Association of vitamin D deficiency and subclinical diabetic peripheral neuropathy in type 2 diabetes patients.

Background: Diabetic peripheral neuropathy (DPN) contributes to disability and imposes heavy burdens, while subclinical DPN is lack of attention so far. We aimed to investigate the relationship between vitamin D and distinct subtypes of subclinical DPN in type 2 diabetes (T2DM) patients. Methods: This cross-sectional study included 3629 T2DM inpatients who undertook nerve conduction study to detect subclinical DPN in Zhongshan Hospital between March 2012 and December 2019. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25(OH)D) level < 50 nmol/L. Results: 1620 (44.6%) patients had subclinical DPN and they were further divided into subgroups: distal symmetric polyneuropathy (DSPN) (n=685), mononeuropathy (n=679) and radiculopathy (n=256). Compared with non-DPN, DPN group had significantly lower level of 25(OH)D (P < 0.05). In DPN subtypes, only DSPN patients had significantly lower levels of 25(OH)D (36.18 ± 19.47 vs. 41.03 ± 18.47 nmol/L, P < 0.001) and higher proportion of vitamin D deficiency (78.54% vs. 72.18%, P < 0.001) than non-DPN. Vitamin D deficiency was associated with the increased prevalence of subclinical DPN [odds ratio (OR) 1.276, 95% confidence interval (CI) 1.086-1.501, P = 0.003] and DSPN [OR 1. 646, 95% CI 1.31-2.078, P < 0.001], independent of sex, age, weight, blood pressure, glycosylated hemoglobin, T2DM duration, calcium, phosphorus, parathyroid hormone, lipids and renal function. The association between vitamin D deficiency and mononeuropathy or radiculopathy was not statistically significant. A negative linear association was observed between 25(OH)D and subclinical DSPN. Vitamin D deficiency maintained its significant association with subclinical DSPN in all age groups. Conclusions: Vitamin D deficiency was independently associated with subclinical DSPN, rather than other DPN subtypes.

Exploring the role of ubiquitin regulatory X domain family proteins in cancers: bioinformatics insights, mechanisms, and implications for therapy.

UBXD family (UBXDF), a group of proteins containing ubiquitin regulatory X (UBX) domains, play a crucial role in the imbalance of proliferation and apoptotic in cancer. In this study, we summarised bioinformatics proof on multi-omics databases and literature on UBXDF's effects on cancer. Bioinformatics analysis revealed that Fas-associated factor 1 (FAF1) has the largest number of gene alterations in the UBXD family and has been linked to survival and cancer progression in many cancers. UBXDF may affect tumour microenvironment (TME) and drugtherapy and should be investigated in the future. We also summarised the experimental evidence of the mechanism of UBXDF in cancer, both in vitro and in vivo, as well as its application in clinical and targeted drugs. We compared bioinformatics and literature to provide a multi-omics insight into UBXDF in cancers, review proof and mechanism of UBXDF effects on cancers, and prospect future research directions in-depth. We hope that this paper will be helpful for direct cancer-related UBXDF studies.

A Novel Method to Improve the Accuracy and Stability of the 3D Guide Template Technique Applied in Upper Cervical Spine Surgery.

AIM: To evaluate the safety and accuracy of C1 and C2 pedicle screw placement using a three-dimensional (3D)-printed double template and compare them with those of the conventional method in a clinical study. MATERIAL AND METHODS: DICOM format data from 60 cases with C1-C2 instability were obtained after computed tomography (CT) was performed. A total of 32 cases underwent surgery via the free-hand technique, whereas 28 cases underwent surgery via a 3D-printed "pointing-drilling" guide template. The ideal trajectory of the C1 and C2 pedicle screws was designed using a baseplate as a separate complementary template for the corresponding posterior C1-C2 anatomical surface, after which the "pointingdrilling" guide template was materialized using a 3D printing machine. The 3D-printed "pointing-drilling" guide template, which was sterilized with low-temperature plasma, was used to locate the starting point and determine the drill trajectory during surgery. The positions of the screws in the axial and sagittal planes of the CT scan were observed and categorized into four grades, after which the operative time, fluoroscopy time, and intraoperative bleeding in the two groups were compared. RESULTS: No significant difference (p > 0.05) in each screw classification grade was observed between the free-hand and "pointingdrilling" template groups; however, a significant difference was observed (p=0.048) between these two groups. A significant difference (p < 0.05) in fluoroscopy times was observed between the free-hand and "pointing-drilling" template groups. Conversely, no significant differences were observed in bleeding (p=0.491) and operative time (p=0.309) between the free-hand and "pointingdrilling" template groups. CONCLUSION: The 3D-printed "pointing-drilling" guide template technique promoted more secure C1 and C2 pedicle screw placement compared with the free-hand technique in clinics.

TMEM216 promotes primary ciliogenesis and Hedgehog signaling through the SUFU-GLI2/GLI3 axis.

Primary cilia are enriched in signaling receptors, and defects in their formation or function can induce conditions such as polycystic kidney disease, postaxial hexadactyly, and microphthalmia. Mammalian Hedgehog (Hh) signaling is important in the development of primary cilia, and TMEM216, a transmembrane protein that localizes to the base of cilia, is also implicated in ciliogenesis in zebrafish. Here, we found that Tmem216-deficient mice had impaired Hh signaling and displayed typical ciliopathic phenotypes. These phenomena were also observed in cells deficient in TMEM216. Furthermore, TMEM216 interacted with core Hh signaling proteins, including SUFU, a negative regulator of Hh, and GLI2/GLI3, transcription factors downstream of Hh. The competition between TMEM216 and SUFU for binding to GLI2/GLI3 inhibited the cleavage of GLI2/GLI3 into their repressor forms, which resulted in the nuclear accumulation of full-length GLI2 and the decreased nuclear localization of cleaved GLI3, ultimately leading to the activation of Hh signaling. Together, these data suggest that the TMEM216-SUFU-GLI2/GLI3 axis plays a role in TMEM216 deficiency-induced ciliopathies and Hh signaling abnormalities.

Intraoperative radiotherapy in recurrent IDH-wildtype glioblastoma with gross total resection: A single-center retrospective study.

BACKGROUND: Isocitrate dehydrogenase-wildtype (IDHwt) glioblastoma (GBM) is one of the most aggressive primary brain tumors. The recurrence of GBM is almost inevitable. As an adjuvant option to surgery, intraoperative radiotherapy (IORT) is gaining increasing attention in the treatment of glioma. This study is aimed to evaluate the therapeutic efficacy of IORT on recurrent IDHwt GBM. METHODS: In total, 34 recurrent IDHwt GBM patients who received a second surgery were included in the analysis (17 in the surgery group and 17 in the surgery + IORT group). RESULTS: The progression-free survival and overall survival after the second surgery were defined as PFS2 and OS2, respectively. The median PFS2 was 7.3 months (95% CI: 6.3-10.5) and 10.6 months (95% CI: 9.3-14.6) for those patients who received surgery and surgery + IORT, respectively. Patients in the surgery + IORT group also had a longer OS2 (12.8 months, 95% CI: 11.4-17.2) than those in the surgery group (9.3 months, 95% CI: 8.9-12.9). The Kaplan-Meier survival curves, analyzed by log-rank test, revealed a statistically significant difference in PFS2 and OS2 between both groups, suggesting that IORT plays an active role in the observed benefits for PFS2 and OS2. The effects of IORT on PFS2 and OS2 were further confirmed by multivariate Cox hazards regression analysis. Two patients in the surgery group developed distant glioma metastases, and no radiation-related complications were observed in the IORT group. CONCLUSIONS: This study suggests that low-dose IORT may improve the prognosis of recurrent IDHwt GBM patients. Future prospective large-scale studies are needed to validate the efficacy and safety of IORT.

Experimental study on particle movement and erosion behavior of the elbow in liquid-solid flow.

Recent investigations into the erosion of elbow junctions predominantly focus on identifying and predicting peak erosion points. Notably, these studies rely heavily on computational fluid dynamics methods, a valid approach but limited by its lack of empirical physical data. Additionally, the majority of these studies concentrate on the extrados, or outer curve of the elbow, neglecting the intrados or the inner curve. To provide a more comprehensive understanding of particle movements and the micro-mechanics of erosion on the elbow intrados, this study utilizes advanced observational technologies. High-speed camera technology, coupled with scanning electron microscopy, is employed to capture and record particle motion and micro-erosion patterns. The erosion rate is then estimated via the weight-loss method. The findings suggest that in low-speed liquid-solid flows (2.5 m/s), particles released from the intrados side of the elbow inlet exhibit a significant trajectory deviation from the centreline at an elbow angle of 60° from the inlet. Particles released from the extrados deviate towards the intrados side at an elbow angle of 30°. Secondary flow contributes to particle acceleration, unexpected trajectory deviation within the elbow, and an upward inclination in erosion on the intrados. The presence of partially overlapping scratches and cracks suggests that continuous ploughing and material fracturing are significant contributors to the micro-mechanics of erosion. When comparing the intrados and extrados, the extrados exhibits longer and shallower scratches, indicating a smaller impact angle. This research provides a more comprehensive understanding of particle trajectories and erosion patterns within elbow junctions during liquid-solid flows, offering new insights into the mechanisms underpinning these processes.

Caffeic acid modulates activation of neutrophils and attenuates sepsis-induced organ injury by inhibiting 5-LOX/LTB4 pathway.

BACKGROUND: Sepsis is a critical systemic inflammatory syndrome which usually leads to multiple organ dysfunction. Caffeic acid (CA), a phenolic compound derived from various plants, has been proved to be essential in neuroprotection, but its role in septic organ damage is unclear. This research aimed to investigate whether CA protects against organ injury in a mouse model of cecal ligation and puncture (CLP). METHODS: CA (30 mg/kg) or vehicle was administered by intraperitoneal injection immediately after CLP. The samples of blood, lungs, and livers were collected 24 h later. Organ injury was assessed by histopathological examination (HE staining), neutrophil infiltration (myeloperoxidase fluorescence), oxidative stress levels (MDA, SOD, HO-1), and inflammatory cytokines (TNF-α, IL-1ß, and IL-6) release in lung and liver tissues. Neutrophil extracellular trap (NET) formation was analyzed by immunofluorescence. In vitro experiments were performed to investigate the potential mechanisms of CA using small interfering RNA (siRNA) techniques in neutrophils, and the effect of CA on neutrophil apoptosis was analyzed by flow cytometry. RESULTS: Results showed that CA treatment improved the 7-day survival rate and attenuated the histopathological injury in the lung and liver of CLP mice. CA significantly reduced neutrophil infiltration in the lungs and livers of CLP mice. TNF-α, IL-1ß, IL-6 and LTB4 were reduced in serum, lung, and liver of CA-treated CLP mice, and phosphorylation of MAPK (p38, ERK, JNK) and p65 NF-κB was inhibited in lungs and livers. CA treatment further increased HO-1 levels and enhanced superoxide dismutase (SOD) activity, but reduced malondialdehyde (MDA) levels and NET formation. Similarly, in vitro experiments showed that CA treatment and 5-LOX siRNA interference inhibited inflammatory activation and NET release in neutrophils, suppressed MAPK and NF-κB phosphorylation in LPS-treated neutrophils, and decreased LTB4 and cfDNA levels. Flow cytometric analysis revealed that CA treatment reversed LPS-mediated delayed apoptosis in human neutrophils, and Western blot also indicated that CA treatment inhibited Bcl-2 expression but increased Bax expression. CA treatment did not induce further changes in neutrophil apoptosis, inflammatory activation, and NET release when 5-LOX was knocked down by siRNA interference. CONCLUSIONS: CA has a protective effect on lung and liver injury in a murine model of sepsis, which may be related to inhibition of the 5-LOX/LTB4 pathway.

Crotonylated BEX2 interacts with NDP52 and enhances mitophagy to modulate chemotherapeutic agent-induced apoptosis in non-small-cell lung cancer cells.

Brain expressed X-linked gene 2 (BEX2) encoded protein was originally identified to promote transcription by interacting with several transcription factors in the DNA-binding complexes. Recently, BEX2 was found to be localized in cytosol and/or mitochondria and regulate apoptosis in cancer cells and tumor growth. However, the molecular mechanism underlying its roles in cancer cells remains unclear. Here, we report that crotonylated BEX2 plays an important role in inhibiting chemotherapeutic agent-induced apoptosis via enhancing mitophagy in human lung cancer cells. BEX2 promotes mitophagy by facilitating interaction between NDP52 and LC3B. Moreover, BEX2 crotonylation at K59 is critical in the BEX2-mediated mitophagy in lung cancer cells. The K59R mutation of BEX2 inhibits mitophagy by affecting the interaction of NDP52 and LC3B. BEX2 expression is elevated after anticancer drug treatment, and its overexpression inhibits chemotherapy-induced apoptosis. In addition, inhibition of BEX2-regulated mitophagy sensitizes tumor cells to apoptosis. Furthermore, BEX2 promotes tumor growth and inhibits apoptosis by regulating mitophagy in vivo. We also confirm that BEX2 is overexpressed in lung adenocarcinoma and is associated with poor prognosis in lymph node metastasis-free cancer. Therefore, combination treatment with pharmaceutical approaches targeting BEX2-induced mitophagy and anticancer drugs may represent a potential strategy for NSCLC therapy.

Correlationship between self-assembly behavior and emulsion stabilization of pea protein-high methoxyl pectin complexes treated with ultrasound at pH 2.0.

This study investigated the effects of ultrasound on the self-assembly behavior of pea protein (PP)-high methoxyl pectin (HMP) complexes at pH 2.0 through transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and intrinsic fluorescence analysis. The emulsion stabilization mechanism of PP-HMP treated with ultrasound (PP-HMP-US) was also elucidated. The results indicated that ultrasound increased the emulsifying activity index (EAI) and emulsifying stability index (ESI) of PP-HMP. Moreover, PP-HMP-US-based emulsions formed small, dispersed oil drops, which were stable during storage. PP-HMP- and PP-HMP-US-based emulsions did not demonstrate any creaming. The TEM results revealed that ultrasound can regulate the self-assembly behavior of PP and HMP to form spherical particles with a core-shell structure. This structure possessed low turbidity, a small particle size, and high absolute zeta potential values. The FTIR and intrinsic fluorescence spectra demonstrated that ultrasound increased the α-helix and ß-sheet contents and exposed the tryptophan groups to more hydrophilic environments. Ultrasound also promoted the PP-HMP self-assembly through electrostatic interaction and improved its oil-water interfacial behavior, as indicated by the EAI and ESI values of PP-HMP-US-based emulsions. The current results provide a reference for the development of an innovative emulsifier prepared by ultrasound-treated protein-pectin complexes at low pH.

The Emerging Roles of circRNAs in Papillary Thyroid Carcinoma: Molecular Mechanisms and Biomarker Potential.

Papillary thyroid carcinoma (PTC) is a common endocrine malignant tumor. The incidence of PTC has increased in the past decades and presents a younger trend. Accumulating evidence indicates that circular RNAs (circRNAs), featured with non-linear, closed-loop structures, play pivotal roles in tumorigenesis and regulate cell biological processes, such as proliferation, migration, and invasion, by acting as microRNA (miRNA) sponges. Additionally, due to their unique stability, circRNAs hold promising potential as diagnostic biomarkers and effective therapeutic targets for PTC treatment. In this review, we systematically arrange the expression level of circRNAs, related clinical characteristics, circRNA-miRNA-mRNA regulatory network, and molecular mechanisms. Furthermore, related signaling pathways and their potential ability of diagnostic biomarkers and therapeutic targets are discussed, which might provide a new strategy for PTC diagnosis, monitoring, and prognosis.

Interaction mechanisms of peanut protein isolate and high methoxyl pectin with ultrasound treatment: The effect of ultrasound parameters, biopolymer ratio, and pH.

Ultrasound could effectively change molecular structure of proteins, polysaccharides, and their interactions, and was used to treat the peanut protein isolate-high methoxy pectin (PPI-HMP) complexes in this study. Effects of different ultrasound parameters, PPI-HMP mixing ratio (40:1-5:2), and pH (2.0-8.0) on the PPI-HMP interactions were investigated. Turbidity, solution appearance, and Zeta-potential analysis revealed an electrostatic interaction between PPI and HMP from pH 2.0 to pH 6.0. Ultrasound changed the tertiary structure conformation of PPI according to the surface hydrophobicity analysis. Increased ultrasound power density and pH broke the hydrogen bonds between the complexes according to Fourier transform infrared spectroscopy analysis. Apparent viscosity and confocal laser scanning microscopy analysis showed that appropriate ultrasound treatment (5.43 W/cm3, 25 min, 25 °C) reduced the viscosity of the complexes, and enhanced the electrostatic and hydrophobic interactions between PPI and HMP. These findings will contribute to the application of PPI-HMP complexes in the food industry.

Transcriptome profiling of the initial segment and proximal caput of mouse epididymis.

Background: The proximal region of the mouse epididymis plays a pivotal role in sperm transport, sperm maturation, and male fertility. Several studies have focused on segment-dependent gene expression of the mouse epididymis through high-throughput sequencing without the precision of the microdissection. Methods and results: Herein, we isolated the initial segment (IS) and proximal caput (P-caput) by physical microdissection using an Lcn9-cre; Rosa26tdTomato mouse model. We defined the transcriptome changes of caput epididymis by RNA sequencing (RNA-seq), which identified 1,961 genes that were abundantly expressed in the IS and 1,739 genes that were prominently expressed in the P-caput. In addition, we found that many differentially expressed genes (DEGs) were predominantly or uniquely expressed in the epididymis and region-specific genes were highly associated with transport, secretion, sperm motility, fertilization, and male fertility. Conclusion: Thus, this study provides an RNA-seq resource to identify region-specific genes in the caput epididymis. The epididymal-selective/specific genes are potential targets for male contraception and may provide new insights into understanding segment-specific epididymal microenvironment-mediated sperm transport, maturation, and male fertility.

ß-Nicotinamide mononucleotide activates NAD+/SIRT1 pathway and attenuates inflammatory and oxidative responses in the hippocampus regions of septic mice.

Sepsis-associated encephalopathy (SAE) is one of the common serious complications in sepsis, and the pathogenesis of SAE remains unclear. Sirtuin 1 (SIRT1) has been reported to be downregulated in the hippocampus and SIRT1 agonists can attenuated the cognitive dysfunction in septic mice. Nicotinamide adenine dinucleotide (NAD+) is a key substrate to maintain the deacetylation activity of SIRT1. As an intermediate of NAD+, ß-Nicotinamide Mononucleotide (NMN) has been reported to be promising in treating neurodegenerative diseases and cerebral ischemic injury. Thus we sought to investigate the potential role of NMN in SAE treatment. The SAE model was established by cecal ligation and puncture (CLP) in vivo, and neuroinflammation model was established with LPS-treated BV-2 cells in vitro. Memory impairment was assessed by Morris water maze and fear conditioning tests. As a result, the levels of NAD+, SIRT1 and PGC-1α were significantly reduced in the hippocampus of septic mice, while the acetylation of total lysine, phosphorylation of P38 and P65 were enhanced. All these changes induced by sepsis were inverted by NMN. Treating with NMN resulted in improved behavior performance in the fear conditioning tests and Morris water maze. Apoptosis, inflammatory and oxidative responses in the hippocampus of septic mice were attenuated significantly after NMN administration. These protective effect of NMN against memory dysfunction, inflammatory and oxidative injuries were reversed by the SIRT1 inhibitor, EX-527. Similarly, LPS-induced activation of BV-2 cells were attenuated by NMN, EX-527 or SIRT1 knockdown could reverse such effect of NMN in vitro. In conclusion, NMN is protective against sepsis-induced memory dysfunction, and the inflammatory and oxidative injuries in the hippocampus region of septic mice. The NAD+/SIRT1 pathway might be involved in one of the mechanisms of the protective effect.

Proline hydroxylation of CREB-regulated transcriptional coactivator 2 controls hepatic glucose metabolism.

Prolyl hydroxylase domain (PHD) enzymes change HIF activity according to oxygen signal; whether it is regulated by other physiological conditions remains largely unknown. Here, we report that PHD3 is induced by fasting and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its association with cAMP-response element binding protein (CREB) and nuclear translocation, and enhanced binding to promoters of gluconeogenic genes by fasting or forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) or prolyl hydroxylase-deficient knockin mice (PHD3 KI) show attenuated fasting gluconeogenic genes, glycemia, and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice, and humans with diabetes. These findings increase our understanding of molecular mechanisms linking protein hydroxylation to gluconeogenesis and may offer therapeutic potential for treating excessive gluconeogenesis, hyperglycemia, and type 2 diabetes.

Mining of long non-coding RNAs with target genes in response to rust based on full-length transcriptome in Kentucky bluegrass.

Kentucky bluegrass (Poa pratensis L.) is an eminent turfgrass species with a complex genome, but it is sensitive to rust (Puccinia striiformis). The molecular mechanisms of Kentucky bluegrass in response to rust still remain unclear. This study aimed to elucidate differentially expressed lncRNAs (DELs) and genes (DEGs) for rust resistance based on the full-length transcriptome. First, we used single-molecule real-time sequencing technology to generate the full-length transcriptome of Kentucky bluegrass. A total of 33,541 unigenes with an average read length of 2,233 bp were obtained, which contained 220 lncRNAs and 1,604 transcription factors. Then, the comparative transcriptome between the mock-inoculated leaves and rust-infected leaves was analyzed using the full-length transcriptome as a reference genome. A total of 105 DELs were identified in response to rust infection. A total of 15,711 DEGs were detected (8,278 upregulated genes, 7,433 downregulated genes) and were enriched in plant hormone signal transduction and plant-pathogen interaction pathways. Additionally, through co-location and expression analysis, it was found that lncRNA56517, lncRNA53468, and lncRNA40596 were highly expressed in infected plants and upregulated the expression of target genes AUX/IAA, RPM1, and RPS2, respectively; meanwhile, lncRNA25980 decreased the expression level of target gene EIN3 after infection. The results suggest that these DEGs and DELs are important candidates for potentially breeding the rust-resistant Kentucky bluegrass.

Immobilization of α-galactosidase in polyvinyl alcohol-chitosan-glycidyl methacrylate hydrogels based on directional freezing-assisted salting-out strategy for hydrolysis of RFOs.

Raffinose family oligosaccharides (RFOs) in food are the main factors causing flatulence in Irritable Bowel Syndrome (IBS) patients and the development of effective approaches for reducing food-derived RFOs is of paramount importance. In this study, polyvinyl alcohol (PVA)-chitosan (CS)-glycidyl methacrylate (GMA) immobilized α-galactosidase was prepared by the directional freezing-assisted salting-out technique, aimed to hydrolyze RFOs. SEM, FTIR, XPS, fluorescence and UV characterization results demonstrated that α-galactosidase was successfully cross-linked in the PVA-CS-GMA hydrogels, forming a distinct porous stable network through the covalent bond between the enzyme and the carrier. Mechanical performance and swelling capacity analysis illustrated that α-gal @ PVA-CS-GMA not only had suitable strength and toughness for longer durability, but also exhibited high water content and swelling capacity for better retention of catalytic activity. The enzymatic properties of α-gal @ PVA-CS-GMA showed an improved Km value, pH and temperature tolerance range, anti-enzymatic inhibitor (melibiose) activity compared to the free α-galactosidase and its reusability was at least 12 times with prolonged storage stability. Finally, it was successfully applied in the hydrolysis of RFOs in soybeans. These findings provide a new strategy for the development of α-galactosidase immobilization system to biological transform the RFOs components in the food for diet intervention of IBS.

Identification of a cellular senescence-related-lncRNA (SRlncRNA) signature to predict the overall survival of glioma patients and the tumor immune microenvironment.

Background: Gliomas are brain tumors that arise from glial cells, and they are the most common primary intracranial tumors with a poor prognosis. Cellular senescence plays a critical role in cancer, especially in glioma. In this study, we constructed a senescence-related lncRNA (SRlncRNA) signature to assess the prognosis of glioma. Methods: The Cancer Genome Atlas was used to collect SRlncRNA transcriptome profiles and clinical data about glioma. Patients were randomized to training, testing, and whole cohorts. LASSO and Cox regression analyses were employed to construct the SRlncRNA signature, and Kaplan-Meier (K-M) analysis was performed to determine each cohort's survival. Receiver operating characteristic (ROC) curves were applied to verify the accuracy of this signature. Gene set enrichment analysis was used to visualize functional enrichment (GSEA). The CIBERSORT algorithm, ESTIMATE and TIMER databases were utilized to evaluate the differences in the infiltration of 22 types of immune cells and their association with the signature. RT-qPCR and IHC were used to identify the consistency of the signature in tumor tissue. Results: An SRlncRNA signature consisting of six long non-coding RNAs (lncRNAs) was constructed, and patients were divided into high-risk and low-risk groups by the median of their riskscore. The KM analysis showed that the high-risk group had worse overall survival, and the ROC curve confirmed that the riskscore had more accurate predictive power. A multivariate Cox analysis and its scatter plot with clinical characteristics confirmed the riskscore as an independent risk factor for overall survival. GSEA showed that the GO and KEGG pathways were mainly enriched in the immune response to tumor cells, p53 signaling pathway, mTOR signaling pathway, and Wnt signaling pathway. Further validation also yielded significant differences in the risk signature in terms of immune cell infiltration, which may be closely related to prognostic differences, and qRT-PCR and IHC confirmed the consistency of the expression differences in the major lncRNAs with those in the prediction model. Conclusion Our findings indicated that the SRlncRNA signature might be used as a predictive biomarker and that there is a link between it and immune infiltration. This discovery is consistent with the present categorization system and may open new avenues for research and personalized therapy.

The droplet breakup model and characteristics of pH-shifted peanut protein isolate-high methoxyl pectin stabilised emulsions under ultrasound.

The effect of pH on the occurrence states of peanut protein isolate (PPI) and high methoxyl pectin (HMP), and droplet breakup model of the emulsions under ultrasound were studied. Particle size distribution and scanning electron microscopy results showed that PPI-HMP existed a soluble complex at pH 5.0, had no interaction at pH 7.0, and was co-soluble at pH 9.0. Droplet breakup model results revealed that the characteristics of emulsion stabilised by PPI-HMP treated at pH 5.0 was different from that at pH 7.0 and 9.0. The average diameter of the droplet well satisfied the model. According to rheological properties, interface tension, and microstructure, the formation mechanism and characteristics of emulsion stabilised by PPI-HMP treated at pH 5.0 was different from that at pH 7.0 and pH 9.0. The research provided a reference for constructing emulsions using pH-shifted PPI-HMP under ultrasound.

Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression.

BACKGROUND AND AIMS: NASH has emerged as a leading cause of chronic liver disease. However, the mechanisms that govern NASH fibrosis remain largely unknown. CREBZF is a CREB/ATF bZIP transcription factor that causes hepatic steatosis and metabolic defects in obesity. APPROACH AND RESULTS: Here, we show that CREBZF is a key mechanism of liver fibrosis checkpoint that promotes hepatocyte injury and exacerbates diet-induced NASH in mice. CREBZF deficiency attenuated liver injury, fibrosis, and inflammation in diet-induced mouse models of NASH. CREBZF increases HSC activation and fibrosis in a hepatocyte-autonomous manner by stimulating an extracellular matrix protein osteopontin, a key regulator of fibrosis. The inhibition of miR-6964-3p mediates CREBZF-induced production and secretion of osteopontin in hepatocytes. Adeno-associated virus -mediated rescue of osteopontin restored HSC activation, liver fibrosis, and NASH progression in CREBZF-deficient mice. Importantly, expression levels of CREBZF are increased in livers of diet-induced NASH mouse models and humans with NASH. CONCLUSIONS: Osteopontin signaling by CREBZF represents a previously unrecognized intrahepatic mechanism that triggers liver fibrosis and contributes to the severity of NASH.

Activated granulocytes and inflammatory cytokine signaling drive T-cell lymphoma progression and disease symptoms.

Peripheral T-cell lymphomas (PTCLs), especially angioimmunoblastic and follicular TCLs, have a dismal prognosis because of the lack of efficient therapies, and patients' symptoms are often dominated by an inflammatory phenotype, including fever, night sweats, weight loss, and skin rash. In this study, we investigated the role of inflammatory granulocytes and activated cytokine signaling on T-cell follicular helper-type PTCL (TFH-PTCL) disease progression and symptoms. We showed that ITK-SYK-driven murine PTCLs and primary human TFH-PTCL xenografts both induced inflammation in mice, including murine neutrophil expansion and massive cytokine release. Granulocyte/lymphoma interactions were mediated by positive autoregulatory cytokine loops involving interferon gamma (CD4+ malignant T cells) and interleukin 6 (IL-6; activated granulocytes), ultimately inducing broad JAK activation (JAK1/2/3 and TYK2) in both cell types. Inflammatory granulocyte depletion via antibodies (Ly6G), genetic granulocyte depletion (LyzM-Cre/MCL1flox/flox), or IL-6 deletion within microenvironmental cells blocked inflammatory symptoms, reduced lymphoma infiltration, and enhanced mouse survival. Furthermore, unselective JAK inhibitors (ruxolitinib) inhibited both TCL progression and granulocyte activation in various PTCL mouse models. Our results support the important role of granulocyte-driven inflammation, cytokine-induced granulocyte/CD4+ TCL interactions, and an intact JAK/STAT signaling pathway for TFH-PTCL development and also support broad JAK inhibition as an effective treatment strategy in early disease stages.