Search

Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions.In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses.We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aβ status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts.Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.

Bispecific T cell engagers (BiTEs) are bispecific antibodies that redirect T cells to target antigen-expressing tumors. We hypothesized that BiTE-secreting T cells could be a valuable therapy in solid tumors, with distinct properties in mono- or multi-valent strategies incorporating chimeric antigen receptor (CAR) T cells. Glioblastomas represent a good model for solid tumor heterogeneity, representing a significant therapeutic challenge. We detected expression of tumor-associated epidermal growth factor receptor (EGFR), EGFR variant III, and interleukin-13 receptor alpha 2 (IL13Rα2) on glioma tissues and cancer stem cells. These antigens formed the basis of a multivalent approach, using a conformation-specific tumor-related EGFR targeting antibody (806) and Hu08, an IL13Rα2-targeting antibody, as the single chain variable fragments to generate new BiTE molecules. Compared with CAR T cells, BiTE T cells demonstrated prominent activation, cytokine production, and cytotoxicity in response to target-positive gliomas. Superior response activity was also demonstrated in BiTE-secreting bivalent T cells compared with bivalent CAR T cells in a glioma mouse model at early phase, but not in the long term. In summary, BiTEs secreted by mono- or multi-valent T cells have potent anti-tumor activity in vitro and in vivo with significant sensitivity and specificity, demonstrating a promising strategy in solid tumor therapy.

Supplementary Figure from Immunologic Features in De Novo and Recurrent Glioblastoma Are Associated with Survival Outcomes

Glioblastoma (GBM) is an immunologically “cold” tumor characterized by poor responsiveness to immunotherapy. Standard of care for GBM is surgical resection followed by chemoradiotherapy and maintenance chemotherapy. However, tumor recurrence is the norm, and recurring tumors are found frequently to have acquired molecular changes (e.g., mutations) that may influence their immunobiology. Here, we compared the immune contexture of de novo GBM and recurrent GBM (rGBM) using high-dimensional cytometry and multiplex IHC. Although myeloid and T cells were similarly abundant in de novo and rGBM, their spatial organization within tumors differed and was linked to outcomes. In rGBM, T cells were enriched and activated in perivascular regions and clustered with activated macrophages and fewer regulatory T cells. Moreover, a higher expression of phosphorylated STAT1 by T cells in these regions at recurrence was associated with a favorable prognosis. Together, our data identify differences in the immunobiology of de novo GBM and rGBM and identify perivascular T cells as potential therapeutic targets.See related Spotlight by Bayik et al., p. 787

Background Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease. There is no cure currently. The discovery that mutations in the gene SOD1 are a cause of ALS marks a breakthrough for the search of effective treatments for ALS. SOD1 is an antioxidant that is highly expressed in motor neurons. Human SOD1 is prone to aberrant modifications. Familial ALS-linked SOD1 variants are particularly susceptible to aberrant modifications. Once modified, SOD1 undergoes conformational changes and becomes misfolded. This study aims to determine the effect of selective removal of misfolded SOD1 on the pathogenesis of ALS. Methods Based on chaperone-mediated protein degradation pathway, we designed a fusion peptide named CT4, and tested its efficiency in knocking down intracellularly misfolded SOD1 and its efficacy in modifying pathogenesis of ALS. Results Expression of plasmid carrying the CT4 sequence in human HEK cells resulted in robust removal of misfolded SOD1 induced by serum deprivation. Co-transfection of the CT4 and the human SOD1 G93A plasmids at various ratios in rat PC12 cells demonstrated a dose-dependent knockdown efficiency on G93A, which could be further increased when misfolding of SOD1 was enhanced by serum deprivation. Application of the full length CT4 peptide to primary cultures of neurons expressing the G93A variant of human SOD1 revealed a time-course of the degradation of misfolded SOD1; misfolded SOD1 started to decrease by 2 h after the application of CT4 and disappeared by 7 h. Intravenous administration of the CT4 peptide at 10 mg/kg to the G93A mice at the age of 4 months old induced reduction of human SOD1 in spinal cord tissue by 68% in 24 h and 54% in 48 h. Intraperitoneal administration of the CT4 peptide starting from 60 days of age significantly delayed the onset of ALS and prolonged the lifespan of the G93A mice. Conclusions The CT4 peptide directs degradation of misfolded SOD1 in high efficiency and specificity. Selective removal of misfolded SOD1 significantly delays the onset of ALS, demonstrating that misfolded SOD1 is the toxic form of SOD1 that causes motor neuron death. The study provides a proof of concept that selective removal of misfolded SOD1 is a promising treatment for ALS.

Glioblastoma (GBM) is an immunologically “cold” tumor characterized by poor responsiveness to immunotherapy. Standard of care for GBM is surgical resection followed by chemoradiotherapy and maintenance chemotherapy. However, tumor recurrence is the norm, and recurring tumors are found frequently to have acquired molecular changes (e.g., mutations) that may influence their immunobiology. Here, we compared the immune contexture of de novo GBM and recurrent GBM (rGBM) using high-dimensional cytometry and multiplex IHC. Although myeloid and T cells were similarly abundant in de novo and rGBM, their spatial organization within tumors differed and was linked to outcomes. In rGBM, T cells were enriched and activated in perivascular regions and clustered with activated macrophages and fewer regulatory T cells. Moreover, a higher expression of phosphorylated STAT1 by T cells in these regions at recurrence was associated with a favorable prognosis. Together, our data identify differences in the immunobiology of de novo GBM and rGBM and identify perivascular T cells as potential therapeutic targets. See related Spotlight by Bayik et al., p. 787

We analyze transposable elements (TEs) in glioblastoma (GBM) patients using a proteogenomic pipeline that combines single-cell transcriptomics, bulk RNA sequencing (RNA-seq) samples from tumors and healthy-tissue cohorts, and immunopeptidomic samples. We thus identify 370 human leukocyte antigen (HLA)-I-bound peptides encoded by TEs differentially expressed in GBM. Some of the peptides are encoded by repeat sequences from intact open reading frames (ORFs) present in up to several hundred TEs from recent long interspersed nuclear element (LINE)-1, long terminal repeat (LTR), and SVA subfamilies. Other HLA-I-bound peptides are encoded by single copies of TEs from old subfamilies that are expressed recurrently in GBM tumors and not expressed, or very infrequently and at low levels, in healthy tissues (including brain). These peptide-coding, GBM-specific, highly recurrent TEs represent potential tumor-specific targets for cancer immunotherapies., We thank all the U932 members, Olivier Lantz, Maude Delost, Nathalie Amzallag, and Florence Faure, for helpful discussions. Also, we are grateful to Joshua J. Waterfall for helpful discussion and bioinformatics advice. In addition, we thank the core facilities at Curie Institute, including the Bioinformatics groups. S.A. received funding from the Institut Curie, Institut National de la Sante´ et de la Recherche Me´ dicale, and Centre National de la Recherche Scientifique. This work has received support under the program « Investissements d’Avenir » launched by the French Government. We thank the Ligue Nationale Contre Le Cancer for the fellowship to Y.A.A.

In the context of climate change, this study uncovers the role of green airlines’ social responsibility in conjunction with the consumers’ switching behavior while considering the effects of latent variables, including green psychology, airline corporate image, green experimental behavior, green service fairness, green alternative attractiveness and switching intention, were examined in the study. In a highly competitive service environment, an organization needs to understand how passengers perceive its corporate image, satisfaction, fairness attractiveness, and behavior of switching intention. The predicted relationship was based on partial least squares structural equation modeling of a convenience sample of 615 valid datasets collected from individuals who used green airline services in China. The findings show that the psychological benefit of greenness, only warm glow, is the main driver of airline corporate image. Furthermore, airline corporate image, green service fairness, and green alternative attractiveness support passengers’ green experiential satisfaction. The evidence demonstrates that green experiential satisfaction and green alternative attractiveness have significantly positive effects on switching intention. However, green service fairness has no significant effect on green switching intention. This study contributes to the literature by understanding airline customers’ perception of the complex relationship in the green constructs. This finding can help marketers facilitate and develop their external communication and craft their image to retain their existing or potential customers.

With the rapid development of niche tourism, green tourism activity has become known to the wider public. By taking into account the extended theory of planned behaviour (TPB), this study takes natural dyeing experience as a case study, with the aim of determining the tourist purchase intention of green products under the destination experience scenario. A quantitative approach was adopted, and 349 valid sets of data were collected from individuals who have participated in natural dyeing activities. Partial least squares–structural equation modelling (PLS–SEM) analysis was conducted to test the conceptual model. The results indicate that experience value (EV) had a significant impact on green purchase conception and intention. In addition, subjective norm had a significant positive influence on tourism green purchase attitude. However, environmental knowledge failed to predict green purchase attitude and perceived behavioural control. The PLS–SEM analysis confirmed the extended TPB model, which showed relatively good predictive validity. Findings suggest that TPB mediated the relationship between EV and purchase intention. The extended model considerably contributes to improving understanding of the impact on green tourism products and dissects theoretical and practical implications to practitioners. Apart from strengthening the experience value from attaining, learning, escapism, and fantasy aspects, on the basis of previous literature, this study concludes that practically, environmental education regarding the experimental environment in tourism destinations in China should return to green activity itself and induce the support of green tourism products. Tourism marketers should trigger personal green knowledge through sense experience in the process of stimulating and promoting green tourism activities, as well as stimulate purchasing power.

ObjectiveAccurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology.MethodsThis case-control study evaluated CSF NfL, total tau, phosphorylated tau, and β-amyloid1-42 in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148). Regression analyses related CSF analytes to longitudinal cognitive decline (follow-up ∼1 year), controlling for demographic variables and core AD CSF analytes.ResultsIn FTLD-TDP with known pathology, CSF NfL is significantly elevated compared with controls and significantly associated with longitudinal decline on specific executive and language measures, after controlling for age, disease duration, and core AD CSF analytes. Similar findings are found in the extended cohort, also including clinically identified likely FTLD-TDP. Although CSF NfL is elevated in FTLD-tau compared with controls, the association between NfL and longitudinal cognitive decline is limited to executive measures.ConclusionCSF NfL is associated with longitudinal clinical decline in relevant cognitive domains in patients with FTLD-TDP after controlling for demographic factors and core AD CSF analytes and may also be related to longitudinal decline in executive functioning in FTLD-tau.

Dopamine is an important neuromodulator involved in reward-processing, movement control, motivational responses, and other aspects of behaviour in most animals. In honey bees (Apis mellifera), the dopaminergic system has been implicated in an elaborate pheromonal communication network between individuals and in the differentiation of females into reproductive (queen) and sterile (worker) castes. Here we have identified and characterised a honey bee dopamine transporter (AmDAT) and a splice variant lacking exon 3 (AmDATdelta-ex3). Both transcripts are present in the adult brain and antennae as well as at lower levels within larvae and ovaries. When expressed separately in the Xenopus oocyte system, AmDAT localises to the oocyte surface whereas the splice variant is retained at an internal membrane. Oocytes expressing AmDAT exhibit a 12-fold increase in the uptake of [3H]dopamine relative to non-injected oocytes, whereas the AmDATdelta-ex3-expressing oocytes show no change in [3H]dopamine transport. Electrophysiological measurements of AmDAT activity revealed it to be a high-affinity, low-capacity transporter of dopamine. The transporter also recognises noradrenaline as a major substrate and tyramine as a minor substrate, but does not transport octopamine, L-Dopa, or serotonin. Dopamine transport via AmDAT is inhibited by cocaine in a reversible manner, but is unaffected by octopamine. Co-expression of AmDAT and AmDATdelta-ex3 in oocytes results in a substantial reduction in AmDAT-mediated transport, which was also detected as a significant decrease in the level of AmDAT protein. This down-regulatory effect is not attributable to competition with AmDATdelta-ex3 for ER ribosomes, nor to a general inhibition of the oocyte’s translational machinery. In vivo, the expression of both transcripts shows a high level of inter-individual variability. Gene-focused, ultra-deep amplicon sequencing detected methylation of the amdat locus at ten 5'-C-phosphate-G-3' dinucleotides (CpGs), but only in 5-10% of all reads in whole brains or antennae. These observations, together with the localization of the amdat transcript to a few clusters of dopaminergic neurons, imply that amdat methylation is positively linked to its transcription. Our findings suggest that multiple cellular mechanisms, including gene splicing and epigenomic communication systems, may be adopted to increase the potential of a conserved gene to contribute to lineage-specific behavioural outcomes.

Purpose– This paper aims to investigate the benefits derived from sustainable office buildings in People’s Republic of China (PRC) through their green features, with particular reference to energy efficiency.Design/methodology/approach– A survey on operating costs, energy impacts, productivities from property managers and tenants of sustainable office buildings was conducted in Shenzhen, PRC. All survey data were collected from a portfolio of 12 sustainable office buildings and from 76 responses out of more than 400 tenants who had moved into these buildings from conventional office buildings.Findings– Most tenants were concerned with sustainable operations, practices and policies. Some of them held that sustainable office buildings contribute to higher productivity and less sick time. These buildings typically consume less electricity and water, and have higher occupancy rates and rents.Research limitations/implications– There are only 40 sustainable office buildings in Shenzhen, and our study, albeit with proper methodology, with 12 sample buildings may not reflect entirely the attitudes of tenants and property managers of sustainable office buildings in Shenzhen. Advisably, future works can be carried out on a larger scale in other main cities of PRC to obtain a more comprehensive and precise evaluation on which strategic sustainable central/local government policies might be formulated.Originality/value– The concept of facilities management on sustainable buildings, especially on their derived benefits, is relatively new in developing countries such as China. This study is one of the first attempts in this area. In addition, this paper also contributes to existing literature by looking into the green lease provisions and operating policies of these sustainable buildings.

In the 1950s, NACA conducted a series of low-speed cascade experiments investigating the performance of NACA 65-series compressor cascades with tests covering multiple airfoils of varying camber and with variations in solidity and air inlet angle. Most of the configurations show transition via laminar separation—both on suction and pressure side—characterized by a relatively flat region in pressure distribution, while turbulent reattachment is characterized by a rapid pressure recovery just downstream of the separated region. In the current study, wall-resolved large-eddy simulation (LES) has been used to predict transition via laminar separation in such compressor configurations as well as the resulting airfoil losses. Six different cascades with local diffusion factor varying from 0.14 to 0.56 (NACA 65-010, 65-410, 65-(12)10, 65-(15)10, 65-(18)10, and 65-(21)10 cascades) were analyzed at design conditions. In addition, the loss bucket for various angles of attack off-design conditions has been computed for the NACA 65-(18)10 cascade. Chord-based Reynolds number for all the experiments considered here was held at 250,000. This allows sufficient grid resolution in these LES analyses at an acceptable computational cost, i.e., up to 20,000 CPU hours per case. Detailed comparisons to test data are presented in the form of surface pressure coefficient, drag coefficient, losses, and momentum thickness ratio. The results show that LES is capable of capturing transition via laminar separation relatively well for most of the cases, and consequently, may constitute a predictive tool for assessing losses of different compressor airfoils.