Lemniscular carbon nanohoops with contiguous conjugation from planar chiral [2.2]paracyclophane: influence of the regioselective synthesis on topological chirality.

We report herein the regioselective synthesis of all-carbon lemniscular nanohoops bis-po-CC and bis-pm-TC by the rational control of ring closures at the different positions of planar chiral tetrasubstituted [2.2]paracyclophane. Topological analyses reveal that bis-pm-TC is topologically chiral while bis-po-CC is topologically achiral. X-ray crystal analysis demonstrates that bis-pm-TC adopts a lemniscular conformation with a contiguous conjugation. CD and CPL measurements further reveal that the chiroptical properties of bis-pm-TC are obviously different from those of bis-po-CC due to their different topological chiralities.

Manganese(ii) complexes stimulate antitumor immunity via aggravating DNA damage and activating the cGAS-STING pathway.

Activating the cyclic GMP-AMP synthase-stimulator of the interferon gene (cGAS-STING) pathway is a promising immunotherapeutic strategy for cancer treatment. Manganese(ii) complexes MnPC and MnPVA (P = 1,10-phenanthroline, C = chlorine, and VA = valproic acid) were found to activate the cGAS-STING pathway. The complexes not only damaged DNA, but also inhibited histone deacetylases (HDACs) and poly adenosine diphosphate-ribose polymerase (PARP) to impede the repair of DNA damage, thereby promoting the leakage of DNA fragments into cytoplasm. The DNA fragments activated the cGAS-STING pathway, which initiated an innate immune response and a two-way communication between tumor cells and neighboring immune cells. The activated cGAS-STING further increased the production of type I interferons and secretion of pro-inflammatory cytokines (TNF-α and IL-6), boosting the tumor infiltration of dendritic cells and macrophages, as well as stimulating cytotoxic T cells to kill cancer cells in vitro and in vivo. Owing to the enhanced DNA-damaging ability, MnPC and MnPVA showed more potent immunocompetence and antitumor activity than Mn2+ ions, thus demonstrating great potential as chemoimmunotherapeutic agents for cancer treatment.

Inhibition of phosphoinositide­3 kinases γ/δ ameliorates pulmonary granuloma by rescuing Treg function in a sarcoidosis model.

Sarcoidosis is a multisystem inflammatory disease characterized by the development of Th1/Th17/regulatory T cells (Tregs)-related non-caseating granulomas. Phosphoinositide-3 kinases δ/γ (PI3Kδ/γ) play an important role in the maintenance of effective immunity, especially for Tregs homeostasis and stability. In the present study, superoxide dismutase A (SodA) stimulation was used to establish the sarcoidosis mouse model. The second immune stimulus was accompanied by CAL-101 (PI3Kδ inhibitor) or AS-605240 (PI3Kδ/γ inhibitor) treatment. To detect the effect of the PI3Kδ/γ inhibitor on the morphology of pulmonary granuloma and the activation of the PI3K signaling pathway, hematoxylin and eosin staining and immunofluorescence and western blotting was used, respectively. Fluorescence-activated cell sorting analysis and reverse transcription-quantitative PCR were adopted to detect the effect of the PI3Kδ/γ inhibitor on the SodA-induced sarcoidosis mouse model in respect to immune cell disorder and the function of Treg cells, with CD4+CD25- T cells and CD4+CD25+ T cells sorted by magnetic cell sorting. The results demonstrated that the inhibition of PI3Kδ/γ by transtracheal CAL-101/AS-605240 administration facilitated pulmonary granuloma formation. These therapeutic effects were associated with certain mechanisms, including suppressing the aberrantly activated PI3K/Akt signaling in both pulmonary granuloma and Tregs, particularly rescuing the suppressive function of Tregs. Notably, CAL-101 was more effective in immune modulation compared with AS-605240 and could overcome the aberrantly activated Akt in the lung and Tregs. These results suggest that PI3K/Akt signaling, especially the PI3Kδ subunit, can play a key role in optimal Tregs-mediated protection against pulmonary sarcoidosis. Therefore, transtracheal usage of PI3Kδ/γ inhibitors is an attractive therapy that may be developed into a new immune-therapeutic principle for sarcoidosis in the future.

Progesterone prevents HGSOC by promoting precancerous cell pyroptosis via inducing fibroblast paracrine.

High-grade serous ovarian carcinoma (HGSOC) is one of the most fatal gynecological cancers and has no effective prevention strategies. Herein, we demonstrated that progesterone significantly inhibited the occurrence, metastasis, and ascites of ovarian cancer in vivo, and the tumor inhibition effect of progesterone was in the tubo-ovarian intrabursal model than in the intraperitoneal or subcutaneous models. Further data demonstrated that progesterone-treated fallopian tube fibroblasts conditioned medium significantly inhibit HGSOC precancerous cell viability by inducing pyroptosis via the IL-6/ROS/NLRP3/GSDMD pathway, implying that the oviduct microenvironment may enhance progesterone's protective effects on ovarian cancer. This study elucidated progesterone inhibiting ovarian cancer mechanism and provided evidence for progesterone as a chemo-preventive role for HGSOC.

Exploring the long-term sequelae of childhood sexual abuse on risky sexual behavior among Chinese transgender women.

Introduction: Childhood sexual abuse (CSA) is a hidden but serious public health issue that can lead to a series of behavioral consequences and health problems in adulthood. It has been well documented that transgender women (TGW) have a high prevalence of CSA victimization. Moreover, risky sexual behaviors are also widespread among TGW; nevertheless, research investigating the associations between CSA victimization and risky sexual behaviors in TGW represents a gap in the literature. Methods: Our research was carried out mainly in Shenyang of China from November 2018 to January 2019. Sociodemographic characteristics, as well as information on participants' HIV awareness and sexual behaviors, were collected through face-to-face interviews. The impact of CSA was examined through hierarchical logistic regression, adjusted for sociodemographic factors and HIV awareness. Results: In the sample of 247 adult TGW, 14.2% of them had a CSA history. In the previous 6 months, 30.8% of the participants reported condomless anal intercourse (CAI) and 38.5% of them had multiple sexual partners (MSP). The findings demonstrated that TGW with CSA history were more likely to take part in CAI (p = 0.001, OR = 4.252) or have MSP (p = 0.004, OR = 3.260) in adulthood. Furthermore, HIV knowledge was not a predictor of CAI or MSP, but higher HIV risk perception was associated with a greater probability of CAI. Conclusion: Transgender women with a history of CSA were more prone to engage in CAI and have MSP in China.

The role of wrist-worn technology in the management of Parkinson's disease in daily life: A narrative review.

Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Its slow and heterogeneous progression over time makes timely diagnosis challenging. Wrist-worn digital devices, particularly smartwatches, are currently the most popular tools in the PD research field due to their convenience for long-term daily life monitoring. While wrist-worn sensing devices have garnered significant interest, their value for daily practice is still unclear. In this narrative review, we survey demographic, clinical and technological information from 39 articles across four public databases. Wrist-worn technology mainly monitors motor symptoms and sleep disorders of patients in daily life. We find that accelerometers are the most commonly used sensors to measure the movement of people living with PD. There are few studies on monitoring the disease progression compared to symptom classification. We conclude that wrist-worn sensing technology might be useful to assist in the management of PD through an automatic assessment based on patient-provided daily living information.

Vitamin B12 alleviates myocardial ischemia/reperfusion injury via the SIRT3/AMPK signaling pathway.

AIM: To examine the protective effect of vitamin B12 against myocardial ischemia/reperfusion (I/R) injury and elucidate its underlying mechanism of action. METHODS: Mice were subjected to myocardial I/R injury by left anterior descending coronary artery (LAD) occlusion followed by 24 h reperfusion. Cardiac function and injury were evaluated by echocardiography, triphenyl tetrazolium chloride (TTC) and cardiac troponin T (cTnT) staining, and measuring lactate dehydrogenase (LDH) levels. In addition, various molecular and biochemical methods, as well as RNA sequencing were used to determine the effects and mechanism of action of vitamin B12 on I/R injury. RESULTS: We found that high doses of vitamin B12 inhibited myocardial I/R injury. Furthermore, our data indicated that vitamin B12 supplementation alleviated cardiac dysfunction and injury by mitigating oxidative stress and apoptosis through downregulation of Nox2, the Ac-SOD2/SOD2 and Bax/Bcl-2 ratios and cleaved caspase-3 expression, and upregulation of SIRT3 expression and AMPK activity. However, these effects were largely reversed following treatment with the SIRT3 inhibitor, 3-TYP. Our RNA-sequencing data further demonstrated that vitamin B12 supplementation reduced inflammation during I/R injury. CONCLUSION: High doses of vitamin B12 supplements improved myocardial I/R injury by suppressing the accumulation of reactive oxygen species and apoptosis of myocardial tissue through modulation of the SIRT3/AMPK signaling pathway, while reducing inflammation. Our findings suggested that vitamin B12 administered at high doses could be a potential therapy for myocardial I/R damage.

Stellate ganglion block alleviates postoperative sleep disturbance in patients undergoing radical surgery for gastrointestinal malignancies.

STUDY OBJECTIVES: To explore the effects of stellate ganglion block (SGB) on postoperative sleep disturbance (POSD) in patients scheduled to undergo radical surgery for gastrointestinal malignancies. METHODS: Forty such patients were randomly assigned to control group (Group C) and preoperative SGB treatment group (Group S). Using actigraphy, sleep quality was evaluated on the first night before the operation and first, second, and third postoperative nights. The Pittsburgh sleep quality index (PSQI) scale was used for sleep state assessment on 1 day preoperatively and first, second, third, fifth, and seventh days postoperatively. Plasma IL-1, IL-6, IL-10, and melatonin levels were checked at 1 day preoperatively and first and third days postoperatively. Mean arterial pressure (MAP), heart rate (HR), and pulse oxygen saturation (SpO2) were recorded before general anesthesia induction, immediately after tracheal intubation, at the beginning of the operation, 1 h and 2 h after the beginning of the operation, at the end of the operation, immediately after extubation, and 30 min after transfer to the post-anesthesia care unit. RESULTS: Compared with Group C, in Group S, sleep efficiency, total sleep time, and sleep maintenance were increased and sleep period change index, number of awakenings, wake after sleep onset, and body movements were reduced on first and second postoperative nights; PSQI scores and occurrence of POSD were lower on first and second nights postoperatively; IL-6 was reduced on first night postoperatively; IL-1 and IL-10 were reduced at third night postoperatively; melatonin was increased on first night postoperatively; and MAP and HR were decreased at before general anesthesia induction, immediately after tracheal intubation, and the end of the operation (all, P < 0.05). CONCLUSIONS: SGB alleviates POSD by reducing postoperative inflammatory response, increasing melatonin levels, and stabilizing perioperative hemodynamics in patients undergoing radical surgery for gastrointestinal malignancies.

Drug-drug interaction potential of SH-1028, a third-generation EGFR-TKI: in vitro and clinical trials.

SH-1028 is an irreversible third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Considering the possibility of combination therapy in patients with NSCLC, we investigated the drug-drug interaction (DDI) potential of SH-1028 both in vitro and in clinical trials. The in vitro studies were conducted to determine the potential of SH-1028 as a substrate, inducer, or inhibitor of cytochrome P450 (CYP) subtypes. A phase I drug-drug interaction study in healthy volunteers was performed to evaluate the impact of co-administering rifampicin (a strong CYP3A4 inducer) and itraconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of SH-1028. The in vitro experiments showed that SH-1028 was mainly metabolized by CYP3A4. The activities of CYP1A2, 2B6, 2C19, 2D6 and 3A4 enzymes were slightly inhibited in vitro with SH-1028. SH-1028 has no obvious induction effect on CYP1A2 and CYP2B6 activities, but has potential induction effect on CYP3A4 mRNA expression. However, SH-1028 may not induce or inhibit human CYPs significantly at the clinically expected dose (200 mg). The geometric mean ratios of pharmacokinetic parameters and their corresponding 90% confidence intervals for SH-1028 in combination and alone did not fall within the range of 80-125%. It is speculated that itraconazole and rifampicin affect the metabolism of SH-1028. In the clinical application of SH-1028, special attention should be paid to the interaction between SH-1028 and drugs or foods that affect the activity of CYP3A4. (Clinical trial registration number: CTR20210558).

How climate change affects electricity consumption in Chinese cities-a differential perspective based on municipal monthly panel data.

Addressing the impacts of climate change has become a global public crisis and challenge. China is characterized by a complex and diverse topography and vast territory, which makes it worthwhile to explore the differential impacts of climate change on urban electricity consumption in different zones and economic development conditions. This study examines the differential impact of climate factors on urban electricity consumption in China based on monthly panel data for 282 prefectures from 2011 to 2019 and projects the potential demand for future urban electricity consumption under different climate change scenarios. The results show that (1) temperature changes significantly alter urban electricity consumption, with cooling degree days (CDD) and heating degree days (HDD) contributing positively to urban electricity consumption in areas with different regional and economic development statuses, with elasticity coefficients of 0.1015-0.1525 and 0.0029-0.0077, respectively. (2) The temperature-electricity relationship curve shows an irregular U-shape. Each additional day of extreme weather above 30 °C and below -12 °C increases urban electricity consumption by 0.52% and 1.52% in the north and by 2.67% and 1.32% in the south. Poor cities are significantly more sensitive to extremely low temperatures than rich cities. (3) Suppose the impacts of climate degradation on urban electricity consumption are not halted. In that case, the possible Shared Socioeconomic Pathways 1-1.9 (SSP1-1.9), SSP1-2.6, and SSP2-4.5 will increase China's urban electricity consumption by 1621.96 billion kWh, 2960.87 billion kWh, and 6145.65 billion kWh, respectively, by 2090. Finally, this study makes some policy recommendations and expectations for follow-up studies.

Correlation of serum adenosine deaminase activity with disease activity in patients with primary Sjögren's syndrome.

BACKGROUND: Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune disease primarily affecting the exocrine glands, which has a variety of clinical manifestations and unclear pathogenic mechanisms. Adenosine deaminase (ADA) is an enzyme involved in the breakdown of purines, and changes in its activity have been associated with a number of autoimmune diseases. This study aims to investigate the relationship between serum ADA activity and disease activity in patients with pSS. METHODS: In this study, 196 patients with pSS and 196 healthy controls were enrolled. Serum ADA activity and clinical laboratory parameters were collected and analyzed in both groups. Pearson correlation analysis was used to examine the correlation between ADA activity and clinical laboratory parameters, as well as the correlation between ADA activity and the disease activity score. RESULTS: Compared with healthy controls, the activity of ADA in the serum of pSS patients was significantly increased (P < 0.0001), and the ADA activity was significantly decreased after immunosuppressive treatment (P < 0.0001). Correlation analysis revealed that the activity of ADA was significantly positively correlated with erythrocyte sedimentation rate (ESR) (r = 0.3, P < 0.0001) and serum immunoglobulin G (IgG) levels (r = 0.5, P < 0.0001), and significantly negatively correlated with high-density lipoprotein (HDL) (r = -0.4, P < 0.0001). Furthermore, there was a significant positive correlation between ADA activity and the disease activity score as measured by the Sjögren's Syndrome Disease Activity Index (SSDAI) (r = 0.4, P < 0.0001). CONCLUSION: This study found that patients with pSS have higher activity of ADA in serum, which is associated with disease activity as measured by SSDAI. These results suggest that ADA activity may be a potential biomarker for evaluating disease activity and treatment efficacy in pSS patients. Additionally, ADA may be a potential target for the treatment of pSS patients.

Genome-wide characterization of major latex protein gene family in peanut and expression analyses under drought and waterlogging stress.

Peanut is an important oilseed crop around the world which provides vegetable oil, protein and vitamins for humans. Major latex-like proteins (MLPs) play important roles in plant growth and development, as well as responses to biotic and abiotic stresses. However, their biological function in peanut is still unclear. In this study, a genome-wide identification of MLP genes in cultivated peanut and two diploid ancestor species was analyzed to determine their molecular evolutionary characteristics and the expression profile under drought and waterlogging stress conditions. Firstly, a total of 135 MLP genes were identified from the genome of tetraploid peanut (Arachis hypogaea) and two diploid species Arachis. duranensis and Arachis. ipaensis. Then, phylogenetic analysis revealed that MLP proteins were divided into five different evolutionary groups. These genes were distributed unevenly at the ends of chromosomes 3, 5, 7, 8, 9 and 10 in three Arachis species. The evolution of MLP gene family in peanut was conserved and led by tandem and segmental duplication. The prediction analysis of cis-acting elements showed that the promoter region of peanut MLP genes contained different proportions of transcription factors, plant hormones-responsive elements and so on. The expression pattern analysis showed that they were differentially expressed under waterlogging and drought stress. These results of this study provide a foundation for further research on the function of the important MLP genes in peanut.

Solid-State Fermentation Improves Tobacco Leaves Quality via the Screened Bacillus subtilis of Simultaneously Degrading Starch and Protein Ability.

The process of tobacco aging plays a significant role in enhancing the smoking experience by improving the flavor and quality of tobacco leaves. During natural aging, the metabolic activity of the microbes on the surface of tobacco leaves will be greatly changed. Besides, starch and protein are two of the main macromolecular compounds causing the poor smoking quality of tobacco leaves which to be degraded for better tobacco quality. In this study, a bacterium with the simultaneously degrading ability of starch (degradation rate of 33.87%) and protein (degradation rate of 20%) has been screened out from high-class tobacco leaf and then inoculated into low-class tobacco leaf by solid-state fermentation for quality improvement. The changes in components related to carbon and nitrogen showed that the strain had an obvious effect on the quality improvement of tobacco leaves. After that, GC-MS analyses displayed the volatile flavor compounds which become rich and the flavor has been improved. It has been proved that inoculation solid-state fermentation by dominant strain could improve tobacco quality, as well as instead of the traditional natural aging process which greatly shortens the aging process. The work also offers a helpful strategy for solid-state products for deep fermentation.

Pharmacokinetic and tissue distribution study of six saponins in the rat after oral administration of Ilex pubescens extract using a validated simultaneous UPLC-qTOF-MS/MS assay.

Ilex pubescens Hook. et Arn is a medicinal plant of the Ilex family that is mainly used for the treatment of cardiovascular diseases. Its main medicinal ingredients are total triterpenoid saponins (IPTS). However, the pharmacokinetics and tissue distribution of the main multi-triterpenoid saponins are lacking. This is the first report that demonstrates a sensitive ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-qTOF-MS/MS) method for the quantification of ilexgenin A (C1), ilexsaponin A1 (C2), ilexsaponin B1 (C3), ilexsaponin B2 (C4), ilexsaponin B3 (DC1) and ilexoside O (DC2) in rat plasma and various tissues of the heart, liver, spleen, lungs, kidney, brain, stomach, duodenum, jejunum, ileum, colon and thoracic aorta. The chromatographic separation was carried out on an Acquity HSS T3 UPLC column (2.1 × 100 mm, 1.8 µm, Waters, USA) with a mobile phase consisting of 0.1% (v/v) formic acid (A) and acetonitrile containing 0.1% (v/v) formic acid (B) at a flow rate of 0.25 mL/min. The MS/MS detection was performed by electrospray ionization (ESI) using selected ion monitoring (SIM) in negative scan mode. The developed quantification method showed good linearity over the concentration range of 10-2000 ng/mL for plasma and 25-5000 ng/mL for tissue homogenates with R2 ≥ 0.990. Lower limits of quantification (LLOQ) was 10 ng/mL in plasma and 25 ng/mL in tissue homogenates. The intra- and inter-day precision were less than 10.39%, and the accuracy was between - 1.03% and 9.13%. The extract recoveries, dilution integrity and matrix effect were well within satisfactory limits. Using the validated method, the pharmacokinetic parameters, including half-life, AUC, Cmax, CL, and MRT, of six triterpenoid saponins in rats after oral administration were provided by establishing their plasma concentration-time curves, while their absolute quantification in various tissues after oral administration was also determined at first, which provides a scientific basis for their clinical application.

circFANCA accelerates the malignant process of OSCC by modulating miR-34a/PA28γ signaling.

OBJECTIVES: To investigate the upstream regulatory molecules of proteasomal activator 28γ (PA28γ), and explore its specific regulatory mechanism and potential clinical significance in OSCC. MATERIALS AND METHODS: qPCR was used to examine miR-34a, circFANCA and PSME3 expression. Western blotting was adopted to detect PA28γ expression. Transwell experiments were conducted to evaluate OSCC cell migration and invasion ability. FISH was used to evaluate the subcellular localization of circFANCA and miR-34a, and RNA pull-down verified the interaction between them. The expression of circFANCA and miR-34a in clinical cohorts was assessed by ISH, and the results were subjected to survival analysis using Kaplan-Meier analysis. RESULTS: Here, we proved that miR-34a expression is lower in highly aggressive OSCC tissues and cell lines. Notably, miR-34a can downregulate PA28γ expression and inhibit OSCC invasion and migration. Next, we confirmed that circFANCA promoted OSCC cell metastatic ability by sponging miR-34a. Importantly, interfering with miR-34a rescued the malignant progression of OSCC induced by silencing circFANCA. Finally, clinical data showed lower miR-34a expression and higher circFANCA expression were associated with poor prognosis in OSCC patients. CONCLUSION: The circFANCA/miR-34a/PA28γ axis facilitates the metastasis of OSCC, and circFANCA and miR-34a have potential to serve as prognostic markers for OSCC patients.

Establishment of an induced pluripotent stem cell (SIAISi016-A) line from a 62-years old Chinese Han patient with Alzheimer's disease.

A 62-years old Alzheimer's disease (AD) male patient donated his Peripheral blood mononuclear cells. The non-integrating episomal vector system used to reprogram PBMCs with Oct3/4, Klf4, Sox2 and c-Myc transcription factors. The pluripotency of transgene-free pluripotent stem cell (iPSC) was confirmed by immunocytochemistry for pluripotency markers-SOX2, NANOG, OCT3/4, SSEA4, TRA1-60, and TRA1-81. The differentiation capacity of the iPSCs into endoderm, mesoderm and ectoderm was assessed by AFP, SMA and ßIII-TUBULIN, respectively. In addition, the iPSC line displayed a normal karyotype. This iPSC line might offer a good cell model to explore the pathological mechanisms and treatment strategies for AD.

A novel algicidal properties of fermentation products from Pseudomonas sp. Ps3 strain on the toxic red tide dinoflagellate species.

The viability of both China's offshore fishing operations and the global marine fishing industry is threatened by the occurrence of red tides caused by Gymnodinium catenatum and Karenia mikimotoi. Effective control of these dinoflagellate-mediated red tides has become a pressing issue that requires immediate attention. In this study, High-efficiency marine alginolytic bacteria were isolated and underwent molecular biological identification to confirm their algicidal properties. Based on a combination of morphological, physiological, biochemical, and sequencing results, Strain Ps3 was identified as belonging to the species Pseudomonas sp. We examine the effects of algicidal bacteria on the red tide species G. catenatum and K. mikimotoi within an indoor experimental setting. Then gas chromatography- mass spectrometry (GC-MS) was used to analyze the structure of the algolytic active substances. This investigation demonstrated that with exposure to the algae-lysis experiment, the Ps3 strain has the best algae-lysis effect, with G. catenatum and K. mikimotoi reaching 83.0 and 78.3%. Our results from the sterile fermentation broth experiment showed that the inhibitory effect on the two red tide algae was positively correlated with the concentration of the treatment. At a treatment concentration of 2.0% (v/v), the 48 h lysis rates of G. catenatum and K. mikimotoi due to exposure to the Ps3 bacterial fermentation broth were 95.2 and 86.7%, respectively. The results of this study suggest that the algaecide may be a rapid and effective method to control dinoflagellate blooms, as evidenced by the observed changes in cellular morphology in all cases. In the ethyl acetate phase of Ps3 fermentation broth, the cyclic (leucine-leucine) dipeptide was the most abundant. The findings of this study contribute to our understanding of red tide prevention and control and provide a theoretical foundation for further research in this field.

Intestinal Reg4 deficiency confers susceptibility to high-fat diet-induced liver steatosis by increasing intestinal fat absorption in mice.

Background & Aims: Regenerating gene family member 4 (REG4) is a novel marker for enteroendocrine cells and is selectively expressed in specialised enteroendocrine cells of the small intestine. However, the exact roles of REG4 are largely unknown. In this study we investigate the effects of REG4 on the development of dietary fat-dependent liver steatosis and the mechanisms involved. Methods: Mice with intestinal-specific Reg4 deficiency (Reg4 ΔIEC ) and Reg4-floxed alleles (Reg4 fl/fl ) were generated to investigate the effects of Reg4 on diet-induced obesity and liver steatosis. Serum levels of REG4 were also measured in children with obesity using ELISA. Results: Reg4 ΔIEC mice fed a high-fat diet demonstrated significantly increased intestinal fat absorption and were prone to obesity and hepatic steatosis. Importantly, Reg4 ΔIEC mice exhibit enhanced activation of adenosine monophosphate-activated protein kinase (AMPK) signalling and increased protein abundance of the intestinal fat transporters, as well as enzymes involved in triglyceride synthesis and packaging at the proximal small intestine. Moreover, REG4 administration reduced fat absorption, and decreased the expression of intestinal fat absorption-related proteins in cultured intestinal cells possibly via the CaMKK2-AMPK pathway. Serum REG4 levels were markedly lower in children with obesity with advanced liver steatosis (p <0.05). Serum REG4 levels were inversely correlated with levels of liver enzymes, homeostasis model assessment of insulin resistance, low-density lipoprotein cholesterol, and triglycerides. Conclusions: Our findings directly link Reg4 deficiency with increased fat absorption and obesity-related liver steatosis, and suggest that REG4 may provide a potential target for prevention and treatment of liver steatosis in children. Impact and Implications: Hepatic steatosis is a key histological feature of non-alcoholic fatty liver disease, which is the leading chronic liver disease in children leading to the development of metabolic diseases; however, little is known about mechanisms induced by dietary fat. Intestinal REG4 acts as a novel enteroendocrine hormone reducing high-fat-diet-induced liver steatosis with decreasing intestinal fat absorption. REG4 may be a novel target for treatment of paediatric liver steatosis from the perspective of crosstalk between intestine and liver.

SPDET: Edge-Aware Self-Supervised Panoramic Depth Estimation Transformer With Spherical Geometry.

Panoramic depth estimation has become a hot topic in 3D reconstruction techniques with its omnidirectional spatial field of view. However, panoramic RGB-D datasets are difficult to obtain due to the lack of panoramic RGB-D cameras, thus limiting the practicality of supervised panoramic depth estimation. Self-supervised learning based on RGB stereo image pairs has the potential to overcome this limitation due to its low dependence on datasets. In this work, we propose the SPDET, an edge-aware self-supervised panoramic depth estimation network that combines the transformer with a spherical geometry feature. Specifically, we first introduce the panoramic geometry feature to construct our panoramic transformer and reconstruct high-quality depth maps. Furthermore, we introduce the pre-filtered depth-image-based rendering method to synthesize the novel view image for self-supervision. Meanwhile, we design an edge-aware loss function to improve the self-supervised depth estimation for panorama images. Finally, we demonstrate the effectiveness of our SPDET with a series of comparison and ablation experiments while achieving the state-of-the-art self-supervised monocular panoramic depth estimation. Our code and models are available at https://github.com/zcq15/SPDET.

The impact of routine frozen section analysis during nephroureterectomy or segmental ureterectomy for urothelial carcinoma on final surgical margin status and long-term oncologic outcome.

OBJECTIVE: The utility of intraoperative frozen section analysis (FSA) at the surgical margins (SMs) in patients with upper urinary tract cancer has not been established. We herein assessed the clinical significance of routine FSA of ureteral SMs during nephroureterectomy (NU) or segmental ureterectomy (SU). MATERIALS AND METHODS: A retrospective review of our Surgical Pathology database identified consecutive patients undergoing NU (n=246) or SU (n=42) for urothelial carcinoma from 2004 to 2018. FSA (n=54) was correlated with the diagnosis of frozen section controls, the status of final SMs, and the prognosis of patients. RESULTS: During NU, FSA was performed in 19 (7.7%) patients and was significantly more often requested in cases with ureteral tumor (13.1%) than in those with renal pelvis/calyx tumor (3.5%). Final SMs at the distal ureter/bladder cuff were positive only in non-FSA cases in the entire NU cohort (8.4%; P=0.375) or those with tumor at the lower ureter (57.6%; P=0.046), but not in any of FSA patients (0%). During SU, FSA was performed in 35 (83.3%) cases, including 19 at either proximal or distal SM and 16 at both SMs (SU-FSA2). Final positive SMs were significantly more often detected in non-FSA patients (42.9%) than in all FSA (8.6%; P=0.048) or SU-FSA2 (0%; P=0.020) patients. Overall, FSAs were reported as positive or high-grade carcinoma (n=7), atypical or dysplasia (n=13), and negative (n=34), and all these diagnoses were confirmed accurate on the frozen section controls, except one with a revision from atypical to carcinoma in situ. Meanwhile, 16 (80.0%) of 20 cases with initial positive/atypical FSA achieved negative conversion by excision of additional tissue. Kaplan-Meier analysis revealed that SU-FSA did not significantly reduce the risk of tumor recurrence in the bladder, disease progression, or cancer-specific mortality. Nonetheless, NU-FSA was strongly associated with reduced progression-free (P=0.023) and cancer-specific (P=0.007) survival rates, compared with non-FSA, which may imply a selection bias (e.g., FSA for clinically more aggressive tumors). CONCLUSIONS: Performing FSA during NU for lower ureteral tumor, as well as during SU, significantly reduced the risk of positive SMs. However, routine FSA for upper urinary tract cancer failed to considerably improve long-term oncologic outcome.