Dynamic profiling and functional interpretation of histone lysine crotonylation and lactylation during neural development.

Metabolites such as crotonyl-CoA and lactyl-CoA influence gene expression by covalently modifying histones, known as histone lysine crotonylation (Kcr) and lysine lactylation (Kla). However, the existence patterns, dynamic changes, biological functions and associations of these modifications with histone lysine acetylation and gene expression during mammalian development remain largely unknown. Here, we find that histone Kcr and Kla are widely distributed in the brain and undergo global changes during neural development. By profiling the genome-wide dynamics of H3K9ac, H3K9cr and H3K18la in combination with ATAC and RNA sequencing, we reveal that these marks are tightly correlated with chromatin state and gene expression, and extensively involved in transcriptome remodeling to promote cell-fate transitions in the developing telencephalon. Importantly, we demonstrate that global Kcr and Kla levels are not the consequence of transcription and identify the histone deacetylases (HDACs) 1-3 as novel 'erasers' of H3K18la. Using P19 cells as an induced neural differentiation system, we find that HDAC1-3 inhibition by MS-275 pre-activates neuronal transcriptional programs by stimulating multiple histone lysine acylations simultaneously. These findings suggest that histone Kcr and Kla play crucial roles in the epigenetic regulation of neural development.

Cytoskeleton-associated gelsolin responds to the midgut distention process in saline meal-fed Aedes aegypti and affects arbovirus dissemination from the midgut.

The mosquito, Aedes aegypti, is the principal vector for several arboviruses. The mosquito midgut is the initial tissue that gets infected with an arbovirus acquired along with a blood meal from a vertebrate host. Blood meal ingestion leads to midgut tissue distention thereby increasing the pore size of the surrounding basal lamina. This allows newly synthesized virions to exit the midgut by traversing the distended basal lamina to infect secondary tissues of the mosquito. We conducted a quantitative label-free proteomic time course analysis with saline meal-fed Ae. aegypti females to identify host factors involved in midgut tissue distention. Around 2000 proteins were detected during each of the seven sampling time points and 164 of those were uniquely expressed. Forty-five of 97 differentially expressed proteins were upregulated during the 96-h time course and most of those were involved in cytoskeleton modulation, metabolic activity, and vesicle/vacuole formation. The F-actin-modulating Ae. aegypti (Aa)-gelsolin was selected for further functional studies. Stable knockout of Aa-gelsolin resulted in a mosquito line, which showed distorted actin filaments in midgut-associated tissues likely due to diminished F-actin processing by gelsolin. Zika virus dissemination from the midgut of these mosquitoes was diminished and delayed. The loss of Aa-gelsolin function was associated with an increased induction of apoptosis in midgut tissue indicating an involvement of Aa-gelsolin in apoptotic signaling in mosquitoes. Here, we used proteomics to discover a novel host factor, Aa-gelsolin, which affects the midgut escape barrier for arboviruses in mosquitoes and apoptotic signaling in the midgut.

Ion transport in nanofluidics under external fields.

Nanofluidic channels with tailored ion transport dynamics are usually used as channels for ion transport, to enable high-performance ion regulation behaviors. The rational construction of nanofluidics and the introduction of external fields are of vital significance to the advancement and development of these ion transport properties. Focusing on the recent advances of nanofluidics, in this review, various dimensional nanomaterials and their derived homogeneous/heterogeneous nanofluidics are first briefly introduced. Then we discuss the basic principles and properties of ion transport in nanofluidics. As the major part of this review, we focus on recent progress in ion transport in nanofluidics regulated by external physical fields (electric field, light, heat, pressure, etc.) and chemical fields (pH, concentration gradient, chemical reaction, etc.), and reveal the advantages and ion regulation mechanisms of each type. Moreover, the representative applications of these nanofluidic channels in sensing, ionic devices, energy conversion, and other areas are summarized. Finally, the major challenges that need to be addressed in this research field and the future perspective of nanofluidics development and practical applications are briefly illustrated.

Facilitation of Behavioral and Cortical Emergence from Isoflurane Anesthesia by GABAergic Neurons in Basal Forebrain.

General anesthesia shares many similarities with natural sleep in behavior and electroencephalogram (EEG) patterns. The latest evidence suggests that general anesthesia and sleep-wake behavior may share overlapping neural substrates. The GABAergic neurons in the basal forebrain (BF) have recently been demonstrated to play a key role in controlling wakefulness. It was hypothesized that BF GABAergic neurons may participate in the regulation of general anesthesia. Here, using in vivo fiber photometry, we found that the activity of BF GABAergic neurons was generally inhibited during isoflurane anesthesia, having obviously decreased during the induction of anesthesia and being gradually restored during the emergence from anesthesia, in Vgat-Cre mice of both sexes. Activation of BF GABAergic neurons with chemogenetic and optogenetic approaches decreased sensitivity to isoflurane, delayed induction, and accelerated emergence from isoflurane anesthesia. Optogenetic activation of BF GABAergic neurons decreased EEG δ power and the burst suppression ratio (BSR) during 0.8% and 1.4% isoflurane anesthesia, respectively. Similar to the effects of activating BF GABAergic cell bodies, photostimulation of BF GABAergic terminals in the thalamic reticular nucleus (TRN) also strongly promoted cortical activation and behavioral emergence from isoflurane anesthesia. Collectively, these results showed that the GABAergic BF is a key neural substrate for general anesthesia regulation that facilitates behavioral and cortical emergence from general anesthesia via the GABAergic BF-TRN pathway. Our findings may provide a new target for attenuating the depth of anesthesia and accelerating emergence from general anesthesia.SIGNIFICANCE STATEMENT The basal forebrain (BF) is a key brain region controlling sleep-wake behavior. Activation of GABAergic neurons in the BF potently promotes behavioral arousal and cortical activity. Recently, many sleep-wake-related brain structures have been reported to participate in the regulation of general anesthesia. However, it is still unclear what role BF GABAergic neurons play in general anesthesia. In this study, we aim to reveal the role of BF GABAergic neurons in behavioral and cortical emergence from isoflurane anesthesia and elucidate the underlying neural pathways. Understanding the specific role of BF GABAergic neurons in isoflurane anesthesia would improve our understanding of the mechanisms of general anesthesia and may provide a new strategy for accelerating emergence from general anesthesia.

Multi-omics analysis revealed the regulation mode of intratumor microorganisms and microbial signatures in gastrointestinal cancer.

OBJECTIVE: Gastrointestinal cancer is one of the most common malignant tumors in the world, and its incidence rate is always high. In recent years, research has shown that microorganisms may play a broad role in the diagnosis, pathogenesis, and treatment of cancer. METHODS: In this study, samples were first classified according to the microbial expression data of Gastrointestinal cancer, followed by functional enrichment and Immunoassay. In order to better understand the role of intratumor microorganisms in the prognosis, we screened gene signatures and constructed risk model through univariate cox and lasso regression and multivariable cox, then screened microbial signatures using zero-inflated model regression model and constructed risk index (RI), and finally predicted the immunotherapeutic effect of the risk model. RESULTS: The results indicate that the composition of tumor microorganisms in the C3 subtype is closely related to tumor angiogenesis, and there is a significant difference in the proportion of innate and acquired immune cells between the C2 and C1 subtypes, as well as differences in the physiological functions of immune cells. There are significant differences in the expression of microbial signatures between high and low risk subtypes, with 9 microbial signatures upregulated in high risk subtypes and 15 microbial signatures upregulated in low risk subtypes. These microbial signatures were significantly correlated with the prognosis of patients. The results of immunotherapy indicate that immunotherapy for high-risk subtypes is more effective. CONCLUSION: Overall, we analyze from the perspective of microorganisms within tumors, pointing out new directions for the diagnosis and treatment of cancer.

Ultra-thin and Mechanically Stable LiCoO2-Electrolyte Interphase Enabled by Mg2+ Involved Electrolyte.

LiCoO2 (LCO) cathode materials have attracted significant attention for its potential to provide higher energy density in current Lithium-ion batteries (LIBs). However, the structure and performance degradation are exacerbated by increasing voltage due to the catastrophic reaction between the applied electrolyte and delithiated LCO. The present study focuses on the construction of physically and chemically robust Mg-integrated cathode-electrolyte interface (MCEI) to address this issue, by incorporating Magnesium bis(trifluoromethanesulfonyl)imide (Mg[TFSI]2) as an electrolyte additive. During formation cycles, the strong MCEI is formed and maintained its 2 nm thickness throughout long-term cycling. Notably, Mg is detected not only in the robust MCEI, but also imbedded in the surface of the LCO lattice. As a result, the parasitic interfacial side reactions, surface phase reconstruction, particle cracking, Co dissolution and shuttling are considerably suppressed, resulting in long-term cycling stability of LCO up to 4.5 V. Therefore, benefit from the double protection of the strong MCEI, the Li||LCO coin cell and the Ah-level Graphite||LCO pouch cell exhibit high capacity retention by using Mg-electrolyte, which are 88.13% after 200 cycles and 90.4% after 300 cycles, respectively. This work provides a novel approach for the rational design of traditional electrolyte additives.

MRI-Based Kinetic Heterogeneity Evaluation in the Accurate Access of Axillary Lymph Node Status in Breast Cancer Using a Hybrid CNN-RNN Model.

BACKGROUND: Accurate evaluation of the axillary lymph node (ALN) status is needed for determining the treatment protocol for breast cancer (BC). The value of magnetic resonance imaging (MRI)-based tumor heterogeneity in assessing ALN metastasis in BC is unclear. PURPOSE: To assess the value of deep learning (DL)-derived kinetic heterogeneity parameters based on BC dynamic contrast-enhanced (DCE)-MRI to infer the ALN status. STUDY TYPE: Retrospective. SUBJECTS: 1256/539/153/115 patients in the training cohort, internal validation cohort, and external validation cohorts I and II, respectively. FIELD STRENGTH/SEQUENCE: 1.5 T/3.0 T, non-contrast T1-weighted spin-echo sequence imaging (T1WI), DCE-T1WI, and diffusion-weighted imaging. ASSESSMENT: Clinical pathological and MRI semantic features were obtained by reviewing histopathology and MRI reports. The segmentation of the tumor lesion on the first phase of T1WI DCE-MRI images was applied to other phases after registration. A DL architecture termed convolutional recurrent neural network (ConvRNN) was developed to generate the KHimage (kinetic heterogeneity of DCE-MRI image) score that indicated the ALN status in patients with BC. The model was trained and optimized on training and internal validation cohorts, tested on two external validation cohorts. We compared ConvRNN model with other 10 models and the subgroup analyses of tumor size, magnetic field strength, and molecular subtype were also evaluated. STATISTICAL TESTS: Chi-squared, Fisher's exact, Student's t, Mann-Whitney U tests, and receiver operating characteristics (ROC) analysis were performed. P < 0.05 was considered significant. RESULTS: The ConvRNN model achieved area under the curve (AUC) of 0.802 in the internal validation cohort and 0.785-0.806 in the external validation cohorts. The ConvRNN model could well evaluate the ALN status of the four molecular subtypes (AUC = 0.685-0.868). The patients with larger tumor sizes (>5 cm) were more susceptible to ALN metastasis with KHimage scores of 0.527-0.827. DATA CONCLUSION: A ConvRNN model outperformed traditional models for determining the ALN status in patients with BC. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Propensity score matched analysis of treatment outcomes in pediatric ureteropelvic junction obstruction: a comparison between horseshoe and non-horseshoe kidneys.

BACKGROUND: Pediatric hydronephrosis poses distinct challenges, particularly in cases involving horseshoe kidneys (HSK). This retrospective study compares treatment outcomes between HSK and non-horseshoe kidneys (NHSK) in pediatric ureteropelvic junction obstruction (UPJO) patients. METHODS: A retrospective cohort study included 35 patients with HSK and 790 patients with NHSK undergoing pyeloplasty. Preoperative, intraoperative, and postoperative parameters were evaluated. Propensity score matching (PSM) balanced patient characteristics in the NHSK group. RESULTS: In comparison with NHSK, HSK exhibited a higher crossing vessel incidence (51.6% vs. 5.12%, P < 0.001) and smaller preoperative anteroposterior pelvic diameter (APD). Post 6 and 12 months, NHSK maintained a larger APD, with a higher P/C ratio at 12 months. PSM retained significantly higher crossing vessel incidence in HSK (51.6 vs. 3.61%, P < 0.001). Laparoscopic pyeloplasty (LP) in HSK showed lower postoperative length of stay (LOS). Postoperative ultrasound parameters favored NHSK. In HSK and NHSK with crossing vessels, HSK demonstrated higher complications even post-PSM (38.5% vs. 0%, P = 0.039). CONCLUSIONS: The study emphasizes the importance of recognizing crossing vessels in HSK-related hydronephrosis. Surgical success, although comparable between HSK and NHSK, requires tailored approaches. This investigation contributes valuable insights to pediatric urology, emphasizing personalized management for optimal outcomes.

Half-life of serum alpha-fetoprotein in prepubertal testicular yolk sac tumors: an index significantly associated with prognosis.

PURPOSE: To evaluate the association between serum alpha-fetoprotein (AFP) half-life (HL) and prognosis in prepubertal children with elevated AFP values 3 to 4 weeks after surgery for testicular yolk sac tumors (YST). METHODS: Prepubertal patients with testicular YST treated with radical orchiectomy between January 2016 and December 2022 were retrospectively reviewed. Negative outcomes were defined as relapse, metastasis or death. Univariate and multivariate logistic regression analyses were conducted to select risk factors for negative outcomes. RESULTS: A total of 42 patients were eventually enrolled into the study. Patients were divided into non-negative and negative outcomes groups, consisting of 35 and 7 patients, respectively. Thirty-five patients were stage I, two cases were stage II, and five cases were stage IV, according to the Children's Oncology Group staging system. The overall survival (OS) rate was 100%. Average AFP values significantly decreased after resection (P < 0.001). A significant positive correlation was shown between pre- and postoperative AFP values (r = 0.60, P < 0.001). Long AFP HL was considered as an independent risk factor for negative outcomes in YST patients underwent radical orchiectomy (P = 0.04). The cut-off value for AFP HL was 5.78 days, regardless of age division. CONCLUSION: Testicular YST is a relatively rare disease in children with an OS of 100%, and salvage chemotherapy is effective even in grade IV patients. The postoperative AFP HL was significantly associated with prognosis in prepubertal patients with testicular YST. The cut-off value for AFP HL is 5.78 days regardless of the effect of physiological AFP elevation.

Seamless phase 2/3 design for trials with multiple co-primary endpoints using Bayesian predictive power.

Seamless phase 2/3 design has become increasingly popular in clinical trials with a single endpoint. Trials that define success based on the achievement of all co-primary endpoints (CPEs) encounter the challenge of inflated type 2 error rates, often leading to an overly large sample size. To tackle this challenge, we introduced a seamless phase 2/3 design strategy that employs Bayesian predictive power (BPP) for futility monitoring and sample size re-estimation at interim analysis. The correlations among multiple CPEs are incorporated using a Dirichlet-multinomial distribution. An alternative approach based on conditional power (CP) was also discussed for comparison. A seamless phase 2/3 vaccine trial employing four binary endpoints under the non-inferior hypothesis serves as an example. Our results spotlight that, in scenarios with relatively small phase 2 sample sizes (e.g., 50 or 100 subjects), the BPP approach either outperforms or matches the CP approach in terms of overall power. Particularly, with n1 = 50 and ρ = 0, BPP showcases an overall power advantage over CP by as much as 8.54%. Furthermore, when the phase 2 stage enrolled more subjects (e.g., 150 or 200), especially with a phase 2 sample size of 200 and ρ = 0, the BPP approach evidences a peak difference of 5.76% in early stop probability over the CP approach, emphasizing its better efficiency in terminating futile trials. It's noteworthy that both BPP and CP methodologies maintained type 1 error rates under 2.5%. In conclusion, the integration of the Dirichlet-Multinominal model with the BPP approach offers improvement in certain scenarios over the CP approach for seamless phase 2/3 trials with multiple CPEs.

The relativity analysis of hypoxia inducible factor-1α in pulmonary arterial hypertension (ascites syndrome) in broilers: a review.

Ascites syndrome (AS) in broiler chickens, also known as pulmonary arterial hypertension (PAH), is a significant disease in the poultry industry. It is a nutritional metabolic disease that is closely associated with hypoxia-inducible factors and rapid growth. The rise in pulmonary artery pressure is a crucial characteristic of AS and is instrumental in its development. Hypoxia-inducible factor 1α (HIF-1α) is an active subunit of a key transcription factor in the oxygen-sensing pathway. HIF-1α plays a vital role in oxygen homeostasis and the development of pulmonary hypertension. Studying the effects of HIF-1α on pulmonary hypertension in humans or mammals, as well as ascites in broilers, can help us understand the pathogenesis of AS. Therefore, this review aims to (1) summarize the mechanism of HIF-1α in the development of pulmonary hypertension, (2) provide theoretical significance in explaining the mechanism of HIF-1α in the development of pulmonary arterial hypertension (ascites syndrome) in broilers, and (3) establish the correlation between HIF-1α and pulmonary arterial hypertension (ascites syndrome) in broilers. HIGHLIGHTSExplains the hypoxic mechanism of HIF-1α.Linking HIF-1α to pulmonary hypertension in broilers.Explains the role of microRNAs in pulmonary arterial hypertension in broilers.

E3 ubiquitin ligase NEDD4L inhibits epithelial-mesenchymal transition by suppressing the ß-catenin/HIF-1α positive feedback loop in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyp (CRSwNP) is a refractory inflammatory disease with epithelial-mesenchymal transition (EMT) as one of the key features. Since ubiquitin modification has been shown to regulate the EMT process in other diseases, targeting ubiquitin ligases may be a potential strategy for the treatment of CRSwNP. In this study we investigated whether certain E3 ubiquitin ligases could regulate the EMT process in CRSwNP, and whether these regulations could be the potential drug targets as well as the underlying mechanisms. After screening the potential drug target by bioinformatic analyses, the expression levels of three potential E3 ubiquitin ligases were compared among the control, eosinophilic nasal polyp (ENP) and non-eosinophilic nasal polyp (NENP) group in clinical samples, and the significant decrement of the expression level of NEDD4L was found. Then, IP-MS, bioinformatics and immunohistochemistry studies suggested that low NEDD4L expression may be associated with the EMT process. In human nasal epithelial cells (hNECs) and human nasal epithelial cell line RPMI 2650, knockdown of NEDD4L promoted EMT, while upregulating NEDD4L reversed this effect, suggesting that NEDD4L inhibited EMT in nasal epithelial cells. IP-MS and Co-IP studies revealed that NEDD4L mediated the degradation of DDR1. We demonstrated that NEDD4L inhibited the ß-catenin/HIF-1α positive feedback loop either directly (degrading ß-catenin and HIF-1α) or indirectly (mediating DDR1 degradation). These results were confirmed in a murine NP model in vivo. This study for the first time reveals the regulatory role of ubiquitin in the EMT process of nasal epithelial cells, and identifies a novel drug target NEDD4L, which has promising efficacy against both ENP and NENP by suppressing ß-catenin/HIF-1α positive feedback loop.

Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

The expression profiles of cyp19a1, sf-1, esrs and gths in the brain-pituitary during gonadal sex differentiation in juvenile Japanese eels.

Eels are gonochoristic species whose gonadal differentiation initiates at the yellow eel stage and is influenced by environmental factors. We revealed some sex-related genes were sex dimorphically expressed in gonads during gonadal sex differentiation of Japanese eel (Anguilla japonica); however, the expression of sex-related genes in the brain-pituitary during gonadal sex differentiation in eels is still unclear. This study aimed to investigate the sex-related gene expressions in the brain-pituitary and tried to clarify their roles in the brain and gonads during gonadal sex differentiation. Based on our previous histological study, the control eels developed as males, and estradiol-17ß (E2) was used for feminization. Our results showed that during testicular differentiation, the brain cyp19a1 transcripts and aromatase proteins were increased significantly; moreover, the cyp19a1, sf-1, foxl2s, and esrs (except gperb) transcripts in the midbrain/pituitary also were increased significantly. Forebrain gnrh1 transcripts increased slightly during gonadal differentiation of both sexes, but the gnrhr1b and gnrhr2 transcripts in the midbrain/pituitary were stable during gonadal differentiation. The expression levels of gths and gh in the midbrain/pituitary were significantly increased during testicular differentiation and were much higher in males than in E2-feminized females. These results implied that endogenous estrogens might play essential roles in the brain/pituitary during testicular differentiation, sf-1, foxl2s, and esrs may have roles in cyp19a1 regulation in the midbrain/pituitary of Japanese eels. For the GnRH-GTH axis, gths, especially fshb, may be regulated by esrs and involved in regulating testicular differentiation and development in Japanese eels.

Radiological characteristics and injury mechanism of Logsplitter injury: a descriptive and retrospective study.

BACKGROUND: Logsplitter Injury is a type of high-energy ankle fracture dislocation. The mechanism of injury has not been described in detail. A detailed understanding of the radiological features and pathological changes can further guide treatment. METHODS: Between April 2009 and December 2018, a retrospective analysis was conducted on 62 patients with Logsplitter injury. The study analysed the characteristics of fibular injury, tibial injury, syndesmosis injury, medial injury and lateral ligament injury on preoperative X-ray and CT scans. The incidence of the different injury types was summarised. The correlation between Logsplitter injuries and the mechanisms causing them were analysed using the Lauge-Hansen classification of ankle fractures. RESULTS: The study provides data on the types of fractures observed. Of the total fractures, 98.4% were open fractures. The fibula injuries were classified as no fracture (1.6%), transverse or short oblique fractures (61.3%), butterfly fragments (25.8%), and comminuted fractures (11.3%). The tibial injuries included compression of lateral articular surfaces (38.7%) and posterior compressions (6.5%). Medial injuries, including medial malleolar fractures, accounted for 87.1%, and deltoid ligament rupture accounted for 12.9%. The study found that injuries to the syndesmosis consisted of simple ligament ruptures (11.3%), Tillaux fractures (8.1%), Volkmann fractures (43.5%), and Tillaux and Volkmann fractures (37.1%). In 12.9% of cases, there was a complete rupture of the lateral collateral ligament. Based on the Lauge-Hansen classification, 87.1% of injuries were pronation-abduction injuries, while 8.1% were pronation and external rotation injuries, and 1.6% were supination external rotation injuries. Furthermore, 3.2% of cases could not be classified. CONCLUSION: The pathoanatomic characteristics of Logsplitter injury are diverse, with some cases accompanied by collateral ligament injury. It is important to note that these evaluations are objective and based on current results. The most common injury mechanism is vertical violence combined with abduction, although in some cases, it may be a vertical combined external-rotation injury. LEVEL OF EVIDENCE: (4) case series. TRIAL REGISTRATION: This study has been approved by the ethical research committee of the Honghui Hospital of Xi'an Jiaotong University, under the code: 202,003,002.

New labdane diterpenoids from Alpinia galanga: A new type of GLP-1 secretagogues targeting the PKA-CREB and PI3K-Akt signaling axes.

Glucagon-like peptide-1 (GLP-1) secretagogues are fascinating pharmacotherapies to overcome the defects of GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors in treating diabetes and obesity. To discover new GLP-1 secretagogues from natural sources, alpigalangols A-Q (1-17), 17 new labdane diterpenoids including four unusual nor-labdane and N-containing ones, were isolated from the fruits of Alpinia galanga. Most of the isolates showed GLP-1 promotive effects in NCl-H716 cells, of which compounds 3, 4, 12, and 14-17 were revealed with high promoting rates of 246.0%-413.8% at 50 µM. A mechanistic study manifested that the most effective compound 12 upregulated the mRNA expression of Gcg and Pcsk1, and the protein phosphorylation of PKA, CREB, and GSK3ß, but was inactive on GPBAR and GPR119 receptors. Network pharmacology analysis indicated that the PI3K-Akt pathway was involved in the GLP-1 stimulation of 12, which was highly associated with AKT1, CASP3, PPARG, and ICAM1 proteins. This study suggests that A. galanga is rich in diverse labdane diterpenoids with GLP-1 promoting effects, representing a new type of antidiabetic candidates from natural sources.

The Doping Effect on the Intrinsic Ferroelectricity in Hafnium Oxide-Based Nano-Ferroelectric Devices.

Hafnium oxide (HfO2)-based ferroelectric tunnel junctions (FTJs) have been extensively evaluated for high-speed and low-power memory applications. Herein, we investigated the influence of Al content in HfAlO thin films on the ferroelectric characteristics of HfAlO-based FTJs. Among HfAlO devices with different Hf/Al ratios (20:1, 34:1, and 50:1), the HfAlO device with Hf/Al ratio of 34:1 exhibited the highest remanent polarization and excellent memory characteristics and, thereby, the best ferroelectricity among the investigated devices. Furthermore, first-principal analyses verified that HfAlO thin films with Hf/Al ratio of 34:1 promoted the formation of the orthorhombic phase against the paraelectric phase as well as alumina impurities and, thus, enhanced the ferroelectricity of the device, providing theoretical support for supporting experimental results. The findings of this study provide insights for developing HfAlO-based FTJs for next-generation in-memory computing applications.

Quantum Phase Transition in Magnetic Nanographenes on a Lead Superconductor.

Quantum spins, also known as spin operators that preserve SU(2) symmetry, lack a specific orientation in space and are hypothesized to display unique interactions with superconductivity. However, spin-orbit coupling and crystal field typically cause a significant magnetic anisotropy in d/f shell spins on surfaces. Here, we fabricate atomically precise S = 1/2 magnetic nanographenes on Pb(111) through engineering sublattice imbalance in the graphene honeycomb lattice. Through tuning the magnetic exchange strength between the unpaired spin and Cooper pairs, a quantum phase transition from the singlet to the doublet state has been observed, consistent with the quantum spin models. From our calculations, the particle-hole asymmetry is induced by the Coulomb scattering potential and gives a transition point about kBTk ≈ 1.6Δ. Our work demonstrates that delocalized π electron magnetism hosts highly tunable magnetic bound states, which can be further developed to study the Majorana bound states and other rich quantum phases of low-dimensional quantum spins on superconductors.

Feasibility and Preliminary Efficacy of American Elderberry Juice for Improving Cognition and Inflammation in Patients with Mild Cognitive Impairment.

Despite data showing that nutritional interventions high in antioxidant/anti-inflammatory properties (anthocyanin-rich foods, such as blueberries/elderberries) may decrease risk of memory loss and cognitive decline, evidence for such effects in mild cognitive impairment (MCI) is limited. This study examined preliminary effects of American elderberry (Sambucus nigra subsp. canadensis) juice on cognition and inflammatory markers in patients with MCI. In a randomized, double-blind, placebo-controlled trial, patients with MCI (n = 24, Mage = 76.33 ± 6.95) received American elderberry (n = 11) or placebo (n = 13) juice (5 mL orally 3 times a day) for 6 months. At baseline, 3 months, and 6 months, patients completed tasks measuring global cognition, verbal memory, language, visuospatial cognitive flexibility/problem solving, and memory. A subsample (n = 12, 7 elderberry/5 placebo) provided blood samples to measure serum inflammatory markers. Multilevel models examined effects of the condition (elderberry/placebo), time (baseline/3 months/6 months), and condition by time interactions on cognition/inflammation outcomes. Attrition rates for elderberry (18%) and placebo (15%) conditions were fairly low. The dosage compliance (elderberry-97%; placebo-97%) and completion of cognitive (elderberry-88%; placebo-87%) and blood-based (elderberry-100%; placebo-100%) assessments was high. Elderberry (not placebo) trended (p = 0.09) towards faster visuospatial problem solving performance from baseline to 6 months. For the elderberry condition, there were significant or significantly trending decreases over time across several markers of low-grade peripheral inflammation, including vasorin, prenylcysteine oxidase 1, and complement Factor D. Only one inflammatory marker showed an increase over time (alpha-2-macroglobin). In contrast, for the placebo, several inflammatory marker levels increased across time (L-lactate dehydrogenase B chain, complement Factor D), with one showing deceased levels over time (L-lactate dehydrogenase A chain). Daily elderberry juice consumption in patients with MCI is feasible and well tolerated and may provide some benefit to visuospatial cognitive flexibility. Preliminary findings suggest elderberry juice may reduce low-grade inflammation compared to a placebo-control. These promising findings support the need for larger, more definitive prospective studies with longer follow-ups to better understand mechanisms of action and the clinical utility of elderberries for potentially mitigating cognitive decline.

Livestock turnover and dynamic livestock carrying capacity are crucial factors for alpine grassland management: The Qinghai-Tibetan plateau as a case study.

Alpine grasslands are distributed widely on high-elevated ranges and plateaus from the wet tropics to polar regions, accounting for approximately 3% of the world's land area. The Qinghai-Tibetan Plateau (QTP) is the highest and largest plateau in the world, and approximately 60% of the plateau consists of alpine grassland, which is used mainly for grazing animals. Livestock structure was determined in Guinan (GN), Yushu (YS) and Maqu counties (MQ) on the QTP by interviewing 235 local pastoralists. Based on data collected from GN, the livestock carrying capacity was calculated using herbage dry matter biomass intake (LCCm) by the livestock, and the metabolizable energy yield (LCCe) and digestible crude protein (LCCp) available in pasture. The pasture area per household differed among the regions of the QTP, which was the main reason for the difference in livestock stocking rate. The householders raised the appropriate proportion of breeding females and young yaks and sheep in GN and MQ, but not in YS, to maintain a constant turnover. Most pasture in YS was used at the community level, especially in summer. The calculated carrying capacities based on metabolizable energy yield (LCCe) of the pasture and dry matter biomass (LCCm) were similar in most months except for August, when the value of LCCe was higher than LCCm. Based on the digestible protein of the pasture, the calculated livestock carrying capacity overestimated the actual carrying capacity during the herbage growing season from May to September. Appropriate practices should be taken in different regions of QTP, such as providing supplementary feed, especially protein, during the forage non-growing season. Livestock carrying capacity should be adjusted dynamically, and calculated by a number of parameters. The stocking rate should be controlled to optimize livestock production and curb or minimize grassland degradation to generate a sustainable system. This study examined the grasslands and LCC on the QTP, but the results could be applied to grasslands worldwide.