Clinicopathologic and Molecular Characterization of Xanthomatous Giant Cell Renal Cell Carcinomas: Further Support for a Close Morphologic Spectrum to Eosinophilic Solid and Cystic Renal Cell Carcinomas.

A recent study described a rare subtype of tuberous sclerosis complex ( TSC )-mutated renal cell carcinoma primarily characterized by Xanthomatous giant cell morphology. Only 2 cases in young individuals have been reported so far, making the correct diagnosis challenging from a pathological perspective. It remains unknown whether this tumor represents an independent subtype or belongs to other TSC -mutated tumors. We conducted a clinicopathologic evaluation and immunohistochemical profiling of 5 cases of Xanthomatous Giant Cell Renal Cell Carcinoma (XGC RCC) with confirmed TSC2 mutations through targeted DNA sequencing. In addition, we analyzed transcriptomic profiles using RNA-seq for the following samples: XGC RCC, Low-grade Oncocytic tumors (LOT), High-grade Oncocytic tumors/Eosinophilic Vacuolar Tumors (HOT/EVT), Eosinophilic Solid and Cystic Renal Cell Carcinomas (ESC RCC), Chromophobe cell Renal Cell Carcinomas (ChRCC), Renal Oncocytomas (RO), clear cell Renal Cell Carcinomas (ccRCC), and normal renal tissues. There were 2 female and 3 male patients, aged 22 to 58 years, who underwent radical nephrectomy for tumor removal. The tumor sizes ranged from 4.7 to 9.5 cm in diameter. These tumors exhibited ill-defined boundaries, showed an expansive growth pattern, and featured distinctive tumor giant cells with abundant eosinophilic to Xanthomatous cytoplasm and prominent nucleoli. All tumors had low Ki-67 proliferation indices (<1%) and demonstrated immune reactivity for CD10, PAX8, CK20, CathepsinK, and GPNMB. Next-generation sequencing confirmed TSC2 mutations in all cases. RNA sequencing-based clustering indicated a close similarity between the tumor and ESC RCC. One patient (1/5) died of an accident 63 months later, while the remaining patients (4/5) were alive without tumor recurrences or metastases at the time of analysis, with a mean follow-up duration of 43.4 months. Our research supports the concept that Xanthomatous giant cell renal cell carcinoma (XGC RCC) shares clinicopathological and molecular characteristics with ESC RCC and shows a relatively positive prognosis, providing further support for a close morphologic spectrum between the two. We propose considering XGC RCC as a distinct subtype of ESC RCC.

Understanding Sorption of Aqueous Electrolytes in Porous Carbon by NMR Spectroscopy.

Ion adsorption at solid-water interfaces is crucial for many electrochemical processes involving aqueous electrolytes including energy storage, electrochemical separations, and electrocatalysis. However, the impact of the hydronium (H3O+) and hydroxide (OH-) ions on the ion adsorption and surface charge distributions remains poorly understood. Many fundamental studies of supercapacitors focus on non-aqueous electrolytes to avoid addressing the role of functional groups and electrolyte pH in altering ion uptake. Achieving microscopic level characterization of interfacial mixed ion adsorption is particularly challenging due to the complex ion dynamics, disordered structures, and hierarchical porosity of the carbon electrodes. This work addresses these challenges starting with pH measurements to quantify the adsorbed H3O+ concentrations, which reveal the basic nature of the activated carbon YP-50F commonly used in supercapacitors. Solid-state NMR spectroscopy is used to study the uptake of lithium bis(trifluoromethanesulfonyl)-imide (LiTFSI) aqueous electrolyte in the YP-50F carbon across the full pH range. The NMR data analysis highlights the importance of including the fast ion-exchange processes for accurate quantification of the adsorbed ions. Under acidic conditions, more TFSI- ions are adsorbed in the carbon pores than Li+ ions, with charge compensation also occurring via H3O+ adsorption. Under neutral and basic conditions, when the carbon's surface charge is close to zero, the Li+ and TFSI- ions exhibit similar but lower affinities toward the carbon pores. Our experimental approach and evidence of H3O+ uptake in pores provide a methodology to relate the local structure to the function and performance in a wide range of materials for energy applications and beyond.

Using neural networks to autonomously assess adequacy in intraoperative cholangiograms.

BACKGROUND: Intraoperative cholangiography (IOC) is a contrast-enhanced X-ray acquired during laparoscopic cholecystectomy. IOC images the biliary tree whereby filling defects, anatomical anomalies and duct injuries can be identified. In Australia, IOC are performed in over 81% of cholecystectomies compared with 20 to 30% internationally (Welfare AIoHa in Australian Atlas of Healthcare Variation, 2017). In this study, we aim to train artificial intelligence (AI) algorithms to interpret anatomy and recognise abnormalities in IOC images. This has potential utility in (a) intraoperative safety mechanisms to limit the risk of missed ductal injury or stone, (b) surgical training and coaching, and (c) auditing of cholangiogram quality. METHODOLOGY: Semantic segmentation masks were applied to a dataset of 1000 cholangiograms with 10 classes. Classes corresponded to anatomy, filling defects and the cholangiogram catheter instrument. Segmentation masks were applied by a surgical trainee and reviewed by a radiologist. Two convolutional neural networks (CNNs), DeeplabV3+ and U-Net, were trained and validated using 900 (90%) labelled frames. Testing was conducted on 100 (10%) hold-out frames. CNN generated segmentation class masks were compared with ground truth segmentation masks to evaluate performance according to a pixel-wise comparison. RESULTS: The trained CNNs recognised all classes.. U-Net and DeeplabV3+ achieved a mean F1 of 0.64 and 0.70 respectively in class segmentation, excluding the background class. The presence of individual classes was correctly recognised in over 80% of cases. Given the limited local dataset, these results provide proof of concept in the development of an accurate and clinically useful tool to aid in the interpretation and quality control of intraoperative cholangiograms. CONCLUSION: Our results demonstrate that a CNN can be trained to identify anatomical structures in IOC images. Future performance can be improved with the use of larger, more diverse training datasets. Implementation of this technology may provide cholangiogram quality control and improve intraoperative detection of ductal injuries or ductal injuries.

Quercetin-loaded mesoporous nano-delivery system remodels osteoimmune microenvironment to regenerate alveolar bone in periodontitis via the miR-21a-5p/PDCD4/NF-κB pathway.

BACKGROUND: Impaired osteo-/angiogenesis, excessive inflammation, and imbalance of the osteoimmune homeostasis are involved in the pathogenesis of the alveolar bone defect caused by periodontitis. Unfortunately, there is still a lack of ideal therapeutic strategies for periodontitis that can regenerate the alveolar bone while remodeling the osteoimmune microenvironment. Quercetin, as a monomeric flavonoid, has multiple pharmacological activities, such as pro-regenerative, anti-inflammatory, and immunomodulatory effects. Despite its vast spectrum of pharmacological activities, quercetin's clinical application is limited due to its poor water solubility and low bioavailability. RESULTS: In this study, we fabricated a quercetin-loaded mesoporous bioactive glass (Quercetin/MBG) nano-delivery system with the function of continuously releasing quercetin, which could better promote the bone regeneration and regulate the immune microenvironment in the alveolar bone defect with periodontitis compared to pure MBG treatment. In particular, this nano-delivery system effectively decreased injection frequency of quercetin while yielding favorable therapeutic results. In view of the above excellent therapeutic effects achieved by the sustained release of quercetin, we further investigated its therapeutic mechanisms. Our findings indicated that under the periodontitis microenvironment, the intervention of quercetin could restore the osteo-/angiogenic capacity of periodontal ligament stem cells (PDLSCs), induce immune regulation of macrophages and exert an osteoimmunomodulatory effect. Furthermore, we also found that the above osteoimmunomodulatory effects of quercetin via macrophages could be partially blocked by the overexpression of a key microRNA--miR-21a-5p, which worked through inhibiting the expression of PDCD4 and activating the NF-κB signaling pathway. CONCLUSION: In summary, our study shows that quercetin-loaded mesoporous nano-delivery system has the potential to be a therapeutic approach for reconstructing alveolar bone defects in periodontitis. Furthermore, it also offers a new perspective for treating alveolar bone defects in periodontitis by inhibiting the expression of miR-21a-5p in macrophages and thereby creating a favorable osteoimmune microenvironment.

Running exercise alleviates hippocampal neuroinflammation and shifts the balance of microglial M1/M2 polarization through adiponectin/AdipoR1 pathway activation in mice exposed to chronic unpredictable stress.

Running exercise has been shown to alleviate depressive symptoms. However, the mechanism underlying the antidepressant effects of running exercise is not fully understood. The imbalance of M1/M2 microglia phenotype/polarization and concomitant dysregulation of neuroinflammation play crucial roles in the pathogenesis of depression. Running exercise increases circulating levels of adiponectin which is known to cross the blood‒brain barrier and suppress inflammatory responses. AdipoR1 is an adiponectin receptor that is involved in regulating microglial phenotypes and activation states. However, whether running exercise regulates hippocampal microglial phenotypes and neuroinflammation through adiponectin/AdipoR1 to exert its antidepressant effects remains unclear. In the current study, 4 weeks of running exercise significantly alleviated the depressive-like behaviors of chronic unpredictable stress (CUS)-exposed mice. Moreover, running exercise decreased the microglial numbers and altered microglial morphology in three subregions of the hippocampus to restore the M1/M2 balance; these effects were accompanied by regulation of pro-/anti-inflammatory cytokine production and secretion in CUS-exposed mice. These effects may involve elevation of peripheral tissue (adipose tissue and muscle) and plasma adiponectin levels, and hippocampal AdipoR1 levels as well as activation of the AMPK-NF-κB/STAT3 signaling pathway by running exercise. When an adeno-associated virus was used to knock down hippocampal AdipoR1, mice showed depressive-like behaviors and alterations in microglia and inflammatory factor expression in the hippocampus that were similar to those observed in CUS-exposed mice. Together, these results suggest that running exercise maintains the M1/M2 balance and inhibits neuroinflammation in the hippocampus of CUS-exposed mice. These effects might occur via adiponectin/AdipoR1-mediated activation of the AMPK-NF-κB/STAT3 signaling pathway.

A xonotlite nanofiber bioactive 3D-printed hydrogel scaffold based on osteo-/angiogenesis and osteoimmune microenvironment remodeling accelerates vascularized bone regeneration.

BACKGROUND: Coordination between osteo-/angiogenesis and the osteoimmune microenvironment is essential for effective bone repair with biomaterials. As a highly personalized and precise biomaterial suitable for repairing complex bone defects in clinical practice, it is essential to endow 3D-printed scaffold the above key capabilities. RESULTS: Herein, by introducing xonotlite nanofiber (Ca6(Si6O17) (OH)2, CS) into the 3D-printed silk fibroin/gelatin basal scaffold, a novel bone repair system named SGC was fabricated. It was noted that the incorporation of CS could greatly enhance the chemical and mechanical properties of the scaffold to match the needs of bone regeneration. Besides, benefiting from the addition of CS, SGC scaffolds could accelerate osteo-/angiogenic differentiation of bone mesenchymal stem cells (BMSCs) and meanwhile reprogram macrophages to establish a favorable osteoimmune microenvironment. In vivo experiments further demonstrated that SGC scaffolds could efficiently stimulate bone repair and create a regeneration-friendly osteoimmune microenvironment. Mechanistically, we discovered that SGC scaffolds may achieve immune reprogramming in macrophages through a decrease in the expression of Smad6 and Smad7, both of which participate in the transforming growth factor-ß (TGF-ß) signaling pathway. CONCLUSION: Overall, this study demonstrated the clinical potential of the SGC scaffold due to its favorable pro-osteo-/angiogenic and osteoimmunomodulatory properties. In addition, it is a promising strategy to develop novel bone repair biomaterials by taking osteoinduction and osteoimmune microenvironment remodeling functions into account.

A multifunctional quercetin/polycaprolactone electrospun fibrous membrane for periodontal bone regeneration.

Image 1.

Antagonizing LINGO-1 reduces activated microglia and alleviates dendritic spine loss in the hippocampus of APP/PS1 transgenic mice.

In Alzheimer's disease (AD), microglia are involved in synaptic pruning and mediate synapse loss. LINGO-1 is a negative regulator of nerve growth, and whether antagonizing LINGO-1 can attenuate synaptic pruning by microglia and rescue dendritic spines in the hippocampus in AD is still unclear. On this basis, the anti-LINGO-1 antibody, which binds to LINGO-1 protein and antagonizes the effects of LINGO-1, was administered to 10-month-old APP/PS1 transgenic mice for 2 months. The Morris water maze test, immunohistochemical and stereological methods, immunofluorescence and 3D reconstruction were used. Compared to wild-type mice, APP/PS1 transgenic mice had worse performance on behavioral tests, fewer dendritic spines but more microglia in the hippocampus. Meanwhile, the microglia in APP/PS1 transgenic mice had more branches of medium length (4-6 µm) and a cell body area with greater variability. Moreover, APP/PS1 transgenic mice had more postsynaptic termini colocalized with microglia in the hippocampus than wild-type mice. The anti-LINGO-1 antibody significantly reversed these changes in AD, indicating that the anti-LINGO-1 antibody can improve hippocampus-dependent learning and memory abilities and effectively rescue dendritic spines in the hippocampus of AD mice and that microglia might participate in this progression in AD. These results provide a scientific basis for further studying the mechanism of the anti-LINGO-1 antibody in AD and help to elucidate the role of LINGO-1 in the treatment of AD.

Darkness promotes dishonesty in a coin toss task: A pre-registered conceptual replication of Experiment 1 of Zhong, Bohns, and Gino (2010).

An earlier study suggested that individuals tend to be more dishonest in darker environments, this phenomenon was attributed to an increase in participants' perceived anonymity. However, instead of using quantifiable measurements, the original experiment depended on the experimenter's subjective observation to construct different brightness conditions, which led to a less precise understanding of the phenomenon. Additionally, the task used in the original experiment has recently been criticized as being unsuitable for dishonesty-detection studies. This study addressed these concerns to retest the effect of brightness on dishonest behavior. This study employed lux as a unit to accurately control the brightness within the experiment room. Moreover, the coin toss task which is frequently employed in dishonesty-detection experiments, was utilized instead of the task in the original experiment. The findings revealed that despite altering the content of the task, dishonesty increased in the dark condition. Contrary to the findings in the original experiment, however, the results did not substantiate that perceived anonymity was the driving factor of the effect of brightness on dishonesty. This discrepancy suggests that further empirical considerations are warranted to unravel the underlying mechanisms.

MPFC PV+ interneurons are involved in the antidepressant effects of running exercise but not fluoxetine therapy.

Depression is a complex psychiatric disorder. Previous studies have shown that running exercise reverses depression-like behavior faster and more effectively than fluoxetine therapy. GABAergic interneurons, including the PV+ interneuron subtype, in the medial prefrontal cortex (MPFC) are involved in pathological changes of depression. It was unknown whether running exercise and fluoxetine therapy reverse depression-like behavior via GABAergic interneurons or the PV+ interneurons subtype in MPFC. To address this issue, we subjected mice with chronic unpredictable stress (CUS) to a 4-week running exercise or fluoxetine therapy. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that running exercise enriched GABAergic synaptic pathways in the MPFC of CUS-exposed mice. However, the number of PV+ interneurons but not the total number of GABAergic interneurons in the MPFC of CUS-exposed mice reversed by running exercise, not fluoxetine therapy. Running exercise increased the relative gene expression levels of the PV gene in the MPFC of CUS-exposed mice without altering other subtypes of GABAergic interneurons. Moreover, running exercise and fluoxetine therapy both significantly improved the length, area and volume of dendrites and the spine morphology of PV+ interneurons in the MPFC of mice exposed to CUS. However, running exercise but not fluoxetine therapy improved the dendritic complexity level of PV+ interneurons in the MPFC of CUS-exposed mice. In summary, the number and dendritic complexity level of PV+ interneurons may be important therapeutic targets for the mechanism by which running exercise reverses depression-like behavior faster and more effectively than fluoxetine therapy.

Long-term voluntary exercise inhibited AGE/RAGE and microglial activation and reduced the loss of dendritic spines in the hippocampi of APP/PS1 transgenic mice.

Alzheimer's disease (AD) is closely related to hippocampal synapse loss, which can be alleviated by running exercise. However, further studies are needed to determine whether running exercise reduces synapse loss in the hippocampus in an AD model by regulating microglia. Ten-month-old male wild-type mice and APP/PS1 mice were randomly divided into control and running groups. All mice in the running groups were subjected to voluntary running exercise for four months. After the behavioral tests, immunohistochemistry, stereological methods, immunofluorescence staining, 3D reconstruction, western blotting and RNA-Seq were performed. Running exercise improved the spatial learning and memory abilities of APP/PS1 mice and increased the total number of dendritic spines, the levels of the PSD-95 and Synapsin Ia/b proteins, the colocalization of PSD-95 and neuronal dendrites (MAP-2) and the number of PSD-95-contacting astrocytes (GFAP) in the hippocampi of APP/PS1 mice. Moreover, running exercise reduced the relative expression of CD68 and Iba-1, the number of Iba-1+ microglia and the colocalization of PSD-95 and Iba-1+ microglia in the hippocampi of APP/PS1 mice. The RNA-Seq results showed that some differentially expressed genes (DEGs) related to the complement system (Cd59b, Serping1, Cfh, A2m, and Trem2) were upregulated in the hippocampi of APP/PS1 mice, while running exercise downregulated the C3 gene. At the protein level, running exercise also reduced the expression of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), C1q and C3 in the hippocampus and AGEs and RAGE in hippocampal microglia in APP/PS1 mice. Furthermore, the Col6a3, Scn5a, Cxcl5, Tdg and Clec4n genes were upregulated in the hippocampi of APP/PS1 mice but downregulated after running, and these genes were associated with the C3 and RAGE genes according to protein-protein interaction (PPI) analysis. These findings indicate that long-term voluntary exercise might protect hippocampal synapses and affect the function and activation of microglia, the AGE/RAGE signaling pathway in microglia and the C1q/C3 complement system in the hippocampus in APP/PS1 mice, and these effects may be related to the Col6a3, Scn5a, Cxcl5, Tdg and Clec4n genes. The current results provide an important basis for identifying targets for the prevention and treatment of AD.

Anti-LINGO-1 antibody protects neurons and synapses in the medial prefrontal cortex of APP/PS1 transgenic mice.

The medial prefrontal cortex (mPFC), one of the most vulnerable brain regions in Alzheimer's disease (AD), plays a critical role in cognition. Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein-1 (LINGO-1) negatively affects nerve growth in the central nervous system; however, its role in the pathological damage to the mPFC remains to be studied in AD. In this study, an anti-LINGO-1 antibody was administered to 10-month-old APP/PS1 mice, and behavioral tests, stereological methods, immunohistochemistry and immunofluorescence were used to answer this question. Our results revealed that LINGO-1 was highly expressed in the neurons of the mPFC of AD mice, and the anti-LINGO-1 antibody improved prefrontal cortex-related function and reduced the protein level of LINGO-1, atrophy of the volume, Aß deposition and massive losses of synapses and neurons in the mPFC of AD mice. Antagonizing LINGO-1 could effectively alleviate the pathological damage in the mPFC of AD mice, which might be an important structural basis for improving prefrontal cortex-related function. Abnormal expression of LINGO-1 in the mPFC may be one of the key targets of AD, and the effect initiated by the anti-LINGO-1 antibody may provide an important basis in the search for drugs for the prevention and treatment of AD.

Glycolytic Regulation of Intestinal Stem Cell Self-Renewal and Differentiation.

BACKGROUND AND AIMS: The intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis. An imbalance in this highly regimented process within the intestinal crypts is associated with several intestinal pathologies. Although metabolic changes are known to play a pivotal role in cell proliferation and differentiation, how glycolysis contributes to intestinal epithelial homeostasis remains to be defined. METHODS: Small intestines were harvested from mice with specific hexokinase 2 (HK2) deletion in the intestinal epithelium or LGR5+ stem cells. Glycolysis was measured using the Seahorse XFe96 analyzer. Expression of phospho-p38 mitogen-activated protein kinase, the transcription factor atonal homolog 1, and intestinal cell differentiation markers lysozyme, mucin 2, and chromogranin A were determined by Western blot, quantitative real-time reverse transcription polymerase chain reaction, or immunofluorescence, and immunohistochemistry staining. RESULTS: HK2 is a target gene of Wnt signaling in intestinal epithelium. HK2 knockout or inhibition of glycolysis resulted in increased numbers of Paneth, goblet, and enteroendocrine cells and decreased intestinal stem cell self-renewal. Mechanistically, HK2 knockout resulted in activation of p38 mitogen-activated protein kinase and increased expression of ATOH1; inhibition of p38 mitogen-activated protein kinase signaling attenuated the phenotypes induced by HK2 knockout in intestinal organoids. HK2 knockout significantly decreased glycolysis and lactate production in intestinal organoids; supplementation of lactate or pyruvate reversed the phenotypes induced by HK2 knockout. CONCLUSIONS: Our results show that HK2 regulates intestinal stem cell self-renewal and differentiation through p38 mitogen-activated protein kinase/atonal homolog 1 signaling pathway. Our findings demonstrate an essential role for glycolysis in maintenance of intestinal stem cell function.

11.2 Gbps 100-meter free-space visible light laser communication utilizing bidirectional reservoir computing equalizer.

In this paper, we introduce an innovative post-equalization technique leveraging bidirectional reservoir computing (BiRC), and apply it to waveform-to-symbol level equalization for visible light laser communication for the first time. This strategy is more resistant to nonlinearities compared to traditional equalizers like least mean square (LMS) equalizer, while requiring less training time and fewer parameters than neural network (NN) -based equalizers. Through this approach, we successfully conduct a 100-meter transmission of a 32-amplitude phase shift keying (32APSK) signal using a green laser operating at a wavelength of 520 nm. Remarkably, our system achieves a high data rate of 11.2 Gbps, all while maintaining a satisfying bit error rate (BER) below the 7% hard decision forward error correction (HD-FEC) threshold of 3.8E-3.

Shared and distinct functional connectivity of hippocampal subregions in schizophrenia, bipolar disorder, and major depressive disorder.

Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) share etiological and pathophysiological characteristics. Although neuroimaging studies have reported hippocampal alterations in SZ, BD, and MDD, little is known about how different hippocampal subregions are affected in these conditions because such subregions, namely, the cornu ammonis (CA), dentate gyrus (DG), and subiculum (SUB), have different structural foundations and perform different functions. Here, we hypothesize that different hippocampal subregions may reflect some intrinsic features among the major psychiatric disorders, such as SZ, BD, and MDD. By investigating resting functional connectivity (FC) of each hippocampal subregion among 117 SZ, 103 BD, 96 MDD, and 159 healthy controls, we found similarly and distinctly changed FC of hippocampal subregions in the three disorders. The abnormal functions of middle frontal gyrus might be the core feature of the psychopathological mechanisms of SZ, BD, and MDD. Anterior cingulate cortex and inferior orbital frontal gyrus might be the shared abnormalities of SZ and BD, and inferior orbital frontal gyrus is also positively correlated with depression and anxiety symptoms in SZ and BD. Caudate might be the unique feature of SZ and showed a positive correlation with the cognitive function in SZ. Middle temporal gyrus and supplemental motor area are the differentiating features of BD. Our study provides evidence for the different functions of different hippocampal subregions in psychiatric pathology.

Fabrication and Effect of Strontium-Substituted Calcium Silicate/Silk Fibroin on Bone Regeneration In Vitro and In Vivo.

Achieving rapid osteogenesis and angiogenesis was the key factor for bone regeneration. In the present study, the strontium-substituted calcium silicate (SrCS)/silk fibroin (SF) composite materials have been constructed by combining the different functional component ratios of SrCS (12.5 wt%, 25 wt%) and SF. Then, the effects of SrCS/SF materials on proliferation, osteogenic differentiation, and angiogenic factor secretion of rat bone marrow-derived mesenchymal stromal cells (rBMSCs) were first evaluated in vitro. Moreover, the in vivo effect of osteogenesis was evaluated in a critical-sized rat calvarial defect model. In vitro studies showed that SrCS/SF significantly enhanced the cell proliferation, alkaline phosphatase (ALP) activity, and the expression of osteogenic and angiogenic factors of rBMSCs as compared with the SF and CS/SF, and the optimum proportion ratio was 25 wt%. Besides, the results also showed that CS/SF achieved enhanced effects on rBMSCs as compared with SF. The in vivo results showed that 25 wt% SrCS/SF could obviously promote new bone formation more than SF and CS/SF. The present study revealed that SrCS could significantly promote the osteogenic and angiogenic activities of SF, and SrCS/SF might be a good scaffold material for bone regeneration.

Ketogenesis Attenuates KLF5-Dependent Production of CXCL12 to Overcome the Immunosuppressive Tumor Microenvironment in Colorectal Cancer.

The dynamic composition of the tumor microenvironment (TME) can markedly alter the response to targeted therapies for colorectal cancer. Cancer-associated fibroblasts (CAF) are major components of TMEs that can direct and induce infiltration of immunosuppressive cells through secreted cytokines such as CXCL12. Ketogenic diets (KD) can inhibit tumor growth and enhance the anticancer effects of immune checkpoint blockade. However, the role of ketogenesis on the immunosuppressive TME is not known. Here, we show that decreased ketogenesis is a signature of colorectal cancer and that an increase in ketogenesis using a KD decreases CXCL12 production in tumors, serum, liver, and lungs. Moreover, increasing ketogenesis by overexpression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) or treatment with the ketone body ß-hydroxybutyrate markedly decreased expression of KLF5, which binds the CXCL12 promoter and induces CXCL12 expression in CAFs. KD decreased intratumoral accumulation of immunosuppressive cells, increased infiltration of natural killer and cytotoxic T cells, and enhanced the anticancer effects of PD-1 blockade in murine-derived colorectal cancer. Furthermore, increasing ketogenesis inhibited colorectal cancer migration, invasion, and metastasis in vitro and in vivo. Overall, ketogenesis is downregulated in the colorectal cancer TME, and increased ketogenesis represses KLF5-dependent CXCL12 expression to improve the immunosuppressive TME, which leads to the enhanced efficacy of immunotherapy and reduced metastasis. Importantly, this work demonstrates that downregulation of de novo ketogenesis in the TME is a critical step in colorectal cancer progression. SIGNIFICANCE: This study identifies ketogenesis as a critical regulator of the tumor microenvironment in colorectal cancer and suggests the potential for ketogenic diets as a metabolic strategy to overcome immunosuppression and prolong survival. See related commentary by Montrose and Galluzzi, p. 1464.

Synergistic Effect of Micro-Nano-Hybrid Surfaces and Sr Doping on the Osteogenic and Angiogenic Capacity of Hydroxyapatite Bioceramics Scaffolds.

BACKGROUND: The synergistic effect of chemical element doping and surface modification is considered a novel way to regulate cell biological responses and improve the osteoinductive ability of biomaterials. METHODS: Hydroxyapatite (HAp) bioceramics with micro-nano-hybrid (a mixture of microrods and nanorods) surfaces and different strontium (Sr) doping contents of 2.5, 5, 10, and 20% (Srx-mnHAp, x: 2.5, 5, 10 and 20%) were prepared via a hydrothermal transformation method. The effect of Srx-mnHAp on osteogenesis and angiogenesis of bone marrow stromal cells (BMSCs) was evaluated in vitro, and the bioceramics scaffolds were further implanted into rat calvarial defects for the observation of bone regeneration in vivo. RESULTS: HAp bioceramics with micro-nano-hybrid surfaces (mnHAp) could facilitate cell spreading, proliferation ability, ALP activity, and gene expression of osteogenic and angiogenic factors, including COL1, BSP, BMP-2, OPN, VEGF, and ANG-1. More importantly, Srx-mnHAp (x: 2.5, 5, 10 and 20%) further promoted cellular osteogenic activity, and Sr10-mnHAp possessed the best stimulatory effect. The results of calvarial defects revealed that Sr10-mnHAp could promote more bone and blood vessel regeneration, with mnHAp and HAp bioceramics (dense and flat surfaces) as compared. CONCLUSION: The present study suggests that HAp bioceramics with micro-nano-hybrid surface and Sr doping had synergistic promotion effects on bone regeneration, which can be a promising material for bone defect repair.

The correlation between mental health status, sleep quality, and inflammatory markers, virus negative conversion time among patients confirmed with 2019-nCoV during the COVID-19 outbreak in China: An observational study.

ABSTRACT: The 2019 coronavirus disease (COVID-19) has spread to the whole world. Psychological and sleep problems among confirmed patients have drawn extensive attention which may be highly related to immune function and inflammatory responses of people. The aim of this study is to examine the correlation of mental health status, sleep quality, and inflammatory markers, virus negative conversion time (NCT) among confirmed patients during the COVID-19 outbreak.A cross-sectional survey was conducted in this study. Data from 66 patients assessed with demographic information, anxious symptom, depressive symptom, stress, and sleep quality were collected using a smartphone-based questionnaire platform and then clinical characteristics and laboratory indicators were collected using case review.Nearly 30% of the participants reported depression, anxiety, perceived pressure, and poor sleep quality. Compared with the group without depression, neutrophil count, and ratio of neutrophil count to lymphocyte count (NLR) in the depression disorder group were increased (P = .028, 0.043). There was also a significant difference in NLR and NCT between the anxiety group and the non-anxiety group (P = .021, .024). Similarly, compared with the good sleep quality group, NLR in the poor sleep quality group was increased (P = .011). Correlation analysis indicated that Self-Rating Depression Scale score was positively related to neutrophil count and NLR (r = 0.366, 0.330, P = .016, .031). The total score of Pittsburgh Sleep Quality Index (PSQI) was negatively related to lymphocyte count (r = -0.317, P = .049), and the sleep disturbance as 1 of the 7 dimensions of PSQI scale was positively correlated with NCT and NLR (r = 0.370, 0.340, P = .020, .034).In our study, confirmed patients were prone to have psychological and sleep problems. The level of inflammation in patients with psychological and sleep problems was higher than that in patients without corresponding problems. The inflammatory level increased with the increase of Self-Rating Depression Scale score, and the lymphocyte count decreased with the increase of the PSQI score. NCT was prolonged in the anxiety group and sleep disturbance was positively correlated with NCT.

Anti-LINGO-1 antibody ameliorates cognitive impairment, promotes adult hippocampal neurogenesis, and increases the abundance of CB1R-rich CCK-GABAergic interneurons in AD mice.

In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aß) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future.