Exploring the gut microbiome's role in colorectal cancer: diagnostic and prognostic implications.

The intricate interplay between the gut microbiome and colorectal cancer (CRC) presents novel avenues for early diagnosis and prognosis, crucial for improving patient outcomes. This comprehensive review synthesizes current findings on the gut microbiome's contribution to CRC pathogenesis, highlighting its potential as a biomarker for non-invasive CRC screening strategies. We explore the mechanisms through which the microbiome influences CRC, including its roles in inflammation, metabolism, and immune response modulation. Furthermore, we assess the viability of microbial signatures as predictive tools for CRC prognosis, offering insights into personalized treatment approaches. Our analysis underscores the necessity for advanced metagenomic studies to elucidate the complex microbiome-CRC nexus, aiming to refine diagnostic accuracy and prognostic assessment in clinical settings. This review propels forward the understanding of the microbiome's diagnostic and prognostic capabilities, paving the way for microbiome-based interventions in CRC management.

Molecular Dynamics Simulations Reveal How Competing Protein-Surface Interactions for Glycine, Citrate, and Water Modulate Stability in Antibody Fragment Formulations.

The design of stable formulations remains a major challenge for protein therapeutics, particularly the need to minimize aggregation. Experimental formulation screens are typically based on thermal transition midpoints (Tm), and forced degradation studies at elevated temperatures. Both approaches give limited predictions of long-term storage stability, particularly at low temperatures. Better understanding of the mechanisms of action for formulation of excipients and buffers could lead to improved strategies for formulation design. Here, we identified a complex impact of glycine concentration on the experimentally determined stability of an antibody Fab fragment and then used molecular dynamics simulations to reveal mechanisms that underpin these complex behaviors. Tm values increased monotonically with glycine concentration, but associated ΔSvh measurements revealed more complex changes in the native ensemble dynamics, which reached a maximum at 30 mg/mL. The aggregation kinetics at 65 °C were similar at 0 and 20 mg/mL glycine, but then significantly slower at 50 mg/mL. These complex behaviors indicated changes in the dominant stabilizing mechanisms as the glycine concentration was increased. MD revealed a complex balance of glycine self-interaction, and differentially preferred interactions of glycine with the Fab as it displaced hydration-shell water, and surface-bound water and citrate buffer molecules. As a result, glycine binding to the Fab surface had different effects at different concentrations, and led from preferential interactions at low concentrations to preferential exclusion at higher concentrations. During preferential interaction, glycine displaced water from the Fab hydration shell, and a small number of water and citrate molecules from the Fab surface, which reduced the protein dynamics as measured by root-mean-square fluctuation (RMSF) on the short time scales of MD. By contrast, the native ensemble dynamics increased according to ΔSvh, suggesting increased conformational changes on longer time scales. The aggregation kinetics did not change at low glycine concentrations, and so the opposing dynamics effects either canceled out or were not directly relevant to aggregation. During preferential exclusion at higher glycine concentrations, glycine could only bind to the Fab surface through the displacement of citrate buffer molecules already favorably bound on the Fab surface. Displacement of citrate increased the flexibility (RMSF) of the Fab, as glycine formed fewer bridging hydrogen bonds to the Fab surface. Overall, the slowing of aggregation kinetics coincided with reduced flexibility in the Fab ensemble at the very highest glycine concentrations, as determined by both RMSF and ΔSvh, and occurred at a point where glycine binding displaced neither water nor citrate. These final interactions with the Fab surface were driven by mass action and were the least favorable, leading to a macromolecular crowding effect under the regime of preferential exclusion that stabilized the dynamics of Fab.

Microbial and Transcriptomic Landscape Associated With Neutrophil Extracellular Traps in Perianal Fistulizing Crohn's Disease.

BACKGROUND: Perianal fistulizing Crohn's disease (pfCD) poses significant healing challenges, closely associated with neutrophil extracellular traps (NETs). This study aimed to investigate the microbe-host interactions influencing NETs in pfCD. METHODS: From January 2019 to July 2022, patients with pfCD were screened at Ren Ji Hospital. Patients in remission following comprehensive treatment were recruited. We documented clinical characteristics, medication regimens, healing outcomes, and infliximab levels in fistula tissues. NET positivity was confirmed by positive results in citrullinated histone H3 (CitH3) enzyme-linked immunosorbent assay (ELISA) and dual immunofluorescence staining for myeloperoxidase and CitH3. Microbial and transcriptomic profiles from fistula tissues, obtained during surgery, were analyzed using 16S rRNA gene sequencing and RNA sequencing. Differences in microbiome and transcriptomic profiles were evaluated, and their relationships were assessed using Mantel's and Spearman's coefficients. RESULTS: Significant differences in microbial communities were found between groups (P = .007). Representatively differential microbes such as Prevotella bivia, Streptococcus gordonii, and Bacteroides dorei were enriched in NETs-positive fistulas (P < .05). Functional analysis of microbes revealed reduced ubiquinol biosynthesis and butanoate production in NETs-negative fistulas (P < .05). Transcriptomic analysis indicated increased neutrophil and monocyte infiltration in NETs-positive fistulas, associated with pathways involving bacterial response, neutrophil chemotaxis, secretory processes, and peptidase activity (P < .05). Species prevalent in NETs-positive fistulas correlated positively with immune responses and wound healing pathways, whereas bacteria in NETs-negative fistulas correlated negatively. NETs were negatively associated with tissue infliximab levels (P = .001) and healing outcomes (P = .025). CONCLUSIONS: Our findings reveal unique microbial and transcriptomic signatures associated with NETs in pfCD, highlighting their profound influence on clinical outcomes.

Neutrophil extracellular traps (NETs) impair fistula healing in perianal fistulizing Crohn's disease (pfCD). Our integrated multi-omics analysis reveals specific microbial and transcriptomic profiles associated with NETs in pfCD. The findings could potentially guide microbiome-targeted therapies to improve healing in pfCD.

TLR2 reprograms glucose metabolism in CD4+ T cells of rheumatoid arthritis patients to mediate cell hyperactivation and TNF-α secretion.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which activated CD4+ T cells participate in the disease process by inducing inflammation. We aimed to investigate the role of Toll-like receptor 2 (TLR2) on CD4+ T cells in RA patients, and to elucidate the underlying mechanisms by which TLR2 contributes to the pathogenesis of RA. METHODS: Serum samples were collected from RA patients and healthy controls. Soluble TLR2 levels were quantified using an enzyme-linked immunosorbent assay (ELISA). Flow cytometry was employed to assess the TLR2 expression level, activation status, cytokine production, reactive oxygen species (ROS) levels, and glucose uptake capacity of CD4+ T cells. Quantitative polymerase chain reaction (qPCR) was used to measure the expression of enzymes associated with glucose and lipid metabolism. The concentration of lactic acid in the culture supernatant was determined using a dedicated detection kit. RESULTS: RA patients had higher levels of TLR2 in their serum, which positively correlated with C-reactive protein and rheumatoid factor. The expression level of TLR2 in CD4+ T cells of RA patients was increased, and TLR2+ cells showed higher activation levels than TLR2- cells. Activation of TLR2 in CD4+ T cells of RA patients promoted their activation, TNF-α secretion, and increased production of ROS. Furthermore, TLR2 activation led to changes in enzymes related to glucose metabolism, causing a shift in glucose metabolism towards the pentose phosphate pathway. Blocking oxidative phosphorylation and the pentose phosphate pathway had varying effects on CD4+ T cell function. CONCLUSION: TLR2 reprograms the glucose metabolism of CD4+ T cells in RA patients, contributing to the development of RA through ROS-mediated cell hyperactivation and TNF-α secretion. Key Points • TLR2 is upregulated in CD4+ T cells of RA patients and correlates with disease severity markers such as CRP and RF. • Activation of TLR2 in CD4+ T cells promotes cell activation, TNF-α secretion, and increased ROS production, contributing to the pathogenesis of RA. • TLR2 activates glucose metabolism in CD4+ T cells, shifting towards the pentose phosphate pathway, which may be a novel therapeutic target for RA treatment. • Blocking glucose metabolism and ROS production can reduce CD4 + T cell hyperactivation and TNF-α secretion, indicating potential therapeutic strategies for RA management.

Research Progress of Deep-Red to Near-Infrared Electroluminescent Materials Based on Organic Cyclometallated Platinum(II) Complexes.

In recent years, the near-infrared (NIR) light-emitting materials have attracted increasing attention due to the broad application prospects in the fields of military industry, aerospace, lighting, display and wearable devices. As the transition metal complexes, platinum(II) complexes have been shown to emit luminescence efficiently in NIR organic light-emitting diodes because of the unique d8 electron structure. This structure ensures that the platinum(II) complex molecules exhibit a high planarity, variety of excited states, and strong intermolecular interactions. This review summarizes the research progress of deep red to NIR organic light-emitting materials based on platinum(II) complexes in recent years and provides a certain reference for the further design and synthesis of NIR platinum(II) complex luminescent materials with superior performance.

Continuous Theta Burst Stimulation Inhibits Oxidative Stress-Induced Inflammation and Autophagy in Hippocampal Neurons by Activating Glutathione Synthesis Pathway, Improving Cognitive Impairment in Sleep-Deprived Mice.

Sleep deprivation (SD) has been reported to have a negative impact on cognitive function. Continuous theta burst stimulation (cTBS) shows certain effects in improving sleep and neurological diseases, and its molecular or cellular role in SD-induced cognition impairment still need further exploration. In this study, C57BL/6 mice were subjected to 48 h of SD and cTBS treatment, and cTBS treatment significantly improved SD-triggered impairment of spatial learning and memory abilities in mice. Additionally, cTBS reduced malondialdehyde levels, increased superoxide dismutase activities, and inhibited the production of inflammatory cytokines, alleviating oxidative stress and inflammation levels in hippocampal tissues of SD model mice. cTBS decreased LC3II/LC3I ratio, Beclin1 protein levels, and LC3B puncta intensity, and elevated p62 protein levels to suppress excessive autophagy in hippocampal tissues of SD-stimulated mice. Then, we proved that inhibiting oxidative stress alleviated inflammation, autophagy, and death of hippocampal neuron cells through an in vitro cellular model for oxidative stress, and cTBS treatment promoted the production of glutathione (GSH), the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the mRNA expression of GSH synthesis-related genes to enhance antioxidant capacity in hippocampal tissues of SD mice. An Nrf2 inhibitor ML385 or a GSH synthesis inhibitor BSO reversed the alleviating effects of cTBS treatment on oxidative stress-associated damage of hippocampal tissues and cognitive impairment in SD model mice. Altogether, our study demonstrated that cTBS mitigates oxidative stress-associated inflammation and autophagy through activating the Nrf2-mediated GSH synthesis pathway, improving cognitive impairment in SD mice.

Anteromedial cortical support reduction of intertrochanteric fractures-A review.

The intertrochanteric fracture is a common fragility fracture typically resulting from low-energy falls. The functional outcome of intertrochanteric fractures is closely linked to the patient's underlying physical condition, intraoperative procedures, and postoperative complications. In terms of surgery, while timely surgery and appropriate internal fixation have demonstrated favorable outcomes, attention to intraoperative reduction is crucial. In recent years, there have been further developments in the evaluation of reduction of intertrochanteric fractures, particularly in the anteromedial cortical reduction, and these advances have been further scientifically elucidated in terms of their ability to provide stable fracture reduction and resist loss of reduction. In order to gain a comprehensive understanding of the anteromedial cortex theory, this article reviewed the anatomy, related theoretical progress, and controversies in recent years.

Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery.

Secondary lymphedema (LE) following breast cancer-related surgery is a life-long complication, which currently has no cure. LE induces significant regional adipose tissue deposition, requiring liposuction as a treatment. Here, we aimed to elucidate the transcriptional, metabolomic, and lipidomic signature of the adipose tissue developed due to the surgery-induced LE in short- and long-term LE patients and compared the transcriptomic landscape of LE adipose tissue to the obesity-induced adipose tissue. Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n = 20 patients). To decipher the molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Differential gene expression data from a cohort of lean and obese patients without LE was used for comparisons. Integrative analysis of functional genomics revealed that inflammatory response, cell chemotaxis, and angiogenesis were upregulated biological processes in the LE arm, indicating a sustained inflammation in the edematous adipose tissue; whereas, epidermal differentiation, cell-cell junction organization, water homeostasis, and neurogenesis were downregulated in the LE arm. Surprisingly, only a few genes were found to be the same in the LE-induced and the obesity-induced adipose tissue expansion, indicating a different type of adipose tissue development in these two conditions. In metabolomics analysis, we found reduced levels of a branched-chain amino acid valine in the LE arm and downregulation of the mRNA levels of its transporter SLC6A15. Lipidomics analyses did not show any significant differences between the LE and non-LE arms, suggesting that other factors affect the lipid composition of the adipose tissue more than the LE in these patients. Our results provide a detailed molecular characterization of adipose tissue in secondary LE after breast cancer-related surgery. We also show distinct differences in transcriptomic signatures between LE-induced adipose tissue and obesity-induced adipose tissue, but only minor differences in metabolome and lipidome between the LE and the non-LE arm.

Ultrasonography-guided canal decompression combined with vertebroplasty and cement-augmented pedicle screw fixation for stage III Kümmell's disease with neurological deficits: a retrospective cohort study.

BACKGROUND: Percutaneous vertebroplasty or kyphoplasty is the preferred procedure for stage I and II Kümmell's diseases (KDs), but there exist controversies on the operative option of stage III KD. This study aimed at exploring the safety and efficacy of ultrasonography-guided canal decompression (UG-CD) combined with vertebroplasty and cement-augmented pedicle screw fixation (CA-PSF) for treating stage III KD with neurological deficit (ND). METHODS: Between September 2017 and December 2023, all patients who received the UG-CD combined with vertebroplasty and CA-PSF for managing stage III KD with NDs were reviewed retrospectively with their demographic and operation data, and complications recorded. Besides, the scores of Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI), together with imaging data including the kyphotic Cobb angle (KCA), wedge angle (WA), spinal canal area (SCA) at the narrowest level as well as anterior (AHR) and middle (MHR) height ratios were measured and compared between pre- and post-operation. RESULTS: A total of eleven patients with a mean age of 70.09 ± 2.98 years old were included in our study with their surgical time, hospitalization length, blood loss, and follow-up time being 150.91 ± 17.94 min, 202.09 ± 39.95 ml, 8.18 ± 1.17 days, and 16.91 ± 4.09 months, respectively. During the final follow-up, the KCA, WA, VAS scores, ODI scores, AHR, MHR, and SCA were significantly improved (P < 0.01). Intraoperatively, one case suffered a transient decrease in the motor evoked potential. Another case experienced a cerebrospinal fluid leakage postoperatively that was then successfully treated. CONCLUSION: UG-CD combined with vertebroplasty and CA-PSF could be a feasible procedure for safely and effectively handling stage III KD with NDs.

Highly stable scalable production of porous graphene-polydopamine nanocomposites for drug molecule sensing.

As atenolol overdosing can lead to severe health complications, the rapid detection of atenolol intake in point-of-care settings is highly desirable. The recent advancement of redox analytical methodologies has facilitated the efficacious quantification of these compounds for drug analysis, but their performance still presents challenges in practical applications. This study addresses these challenges by controlling the electropolymerization of polydopamine (PDA) on highly porous laser-induced graphene (LIG) electrodes with enhanced electrochemical redox activity for the detection of drug molecules such as atenolol, with minimized interference with the other active substances to induce variation of electrochemical behavior. The enhanced sensitivity of atenolol is attributed to the superhydrophilicity and increased number of active surface sites and -NH2 groups in the PDA polymer through a controlled polymerization process. Moreover, the simulation results further reveal that highly sensitive sensing of atenolol molecules relies on optimal adsorption of the atenolol molecule on dopamine or dopaminequinone structural units. The resulting sensors with high repeatability and reproducibility can achieve a low detection limit of 80 µM and a sensitivity of 0.020 ± 0.04 µA/µM within a linear range from 100 to 800 µM. The materials and surface chemistry in the electrode design based on highly porous LIG provide insights into the integration and application of future scalable and cost-effective electrochemical sensors for use in point-of-care or in-field applications.

Nicotinamide enhances Treg differentiation by promoting Foxp3 acetylation in immune thrombocytopenia.

Imbalanced nicotinamide adenine dinucleotide (NAD+) homeostasis has been reported in multiple autoimmune diseases and supplementation with NAD+ precursors has consistently demonstrated positive therapeutic benefits for these conditions. Immune thrombocytopenia (ITP) is an acquired autoimmune disease, in which the decreased number and impaired function of regulatory T cells (Tregs) contribute to the main pathogenesis. Here we found NAD+ level was decreased in the plasma and CD4+ T cells of ITP patients. Supplementation with NAD+ precursor nicotinamide (NAM), but not nicotinamide mononucleotide (NMN), increased Treg frequency and ameliorated thrombocytopenia in an ITP murine model. Moreover, whilst both NAM and NMN restored cytosolic NAD+ level in the CD4+ T cells from ITP patients, only NAM promoted Treg differentiation. Mechanistically, Sirtuin1 (Sirt1), a major consumer of NAD+, was highly expressed in the CD4+ T cells of ITP patients, potentially contributing to the low level of NAD+. NAM, which could act as Sirt1 inhibitor, promoted Foxp3 acetylation and stability in induced Tregs derived from naïve CD4+ T cells of ITP patients. These findings suggest that NAM holds promise as a novel therapeutic strategy for restoring immune balance in ITP.

Effects of Thyroid Hormones on Cellular Development in Human Ovarian Granulosa Tumor Cells (KGN).

Ovarian cancer is a common malignant tumor in the female reproductive system, and Granulosa cell tumor (GCT) of the ovary is a rare type of ovarian cancer, which significantly threatens women's reproductive health. It has been reported that dysregulation of thyroid hormones (THs) may be closely related to the progression and prognosis of ovarian cancer. Moreover, THs regulate phosphorylation of signal transducer and activator of transcription (STAT3) and Octamer-binding transcription factor 4 (OCT4) expression. It has been reported that STAT3 and OCT4 play important roles in cellular development and tumorigenesis. However, the mechanisms by which THs affect the development of GCT are still remained unclear. To evaluate the effect of THs on human ovarian granulosa tumor cells (KGN), cells were treated with 3,5,3' -triiodothyronine (T3). Oct4 small interfering (Oct4 siRNA) or STAT3 inhibitor C188-9 was also co-cultured with cells in some experiments, respectively. The cell viability, proliferation, and proteins content were detected by CCK-8, EdU, and Western Blotting, respectively. The results showed that T3 enhanced cell viability and proliferation. Moreover, T3 also increased the expression of thyroid hormone receptor (TR), p-STAT3, and OCT4 proteins. The effects of T3 on both p-STAT3 and OCT4 expression were blocked by TR antagonist 1-850. Meanwhile, C188-9, an inhibitor of STAT3, decreased T3-induced cellular viability, proliferation, and OCT4 expression, highlighting that p-STAT3 can regulate the expression of OCT4 and affect cellular viability, and proliferation. Furthermore, T3-induced cellular growth was reduced by Oct4 siRNA, which indicates that T3 regulates cellular development through OCT4. These findings suggest that T3 increases cellular development via OCT4, which is mediated by phosphorylation of STAT3, and TR is also involved in these processes.

Responsive Magnetic Particle Imaging Tracer: Overcoming "Always-On" Limitation, Eliminating Interference, and Ensuring Safety in Adaptive Therapy.

Magnetic particle imaging (MPI) has emerged as a novel technology utilizing superparamagnetic nanoparticles as tracers, essential for disease diagnosis and treatment guidance in preclinical animal models. Unlike other modalities, MPI provides high sensitivity, deep tissue penetration, and no signal attenuation. However, existing MPI tracers suffer from "always-on" signals, which complicate organ-specific imaging and hinder accuracy. To overcome these challenges, we have developed a responsive MPI tracer using pH-responsive PdFe alloy particles coated with a gatekeeper polymer. This tracer exhibits pH-sensitive Fe release and modulation of the MPI signal, enabling selective imaging with a higher signal-to-noise ratio and intratumoral pH quantification. Notably, this responsive tracer facilitates subtraction-enhanced MPI imaging, effectively eliminating interference from liver uptake and expanding the scope of abdominal imaging. Additionally, the tracer employs a dual-function mechanism for adaptive cancer therapy, combining pH-switchable enzyme-like catalysis with dual-key co-activation of ROS generation, and Pd skeleton that scavenges free radicals to minimize Fe-related toxicity. This advancement promises to significantly expand MPI's applicability in diagnostics and therapeutic monitoring, marking a leap forward in imaging technology.

The Association Between Inflammatory Dietary Pattern and Risk of Cognitive Impairment Among Older Adults with Chronic Diseases and Its Multimorbidity: A Cross-Sectional Study.

Background: The present study aimed to explore the association between the inflammatory potential of diet, assessed by energy-adjusted dietary inflammatory index (E-DII) and reduced rank regression (RRR)-derived inflammatory dietary pattern, and the risk for cognitive impairment (CI) in community-dwelling older adults, especially in older adults with chronic diseases and multimorbidity. Methods: A total of 549 older adults from Taiyuan city were included in the present cross-sectional study. The Chinese Version of the Mini-Mental State Examination (CMMSE) was used for the evaluation of cognitive function. E-DII score was calculated based on semi-quantitative food frequency questionnaire (FFQ). Blood samples, including interleukin (IL)-1ß, interleukin (IL)-18, tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP), were tested for calculating RRR-derived inflammatory dietary pattern. Logistic regression was used to assess the association between inflammatory dietary pattern and risk of CI. In addition, patients with diabetes, hypertension, hyperlipidemia and multimorbidity were screened for further analysis among 549 older adults. Results: In those 549 older adults, adjusting for demographic characteristics and chronic disease status, there was no association between E-DII score tertile (OR T3VST1 : 1.357, 95%CI:0.813~2.265, P trend = 0.267), RRR-derived inflammatory dietary pattern score tertile (OR T3VST1 : 1.092, 95%CI:0.679~ 1.758, P trend = 0.737) and risk of CI. However, in older adults with diabetes and multimorbidity, the score tertile of E-DII and RRR-derived inflammatory dietary pattern were positively correlated with risk of CI in a dose-responsive manner (All P trend < 0.05). There is insufficient evidence to reach similar conclusion in patients with hypertension and hyperlipidemia (All P trend > 0.05). Conclusion: In the present study, pro-inflammatory diet contributed to the increased risk of CI in older adults with diabetes and multimorbidity. These results supplemented vital evidence for the prevention and treatment of CI in older adults with chronic diseases.

Antigen-independent activation is critical for the durable antitumor effect of GUCY2C-targeted CAR-T cells.

BACKGROUND: Chimeric antigen receptor (CAR)-T cells face many obstacles in solid tumor therapy, including heterogeneous antigen expression and inefficient T cell persistence. Guanylyl cyclase C (GUCY2C) has been identified as a suitable tumor antigen for targeted therapy due to its intestinal-restricted expression pattern in normal tissues and steady overexpression in gastrointestinal tumors, especially colorectal cancer. An antigen-sensitive and long-lasting CAR-T cell targeting GUCY2C was investigated in this study. METHODS: Using constructed tumor cell lines with various GUCY2C expression densities, we screened out an antigen-sensitive single chain variable fragment (scFv) that enabled CAR-T cells to efficiently eradicate the GUCY2C lowly expressed tumor cells. CAR-T cells with different compositions of the hinge, transmembrane and costimulatory domains were also constructed for selection of the long-lasting CAR-T format with durable antitumor efficacy in vitro and in tumor-bearing mice. The underlying mechanism was further investigated based on mutation of the hinge and transmembrane domains. RESULTS: We found that the composition of the antigen-sensitive scFv, CD8α hinge, CD8α transmembrane, and CD28 costimulatory domains boosted CAR-T cells to rapidly kill tumors, maintain high expansion capacity, and long-term efficacy in various colorectal cancer models. The durable antitumor function was attributed to the optimal CAR tonic signaling that conferred CAR-T cells with autonomous activation, proliferation, survival and cytokine release in the absence of antigen stimulation. The tonic signaling was associated with the length and the cysteine residues in the CD8α hinge and transmembrane domains. CONCLUSIONS: This study demonstrated a potent GUCY2C-targeted CAR-T cell for gastrointestinal tumor therapy and highlights the importance of adequate tonic signaling for effective CAR-T cell therapy against solid tumors.

Central NUCB2/nesfatin-1 signaling ameliorates liver steatosis through suppression of endoplasmic reticulum stress in the hypothalamus.

BACKGROUND & AIMS: Nucleobindin-2 (NUCB2)/nesfatin-1, a signal with recognized anorexigenic and insulin-sensitizing properties in peripheral tissues, is expressed within the hypothalamus. However, the potential involvement of central nesfatin-1 signaling in the pathophysiology of hepatic steatosis remains unknown. This study aimed to determine whether and how central NUCB2/nesfatin-1 plays a role in liver steatosis. METHODS: We generated Nucb2 knockout (Nucb2-/-) rats and administered continuous intracerebroventricular (ICV) nesfatin-1 infusion, while observing its effect on liver steatosis. The molecular mechanism of action of nesfatin-1 was elucidated via proteomics, phosphoproteomics and molecular biology methods. RESULTS: Herein, we present compelling evidence indicating diminished NUCB2 expression in the hypothalamus of obese rodents. We demonstrated that chronic ICV infusion of nesfatin-1 mitigated both diet-induced obesity and liver steatosis in high-fat diet (HFD)-fed Nucb2-/- rats by regulating hypothalamic endoplasmic reticulum (ER) stress and Akt phosphorylation. Furthermore, we revealed that the increase in hypothalamic insulin resistance (IR) and ER stress induced by tunicamycin infusion or Ero1α overexpression exacerbated hepatic steatosis and offset the favorable influence of central nesfatin-1 on hepatic steatosis. The metabolic action of central nesfatin-1 is contingent upon vagal nerve transmission to the liver. Mechanistically, nesfatin-1 impedes ER stress and interacts with Ero1α to repress its Ser106 phosphorylation. This leads to the enhancement of Akt activity in the hypothalamus, culminating in the inhibition of hepatic lipogenesis. CONCLUSIONS: These findings underscore the importance of hypothalamic NUCB2/nesfatin-1 as a key mediator in the top-down neural mechanism that combats diet-induced liver steatosis.

Comparative analysis of reproductive hormones, serum biochemical indexes and ovarian metabolites in Muscovy breeder duck at different laying stages.

The hypothalamic-pituitary-gonadal (HPG) axis regulates egg laying through control hormones secretion in poultry. In this study, the serum hormones (12 samples per stage), serum biochemical indexes (12 samples per stage), and ovarian metabolites (8 samples per stage) of Muscovy breeder ducks were detected at prelaying stage (PT), start of laying stage (ST), high laying stage (HT), and the end of laying stage (ET). The serum hormones of Muscovy ducks were measured at 8:00, 13:00, 18:00, 23:00, and 4:00 within 1 d. The TG, TP, ALB, and GLB were significantly increased, while HDL-C was significantly decreased at ST as compared to PT (P < 0.05). Serum Na, Cl, Ca, P, and K showed significant rise at ST as compared to PT. Serum Na, Cl, Ca, and K were significantly declined, while P was significantly increased at ET as compared to HT (P < 0.05). Serum FSH, LH, PRL, E2, P4 levels peaked at ST (P < 0.05) with only FSH and LH fluctuated significantly within 1 ovulation cycle at ST (P < 0.05). Differential metabolites showed continued ovarian aging. The decline of nucleic acid metabolism occured in ST, the decline of sugar metabolism occurred in ET, and the decline of amino acid metabolism continued at all stages. Temporal expression patterns and correlation analyses indicated a high correlation between ovarian cAMP and serum reproductive hormone levels across different reproductive stages. In conclusion, this study revealed the changes in serum hormones, serum biochemical indicators, and ovarian metabolites, as well as the relationship between serum hormones and ovarian metabolites.

Protective effect of fructooligosaccharide against oxidative stress and apoptosis induced by Aeromonas hydrophila in Megalobrama amblycephala.

This research aimed to investigate the effects of dietary fructooligosaccharides (FOS) on attenuating the Aeromonas hydrophila (A. hydrophila)-induced oxidative stress and apoptosis in blunt snout bream Megalobrama amblycephala. Fish were divided into three groups as follows: C1 (Control), T1 (A. hydrophila), and T2 (A. hydrophila + 4 g/kg FOS). The results showed that the activities of antioxidant enzymes increased, the liver morphology had disorderly arrangement, and extensive cell necrosis occurred because of A. hydrophila-infection. While the dietary FOS improved the above-mentioned liver damage. Additionaly, FOS elevated mRNA levels of pro-apoptotic molecules, including caspase-8 and 9, and down-regulated mRNA levels of the anti-apoptotic molecule Bcl-2, which is triggered by A. hydrophila-infection. The transcriptome analysis showed that the oxidative stress-related DEGs pathways were activated in intestine of blunt snout bream by A. hydrophila-infection. The FOS-added group led to the enrichment of more pathways to health. Further WGCNA co-expression network analysis showed that the screened single genes were clustered into 49 modules. The two modules with the highest association to the five traits (10 hub genes) were chosen to build the network by combining the physiological and biochemical characteristic. In summary, this research offers a foundation for the exploring of A. hydrophila-restoration genes in dietary FOS, and also lays a theoretical foundation for aquaculture in the future.

Impact of mini-dose dexmedetomidine supplemented analgesia on sleep structure in patients at high risk of obstructive sleep apnea: a pilot trial.

Background: Obstructive sleep apnea (OSA) is common in surgical patients and associated with worse perioperative outcomes. Objectives: To investigate the effect of mini-dose dexmedetomidine supplemented analgesia on postoperative sleep quality pattern in patients at high risk of OSA. Design: A pilot randomized, double-blind, placebo-controlled trial. Setting: A tertiary university hospital in Beijing, China. Patients: One hundred and fifty-two adult patients who had a STOP-Bang score ≥3 and a serum bicarbonate level ≥28 mmol/L and were scheduled for major noncardiac surgery between 29 January 2021 and 20 September 2022. Intervention: After surgery, patients were provided with high-flow nasal cannula and randomized in a 1:1 ratio to receive self-controlled opioid analgesia supplemented with either mini-dose dexmedetomidine (median 0.02 µg/kg/h) or placebo. We monitored polysomnogram from 9:00 pm to 6:00 am during the first night. Main outcome measures: Our primary outcome was the percentage of stage 2 non-rapid eye movement (N2) sleep. Secondary and exploratory outcomes included other postoperative sleep structure parameters, sleep-respiratory parameters, and subjective sleep quality (Richards-Campbell Sleep Questionnaire; 0-100 score range, higher score better). Results: All 152 patients were included in intention-to-treat analysis; 123 patients were included in sleep structure analysis. Mini-dose dexmedetomidine supplemented analgesia increased the percentage of stage N2 sleep (median difference, 10%; 95% CI, 1 to 21%; p = 0.029); it also decreased the percentage of stage N1 sleep (median difference, -10%; 95% CI, -20% to -1%; p = 0.042). Other sleep structure and sleep-respiratory parameters did not differ significantly between the two groups. Subjective sleep quality was slightly improved with dexmedetomidine on the night of surgery, but not statistically significant (median difference, 6; 95% CI, 0 to 13; p = 0.060). Adverse events were similar between groups. Conclusion: Among patients at high risk of OSA who underwent noncardiac surgery, mini-dose dexmedetomidine supplemented analgesia may improve sleep quality without increasing adverse events. Clinical trial registration: Clinicaltrials.gov, identifier NCT04608331.

Multifunctional Nanocomposite Polymer-integrated Ca-doped CeO2 Electrolyte for Robust and High-rate All-solid-state Sodium-ion Batteries.

Due to the seamless interfaces between solid polymer electrolytes (SPEs) and electrode materials, SPEs-based all-solid-state sodium-ion batteries (ASSSIBs) are considered promising energy storage systems. However, the sluggish Na+ transport and uncontrollable Na dendrite propagation still hinder the practical application of SPEs-based ASSSIBs. Herein, Ca-doped CeO2 (Ca-CeO2) nanotube framework is synthesized and integrated with poly (ethylene oxide) methyl ether acrylate-perfluoropolyether copolymer (PEOA-PFPE), resulting in multifunctional solid nanocomposite electrolytes (namely SNEs, i.e., PEOA-PFPE/Ca-CeO2). Our investigations demonstrate that the fluorous effect incurred by the fluorine-containing PEOA-PFPE and the oxygen vacancy effect induced by the Ca-CeO2 framework could synergistically promote the dissociation of sodium salt, ultimately enhancing the Na+ mobility in SNEs. Besides, the resultant SNEs construct rapid Na+ transport channels and homogenize the Na deposition in SNEs/Na interface, which effectively prevents the Na dendrite growth. Furthermore, the assembled carbon-coated sodium vanadium phosphate (NVP@C)||PEOA-PFPE/Ca-CeO2||Na coin cell delivers impressive rate capability of 97.9 mA h g-1 at 2 C and outstanding cycling stability with capacity retention of 84.3% after 300 cycles at 1 C. This work illustrates that constructing multifunctional SNEs via incorporating functional inorganic frameworks into fluorine-containing SPEs could be a promising strategy for the commercialization of robust and high-performance ASSSIBs.