and the anchoring reaction force of the roots above the sliding surface, based on the geometric characteristics of the sliding surface. When the roots of an 11-year-old C. korshinskii roots were anchored on different sliding blocks of a shallow landslide with a maximum thickness of 2 meters, the stability coefficient of the potential sliding surface increased by 0.020% to 0.408%. When the roots of a single plant were anchored in the middle and upper parts of the potential sliding surface, the stability coefficient of the potential sliding surface was relatively higher than when the plant roots were anchored at the top and bottom positions. Moreover, when four C. korshinskii roots were anchored to the shallow landslide with a row spacing of two sliding blocks (approximately 3 m), the stability coefficient of the potential sliding surface increased by 1.035% to 1.111%, which was significantly higher than when a single C. korshinskii root was anchored (P

Abstract. Background:. We have recently developed a new Coronary Artery Tree description and Lesion EvaluaTion (CatLet) angiographic scoring system. Our preliminary studies have demonstrated its superiority over the the Synergy between percutaneous coronary intervention (PCI) with Taxus and Cardiac Surgery (SYNTAX) score with respect to outcome predictions for acute myocardial infarction (AMI) patients. The current study hypothesized that the residual CatLet (rCatLet) score predicts clinical outcomes for AMI patients and that a combination with the three clinical variables (CVs)—age, creatinine, and ejection fraction, will enhance its predicting values. Methods:. The rCatLet score was calculated retrospectively in 308 consecutively enrolled patients with AMI. Primary endpoint, major adverse cardiac or cerebrovascular events (MACCE) including all-cause mortality, non-fatal AMI, transient ischemic attack/stroke, and ischemia-driven repeat revascularization, was stratified according to rCatLet score tertiles: rCatLet_low ≤3, rCatLet_mid 4-11, and rCatLet_top ≥12, respectively. Cross-validation confirmed a reasonably good agreement between the observed and predicted risks. Results:. Of 308 patients analyzed, the rates of MACCE, all-cause death, and cardiac death were 20.8%, 18.2%, and 15.3%, respectively. Kaplan-Meier curves for all endpoints showed increasing outcome events with the increasing tertiles of the rCatLet score, with P values

Abstract Stitched fluorescence microscope images inevitably exist in various types of stripes or artifacts caused by uncertain factors such as optical devices or specimens, which severely affects the image quality and downstream quantitative analysis. Here, we present a deep learning-based Stripe Self-Correction method, so-called SSCOR. Specifically, we propose a proximity sampling scheme and adversarial reciprocal self-training paradigm that enable SSCOR to utilize stripe-free patches sampled from the stitched microscope image itself to correct their adjacent stripe patches. Comparing to off-the-shelf approaches, SSCOR can not only adaptively correct non-uniform, oblique, and grid stripes, but also remove scanning, bubble, and out-of-focus artifacts, achieving the state-of-the-art performance across different imaging conditions and modalities. Moreover, SSCOR does not require any physical parameter estimation, patch-wise manual annotation, or raw stitched information in the correction process. This provides an intelligent prior-free image restoration solution for microscopists or even microscope companies, thus ensuring more precise biomedical applications for researchers.

This study designs and proposes a method for evaluating the configuration of energy storage for integrated renewable generation plants in the power spot market, which adopts a two-level optimization model of “system simulation + plant optimization”. The first step is “system simulation” which is using the power market simulation model to obtain the initial nodal marginal price and curtailment of the integrated renewable generation plant. The second step is “plant optimization” which is using the operation optimization model of the integrated renewable generation plant to optimize the charge-discharge operation of energy storage. In the third step, “system simulation” is conducted again, and the combined power of renewable and energy storage inside the plant is brought into the system model and simulated again for 8,760 h of power market year-round to quantify and compare the power generation and revenue of the integrated renewable generation plant after applying energy storage. In the case analysis of the provincial power spot market, an empirical analysis of a 1 GW wind-solar-storage integrated generation plant was conducted. The results show that the economic benefit of energy storage is approximately proportional to its capacity and that there is a slowdown in the growth of economic benefits when the capacity is too large. In the case that the investment benefit of energy storage only considers the income of electric energy-related incomes and does not consider the income of capacity mechanism and auxiliary services, the income of energy storage cannot fulfill the economic requirements of energy storage investment.

Nonalcoholic fatty liver disease (NAFLD) affects over a third of the US population and 25% globally, with current treatments proving ineffective. This study investigates whether manipulating brown adipose tissue (BAT) and beige fat activity by housing C57BL/6J mice at thermoneutral (27 °C) or standard temperatures (22 °C) impacts NAFLD development. Male mice were fed either a chow diet (CHD) or a “fast food” diet (FFD) for 10 weeks. Mice at 27 °C had reduced food intake but increased body weight and plasma leptin levels. FFD-fed mice at 27 °C had greater liver weight (2.6 vs. 1.8 g), triglyceride content (7.6 vs. 3.9 mg/g), and hepatic steatosis compared to those at 22 °C. Gene expression of fatty acid synthase, sterol regulatory element-binding protein 1, and fatty acid translocase CD36 was elevated in FFD-fed mice at 27 °C, but not in CHD-fed mice. Thermoneutral housing also reduced expression of thermogenic markers in BAT and inguinal white adipose tissue (WAT) and caused BAT whitening. In conclusion, thermoneutrality inhibits thermogenic markers and exacerbates NAFLD. Activating BAT or promoting WAT browning via cold exposure or other stimuli may offer a strategy for managing NAFLD.

This study addresses the issue of construction stagnation affecting the adhesion and tensile properties of hydraulic asphalt concrete with acid aggregate. It investigates the impact of rest periods on the tensile characteristics of such materials under standard construction conditions. The influence of varying rest durations and asphalt temperatures on the tensile behavior of the concrete is assessed through indoor experiments. The bonding between asphalt and aggregate is examined, along with the tensile property variations of the concrete. The study found that the standstill time significantly affects the adhesion of asphalt, with the adhesion decreasing progressively with increased temperature and rest time, irrespective of the addition of anti-stripping agents. However, the inclusion of these agents can mitigate the reduction in adhesion. Furthermore, the study identified that rest duration has a more substantial impact on adhesion than temperature. The splitting tests demonstrate that the tensile properties of asphalt concrete are considerably affected by the resting time. Over a period of 0, 10, 20, and 30 days of rest, an increase in splitting strength and a decrease in splitting displacement were observed. The findings offer valuable insights for predicting the tensile performance of asphalt concrete in practical engineering applications after a period of rest.