Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells.

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments

Culturally adaptive storytelling intervention versus didactic intervention to improve hypertension control in Vietnam- 12 month follow up results: A cluster randomized controlled feasibility trial

INTRODUCTION: Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. The country needs novel, large-scale, and sustainable interventions to improve hypertension control. We report the 12 month follow-up results of a cluster randomized feasibility trial in Hung Yen province, Vietnam, which evaluated the feasibility and acceptability of two community-based interventions to improve hypertension control: a storytelling and a didactic intervention. METHODS: The storytelling intervention included stories in the patients\u27 own words about coping with hypertension and didactic content about the importance of healthy lifestyle behaviors in controlling elevated blood pressure levels. The didactic intervention included only didactic content, which were general recommendations for managing several important risk factors for hypertension and other non-communicable diseases. The storytelling intervention was delivered by two DVDs three months apart; the didactic intervention included only one DVD. The trial was conducted in patients with poorly controlled hypertension from 4 communes (communities), which were equally randomized to the two interventions. RESULTS: The mean age of the 160 patients was 66 years and 54% were men. Between baseline enrollment and the 12 month follow-up, mean systolic blood pressure declined by 10.8 mmHg (95% CI: 6.5-14.9) in the storytelling group and by 5.8 mmHg (95% CI: 1.6-10.0) in the didactic content group. The storytelling group also experienced more improvement in several health behaviors, including increased levels of physical activity and reduced consumption of salt and alcohol. CONCLUSIONS: We observed considerable long-term beneficial effects of both interventions, especially of our storytelling intervention, among patients with inadequately controlled hypertension. A large scale randomized trial should more systematically compare the short and long-term effectiveness of the two interventions in controlling hypertension. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02483780

Culturally adaptive storytelling intervention versus didactic intervention to improve hypertension control in Vietnam: a cluster-randomized controlled feasibility trial

BACKGROUND: Vietnam is experiencing an epidemiologic transition with an increased prevalence of non-communicable diseases. Novel, large-scale, effective, and sustainable interventions to control hypertension in Vietnam are needed. We report the results of a cluster-randomized feasibility trial at 3 months follow-up conducted in Hung Yen province, Vietnam, designed to evaluate the feasibility and acceptability of two community-based interventions to improve hypertension control: a storytelling intervention, We Talk about Our Hypertension, and a didactic intervention. METHODS: The storytelling intervention included stories about strategies for coping with hypertension, with patients speaking in their own words, and didactic content about the importance of healthy lifestyle behaviors including salt reduction and exercise. The didactic intervention included only didactic content. The storytelling intervention was delivered by two DVDs at 3-month intervals; the didactic intervention included only one installment. The trial was conducted in four communes, equally randomized to the two interventions. RESULTS: The mean age of the 160 study patients was 66 years, and 54% were men. Most participants described both interventions as understandable, informative, and motivational. Between baseline and 3 months, mean systolic blood pressure declined by 8.2 mmHg (95% CI 4.1-12.2) in the storytelling group and by 5.5 mmHg (95% CI 1.4-9.5) in the didactic group. The storytelling group also reported a significant increase in hypertension medication adherence. CONCLUSIONS: Both interventions were well accepted in several rural communities and were shown to be potentially effective in lowering blood pressure. A large-scale randomized trial is needed to compare the effectiveness of the two interventions in controlling hypertension. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02483780

Root-colonizing bacteria enhance the levels of (E)-β-caryophyllene produced by maize roots in response to rootworm feeding.

When larvae of rootworms feed on maize roots they induce the emission of the sesquiterpene (E)-β-caryophyllene (EβC). EβC is attractive to entomopathogenic nematodes, which parasitize and rapidly kill the larvae, thereby protecting the roots from further damage. Certain root-colonizing bacteria of the genus Pseudomonas also benefit plants by promoting growth, suppressing pathogens or inducing systemic resistance (ISR), and some strains also have insecticidal activity. It remains unknown how these bacteria influence the emissions of root volatiles. In this study, we evaluated how colonization by the growth-promoting and insecticidal bacteria Pseudomonas protegens CHA0 and Pseudomonas chlororaphis PCL1391 affects the production of EβC upon feeding by larvae of the banded cucumber beetle, Diabrotica balteata Le Conte (Coleoptera: Chrysomelidae). Using chemical analysis and gene expression measurements, we found that EβC production and the expression of the EβC synthase gene (tps23) were enhanced in Pseudomonas protegens CHA0-colonized roots after 72 h of D. balteata feeding. Undamaged roots colonized by Pseudomonas spp. showed no measurable increase in EβC production, but a slight increase in tps23 expression. Pseudomonas colonization did not affect root biomass, but larvae that fed on roots colonized by P. protegens CHA0 tended to gain more weight than larvae that fed on roots colonized by P. chlororaphis PCL1391. Larvae mortality on Pseudomonas spp. colonized roots was slightly, but not significantly higher than on non-colonized control roots. The observed enhanced production of EβC upon Pseudomonas protegens CHA0 colonization may enhance the roots' attractiveness to entomopathogenic nematodes, but this remains to be tested

Magnetic resonance imaging characteristics of LGI1-antibody and CASPR2-antibody encephalitis

Importance Rapid and accurate diagnosis of autoimmune encephalitis encourages prompt initiation of immunotherapy toward improved patient outcomes. However, clinical features alone may not sufficiently narrow the differential diagnosis, and awaiting autoantibody results can delay immunotherapy. Objective To identify simple magnetic resonance imaging (MRI) characteristics that accurately distinguish 2 common forms of autoimmune encephalitis, LGI1- and CASPR2-antibody encephalitis (LGI1/CASPR2-Ab-E), from 2 major differential diagnoses, viral encephalitis (VE) and Creutzfeldt-Jakob disease (CJD). Design, Setting, and Participants This cross-sectional study involved a retrospective, blinded analysis of the first available brain MRIs (taken 2000-2022) from 192 patients at Oxford University Hospitals in the UK and Mayo Clinic in the US. These patients had LGI1/CASPR2-Ab-E, VE, or CJD as evaluated by 2 neuroradiologists (discovery cohort; n = 87); findings were validated in an independent cohort by 3 neurologists (n = 105). Groups were statistically compared with contingency tables. Data were analyzed in 2023. Main Outcomes and Measures MRI findings including T2 or fluid-attenuated inversion recovery (FLAIR) hyperintensities, swelling or volume loss, presence of gadolinium contrast enhancement, and diffusion-weighted imaging changes. Correlations with clinical features. Results Among 192 participants with MRIs reviewed, 71 were female (37%) and 121 were male (63%); the median age was 66 years (range, 19-92 years). By comparison with VE and CJD, in LGI1/CASPR2-Ab-E, T2 and/or FLAIR hyperintensities were less likely to extend outside the temporal lobe (3/42 patients [7%] vs 17/18 patients [94%] with VE; P  Conclusions and Relevance In this study, T2 and/or FLAIR hyperintensities confined to the temporal lobes, without diffusion restriction or contrast enhancement, robustly distinguished LGI1/CASPR2-Ab-E from key differential diagnoses. These observations should assist clinical decision-making toward expediting immunotherapy. Their generalizability to other forms of autoimmune encephalitis and VE should be examined in future studies

Age- and Sex-Specific Analyses of Diet Quality and 4-Year Weight Change in Nonobese Adults Show Stronger Associations in Young Adulthood

Background: Although the general importance of diet quality in the prevention of unintentional weight gain is known, it is unknown whether its influence is age or sex dependent. Objective: The aim of this study was to investigate whether the strength of the association between diet quality and 4-y weight change was modified by age and sex. Methods: From the Dutch population-based Lifelines Cohort, 85,618 nonobese adult participants (age 18-93 y), recruited between 2006 and 2013, were included in the study. At baseline, diet was assessed with a 110-item food-frequency questionnaire. The Lifelines Diet Score, based on international evidence for diet-disease relations at the food group level, was calculated to assess diet quality. For analyses, the score was divided in quintiles (Qs). Body weight was objectively measured at baseline and after a median follow-up of 44 mo (25th-75th percentile: 35-51 mo). In between, body weight was self-reported twice. Linear mixed models were used to investigate the association between diet quality and weight change by sex and in 6 age categories (18-29, 30-39, 40-49, 50-59, 60-69, and ≥70 y). Results: Mean 4-y weight change decreased over age categories. Confounder-adjusted linear mixed models showed that the association between diet quality and weight change was modified by sex (P-interaction = 0.001). In women, the association was also modified by age (P-interaction = 0.001). Poor diet quality was most strongly associated with weight gain in the youngest men [Q1 compared with Q5: +0.33 kg/y (95% CI: 0.10, 0.56)] and women [+0.22 kg/y (95% CI: 0.07, 0.37)]. In contrast, in women aged ≥70 y, poor diet quality was associated with greater weight loss [-0.44 kg/y (95% CI: -0.84, -0.05)]. Conclusions: Poor diet quality was related to higher weight gain, especially in young adults. Oppositely, among women aged ≥70 y, poor diet quality was related to higher weight loss. Therefore, a healthful diet is a promising target for undesirable weight changes in both directions

Interlaboratory exercise for the analysis of carotenoids and related compounds in dried mango fruit (Mangifera indica L.)

An interlaboratory comparison was done for the analysis of carotenoids in freeze-dried mango. The study was performed from July to September 2018. Mango fruit was freeze-dried, homogenized, and packaged under vacuum conditions in portions of 6 g (test sample). Two test samples were sent to the participating laboratories for analysis. Laboratory results were rated using Z-scores in accordance with ISO 13528 and ISO 17043. The standard deviation for proficiency assessment (also called target standard deviation) was determined using a modified Horwitz function and varied between 10% and 25%, depending on the analyte. Out of 14 laboratories from 10 different countries, 9 laboratories (64%) obtained a satisfactory performance (Z ≤ 2) for the analysis of β-carotene. While for 7 laboratories that analyzed α-carotene, (9Z)-β-carotene, β-cryptoxanthin, and zeaxanthin, 4 laboratories (57%) obtained a satisfactory performance. However, only 2 laboratories out of 7 (29%) obtained a satisfactory performance for lutein. Based on the comparability of the analytical results, this study concludes that freeze-dried mango pulp can be used as a reference material for the analysis of α and β-carotene, (9Z)-β-carotene, β-cryptoxanthin, and zeaxanthin by applying different analytical procedures for their extraction and quantification

Broadly neutralizing antibodies abrogate established hepatitis C virus infection

In most exposed individuals, hepatitis C virus (HCV) establishes a chronic infection; this long-term infection in turn contributes to the development of liver diseases such as cirrhosis and hepatocellular carcinoma. The role of antibodies directed against HCV in disease progression is poorly understood. Neutralizing antibodies (nAbs) can prevent HCV infection in vitro and in animal models. However, the effects of nAbs on an established HCV infection are unclear. We demonstrate that three broadly nAbs—AR3A, AR3B, and AR4A—delivered with adeno-associated viral vectors can confer protection against viral challenge in humanized mice. Furthermore, we provide evidence that nAbs can abrogate an ongoing HCV infection in primary hepatocyte cultures and in a human liver chimeric mouse model. These results showcase a therapeutic approach to interfere with HCV infection by exploiting a previously unappreciated need for HCV to continuously infect new hepatocytes to sustain a chronic infection

Comparison of MRI lesion evolution in different central nervous system demyelinating disorders

Background and Objective: There are few studies that compare lesion evolution across different CNS demyelinating diseases, yet knowledge of this may be important for diagnosis and understanding differences in disease pathogenesis. We sought to compare MRI T2-lesion evolution in myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD), and multiple sclerosis (MS). Methods: In this descriptive study, we retrospectively identified Mayo Clinic patients with MOGAD, AQP4-IgG-NMOSD, or MS and: 1) brain or myelitis attack; 2) available attack MRI within 6 weeks; and 3) follow-up MRI beyond 6 months without interval relapses in that region. Two neurologists identified the symptomatic or largest T2-lesion for each patient (index lesion). MRIs were then independently reviewed by two neuroradiologists blinded to diagnosis to determine resolution of T2-lesions by consensus. The index T2-lesion area was manually outlined acutely and at follow-up to assess variation in size. Results: We included 156 patients (MOGAD, 38; AQP4-IgG-NMOSD, 51; MS, 67) with 172 attacks (brain, 81; myelitis, 91). The age (median [range]) differed between MOGAD (25 [2-74]), AQP4-IgG-NMOSD (53 [10-78]) and MS (37 [16-61]) (p<0.01) and female sex predominated in the AQP4-IgG-NMOSD (41/51 [80%]) and MS (51/67 [76%]) groups but not among those with MOGAD (17/38 [45%]). Complete resolution of the index T2-lesion was more frequent in MOGAD (brain, 13/18[72%]; spine, 22/28[79%]) than AQP4-IgG-NMOSD (brain, 3/21[14%]; spine, 0/34[0%]) and MS (brain, 7/42[17%]; spine, 0/29[0%]), p<0.001. Resolution of all T2-Lesions occurred most often in MOGAD (brain, 7/18[39%]; spine, 22/28[79%]) than AQP4-IgG-NMOSD (brain, 2/21[10%]; spine, 0/34[0%]), and MS (brain, 2/42[5%]; spine, 0/29[0%]), p< 0.01. There was a larger median (range) reduction in T2-lesion area in mm2 on follow-up axial brain MRI with MOGAD (213[55-873]) than AQP4-IgG-NMOSD (104[0.7-597]) (p=0.02) and MS, 36[0-506]) (p< 0.001) and the reductions in size on sagittal spine MRI follow-up in MOGAD (262[0-888]) and AQP4-IgG-NMOSD (309[0-1885]) were similar (p=0.4) and greater than MS (23[0-152]) (p<0.001)