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Abstract Currently, cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients. Theophylline, an alkaloid and the most primary metabolite of caffeine, is a readily available compound found in tea and coffee. It functions primarily as a bronchodilator and respiratory stimulant, making it a mainstay treatment for lung diseases like asthma. Theophylline’s additional potential benefits, including anti-inflammatory and anticancer properties, and its possible role in neurological disorders, have garnered significant research interest. Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects. This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF. Notably, cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs. The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures. Graphical Abstract

Abstract The hallmarks of stem cells, such as proliferation, self-renewal, development, differentiation, and regeneration, are critical to maintain stem cell identity which is sustained by genetic and epigenetic factors. Super-enhancers (SEs), which consist of clusters of active enhancers, play a central role in maintaining stemness hallmarks by specifically transcriptional model. The SE-navigated transcriptional complex, including SEs, non-coding RNAs, master transcriptional factors, Mediators and other co-activators, forms phase-separated condensates, which offers a toggle for directing diverse stem cell fate. With the burgeoning technologies of multiple-omics applied to examine different aspects of SE, we firstly raise the concept of “super-enhancer omics”, inextricably linking to Pan-omics. In the review, we discuss the spatiotemporal organization and concepts of SEs, and describe links between SE-navigated transcriptional complex and stem cell features, such as stem cell identity, self-renewal, pluripotency, differentiation and development. We also elucidate the mechanism of stemness and oncogenic SEs modulating cancer stem cells via genomic and epigenetic alterations hijack in cancer stem cell. Additionally, we discuss the potential of targeting components of the SE complex using small molecule compounds, genome editing, and antisense oligonucleotides to treat SE-associated organ dysfunction and diseases, including cancer. This review also provides insights into the future of stem cell research through the paradigm of SEs.

Abstract Background Chemokine (C-C motif) receptor 8 (CCR8) is a chemokine receptor selectively expressed on tumor-infiltrating regulatory T cells (Tregs). Strong immunosuppression mediated by CCR8+ Tregs observed in breast and lung malignancies suggest for their functional significance in cancer therapy. To date, detailed characterization of tumor-infiltrating CCR8+ Tregs cells in colorectal cancer (CRC) is limited. Methods To study the presence and functional involvement of CCR8+ Tregs in CRC, we analyzed the proportions of CCR8-expressing T cells in different T cell subsets in tumor and adjacent normal tissues and peripheral blood mononuclear cells (PBMCs) from CRC patients by Flow cytometry. Also, we compared the distribution of CCR8+ T cells in malignant tissues and peripheral lymphoid organs from a subcutaneous CRC murine model. Bioinformatic analysis was performed to address the significance of CCR8 expression levels in CRC prognosis, immune regulatory gene expression profiles and potential molecular mechanisms associated with CCR8+ Tregs in CRC tumors. Further, we administrated an anti-CCR8 monoclonal antibody to CT26 tumor-bearing mice and examined the antitumor activity of CCR8-targeted therapy both in vivo and in an ex vivo confirmative model. Results Here, we showed that Tregs was predominantly presented in the tumors of CRC patients (13.4 ± 5.8, p

Abstract Objective To explore the role of different cells and molecules in the pathogenesis of allergic rhinitis (AR) with positive Artemisia allergen by detecting their expression levels. Methods From January 2021 to December 2022,200 AR patients diagnosed in the Otolaryngology Clinic of Ordos Central Hospital were selected as the AR group, and 50 healthy people who underwent physical examination in the hospital during the same period were randomly selected as the healthy control (HC) group. The levels of GATA-3mRNA, RORγtmRNA and FoxP3mRNA in peripheral blood mononuclear cells were detected by real-time fluorescence quantitative PCR (qRT-PCR). The proportions of Th2, Th17 and Treg cells were detected by flow cytometry. The concentrations of IL-4, IL-5, IL-17 and IL-10 in serum were detected by enzyme-linked immunosorbent assay. The differences of transcription gene level, immune cell ratio and cytokine concentration between the two groups were analyzed. Results There was no difference in age and gender between the two groups. The levels of GATA-3mRNA and RORγtmRNA transcription genes in peripheral blood mononuclear cells, the percentage of Th2, Th17 and Treg immune cells, the levels of eosinophils and basophils in peripheral blood, the concentrations of IL-4, IL-5, IL-17, IL-10 cytokines and IgE in serum of AR patients were significantly higher than those in HC group (P

Abstract Patulin (PAT) is a common mycotoxin in moldy fruits that causes gastrointestinal injury if accidentally ingested. Some studies have reported the symptoms of intestinal injury caused by PAT. However, the effects of PAT on the gut microbiota and gut metabolism remain to be investigated, which is important for clarifying the toxicological mechanisms. Thus, C57/BL6J mice were gavaged once with 0, 1, 4, and 16 mg/kg body weight PAT, and the small intestinal and colonic contents were collected. The 16S rRNA sequencing and targeted and untargeted metabolomics were applied to assess the alterations in microbiota and metabolism, respectively. The results showed that Mycoplasma, Dubosiella, and Enterorhabdus were jointly affected by acute PAT exposure in the small intestinal and colonic contents. Some inflammation‐related bacteria, such as Mycoplasma in the small intestine and Mycoplasma, Alistipes, Eubacterium_coprostanoligenes_group, and Candidatus_saccharimona in the colon, increased with increasing doses of PAT. In metabolic results, amino acids decreased and bile acids elevated in both intestinal contents; lipids increased in the small intestinal contents but decreased in the colonic contents. PAT mainly affected host amino acid and lipid metabolism; it also downregulated microbial tryptophan metabolism and short‐chain fatty acid levels (mainly in the colon), which could be explained by the decrease of Bacteroides and Lactobacillus. These influences in microbial abundances and metabolic levels persisted after PAT and its products were cleared. These results fill a gap in the effects of PAT on the gut microbiota and provide a theoretical basis for elucidating the toxic mechanism of mycotoxins.

Abstract Background “Multidisciplinary fast-track” (MFT) care can accelerate recovery and improve prognosis after surgery, but whether it is effective in older people after hip fracture surgery is unclear. Methods We retrospectively compared one-year all-cause mortality between hip fracture patients at least 80 years old at our institution who underwent hip fracture surgery between January 2014 and December 2018 and who then received MFT or conventional care. Multivariable regression was used to assess the association between MFT care and mortality after adjustment for confounders. Results The final analysis included 247 patients who received MFT care and 438 who received conventional orthopedic care. The MFT group showed significantly lower one-year mortality (8.9% vs. 14.4%, P = 0.037). Log-rank testing of Kaplan-Meier survival curves confirmed the survival advantage. However, the two groups did not differ significantly in rates of mortality during hospitalization or at 30 or 90 days after surgery. Regression analysis confirmed that MFT care was associated with lower risk of one-year mortality (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.281–0.788, P = 0.04), and the survival benefit was confirmed in subgroups of patients with anemia (HR 0.453, 95% CI 0.268–0.767, P = 0.003) and patients with American Society of Anesthesiologists grade III (HR 0.202, 95% CI 0.08–0.51, P = 0.001). Conclusions MFT care can reduce one-year mortality among hip fracture patients at least 80 years old. This finding should be verified and extended in multi-center randomized controlled trials.

Abstract Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients.

Summary: Background: The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Methods: Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n = 59) or progressive disease after radiotherapy (cohort B, n = 19) were enrolled and received pyrotinib (400 mg once daily) and capecitabine (1000 mg/m2 twice daily on days 1–14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). Findings: As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1–39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6–14.6) in cohort A and 5.7 months (95% CI, 3.4–11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6–33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0–15.8) in cohort A and 5.7 months (95% CI, 3.4–11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. Interpretation: These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. Funding: National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

In recent years, overwhelming evidence has emphasized the crucial role of inflammation in the pathogenesis of PD. However, the exact mechanisms by which inflammation damages dopaminergic neurons in PD are still unclear. Therefore, we generated a MPTP-induced PD mouse model and performed spatial transcriptomic sequencing to provide more insight into the process of PD development at specific brain regions. Our results indicate that the pathological changes of PD are mainly manifested in the midbrain, especially in the substantia nigra region, with significant reductions in oligodendrocytes and Agt-labeled astrocytes and an increase in Gfap-labeled astrocytes. Macrophages displayed an increasing trend in the PD environment, indicating a pattern of immune modulation induced by PD. Moreover, pathway analysis revealed significant impairments in ion migration ability, abnormal Ca2+ channels, cAMP signaling, and synaptic damage in PD. Significant downregulation of Mt1 and Mt2 and upregulation of Atp1b2, Gpi1, and Cox6a1 in PD further underscored the occurrence of intense inflammation and immune alterations. On the basis of these findings, we have validated the significant accumulation of Ca2+ in the midbrain tissue in the PD environment by measuring its content. Additionally, we have demonstrated a close association between the reduction of dopaminergic neurons, represented by the midbrain region, and ferroptosis by evaluating the iron content, malondialdehyde (MDA) levels, and the protein expression of GPX4 and TH in the tissue. We propose the hypothesis that PD-related inflammation and immune changes can induce neuronal and oligodendrocyte damage through the induction of ferroptosis, thereby further accelerating the progression of PD.

Mangroves, primarily found along tropical and subtropical coastlines, are crucial ecosystems that offer significant ecological services, including coastal protection, carbon sequestration, and biodiversity support. However, these ecosystems are under severe threat from human activities such as aquaculture, agriculture, and urban development, leading to deforestation and degradation. This study aims to develop a comprehensive framework for assessing the health of mangrove ecosystems using the Pressure-State-Response (PSR) model with annual temporal resolution from 2019 to 2023. It consists of three dimensions: Pressure (human activities and natural factors affecting the ecosystem), State (current condition of the ecosystem), and Response (efforts to mitigate adverse effects and restore health). This study incorporates innovative physical and structural parameters alongside traditional indicators to improve the accuracy of the assessment. The method offers advantages such as ease of measurement, low cost, early warning capabilities for ecosystem damage, and high sensitivity to ecological changes. It provides valuable insights for decision-makers and enhances the ability to detect trends in mangrove health over time through a large-scale, multi-temporal analysis. Using remote sensing techniques and the Analytic Hierarchy Process (AHP), we identified 12 key indicators. The AHP method was used to determine the weight of each indicator, achieving a consistency ratio (CR) of less than 0.1, which ensures the reliability of the assessment. The evaluation included calculating and analysing the Comprehensive Health Index (CHI), Pressure (PHI), State (SHI), and Response (RHI) health indices. Results indicated that the mangrove ecosystems in the Beibu Gulf region were “healthy” state by 2019 through 2022. However, in 2023, the health status declined to “relatively healthy,” indicating a downward trend. In conclusion, this study presents a robust framework for assessing mangrove ecosystem health using the PSR model. The findings underscore the urgent need for conservation efforts to reverse the declining health trend and ensure the long-term sustainability of mangrove ecosystems in the Beibu Gulf.

Background: It is unclear how perioperative hemoglobin decrease (ΔHb) influences the balance between risks and benefits of red blood cell transfusion after cardiac surgery. Methods: We retrospectively analyzed data on 8186 adults who underwent valve surgery and/or coronary artery bypass grafting under cardiopulmonary bypass at two large cardiology centers. We explored the potential association of ΔHb, defined relative to the preoperative level and postoperative nadir, with a composite outcome of in-hospital mortality, myocardial infarction, stroke, and acute kidney injury using multivariable logistic regression, restricted cubic spline, and piecewise-linear models. Results: Among 6316 patients without preoperative anemia, ΔHb ≥ 50 % was associated with an elevated risk of the composite outcome [adjusted odds ratio (aOR) 1.95, 95 % confidence interval (CI) 1.81–2.35]. Among 869 patients without preoperative anemia and with ΔHb ≥ 50 %, postoperative transfusion of no more than four units of red blood cell appeared to decrease the risk of the composite outcome, whereas transfusion of more than six units increased risk. Among 5447 patients without preoperative anemia and with ΔHb < 50 %, postoperative transfusion appeared not to decrease the risk of the composite outcome. Among 1870 patients with preoperative anemia, ΔHb ≥ 30 % significantly increased the risk of the composite outcome (aOR 1.61, 95 % CI 1.23–2.10), and this risk might be moderated by postoperative transfusion of no more than four units of red blood cell, but increased by transfusion of more than six units. Conclusions: ΔHb may influence the balance between risks and benefits of red blood cell transfusion after cardiac surgery.

BackgroundUnilateral or bilateral anterolateral thoracotomy May lead to severe acute pain in lung transplantation (LTx). Although serratus anterior plane block (SAPB) is apparently effective for pain control after open thoracic surgery, there remains a lack of evidence for the application of SAPB for postoperative analgesia after LTx.ObjectiveIn this case series pilot study, we describe the feasibility of continuous SAPB after lung transplantation and provide a preliminary investigation of its safety and efficacy.MethodsAfter chest incisions closure was complete, all patients underwent ultrasound-guided SAPB with catheter insertion. Numerical rating scale (NRS), additional opioid consumption, time to endotracheal tube removal, ICU length of stay, and catheter-related adverse events were followed up and recorded for each patient within 1 week after the procedure.ResultsA total of 14 patients who received LTx at this center from August 2023 to November 2023 were included. All patients received anterolateral approaches, and 10 (71.4%) of them underwent bilateral LTx. The duration of catheter placement was 2 (2–3) days, and the Resting NRS during catheter placement was equal to or less than 4. A total of 11 patients (78.6%) were supported by extracorporeal membrane oxygenation (ECMO) in LTx, whereas 8 patients (57.1%) removed the tracheal tube on the first day after LTx. Intensive care unit (ICU) stay was 5 (3–6) days, with tracheal intubation retained for 1 (1–2) days, and only one patient was reintubated. The morphine equivalent dose (MED) in the first week after LTx was 11.95 mg, and no catheter-related adverse events were detected.LimitationsWe did not assess the sensory loss plane due to the retrospective design. In addition, differences in catheter placement time May lead to bias in pain assessment.ConclusionAlthough continuous SAPB May be a safe and effective fascial block technique for relieving acute pain after LTx, it should be confirmed by high-quality clinical studies.

ObjectiveDelayed enhancement cardiac computed tomography (CT) empowers the diagnosis of left atrial appendage thrombus while limited to scanning heterogeneity. We optimized the spectral CT scan and post-process protocols, incorporating delayed enhancement and spectral iodine analysis to discriminate left atrial appendage (LAA) thrombus with better morphological relationships between the left atrium, pulmonary vein, and esophagus.MethodsA total of 278 consecutive patients were retrieved from January 2019 to June 2023. All patients underwent transesophageal echocardiography (TEE) and spectral CT scan of the left atrial and pulmonary vein, with a complete period including the pulmonary venous phase and three delay phases. TEE diagnosis was used as the standard reference. For patients exhibiting LAA filling defects during the pulmonary venous phase, a delayed scan of 30 s (phase I) was performed. If the filling defects persisted, a further delayed scan of 1 min (phase II) was conducted. In cases where the filling defects persisted, an additional delayed scan of 2 min (phase III) was carried out. Iodine concentration in the filled defect area of LAA and the left atrium was measured in phase III. Moreover, 30 patients were randomly selected for water-swallowing and the other 30 for calm breathing. The image quality and esophageal dilation of the two groups were assessed by two experienced surgeons specializing in radiofrequency ablation.ResultsIn total, 14 patients were diagnosed with thrombi by TEE. The sensitivity, specificity, positive predictive values, negative predictive values, and AUC of phase III delayed combined with iodine quantification for thrombi diagnosis were all 100%. The water-swallowing group exhibited significantly greater esophageal filling and expansion than the calm-breathing group, contributing to a better morphology assessment with no significant difference in image quality.ConclusionCombined with iodine quantification, delayed enhancement of spectral CT imaging presents a promising diagnostic potency for LAA thrombus. Incorporating water swallowing into the CT scan process further enables anatomical visualization of the esophagus, left atrium, and pulmonary vein, thereby providing more objective and authentic imaging evidence to assess the esophageal morphology and positional relationships.

Turpan-Hami (Tuha) Basin is in an extremely arid area, surrounded by mountains and desert with sparse vegetation. It has experienced serious desertification over the past 30 years, resulting in ecological environment and socio-economic issues. To reveal the temporal and spatial evolutions of desertification degrees in Tuha Basin, we first constructed an evaluation system for the desertification degree classification using vegetation and soil-related indices; then long-time series Landsat 5 TM/ Landsat8 OLI images and a C5.0 decision tree (DT) model were used to monitor large-scale desertification from 1990 to 2020. We applied a geographic detector to discover the driving forces between desertification changes and natural and human factors. The results demonstrated that the severe desertification (SD) accounted for the largest desertification degree, and the transitions of various desertification degrees mainly occurred between extremely severe desertification (ESD) and SD, which were considered the most active degrees. Only 9.4 % of Tuha Basin showed an expansion trend in desertification degree, with the most significant expansion occurred in 1990–1995. The proportion of 13.6 % desertification showed a reversion trend, with the most significant reversion occurred in 1995–2010. The main driving factors affecting the evolution of desertification degrees were precipitation and temperature, with the average q value higher than 0.95. Human activity factors such as year-end cropland area and population also impacted the patterns of desertification degree, with the q values of 0.9 and 0.7, respectively. The interactive detection enhanced the driving forces and the interaction between precipitation and other factors played a leading role in desertification degree changes. The results provide scientific data and a basis for desertification control and ecological protection in arid areas.

Abstract Chronic pain after lung transplantation (LTx) can substantially reduce quality of life (QoL), yet current consensus guidelines say little about how to prevent or manage it. Research on pain after LTx has tended to focus on acute rather than chronic pain, and it has not extensively examined the factors associated with onset or resolution of chronic pain, which differ from factors influencing chronic pain after general thoracic surgery. This narrative review explores what is known about the epidemiology and risk factors of chronic pain after LTx, as well as effective ways to treat or prevent it. The review identifies key questions and issues that should be the focus of future research.

In order to further clarify the influence of multistage pulse ultrasound on the characteristics of gas desorption in water-bearing coal, the ultrasonic stimulation test system of gas-containing coal is used to analyze the pore structure and gas desorption of coal under the condition of continuous ultrasonic stimulation of coal with different moisture contents and multistage pulse stimulation of water-saturated coal, and the mechanism of multistage pulse stimulation of water-bearing coal is revealed. The results show that the average pore diameter, specific surface area and total pore volume of coal increase with the increase of ultrasonic power and water saturation degree. When ultrasonic power is 1000 W, compared with dry coal, the increase of specific surface area and total pore volume of coal increases from 4.369% and 3.504% of 25% moisture content to 7.699% and 8.992% of 100% moisture content, respectively. There is a Langmuir-type relationship between coal gas desorption and time, and coal gas desorption amount and desorption rate are positively correlated with ultrasonic power and water saturation degree of coal. Compared with dry coal, the gas desorption capacity and desorption rate increase linearly with the increase of water saturation degree of coal, and ultrasonic stimulation has the best effect on the pore reconstruction and gas desorption of water saturated coal. With the increase of ultrasonic multistage pulse times, the specific surface area, total pore volume, gas desorption capacity and desorption rate of water-saturated coal increase. Compared with the 1000 W ultrasonic excitation, the increase of specific surface area and total pore volume of coal is a positive power function of the number of multistage pulses. The increase of gas desorption amount and desorption rate of coal increases from 2.745% and 4.598% of the first multistage pulse to 27.222% and 11.106% of the third multistage pulse, respectively, which is in a positive linear relationship with the number of multistage pulses. The combined effect of vibration and cavitation generated by multi-stage pulse ultrasonic stimulation of water-bearing coal causes fatigue damage to the coal matrix, strengthens the pore transformation of coal, and increases the molecular kinetic energy of gas, thus promoting gas desorption in coal. On site, the gas extraction in coal seam can be enhanced through the development of multi-stage pulse ultrasonic emitter combined with hydraulic technology.

Abstract AURKA is an established target for cancer therapy; however, the efficacy of its inhibitors in clinical trials is hindered by differential response rates across different tumor subtypes. In this study, we demonstrate AURKA regulates amino acid synthesis, rendering it a vulnerable target in KEAP1-deficient non-small cell lung cancer (NSCLC). Through CRISPR metabolic screens, we identified that KEAP1-knockdown cells showed the highest sensitivity to the AURKA inhibitor MLN8237. Subsequent investigations confirmed that KEAP1 deficiency heightens the susceptibility of NSCLC cells to AURKA inhibition both in vitro and in vivo, with the response depending on NRF2 activation. Mechanistically, AURKA interacts with the eIF2α kinase GCN2 and maintains its phosphorylation to regulate eIF2α-ATF4-mediated amino acid biosynthesis. AURKA inhibition restrains the expression of asparagine synthetase (ASNS), making KEAP1-deficient NSCLC cells vulnerable to AURKA inhibitors, in which ASNS is highly expressed. Our study unveils the pivotal role of AURKA in amino acid metabolism and identifies a specific metabolic indication for AURKA inhibitors. These findings also provide a novel clinical therapeutic target for KEAP1-mutant/deficient NSCLC, which is characterized by resistance to radiotherapy, chemotherapy, and targeted therapy.

Abstract Reservoir computing originates in the early 2000s, the core idea being to utilize dynamical systems as reservoirs (nonlinear generalizations of standard bases) to adaptively learn spatiotemporal features and hidden patterns in complex time series. Shown to have the potential of achieving higher-precision prediction in chaotic systems, those pioneering works led to a great amount of interest and follow-ups in the community of nonlinear dynamics and complex systems. To unlock the full capabilities of reservoir computing towards a fast, lightweight, and significantly more interpretable learning framework for temporal dynamical systems, substantially more research is needed. This Perspective intends to elucidate the parallel progress of mathematical theory, algorithm design and experimental realizations of reservoir computing, and identify emerging opportunities as well as existing challenges for large-scale industrial adoption of reservoir computing, together with a few ideas and viewpoints on how some of those challenges might be resolved with joint efforts by academic and industrial researchers across multiple disciplines.

Abstract Sarcopenia, a progressive and prevalent neuromuscular disorder, is characterized by age-related muscle wasting and weakening. Despite its widespread occurrence, the molecular underpinnings of this disease remain poorly understood. Herein, we report that levels of Agrin, an extracellular matrix (ECM) protein critical for neuromuscular formation, were decreased with age in the skeletal muscles of mice. The conditional loss of Agrin in myogenic progenitors and satellite cells (SCs) (Pax7 Cre:: Agrin flox/flox) causes premature muscle aging, manifesting a distinct sarcopenic phenotype in mice. Conversely, the elevation of a miniaturized form of Agrin in skeletal muscle through adenovirus-mediated gene transfer induces enhanced muscle capacity in aged mice. Mechanistic investigations suggest that Agrin-mediated improvement in muscle function occurs through the stimulation of Yap signaling and the concurrent upregulation of dystroglycan expression. Collectively, our findings underscore the pivotal role of Agrin in the aging process of skeletal muscles and propose Agrin as a potential therapeutic target for addressing sarcopenia.

Background: Dalpiciclib is a novel cyclin-dependent kinase 4/6 inhibitor which showed tolerability and preliminary efficacy as monotherapy for pretreated advanced breast cancer (BC). Objectives: To further assess dalpiciclib with endocrine therapy (ET) in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative BC. Design: A multicenter, open-label, phase Ib trial. Methods: Patients with locally recurrent or metastatic BC were enrolled in five cohorts. Patients without prior treatment for advanced disease (cohorts 1–2) were given dalpiciclib (125 or 150 mg) plus letrozole/anastrozole; patients who progressed after ET (cohorts 3–5) were given dalpiciclib (125, 150, or 175 mg) plus fulvestrant. Dalpiciclib was administered orally once daily in 3-weeks-on/1-week off schedule. The primary endpoint was safety. Results: A total of 58 patients received dalpiciclib with letrozole/anastrozole and 46 received dalpiciclib with fulvestrant. No maximum tolerated dose of dalpiciclib was reached with letrozole/anastrozole or fulvestrant. Across all cohorts, 86.7%–93.8% of patients had a grade ⩾3 adverse event, with the most common being neutropenia (grade 3, 40.0% for dalpiciclib 175 mg and 61.8%–87.5% for lower doses; grade 4, 46.7% and 4.2%–20.6%, respectively) and leukopenia (grade 3, 80.0% for 175 mg and 33.3%–54.2% for lower doses; grade 4, 0% for all doses). At tested dose levels, steady-state areas under the concentration curve and peak concentration of dalpiciclib increased with dose when combined with letrozole/anastrozole and fulvestrant. Dalpiciclib at 150 mg was associated with a numerically higher objective response rate in both patients untreated for advanced disease (67.6%; 95% confidence interval (CI) 49.5–82.6) and patients progressing after ET (53.3%; 95% CI 26.6–78.7); as of July 30, 2022, the median progression-free survival with dalpiciclib 150 mg was 24.1 months (95% CI 16.9–46.0) with letrozole/anastrozole and 16.7 months (95% CI 1.9–24.1) with fulvestrant. Conclusion: Dalpiciclib plus letrozole/anastrozole or fulvestrant showed an acceptable safety profile. The recommended phase III dose of dalpiciclib was 150 mg. Trial registration: ClinicalTrials.gov identifier: NCT03481998.

Aeolian sandy soil and loess soil of the Mu Us Sandy Land are used as the research material in this study to investigate the effect of soil compounding on the improvement of aeolian sandy soil and to provide a feasible approach for sand prevention and sand control. In particular, loess soils were compounded at 0%, 20%, 40%, 60%, 80%, and 100% by volume percentage of the compounded soils. The improvement benefits of compounded soils on their textural properties, water-holding capacity, and fertilizer-retention capacity at different blending ratios were evaluated. The results showed that following the compounding of aeolian sandy and loess soils, with the increase of the loess proportion, the texture type of the compounded soil transforms from sandy soil to loamy sandy soil to sandy loam to loamy soil to powdery loam. Moreover, granular gradation was observed, the bulk density gradually decreased, the capillary porosity gradually increased, and the performance of water- and fertilizer-holding properties gradually increased and strengthened. The spatial variability of compounded soil bulk density, capillary porosity, and the water-holding and fertilizer-retention properties was almost entirely controlled by the proportion of loess soil. A theoretical basis is provided in this study for aeolian sandy soil improvement in the Mu Us Sandy Land that can be extended to similar areas, providing a feasible sand management approach.

Sediment grain size characterization is one of the main components of aeolian geomorphology research. Sand particle size can determine the basic form of sand movement. The distribution and form of grain size parameters of different types of sediments were calculated using six surface types of sediments around Qixing Lake in the Kubuqi Desert: Mobile dune Semi-fixed dune Fixed dune Lakeshore terrace Wetland and Grassy flat wetland The results showed that the surface sediments were mainly composed of medium sand and fine sand, and all types were negatively skewed. The differentiation pattern of the saltation component and suspended component of the surface sediment is characterized by a two-stage pattern. The percentage contribution of suspended components in lakeshore terraces, wetlands, and Grassy flat wetlands (total average 21.07%) is more than twice that of mobile dunes, semifixed dunes, and fixed dunes (total average 9.47%). This suggests that mobile dunes, semi-fixed dunes, and fixed dunes are not the main contributing surface type of suspended material in the Qixing Lake area.

SOCS (Suppressor of Cytokine Signalling) proteins are intracellular negative regulators that primarily modulate and inhibit cytokine-mediated signal transduction, playing a crucial role in immune homeostasis and related inflammatory diseases. SOCS act as inhibitors by regulating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway, thereby intervening in the pathogenesis of inflammation and autoimmune diseases. Recent studies have also demonstrated their involvement in central immunity and neuroinflammation, showing a dual functionality. However, the specific mechanisms of SOCS in the central nervous system remain unclear. This review thoroughly elucidates the specific mechanisms linking the SOCS-JAK-STAT pathway with the inflammatory manifestations of neurodegenerative diseases. Based on this, it proposes the theory that SOCS proteins can regulate the JAK-STAT pathway and inhibit the occurrence of neuroinflammation. Additionally, this review explores in detail the current therapeutic landscape and potential of targeting SOCS in the brain via the JAK-STAT pathway for neuroinflammation, offering insights into potential targets for the treatment of neurodegenerative diseases.

Necroptosis, a recently discovered form of cell-programmed death that is distinct from apoptosis, has been confirmed to play a significant role in the pathogenesis of bacterial infections in various animal models. Necroptosis is advantageous to the host, but in some cases, it can be detrimental. To understand the impact of necroptosis on the pathogenesis of bacterial infections, we described the roles and molecular mechanisms of necroptosis caused by different bacterial infections in this review.

Objective: Bisphenol A (BPA) is a common environmental endocrine disruptor that negatively impairs male reproductive ability. This study aimed to explore the alterations in serum metabolomics that occur following BPA exposure and the mechanism via which BPA induces the death of testicular cells in a male mouse model. Methods: The mice were classified into two groups: BPA-exposed and control groups, and samples were collected for metabolomic determination, semen quality analysis, electron microscopy, enzyme-linked immunosorbent assay, quantitative real-time PCR, pathological staining, and Western blot analysis. Results: BPA exposure caused testicular damage and significantly decreased sperm quality in mice. Combined with non-target metabolomic analysis, this was closely related to ferroptosis induced by abnormal metabolites of arachidonic acid and phosphatidylcholine, and the expression of its related genes, acyl CoA synthetase 4, glutathione peroxidase 4, lysophosphatidylcholine acyltransferase 3, and phosphatidylethanolamine-binding protein 1 were altered. Conclusion: BPA induced ferroptosis, caused testicular damage, and reduced fertility by affecting lipid metabolism in male mice. Inhibiting ferroptosis may potentially function as a therapeutic strategy to mitigate the male reproductive toxicity induced by BPA.

The sustainability of port cities affects the competitiveness of their hinterland in international shipping and maritime trade, however, the coordinated relationship between urbanization and ecological environment in port cities has received less attention. In this study, we quantitatively analyzed the urban expansion process and vegetation cover changes in 44 port cities along the Maritime Silk Road during 2000–2020 based on multi-source remote sensing data. Adopting the urbanization-vegetation cover index (UVCI), we measured the coordination relationship between urban expansion and vegetation cover and the dynamics during 2000–2020. The results found that all port cities experienced dramatic development from 2000 to 2020, with an average increase in artificial surface area of 127.81%. The 63.64% of port cities experienced increased vegetation cover, thus the overall UVCI in the port city moved toward a more coordinated and sustainable pattern with significant heterogeneity at the economic levels. High-economy port cities have generally become more coordinated, while most low- and medium-economy cities still face challenges of conflicting urban expansion and ecological preservation. This study contributes to the development of government policies that support green and sustainable urban development in port cities, and provides insights for rationalizing development policies in port cities worldwide.

Abstract Objectives Although several independent risk factors for postoperative pulmonary complications (PPCs) after spinal tumor surgery have been studied, a simple and valid predictive model for PPC occurrence after spinal tumor surgery has not been developed. Patients and methods We collected data from patients who underwent elective spine surgery for a spinal tumor between 2013 and 2020 at a tertiary hospital in China. Data on patient characteristics, comorbidities, preoperative examinations, intraoperative variables, and clinical outcomes were collected. We used univariable and multivariable logistic regression models to assess predictors of PPCs and developed and validated a nomogram for PPCs. We evaluated the performance of the nomogram using the area under the receiver operating characteristic curve (ROC), calibration curves, the Brier Score, and the Hosmer–Lemeshow (H–L) goodness-of-fit test. For clinical use, decision curve analysis (DCA) was conducted to identify the model’s performance as a tool for supporting decision-making. Results Among the participants, 61 (12.4%) individuals developed PPCs. Clinically significant variables associated with PPCs after spinal tumor surgery included BMI, tumor location, blood transfusion, and the amount of blood lost. The nomogram incorporating these factors showed a concordance index (C-index) of 0.755 (95% CI: 0.688–0.822). On internal validation, bootstrapping with 1000 resamples yielded a bias-corrected area under the receiver operating characteristic curve of 0.733, indicating the satisfactory performance of the nomogram in predicting PPCs. The calibration curve demonstrated accurate predictions of observed values. The decision curve analysis (DCA) indicated a positive net benefit for the nomogram across most predicted threshold probabilities. Conclusions We have developed a new nomogram for predicting PPCs in patients who undergo spinal tumor surgery.

Abstract Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease.

NASA's (National Aeronautics and Space Administration) ICESat-2 with a Photon Counting LiDAR (Light Detection And Ranging) Sensor sensitively detects signal photons at high speed with an advanced detection system called the Advanced Topographic Laser Altimeter System (ATLAS). However, the sensor also extracts a large amount of background photon noise coming from the atmosphere, ground, sun, or other radiation. This condition is particularly evident in forest areas. This study proposes an automatic machine learning approach to utilize data for forestry applications to improve data availability compared to NASA's official product. Our method uses only a very limited number (10%) of sample points for training, ensuring operational efficiency and training accuracy. We conclude that the integrated learning performance generally outperforms single models, and the mean F1 score of all tests is approximately 0.9. The mean F1 score of the Stacked Ensembles model is 0.957 ahead of the other models. The top three variables used in training models are kNNdist5, kNNdist10, and h. These three variables could explain 51.6% of the components of the models. Over the regions tested, the proposed method could improve the proportion of signals correctly identified by 6.4%, 12.2%, 2.7%, 9.3%, and 1.4% in five datasets. The model performs better in low signal-to-noise (SNR) datasets less than 7.5. The method would be largely unaffected by differences in topography, noise distribution, and SNR. The classifiers could correct misclassified labels in ATL08 products and show good stability in different conditions.

Abstract Background Cellular states of different immune cells can affect the activity of the whole immune microenvironment. Methods Here, leveraging reference profiles of microenvironment cell states that were constructed based on single-cell RNA-seq data of melanoma, we dissected the composition of microenvironment cell states across 463 skin cutaneous melanoma (SKCM) bulk samples through CIBERSORT-based deconvolution of gene expression profiles and revealed high heterogeneity of their distribution. Correspondence analysis on the estimated cellular fractions of melanoma bulk samples was performed to identify immune phenotypes. Based on the publicly available clinical survival and therapy data, we analyzed the relationship between immune phenotypes and clinical outcomes of melanoma. Results By analysis of the relationships among those cell states, we further identified three distinct tumor microenvironment immune phenotypes: “immune hot/active”, “immune cold-suppressive” and “immune cold-exhausted”. They were characterized by markedly different patterns of cell states: most notably the CD8 T Cytotoxic state, CD8 T Mixed state, B non-regulatory state and cancer-associated fibroblasts (CAFs), depicting distinct types of antitumor immune response (or immune activity). These phenotypes had prognostic significance for progression-free survival and implications in response to immune therapy in an independent cohort of anti-PD1 treated melanoma patients. Conclusions The proposed strategy of leveraging single-cell data to dissect the composition of microenvironment cell states in individual bulk tumors can also extend to other cancer types, and our results highlight the importance of microenvironment cell states for the understanding of tumor immunity.

The reliable operation of scroll compressors is crucial for the efficiency of rotating machinery and refrigeration systems. To address the need for efficient and accurate fault diagnosis in scroll compressor technology under varying operating states, diverse failure modes, and different operating conditions, a multi-branch convolutional neural network fault diagnosis method (SSG-Net) has been developed. This method is based on the Swin Transformer, the Global Attention Mechanism (GAM), and the ResNet architecture. Initially, the one-dimensional time-series signal is converted into a two-dimensional image using the Short-Time Fourier Transform, thereby enriching the feature set for deep learning analysis. Subsequently, the method integrates the window attention mechanism of the Swin Transformer, the 2D convolution of GAM attention, and the shallow ResNet’s two-dimensional convolution feature extraction branch network. This integration further optimizes the feature extraction process, enhancing the accuracy of fault feature recognition and sensitivity to data variability. Consequently, by combining the global and local features extracted from these three branch networks, the model significantly improves feature representation capability and robustness. Finally, experimental results on scroll compressor datasets and the CWRU dataset demonstrate diagnostic accuracies of 97.44% and 99.78%, respectively. These results surpass existing comparative models and confirm the model’s superior recognition precision and rapid convergence capabilities in complex fault environments.

BackgroundAn association between depression and migraine has been reported in observational studies; however, conventional observational studies are prone to bias. This study aims to investigate the causal relationship between depression and migraine and to quantify the mediating effects of known risk factors.MethodsWe applied two-sample Mendelian randomization and utilized single nucleotide polymorphisms as genetic instruments for exposure (depression) and mediators (sleep traits). We utilized summary data on genome-wide association studies for depression, sleep-related traits mediators and migraine. For depression, genome-wide association studies (depression) were utilized as a test cohort for the primary analysis. Moreover, genome-wide association studies (major depressive disorder) were utilized to test the stability of the results for the validation cohort. IVW and MR-Egger regression were applied to test the heterogeneity, and Cochran’s Q statistics were calculated to quantitatively evaluate the heterogeneity. MR-PRESSO analyses were utilized to examine and correct possible horizontal pleiotropy through removing outliers, and leave-one-out analyses were utilized to identify outlier SNPs.ResultsGenetically predicted depression was associated with migraine (OR = 1.321, 95% CI: 1.184–1.473, p < 0.001). Furthermore, risk factors insomnia was associated with migraine risk (OR = 1.766, 95% CI: 1.120–2.784, p = 0.014). The mediator insomnia accounted for 19.5% of the total effect of depression on migraine.ConclusionThese results support a potential causal effect of depression on migraine, partly mediated by insomnia. Therefore, the enhancement of sleep quality and difficulty in falling asleep may reduce the migraine burden occasioned by depression.

BackgroundCurrently, the association between the consumption of polyunsaturated fatty acids (PUFAs) and the susceptibility to autoimmune rheumatic diseases (ARDs) remains conflict and lacks substantial evidence in various clinical studies. To address this issue, we employed Mendelian randomization (MR) to establish causal links between six types of PUFAs and their connection to the risk of ARDs.MethodsWe retrieved summary-level data on six types of PUFAs, and five different types of ARDs from publicly accessible GWAS statistics. Causal relationships were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the reliability of our research findings, we used four complementary approaches and conducted multivariable MR analysis (MVMR). Additionally, we investigated reverse causality through a reverse MR analysis.ResultsOur results indicate that a heightened genetic predisposition for elevated levels of EPA (ORIVW: 0.924, 95% CI: 0.666–1.283, PIVW = 0.025) was linked to a decreased susceptibility to psoriatic arthritis (PsA). Importantly, the genetically predicted higher levels of EPA remain significantly associated with an reduced risk of PsA, even after adjusting for multiple testing using the FDR method (PIVW–FDR–corrected = 0.033) and multivariable MR analysis (PMV-IVW 0.05) and multiple testing using the FDR method (PIVW–FDR–corrected = 0.062). Moreover, effects of total omega-3 PUFAs, DHA, EPA, and LA on PsA, were massively driven by SNP effects in the FADS gene region. Furthermore, no causal association was identified between the concentrations of other circulating PUFAs and the risk of other ARDs. Further analysis revealed no significant horizontal pleiotropy and heterogeneity or reverse causality.ConclusionOur comprehensive MR analysis indicated that EPA is a key omega-3 PUFA that may protect against PsA but not other ARDs. The FADS2 gene appears to play a central role in mediating the effects of omega-3 PUFAs on PsA risk. These findings suggest that EPA supplementation may be a promising strategy for preventing PsA onset. Further well-powered epidemiological studies and clinical trials are warranted to explore the potential mechanisms underlying the protective effects of EPA in PsA.

Managing severe chronic pain is a challenging task, given the limited effectiveness of available pharmacological and non-pharmacological treatments. This issue continues to be a significant public health concern, requiring a substantial therapeutic response. Ziconotide, a synthetic peptide initially isolated from Conus magus in 1982 and approved by the US Food and Drug Administration and the European Medicines Agency in 2004, is the first-line intrathecal method for individuals experiencing severe chronic pain refractory to other therapeutic measures. Ziconotide produces powerful analgesia by blocking N-type calcium channels in the spinal cord, which inhibits the release of pain-relevant neurotransmitters from the central terminals of primary afferent neurons. However, despite possessing many favorable qualities, including the absence of tolerance development, respiratory depression, and withdrawal symptoms (largely due to the absence of a G-protein mediation mechanism), ziconotide's application is limited due to factors such as intrathecal administration and a narrow therapeutic window resulting from significant dose-related undesired effects of the central nervous system. This review aims to provide a comprehensive and clinically relevant summary of the literatures concerning the pharmacokinetics and metabolism of intrathecal ziconotide. It will also describe strategies intended to enhance clinical efficacy while reducing the incidence of side effects. Additionally, the review will explore the current efforts to refine the structure of ziconotide for better clinical outcomes. Lastly, it will prospect potential developments in the new class of selective N-type voltage-sensitive calcium-channel blockers.

Mycotoxin contamination has become a major food safety issue and greatly threatens human and animal health. Patulin (PAT), a common mycotoxin in the environment, is exposed through the food chain and damages the gastrointestinal tract. However, its mechanism of enterotoxicity at the genetic and metabolic levels remains to be elucidated. Herein, the intestinal histopathological and biochemical indices, transcriptome, and metabolome of C57BL/6 J mice exposed to different doses of PAT were successively assessed, as well as the toxicokinetics of PAT in vivo. The results showed that acute PAT exposure induced damaged villi and crypts, reduced mucus secretion, decreased SOD and GSH-Px activities, and enhanced MPO activity in the small intestine and mild damage in the colon. At the transcriptional level, the genes affected by PAT were dose-dependently altered in the small intestine and fluctuated in the colon. PAT primarily affected inflammation-related signaling pathways and oxidative phosphorylation in the small intestine and immune responses in the colon. At the metabolic level, amino acids decreased, and extensive lipids accumulated in the small intestine and colon. Seven metabolic pathways were jointly affected by PAT in two intestinal sites. Moreover, changes in PAT products and GST activity were detected in the small intestinal tissue but not in the colonic tissue, explaining the different damage degrees of the two sites. Finally, the integrated results collectively explained the toxicological mechanism of PAT, which damaged the small intestine directly and the colon indirectly. These results paint a clear panorama of intestinal changes after PAT exposure and provide valuable information on the exposure risk and toxic mechanism of PAT.

The balance between ecosystem service supply–demand and landscape ecological risk are two crucial aspects influencing the sustainable development of regional ecosystems. Current evaluations ignore these aspects and lead to partial landscape planning in urban areas. As a result, a framework was built for regional planning in urban areas based on multidimensional evaluations of ecosystems for high-efficiency land use planning. First, to determine the ecosystem service balance in regional scale, the supply and demand of five ecosystem services were quantified—biodiversity conservation, carbon sequestration, water conservation, food production, and landscape recreation. Second, landscape ecological risks were identified using the “natural–social–landscape” research framework combined with spatial principal component analysis. Third, spatial clustering analysis of ecosystem service supply–demand ratios and landscape ecological risks was then performed through spatial autocorrelation, which aimed to identify areas for protection and restoration priority. Finally, GeoDetector was used to determine the main factors influencing ecosystem service balance and landscape ecological risks and develop targeted planning measures. The results revealed an imbalance in total ecosystem service supply–demand in Beijing's plain area, coupled with a high level of landscape ecological risk. The combined ecosystem service supply–demand ratios exhibited a significant negative correlation and aggregation with landscape ecological risk, and the significant area accounted for approximately 31.9% of the total area. Priority areas for protection and restoration accounted for 10.39% and 19.94%, respectively, of the total regional area. Land use, distance to settlements, and vegetation cover were the primary environmental variables influencing the distributions of the combined ecosystem service supply–demand ratios and landscape ecological risk. So, this study emphasizes the need to strengthen intensive land use and prevent the uncontrolled expansion of urban land and settlements. It is crucial to enhance urban green infrastructure construction, promote the development of biodiversity-friendly agriculture, and implement measures such as afforestation restoration to increase regional vegetation cover. Overall, by integrating a framework of ecosystem services and landscape ecological risk, a comprehensive scientific reference can be provided for the efficient land use and sustainable development planning in urban areas.

PHD finger protein 10 (PHF10) plays an important role in the tumorigenesis of gastric cancer (GC). However, clinical significance and underlying molecular mechanisms about PHF10 is unclear. In the article, it suggested that PHF10 involved in tumor progression and metastasis based on the analysis of datasets and 190 cases of tumor tissues in GC. And PHF10 provided the diagnostic value with areas under the receiver operating characteristics curve of 0.71 ± 0.069. Then we established GC cell lines MKN28 with PHF10 overexpression and SGC7901 with PHF10 knockdown. CCK8 assay and tumor xenograft experiment showed that upregulation of PHF10 could promote MKN28 cell proliferation, while PHF10 knockdown would inhibit the proliferation of SGC7901 in vitro and vivo. Nevertheless, PHF10 could upregulate CD44 mRNA expression by acting on its promoter at the level of transcription. This effect could be associated with BRG, BAF155 and SNF5, which were conserved subunits of switch/sucrose non-fermentable (SWI/SNF) complex. In conclusion, PHF10 targeting CD44 plays an essential part during the modulation of proliferation of GC cell and may offer a new therapeutic direction for GC.

Root rot is one of the main reasons for yield losses of red kidney bean (Phaseolus vulgaris) production. Pre-inoculation with Trichoderma harzianum can effectively lower the incidence of red kidney bean root rot. In this study, four treatments including CK (control), Fu13 (Fusarium oxysporum), T891 (T. harzianum) and T891 + Fu13 (T. harzianum + F. oxysporum) were arranged in a pot experiment to investigate how T891 affected the incidence and severity of root rot, plant growth, and changes of defense enzyme activity in red kidney bean plants. Community composition and diversity of the rhizosphere microbiota was evaluated through high-throughput sequencing, and co-occurrence network was analyzed. The results showed that when compared to the Fu13 treatment, pre-inoculation with T891 reduced the incidence and severity of red kidney bean root rot by 40.62 and 68.03% (p

Background: The progression and metastasis of tumors are typically accompanied by angiogenesis. Crucially, vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a significant role in tumor-associated angiogenesis. In this study, the aim was to investigate the antitumor effect of combining bevacizumab (Bev) with anlotinib (An) on colorectal cancer (CRC). Methods: The CCK-8 assay, EdU assay, and Annexin V staining were conducted to evaluate the proliferation and apoptosis of CRC cells in vitro. The migration capability of CRC cells and HUVECs was assessed using the Transwell assay. Additionally, the tube formation capability of HUVECs was investigated. Furthermore, the antitumor and antiangiogenic effects were evaluated in the BALB/c mice model using immunohistochemistry, TUNEL staining, and 18F-FDG PET/CT imaging. Finally, we analyzed the inhibitory effect of Bev and/or An on related signaling effectors through western blotting. Results: The in vivo CRC mice model revealed that the combination of Bev + An significantly suppressed tumor formation and angiogenesis. Bev + An inhibited tumor glucose metabolism and increased the median survival period in tumor-bearing mice. Mechanistically, the expressions of VEGF, VEGFR2, PDGFR, and FGFR, as well as the phosphorylation levels of AKT, were inhibited after Bev+An treatment. In conclusion, the dual vertical targeting of VEGF and VEGFR in the CRC mice model strongly inhibited tumor growth and angiogenesis, with the suppression of the AKT signaling pathway playing a partial role.

Abstract Phenol, an important bioactive substance in jujube fruit, is one of the most important indexes of fruit quality. In order to clarify the phenolic substance composition, content and distribution characteristics of different varieties of jujube fruits, this study measured and compared the content of total phenols, total flavonoids and phenolic substance composition in different parts of fruits of six jujube varieties, and combined with the principal component analysis, the results showed that: Fourteen phenolic substances were identified in the fruits of different jujube varieties, and proanthocyanidins, epicatechin, catechin and rutin were the main components, accounting for 58.60%, 16.08%, 13.56% and 5.57% of the total phenolic substances, respectively. The total phenolic and total flavonoid contents of jujube fruits of each variety were between 18.11 and 21.45 mg GAE/g DW and 10.56–20.25 mg RE/g DW, respectively, and the differences in the contents between the varieties were significant, and the contents of ‘Junzao’ and ‘Jinlingyuanzao’ were higher than those of other varieties.The phenolic content of different parts of jujube fruits showed spatial distribution differences, manifested as the total phenols, total flavonoids and their fractions of the peel were significantly higher than that of the pulp, while the content of the pulp near the kernel was significantly higher than that of other parts of the pulp, This study provides a theoretical basis for analysing the differences in phenolic substances in jujube fruits.

In the process of mining coal resources, the abnormal emission of gas associated with coal may lead to serious gas overrun, and trigger problems such as gas disaster or greenhouse effect. Many studies have shown that injecting surfactant solutions into coal seam is one of the effective and important means of gas management. Surfactant mixed with gas is easy to form stable foam. However, there are few studies on the influence of foam properties on gas desorption. Therefore, this paper studied the influence of surfactant foam properties on the slow release law of gas. Two surfactants, sodium dodecyl benzene sulfonate (SDBS) and alkyl glycoside (APG0810), were selected to test the surface tension, viscosity, foaming, stability and foam morphology of solutions. The effects of surfactant foam properties on gas release was investigated using a self-developed experimental apparatus. The experimental results shown that with the increase of surfactant mass fraction, the surface tension of liquid decreased greatly at first, the foaming rate increased obviously, and the foaming stability increased gradually. When approaching the critical micelle concentration, the decrease amplitude of surface tension slowed down, and the foaming and foaming stability increased gently. At a mass fraction of 0.15%, the foaming heights of SDBS and APG0810 after air injection were 44 mm and 40 mm, respectively, and the maximum half-life of SDBS foam was 786.5 s. The slow release effect of solution foam on gas was well correlated with its foaming rate and half-life. At the same mass fraction, SDBS was generally better than APG0810 in the slow release of gas. At a mass fraction of 0.15%, the gas slow release rate of APG0810 and SDBS within 10 min were about 37.4% and 12.7%, respectively, and that of SDBS within 2 h was still about 50.84%. This study can provide a new perspective to investigate the inhibition and its mechanism of gas desorption in coal by surfactants, and also a certain theoretical support for the prevention and control of gas in mines and the green mining of coal.

Abstract Immunotherapy combined with chemotherapy has been demonstrated to be effective in early triple-negative breast cancer (TNBC). In this single-arm, phase II study with Simon’s two-stage design, we investigated the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy in patients with early TNBC (NCT04213898). Eligible female patients aged 18 years or older with histologically confirmed treatment-naïve early TNBC were treated with camrelizumab (200 mg, on day 1), nab-paclitaxel (125 mg/m2, on days 1, 8, and 15), and epirubicin (75 mg/m2, on day 1) every three weeks for six cycles. The primary end point was the pathological complete response; secondary endpoints included safety, objective response rate, and long-term survival outcomes of event-free survival, disease-free survival, and distant disease-free survival. A total of 39 patients were enrolled between January 2020 and October 2021. Twenty-five patients achieved a pathological complete response (64.1%, 95%CI: 47.2, 78.8). The objective response rate was 89.7% (95%CI: 74.8, 96.7), including 35 patients with partial responses. Treatment-related adverse events of grade 3 or 4 occurred in 30 (76.9%) patients. In conclusion, the trial meets the prespecified endpoints showing promising efficacy and manageable safety of neoadjuvant camrelizumab plus nab-paclitaxel and epirubicin chemotherapy in female patients with early TNBC. Long-term survival outcomes are still pending.

Abstract Ciprofol (also known as HSK3486) is a promising intravenous anesthetic candidate derived from propofol and independently developed by Haisco Pharmaceutical Group Co., Ltd. (Chengdu, China). Compared with propofol, ciprofol has the potential to reduce the dose required and the associated risks. Ciprofol is extensively metabolized in vivo, and its interaction with other concurrently administered drugs during clinical application is worthy of attention. Therefore, an open‐label, two‐stage sequential study was performed in healthy subjects who received either a single administration of ciprofol injection or ciprofol injection after oral administration of sodium divalproex. The aim of the study was to evaluate the effects of sodium divalproex on ciprofol with respect to pharmacokinetics, pharmacodynamics, and safety, thus providing a basis for the rational clinical use of ciprofol and sodium divalproex.

Abstract CDK4/6 inhibitors have shown a synergistic effect with anti-HER2 therapy in hormone receptor (HR)-positive and HER2-positive breast cancer (BC). In this phase 2 study (NCT04293276), we aim to evaluate a dual-oral regimen of CDK4/6 inhibitor dalpiciclib combined with HER2 tyrosine kinase inhibitor pyrotinib as front-line treatment in women with HER2-positive advanced BC (n = 41) including those with HR-negative disease. The primary endpoint is the objective response rate, and secondary endpoints include progression-free survival (PFS), overall survival (OS), and safety. With a median follow-up of 25.9 months, 70% (28/40) of assessable patients have a confirmed objective response, meeting the primary endpoint. The median PFS is 11.0 months (95% CI = 7.3–19.3), and OS data are not mature. The most common grade 3 or 4 treatment-related adverse events (AEs) are decreased white blood cell count (68.3%), decreased neutrophil count (65.9%), and diarrhea (22.0%). Most AEs are manageable, and no treatment-related deaths occur. These findings suggest that this combination may have promising activity and manageable toxicity. Further investigation is needed.

Proanthocyanidin (PA) is an important bioactive compound with multiple physiological benefits in jujube (Ziziphus jujube Mill.). However, the molecular mechanisms underlying PA biosynthesis in jujube fruit have not been investigated. Here, the profiling of PA, (+)-catechin and (–)-epicatechin and transcriptome sequencing of three jujube cultivars from Xinjiang Uyghur Autonomous Region of China at five developmental stages were analyzed. The levels of total PAs and catechin exhibited a decreased trend over jujube ripening, and epicatechin content of two jujube cultivars increased first and then declined. Transcriptome analysis revealed that the differentially expressed genes (DEGs) were mainly enriched in ribosome, glycolysis/gluconeogenesis, fructose and mannose metabolism. 17 DEGs encoding PAL, CHS, CHI, CHS, F3’H, LAR, ANR, C4Hs, 4CLs, FLSs, DFRs and UFGTs involved in PA biosynthesis were relatively abundant. The highly transcribed LAR gene may greatly contribute to epicatechin accumulation. A weighted gene co-expression network analysis (WGCNA) was performed, and a network module including 1620 genes highly correlated with content of Pas and catechin was established. We identified 58 genes including 9 structural genes and 49 regulatory genes related to PA biosynthesis and regulation in the WGCNA module. Sixteen genes encoding 9 families of transcriptional factors (i.e., MYB, bHLH, ERF, bZIP, NAC, SBP, MIKC, HB, WRKY) were considered as hub genes. The results of qRT-PCR analysis validating 10 genes were well consistent with the transcriptome data. These findings provide valuable knowledge to facilitate its genetic studies and molecular breeding.

Jujube is a plant of the genus Ziziphus in the family Rhamnaceae; its fruit has high nutritional value, and it is rich in polyphenols, flavonoids, and other secondary metabolites. The color of its peel is an important indicator for evaluating the appearance of the fruit. However, the mechanism of the difference in color presentation between the seedling offspring of the ‘Red Fruit’ (TLHH) and the ‘Green Fruit’ (TLHL) of the fresh jujube cultivar ‘Tailihong’ is not clear. Therefore, this study used targeted metabolomics techniques to accurately and quantitatively analyze the metabolic pathways of carotenoid and anthocyanin metabolites during the ripening process of two color-presenting types of jujube fruits. Through the analysis of the dynamic changes in the pigment content of the jujube peel, it was found that 30 DAP (days after pollination), 80 DAP, and 110 DAP were the key periods for the development of the color of the peel of ‘TLHL’ and ‘TLHH’ jujube and that the substances responsible for the main differences were chlorophyll, carotenoids, and anthocyanins. Furthermore, we used an LC-MS/MS metabolic analysis to compare the differences in the carotenoids and anthocyanin metabolites between the two color-presenting types of jujube peels at the key periods of 30 DAP, 80 DAP, and 110 DAP. We detected 32 carotene metabolites and 75 anthocyanin metabolites, respectively, among which lutein had the highest content of carotenoids; it reached the maximum value (93.05 µg/g) and was higher than that of ‘TLHH’ (74.14 µg/g) at 30 DAP of ‘TLHL’. Both showed a decreasing trend with fruit ripening. The anthocyanin with the highest content was cyanidin-3-O-(tartaryl)rhamnoside-5-O-glucoside, which reached the maximum value (258.32 µg/g) at 30 DAP of ‘TLHH’ and was 51.6 times that of ‘TLHL’; similarly, both showed a decreasing trend with fruit ripening. These results elucidate the main metabolites of carotenoids and anthocyanins in the two types of jujube peel and their accumulation characteristics, suggesting that the key metabolites of the difference in color between ‘TLHL’ and ‘TLHH’ jujube fruits were lutein and cyanidin-3-O-(tartaryl)rhamnoside-5-O-glucoside, increasing the understanding of the color mechanism of jujube peel and providing a reference for targeted genetic breeding of jujube peel color.

The exploration of continental shale oil in China has made a breakthrough in many basins, but the pure shale type has only been found in the Qingshankou Formation, Gulong Sag, Songliao Basin, and the evaluation of shale oil occurrence and sweet spot faces great challenges. Using information about the total organic carbon (TOC), Rock-Eval pyrolysis, vitrinite reflectance (Ro), kerogen elemental composition, carbon isotopes, gas chromatography (GC), bitumen extraction, and component separation, this paper systematically studies the organic geochemical characteristics and shale oil occurrence at the Qingshankou Formation. The G1 well, which was cored through the entire section of the Qingshankou Formation in the Gulong Sag, was the object of this study. On this basis, the favorable sweet spots for shale oil exploration are predicted. It is concluded that the shale of the Qingshankou Formation has high organic heterogeneity in terms of organic matter features. The TOC content of the source rocks in the Qingshankou Formation is enhanced with the increase in the burial depth, and the corresponding organic matter types gradually changed from Ⅱ2 and Ⅱ1 types to the Ⅰ type. The distribution of Ro ranges from 1.09% to 1.67%, and it is the mature to high-mature evolution stage that generates a large amount of normal crude oil and gas condensate. The high-quality source rocks of good to excellent grade are mainly distributed in the Qing 1 member and the lower part of the Qing 2 member. After the recovery of light hydrocarbons and the correction of pyrolytic heavy soluble hydrocarbons, it is concluded that the occurrence state of shale oil in the Qingshankou Formation is mainly the free-state form, with an average value of 6.9 mg/g, and there is four times as much free oil as adsorbed oil. The oil saturation index (OSI), mobile hydrocarbon content, Ro, and TOC were selected to establish the geochemical evaluation criteria for shale oil sweet spots in the Qingshankou Formation. The evaluation results show that interval 3 and interval 5 of the Qingshankou Formation in the G1 well are the most favorable sections for shale oil exploration.

【Objective】The soil environment of tobacco planting can be impacted by plastic film mulching, which affects the structure of the soil microbial community and the growth and development of flue-cured tobacco. The purpose of this study is to investigate the effect of a full growth period mulching on the physicochemical properties and bacterial community structure of tobacco planting soil.【Method】16S rDNA sequencing was applied to compare the differences in the structure and diversity of bacterial communities in different treatments by various analytical methods. The connection between soil physicochemical properties and bacterial communities was discovered through redundancy analysis (RDA) based on soil physicochemical properties.【Result】The output value of flue-cured tobacco was significantly increased by film mulching during the growth period. The yield was increased by 13.33%, 18.24%, and 21.36% by the double color film mulching (SY), black film mulching (HY), and white film mulching (BY) treatments, respectively, compared to the control (CK); Output value added was 20.26%, 15.87%, and 13.28%. At the same time, film mulching will also increase tobacco-planting soil temperature, total potassium, total phosphorus, total iron and effective copper contents, and decrease soil pH value, alkaline dissolved nitrogen, effective iron, total copper and total zinc contents. The contents of total phosphorus and available copper increased the most significantly, reaching 3.11%-27.33% and 4.76%-19.05%, respectively. The most significant decrease in alkali hydrolyzed nitrogen, available iron, and total zinc occurred at 10.45%-14.50%, 3.36%-13.43%, and 7.69%-10.01%, respectively. Plastic covering during the whole growth period has a certain negative impact on the abundance of bacterial communities. The abundance index Chao 1 of the control was significantly higher than the three mulching treatments and was 14.09%, 24.20%, and 24.81% higher than that of the white film mulching, double color film mulching, and black film mulching treatments, respectively. Redundancy analysis shows that the main soil physicochemical factors affecting the horizontal community structure of the bacterial phylum are soil temperature, alkaline nitrogen, available iron, total iron, available copper, and total copper content. Three shared genera with significantly different abundance from the control were present in the white film mulching and double color film mulching treatments, which belonged to three families in the phylum Proteobacteria: Sphingomonadaceae, Burkholderiaceae, and Xanthomonadaceae.【Conclusion】The full-life stage mulching cultivation will significantly affect the physicochemical properties and bacterial community structure of tobacco-planting soil, and improve the amount of output value of roasted tobacco, suitable for matching the color of the film is black and white bicolor film.

Abstract PPARα corepressor NCoR1 is a key regulator of fatty acid β-oxidation and ketogenesis. However, its regulatory mechanism is largely unknown. Here, we report that oncoprotein p21-activated kinase 4 (PAK4) is an NCoR1 kinase. Specifically, PAK4 phosphorylates NCoR1 at T1619/T2124, resulting in an increase in its nuclear localization and interaction with PPARα, thereby repressing the transcriptional activity of PPARα. We observe impaired ketogenesis and increases in PAK4 protein and NCoR1 phosphorylation levels in liver tissues of high fat diet-fed mice, NAFLD patients, and hepatocellular carcinoma patients. Forced overexpression of PAK4 in mice represses ketogenesis and thereby increases hepatic fat accumulation, whereas genetic ablation or pharmacological inhibition of PAK4 exhibites an opposite phenotype. Interestingly, PAK4 protein levels are significantly suppressed by fasting, largely through either cAMP/PKA- or Sirt1-mediated ubiquitination and proteasome degradation. In this way, our findings provide evidence for a PAK4-NCoR1/PPARα signaling pathway that regulates fatty acid β-oxidation and ketogenesis.