Programmed Death Ligand 1 Expression in Circulating Tumor Cells as a Predictor and Monitor of Response to Atezolizumab plus Bevacizumab Treatment in Patients with Hepatocellular Carcinoma.

There remains no reliable biomarker of therapeutic efficacy in hepatocellular carcinoma (HCC) for the PD-L1 inhibitor atezolizumab and bevacizumab (Atezo/Bev). Circulating tumor cells (CTCs) enable the serial collection of living tumor cells. Pre-treatment and serial CTC gene expression changes and tumor histology were evaluated to identify predictors of response to Atezo/Bev. Peripheral blood from 22 patients with HCC treated with Atezo/Bev and 24 patients treated with lenvatinib was serially collected. The RNA expression in CTCs was analyzed using qRT-PCR. Higher PD-L1 expression in pre-treatment CTCs was associated with response and improved prognosis with Atezo/Bev treatment, but not with lenvatinib. There was no correlation between PD-L1 expression in CTCs and that in liver tumor biopsy specimens scored using imaging software. Furthermore, PD-L1 RNA expression in CTCs was dynamically altered by Atezo/Bev, decreasing during effective response and increasing upon progression. CTC-derived RNA collected during Atezo/Bev indicates that patients with higher PD-L1 expression in CTCs at baseline were 3.9 times more responsive to treatment. Therefore, PD-L1 RNA levels in CTCs are an accurate response predictor and may be a monitorable biomarker that changes dynamically to reflect the response during Atezo/Bev treatment.

Isolation of mucosa-associated microbiota dysbiosis in the ascending colon in hepatitis C virus post-sustained virologic response cirrhotic patients.

Background: Achieving sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) reduces all-cause mortality. However, the mechanisms and risk factors for liver fibrosis and portal hypertension post-SVR remain incompletely understood. In the gut-liver axis, mucosa-associated microbiota (MAM) substantially influence immune and metabolic functions, displaying spatial heterogeneity at the anatomical intestinal site. We analyzed MAM composition and function to isolate the locoregional MAM involved in chronic liver disease progression in HCV post-SVR patients. Methods: We collected MAM samples from three intestinal sites (terminal ileum, ascending colon, and sigmoid colon) via brushing during colonoscopy in 23 HCV post-SVR patients and 25 individuals without liver disease (controls). The 16S rRNA of bacterial DNA in specimens collected with a brush and in feces was sequenced. The molecular expression of intestinal tissues and hepatic tissues were evaluated by quantitative real-time PCR. Results: In the post-SVR group, the microbial ß-diversity of MAM, especially in the ascending colon, differed from the control group and was associated with liver fibrosis progression. In PICRUSt analysis, MAM in the ascending colon in the liver cirrhosis (LC) group showed compromised functions associated with the intestinal barrier and bile acid production, and FGF19 expression was markedly decreased in the terminal ileum biopsy tissue in the LC group. At the genus level, six short-chain fatty acid (SCFA)-producing bacterial genera, Blautia, Alistipes, Roseburia, Agathobaculum, Dorea, and Pseudoflavonifractor were reduced in the ascending colon of post-SVR LC patients. Conclusion: In patients of HCV post-SVR, we identified the association between the degree of liver fibrosis and dysbiosis of mucosa-associated SCFA-producing bacterial genera that may be related to intestinal barrier and bile acid production in the ascending colon.

Rapid multiplex real-time PCR assay using a portable device for the detection of oral pathogens.

Colonization by several oral pathogens and the onset of oral diseases, such as dental caries and periodontal diseases, are closely related. Therefore, the analysis of pathogens in oral specimens would be helpful for the risk assessment of oral diseases. We developed a rapid multiplex real-time polymerase chain reaction (PCR) method using a portable device and newly designed probe/primer sets to detect the oral pathogens Streptococcus mutans, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. The theoretical minimum detectable cell numbers of S. mutans, P. gingivalis, T. denticola, and T. forsythia were 1, 1, 4, and 3, respectively. The multiplex real-time PCR system simultaneously detected the colonization of S. mutans and P. gingivalis in human saliva. These results suggest that the multiplex real-time PCR system may be useful for the risk assessment of oral diseases.

Effectiveness of non-pharmacological interventions to prevent anemia in pregnant women: a quantitative systematic review protocol.

OBJECTIVE: This review aims to identify the effectiveness of non-pharmacological interventions in preventing iron deficiency anemia in pregnant women with a normal course of pregnancy. INTRODUCTION: The global prevalence of anemia among pregnant women is 36.5%, posing risks to women and fetuses. This underscores the need for effective prevention; however, the effectiveness of non-pharmacological approaches in preventing pregnancy anemia remains unclear. INCLUSION CRITERIA: This review will encompass experimental and quasi-experimental studies on the following approaches to prevent anemia during pregnancy: recommendations for dietary supplements, oral iron supplements (over the counter), provision of supplements to promote iron absorption, participation in anemia prevention education, and provision of information. There will be no restrictions on the duration or frequency of intervention, and longitudinal intervention studies will be included. In studies with a control group, the comparator may be usual care or pharmacological interventions; in studies without, it may involve no intervention, temporal comparisons, or baseline periods without non-pharmacological interventions. Evaluation of hemoglobin, hematocrit, and ferritin will be included as primary outcomes. Low birth weight, preterm birth, amount of blood loss at delivery, small for gestational age, and Apgar scores will be included as secondary outcomes. METHODS: A search will be conducted of MEDLINE (Ovid), Embase, CINAHL (EBSCOhost), Scopus, Australian New Zealand Clinical Trials Registry, Cochrane Central Register of Controlled Trials, and ICHUSHI-Web. Researchers will screen studies, extract data, assess the quality of studies, and analyze the data in accordance with the JBI guidance for systematic reviews of effectiveness. GRADE will be used to assess the certainty of the findings. REVIEW REGISTRATION NUMBER: PROSPERO CRD42022344155.

Rescue of murine hind limb ischemia via angiogenesis and lymphangiogenesis promoted by cellular communication network factor 2.

Critical limb ischemia (CLI) is caused by severe arterial blockage with reduction of blood flow. The aim of this study was to determine whether therapeutic angiogenesis using cellular communication network factor 2 (CCN2) would be useful for treating CLI in an animal model. Recombinant CCN2 was administered intramuscularly to male C57BL/6J mice with hind limb ischemia. The therapeutic effect was evaluated by monitoring blood flow in the ischemic hind limb. In an in vivo assay, CCN2 restored blood flow in the ischemic hind limb by promoting both angiogenesis and lymphangiogenesis. VEGF-A and VEGF-C expression levels increased in the ischemic limb after treatment with CCN2. In an in vitro assay, CCN2 promoted proliferation of vascular and lymphatic endothelial cells, and it upregulated expression of Tgfb1 followed by expression of Vegfc and Vegfr3 in lymphatic endothelial cells under hypoxia. Suppression of Tgfb1 did not affect the activity of CCN2, activation of the TGF-ß/SMAD signaling pathway, or expression of Vegfr3 in lymphatic endothelial cells. In summary, treatment using recombinant CCN2 could be a promising therapeutic strategy for CLI.

[Cingulate seizure as a clinical manifestation of anti-myelin oligodendrocyte glycoprotein antibody-positive cerebral cortical encephalitis of two cases].

We report two male patients who had a sensory seizure, which evolved into a focal impaired awareness tonic seizure, and after that, focal to bilateral tonic-clonic seizure. The first case, a 20-year-old man had been treated with steroids for anti-myelin oligodendrocyte glycoprotein (MOG) antibody-positive optic neuritis. His seizure started with abnormal sensation in the little finger of the left hand, which spread to the left upper and then to the left lower limb. The seizure then evolved into tonic seizures of the upper and lower limbs and he finally lost awareness. The second case, a 19-year-old man experienced floating dizziness while walking, followed by numbness and a pain-like electrical shock in the right upper limb. The right arm somatosensory seizure evolved into a right upper and lower limb tonic seizure, which spread to the bilateral limbs, and finally he lost awareness. Symptoms of both patients improved after the treatment with steroids. Both patients shared a similar high-intensity FLAIR lesion in the posterior midcingulate cortex. Both patients were diagnosed with MOG antibody-positive cerebral cortical encephalitis because of a positive titer of anti-MOG antibody in the serum. Several reports showed involvement of the cingulate gyrus in MOG antibody-positive cerebral cortical encephalitis, but only a few reported seizure semiology in detail. The semiology reported here is consistent with that of cingulate epilepsy or the findings of electrical stimulation of the cingulate cortex, namely, somatosensory (electric shock or heat sensation), motor (tonic posture), and vestibular symptoms (dizziness). Cingulate seizures should be suspected when patients show somatosensory seizures or focal tonic seizures. MOG antibody-positive cerebral cortical encephalitis should be considered as one of the differential diagnoses when the young patient shows the unique symptoms of an acute symptomatic cingulate seizure.

Factor Structure and Measurement and Structural Invariance of the Edinburgh Postnatal Depression Scale during the Perinatal Period among Japanese Women: What Is the Best Model?

The Edinburgh Postnatal Depression Scale (EPDS) is a widely used screening tool for perinatal depression. Its factor structure is still a debatable topic. Our study aimed to examine the factor structure and measurement invariances of the Japanese version of the EPDS from late pregnancy to early postpartum. A total of 633 women were followed with the EPDS at three times over the perinatal period: late pregnancy (n = 633), 5 days after childbirth (n = 445), and 1 month after childbirth (n = 392). We randomly divided the participants into two groups: one for exploratory factor analyses (EFAs) and another for confirmatory factor analyses (CFAs). The result of the EFAs indicated different factor models at each time point. Hence, CFAs were performed using the second sample set to compare different models including the ones previously reported. A 3-factor model consisting of depression (items 7, 9), anxiety (items 4, 5), and anhedonia (items 1, 2) (Kubota et al., 2018) was consistently stable during the whole perinatal period. Kubota's 3-factor model showed invariance across the perinatal period.

Differentiation of human adipose tissue-derived mesenchymal stromal cells into steroidogenic cells by adenovirus-mediated overexpression of NR5A1 and implantation into adrenal insufficient mice.

BACKGROUND AIMS: Cell therapy for adrenal insufficiency is a potential method for physiological glucocorticoid and mineralocorticoid replacement. We have previously shown that mouse mesenchymal stromal cells (MSCs) differentiated into steroidogenic cells by the viral vector-mediated overexpression of nuclear receptor subfamily 5 group A member 1 (NR5A1), an essential regulator of steroidogenesis, and their implantation extended the survival of bilateral adrenalectomized (bADX) mice. METHODS: In this study, we examined the capability of NR5A1-induced steroidogenic cells prepared from human adipose tissue-derived MSCs (MSC [AT]) and the therapeutic effect of the implantation of human NR5A1-induced steroidogenic cells into immunodeficient bADX mice. RESULTS: Human NR5A1-induced steroidogenic cells secreted adrenal and gonadal steroids and exhibited responsiveness to adrenocorticotropic hormone and angiotensin II in vitro. In vivo, the survival time of bADX mice implanted with NR5A1-induced steroidogenic cells was significantly prolonged compared with that of bADX mice implanted with control MSC (AT). Serum cortisol levels, which indicate hormone secretion from the graft, were detected in bADX mice implanted with steroidogenic cells. CONCLUSIONS: This is the first report to demonstrate steroid replacement by the implantation of steroid-producing cells derived from human MSC (AT). These results indicate the potential of human MSC (AT) to be a source of steroid hormone-producing cells.

Utility of balanced steady-state field precession sequence in the evaluation of retinal and subdural hemorrhages in patients with abusive head trauma.

Abusive head trauma is the leading cause of physical child abuse deaths in children under 5 years of age in the United States. To evaluate suspected child abuse, radiologic studies are typically the first to identify hallmark findings of abusive head trauma including intracranial hemorrhage, cerebral edema, and ischemic injury. Prompt evaluation and diagnosis are necessary as findings may change rapidly. Current imaging recommendations include brain magnetic resonance imaging with the addition of a susceptibility weighted imaging (SWI) sequence which can detect additional findings that suggest abusive head trauma including cortical venous injury and retinal hemorrhages. However, SWI is limited due to blooming artifacts and artifacts from the adjacent skull vault or retroorbital fat, which can affect the evaluation of retinal, subdural, and subarachnoid hemorrhages. This work explores the utility of the high-resolution, heavily T2 weighted balanced steady-state field precession (bSSFP) sequence to identify and characterize retinal hemorrhage and cerebral cortical venous injury in children with abusive head trauma. The bSSFP sequence provides distinct anatomical images to improve the identification of retinal hemorrhage and cortical venous injury.

The mouse model of intellectual disability by ZBTB18/RP58 haploinsufficiency shows cognitive dysfunction with synaptic impairment.

ZBTB18/RP58 (OMIM *608433) is one of the pivotal genes responsible for 1q43q44 microdeletion syndrome (OMIM #612337) and its haploinsufficiency induces intellectual disability. However, the underlying pathological mechanism of ZBTB18/RP58 haploinsufficiency is unknown. In this study, we generated ZBTB18/RP58 heterozygous mice and found that these mutant mice exhibit multiple behavioral deficits, including impairment in motor learning, working memory, and memory flexibility, which are related to behaviors in people with intellectual disabilities, and show no gross abnormalities in their cytoarchitectures but dysplasia of the corpus callosum, which has been reported in certain population of patients with ZBTB18 haploinsufficiency as well as in those with 1q43q44 microdeletion syndrome, indicating that these mutant mice are a novel model of ZBTB18/RP58 haploinsufficiency, which reflects heterozygotic ZBTB18 missense, truncating variants and some phenotypes of 1q43q44 microdeletion syndrome based on ZBTB18/RP58 haploinsufficiency. Furthermore, these mice show glutamatergic synaptic dysfunctions, including a reduced glutamate receptor expression, altered properties of NMDA receptor-mediated synaptic responses, a decreased saturation level of long-term potentiation of excitatory synaptic transmission, and distinct morphological characteristics of the thick-type spines. Therefore, these results suggest that ZBTB18/RP58 haploinsufficiency leads to impaired excitatory synaptic maturation, which in turn results in cognitive dysfunction in ZBTB18 haploinsufficiency.

Development of an in vitro biofilm formation model for screening anti-periodontal disease agents.

PURPOSE: To devise a method for artificial biofilm formation using Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, and Streptococcus gordonii, as well as a method for evaluating the effects of various ingredients on the artificial biofilm. METHODS: An artificial biofilm was developed using P. gingivalis, T. forsythia, T. denticola, and S. gordonii, which was then observed using scanning electron microscopy and evaluated by microflora analysis. The artificial biofilm was exposed to chlorhexidine gluconate and stained with a fluorescent dye. Then, the fluorescent-stained biofilm was observed using a confocal laser microscope and measured using a fluorescent microplate reader. RESULTS: The microflora analysis confirmed that the culture medium developed was capable of culturing four different bacterial species at the same time. The distribution of dead bacteria differed according to the difference in the concentration of exposed chlorhexidine gluconate. Moreover, the rate of attachment of viable cells decreased in a concentration-dependent manner. Many bacteria were detached from the biofilm in the group exposed to 0.09% chlorhexidine gluconate. Exposure to chlorhexidine gluconate induced a concentration-dependent decrease in living microorganisms and an increase in dead microorganisms in the biofilm. CLINICAL SIGNIFICANCE: The results of this study revealed that S. gordonii, P. gingivalis, T. forsythia, and T. denticola could be used to develop artificial biofilms. The effects of chlorhexidine gluconate on the biofilm showed that evaluating the change in the artificial biofilm caused by the component effect in the experiments was possible via exposure to chlorhexidine gluconate. This method can efficiently evaluate the component effect and has a high potential for use as an indicator. This study demonstrated that this simulation could help develop preventive measures.

Preclinical study for the treatment of diabetes mellitus using ß-like cells derived from human dental pulp stem cells.

Aim: The current study assessed whether insulin-producing cells obtained from dental pulp stem cells (DPSCs) can be a new therapeutic approach in a rat model of diabetes mellitus (DM). Materials & methods: Stem cells were differentiated into pancreatic ß cells under hydrogen sulfide exposure via 2D and 3D methods. Each ß-like cell was immunostained and transplanted into DM rats, after which the in vivo therapeutic effect was determined. Results: Immunostaining revealed the expression of various ß-cell markers in each ß-like cell differentiated using the 3D method. DPSC-derived ß-like cell differentiated via the 3D method promoted a sufficient therapeutic effect. Conclusion: The 3D method promoted islet differentiation, indicating that DPSC-derived ß-like cell transplantation could be a new approach for DM treatment.

A rare case of eosinophilic gastritis induced by nivolumab therapy for metastatic melanoma.

Cancer immunotherapy using immune checkpoint inhibitors can cause immune reactions at various sites as a side effect called immune-related adverse events (irAEs). The gastrointestinal tract is susceptible to irAEs, however, the degree and presentation vary considerably from case to case. A 76-year-old woman was diagnosed with anal mucosal melanoma. She underwent radical surgery and received postoperative adjuvant therapy. However, because new metastases were also found in bilateral inguinal lymph nodes, immunotherapy with nivolumab was performed. Approximately 10 months after the initiation of nivolumab administration, she presented with epigastric discomfort and nausea, and her laboratory data showed severe eosinophilia (1938/mm3). Computed tomography demonstrated a diffuse thickening of the gastric wall. Esophagogastroduodenoscopy and endoscopic ultrasonography showed mucosal thickening due to edema, and histologic examination revealed severe invasion of eosinophils in the lamina propria. Subsequently, she was diagnosed with eosinophilic gastritis due to irAEs induced by nivolumab. Oral administration of prednisolone rapidly normalized her endoscopic and histologic findings, dramatically reducing her symptoms. This is a very rare and important case report of nivolumab-induced severe eosinophilic gastritis. Although gastric lesions as IrAEs is rare, it is necessary to differentiate eosinophilic gastritis if unexplained nausea occurred during the administration of immune checkpoint inhibitors.

Induction of potassium channel regulator KCNE4 in a submandibular lymph node metastasis model.

Cancer cells often metastasize to the lymph nodes (LNs) before disseminating throughout the body. Clinically, LN metastasis correlates with poor prognosis and influences treatment options. Many studies have shown that cancer cells communicate with immune and stromal cells to prepare a suitable niche for metastasis. In this study, mice were injected with B16-F10 murine melanoma cells to generate a tongue submandibular lymph node (SLN) metastasis model in which genes of interest could be investigated. Microarray analyses were performed on SLNs, identifying 162 upregulated genes, some of which are known metastasis genes. Among these upregulated genes, Kcne4, Slc7a11, Fscn1, and Gadd45b were not associated with metastasis, and increased expression of Kcne4 and Slc7a11 was confirmed by real-time PCR and immunohistochemistry. The roles of KCNE4 in chemokine production and cell adhesion were examined using primary lymphatic endothelial cells, and demonstrated that Ccl17 and Ccl19, which are involved in melanoma metastasis, were upregulated by KCNE4, as well as Mmp3 matrix metalloproteinase. Expression of KCNE4 was detected in human LNs with metastatic melanoma. In conclusion, we found that LN metastatic melanoma induces KCNE4 expression in the endothelium of LNs.

Transcription factor NTL9 negatively regulates Arabidopsis vascular cambium development during stem secondary growth.

In plant stems, secondary vascular development is established through the differentiation of cylindrical vascular cambium, producing secondary xylem (wood) and phloem (bast), which have economic importance. However, there is a dearth of knowledge on the genetic mechanism underlying this process. NAC with Transmembrane Motif 1-like transcription factor 9 (NTL9) plays a central role in abiotic and immune signaling responses. Here, we investigated the role of NTL9 in vascular cambium development in Arabidopsis (Arabidopsis thaliana) inflorescence stems by identifying and characterizing an Arabidopsis phloem circular-timing (pct) mutant. The pct mutant exhibited enhanced vascular cambium formation following secondary phloem production. In the pct mutant, although normal organization in vascular bundles was maintained, vascular cambium differentiation occurred at an early stage of stem development, which was associated with increased expression of cambium-/phloem-related genes and enhanced cambium activity. The pct mutant stem phenotype was caused by a recessive frameshift mutation that disrupts the transmembrane (TM) domain of NTL9. Our results indicate that NTL9 functions as a negative regulator of cambial activity and has a suppressive role in developmental transition to the secondary growth phase in stem vasculature, which is necessary for its precise TM domain-mediated regulation.

The Effects of Preoperative Administration of Erythropoietin in Pediatric Patients Undergoing Cranial Vault Remodeling for Craniosynostosis.

BACKGROUND AND PURPOSE: Over 90% of patients undergoing cranial vault remodeling for craniosynostosis receive blood transfusions to compensate for intraoperative blood loss. However, transfusions are not without risk and can lead to allergic and immune transfusion reactions as well as rare cases of infectious transmissions. Preoperative use of erythropoietin in cranial vault remodeling has been demonstrated to be safe and to reduce transfusion requirements in prior studies. This study's purpose is to add to the body of data supporting the safe use of a protocolized erythropoietin alfa regimen before cranial vault remodeling and strip craniectomy procedures with decreased blood transfusion requirements and other favorable outcomes. METHODS: A retrospective chart review was performed on patients who underwent cranial vault remodeling between 2006 and 2021 at our tertiary care center. Two groups were identified: in the first, preoperative erythropoietin was administered under protocol; and in the second, preoperative erythropoietin was not administered. The groups were compared with respect to age, perioperative hemoglobin levels, estimated blood loss during surgery, packed red blood cell transfusion volume, length of hospital stay, and length of surgery. RESULTS: Demographics were not significantly different in terms of age, weight, diagnosis, gender, and type of procedure. Patients who were administered preoperative erythropoietin were found to have significantly increased preoperative hemoglobin levels (13.6 versus 12.3 g/dL), as well as decreased estimated intraoperative blood loss (376 versus 1099 mL), the volume of packed red blood cells transfused (316 versus 897 mL), length of hospital stay, and length of surgery. Postoperative hemoglobin levels were not found to be significantly different. CONCLUSIONS: In this study, preoperative administration of erythropoietin with elemental iron was beneficial for patients undergoing cranial vault remodeling for craniosynostosis. Specifically, it decreased the need for red blood cell transfusion, intraoperative blood loss, and length of hospital stay. No adverse events were recorded in the treatment arm. Further studies may include a separate group administered iron alone.

Inhibition of NR5A1 Phosphorylation Alleviates a Transcriptional Suppression Defect Caused by a Novel NR0B1 Mutation.

Context: Mutations in the NR0B1 gene, also well-known as the DAX1 gene, are known to cause congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism. The abnormal NR0B1 protein fails to suppress the transcription of promoters of steroidogenic enzymes, which are also targets of NR5A1 protein, also well-known as Ad4BP/SF-1 protein. Since NR5A1 and NR0B1 have antagonistic effects on steroidogenesis, the loss of function due to NR0B1 mutations may be compensated by inducing loss of function of NR5A1 protein. Patient: A middle-aged man was diagnosed with congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism and genetic analysis revealed him to have a novel NR0B1 mutation, c.1222C>T(p.Gln408Ter). Methods: NR0B1 activity was evaluated in CLK1/4 inhibitor-treated 293T cells via immunoblotting and luciferase assays of the STAR promoter. Results: TG003 treatment suppressed NR5A1 protein function to compensate for the mutant NR0B1 showing inhibited suppression of transcription. Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor. Conclusion: The specific reduction of NR5A1 phosphorylation by a CLK1/4 inhibitor may alleviate developmental defects in patients with NR0B1 mutations.

CCN2-induced lymphangiogenesis is mediated by the integrin αvß5-ERK pathway and regulated by DUSP6.

Lymphangiogenesis is essential for the development of the lymphatic system and is important for physiological processes such as homeostasis, metabolism and immunity. Cellular communication network factor 2 (CCN2, also known as CTGF), is a modular and matricellular protein and a well-known angiogenic factor in physiological and pathological angiogenesis. However, its roles in lymphangiogenesis and intracellular signaling in lymphatic endothelial cells (LECs) remain unclear. Here, we investigated the effects of CCN2 on lymphangiogenesis. In in vivo Matrigel plug assays, exogenous CCN2 increased the number of Podoplanin-positive vessels. Subsequently, we found that CCN2 induced phosphorylation of ERK in primary cultured LECs, which was almost completely inhibited by the blockade of integrin αvß5 and partially decreased by the blockade of integrin αvß3. CCN2 promoted direct binding of ERK to dual-specific phosphatase 6 (DUSP6), which regulated the activation of excess ERK by dephosphorylating ERK. In vitro, CCN2 promoted tube formation in LECs, while suppression of Dusp6 further increased tube formation. In vivo, immunohistochemistry also detected ERK phosphorylation and DUSP6 expression in Podoplanin-positive cells on CCN2-supplemented Matrigel. These results indicated that CCN2 promotes lymphangiogenesis by enhancing integrin αvß5-mediated phosphorylation of ERK and demonstrated that DUSP6 is a negative regulator of excessive lymphangiogenesis by CCN2.

Cliniatines A-C, new Amaryllidaceae alkaloids from Clivia miniata, inhibiting Acetylcholinesterase.

Cliniatines A-C (1-3), three new Amaryllidaceae alkaloids, consisting of 2,6-dimetylpyridine and lycorine-type and/or galanthamine-type were isolated from Clivia miniata (Lindl.) Bosse. The structures and absolute configurations of 1-3 were elucidated based on spectroscopic data and chemical correlation. Cliniatines A-C showed moderate inhibitory activity against acetylcholinesterase.

High-sucrose diets contribute to brain angiopathy with impaired glucose uptake and psychosis-related higher brain dysfunctions in mice.

Metabolic dysfunction is thought to contribute to the severity of psychiatric disorders; however, it has been unclear whether current high­simple sugar diets contribute to pathogenesis of these diseases. Here, we demonstrate that a high-sucrose diet during adolescence induces psychosis-related behavioral endophenotypes, including hyperactivity, poor working memory, impaired sensory gating, and disrupted interneuron function in mice deficient for glyoxalase-1 (GLO1), an enzyme involved in detoxification of sucrose metabolites. Furthermore, the high-sucrose diet induced microcapillary impairments and reduced brain glucose uptake in brains of Glo1-deficient mice. Aspirin protected against this angiopathy, enhancing brain glucose uptake and preventing abnormal behavioral phenotypes. Similar vascular damage to our model mice was found in the brains of randomly collected schizophrenia and bipolar disorder patients, suggesting that psychiatric disorders are associated with angiopathy in the brain caused by various environmental stresses, including metabolic stress.