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IntroductionThe immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could be used to directly target myeloid-derived suppressor cells (MDSCs), a major cellular component of the GBM TME. Here, we explored if MDSC express IL15Rα and the feasibility of exploiting its expression as an immunotherapeutic target.MethodsRNA-seq, RT-qPCR, and flow cytometry were used to determine IL15Rα expression in paired peripheral and tumor-infiltrating immune cells of GBM patients and two syngeneic murine GBM models. We generated murine T cells expressing IL13Rα2-CARs and secretory IL15 (CAR.IL15s) or IL13Rα2-CARs in which IL15 was fused to the CAR to serve as an IL15Rα-targeting moiety (CAR.IL15f), and characterized their effector function in vitro and in syngeneic IL13Rα2+glioma models.ResultsIL15Rα was preferentially expressed in myeloid, B, and dendritic cells in patients’ and syngeneic GBMs. In vitro, CAR.IL15s and CAR.IL15f T cells depleted MDSC and decreased their secretion of immunosuppressive molecules with CAR.IL15f T cells being more efficacious. Similarly, CAR.IL15f T cells significantly improved the survival of mice in two GBM models. TME analysis showed that treatment with CAR.IL15f T cells resulted in higher frequencies of CD8+T cells, NK, and B cells, but a decrease in CD11b+cells in tumors compared with therapy with CAR T cells.ConclusionsWe demonstrate that MDSC of the glioma TME express IL15Ra and that these cells can be targeted with secretory IL15 or an IL15Rα-targeting moiety incorporated into the CAR. Thus, IL15-modified CAR T cells act as a dual targeting agent against tumor cells and MDSC in GBM, warranting their future evaluation in early-phase clinical studies.

Trade credit insurance (TCI) is a risk management tool commonly used by suppliers to guarantee against payment default by credit buyers. TCI contracts can be either cancelable (the insurer has the discretion to cancel this guarantee during the insured period) or noncancelable (the terms cannot be renegotiated within the insured period). This paper identifies two roles of TCI: the (cash flow) smoothing role (smoothing the supplier’s cash flows) and the monitoring role (tracking the buyer’s continued creditworthiness after contracting, which enables the supplier to make efficient operational decisions regarding whether to ship goods to the credit buyer). We further explore which contracts better facilitate these two roles of TCI by modeling the strategic interaction between the insurer and the supplier. Noncancelable contracts rely on the deductible to implement both roles, which may result in a conflict: a high deductible inhibits the smoothing role, whereas a low deductible weakens the monitoring role. Under cancelable contracts, the insurer’s cancelation action ensures that the information acquired is reflected in the supplier’s shipping decision. Thus, the insurer has adequate incentives to perform its monitoring function without resorting to a high deductible. Despite this advantage, we find that the insurer may exercise the cancelation option too aggressively; this thereby restores a preference for noncancelable contracts, especially when the supplier’s outside option is unattractive and the insurer’s monitoring cost is low. Noncancelable contracts are also relatively more attractive when the acquired information is verifiable than when it is unverifiable. This paper was accepted by Vishal Gaur, operations management.

A practical textbook, based on a problem-oriented workflow, that will improve patients' likelihood of full recovery from stroke and prevent future strokes from occurring Stroke is the leading cause of adult disability and is in the top five causes of death globally. Warlow's Stroke: Practical Management, 4th Edition takes a problem-oriented approach and addresses the questions posed by a stroke patient in the order they are likely to present in clinical practice, for instance, 'Is it a stroke?', 'What sort of stroke?', 'What caused it?', and 'What can be done about it?'. Beginning with chapters phrased as questions, the book walks the reader through a standard clinical workflow, exploring the practical skills and assessment required at each stage of patient management. Early chapters cover: locating the vascular lesion, identifying the involved arterial territory, the role imaging should play, and the application thereof. Subsequent chapters look at what causes a transient or persistent ischemic event, an intracerebral hemorrhage and a subarachnoid hemorrhage. Unusual causes of ischemic stroke and transient ischemic attack are also covered. The book then presents a practical approach to the management of stroke and transient ischemic attack; offers specific treatments for acute ischemic stroke and aneurysmal subarachnoid hemorrhage; provides ways for professionals to prevent first or recurrent stroke; and more. Final chapters of the book discuss rehabilitation after stroke, how patients and carers can be supported in the short term and long term, prevention of recurrent stroke, and the organization of stroke services. Warlow's Stroke: Practical Management, 4th Edition * Follows clinical workflow for stroke analysis * Features evidence-based approach throughout * Offers practical application aimed at improving patient outcomes * Written and edited by internationally renowned experts in the field An essential resource for all practitioners involved in the care of patients who suffer from cerebrovascular disease, but particularly suitable for neurologists, residents, geriatricians, stroke physicians, radiologists and primary care physicians.

Aging is associated with many complex diseases. Reliable prediction of the aging process is important for assessing the risks of aging-associated diseases. However, despite intense research, so far there is no reliable aging marker. Here we addressed this problem by examining whether human 3D facial imaging features could be used as reliable aging markers. We collected 〉 300 3D human facial images and blood profiles well-distributed across ages of 17 to 77 years. By analyzing the morphological profiles, we generated the first comprehensive map of the aging human facial phenome. We identified quantitative facial features, such as eye slopes, highly associated with age. We constructed a robust age predictor and found that on average people of the same chronological age differ by ~ 6 years in facial age, with the deviations increasing after age 40. Using this predictor, we identified slow and fast agers that are significantly supported by levels of health indicators. Despite a close relationship between facial morphological features and health indicators in the blood, facial features are more reliable aging biomarkers than blood profiles and can better reflect the general health status than chronological age.

Despite intense interests in developing blood measurements of Alzheimer’s disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. Here, we present a dedicated analytical platform for measuring different populations of circulating amyloid β (Aβ) proteins – exosome-bound vs. unbound – directly from blood. The technology, termed a mplified p lasmonic ex osome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. It demonstrates superior sensitivity (~200 exosomes), and enables diverse target co-localization in exosomes. Employing the platform, we find that prefibrillar Aβ aggregates preferentially bind with exosomes. We thus define a population of Aβ as exosome-bound (Aβ42+ CD63+) and measure its abundance directly from AD and control blood samples. As compared to the unbound or total circulating Aβ, the exosome-bound Aβ measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups. Detecting Alzheimer’s disease from blood samples is challenging because amyloid β blood levels are lower than the ELISA detection limit. Here the authors capture amyloid β bound to circulating exosomes on a plasmonic nanosensor, followed by enzymatic amplification to improve detection sensitivity.

In a phase 3 trial, participants with early Alzheimer’s disease who received the monoclonal antibody lecanemab had less decline on measures of cognition and function at 18 months than those who received placebo.

In a placebo-controlled, phase 2–3 trial, one dose of mRNA-1345 led to a lower incidence of RSV disease among adults 60 years of age or older. Solicited local and systemic adverse reactions occurred more often with the vaccine.

Older patients hospitalized for heart failure were randomly assigned to a rehabilitation intervention (which included multiple function domains) or control; the intervention began during, or early after, hospitalization and continued for 3 months. At 3 months, physical function, as assessed by the Short Physical Performance Battery, was better in the intervention group than in the control group.

Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mouse blood–brain barrier (BBB), LY6A or LY6C1. The in vivo tropisms of these capsids are predictable as they are dependent on the cell- and strain-specific expression of their target protein. This approach generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms within a single round of screening in vitro and secondary validation in vivo thereby reducing the use of animals in comparison to conventional multi-round in vivo selections. The reproducible and quantitative data derived via this method enabled both saturation mutagenesis and machine learning (ML)-guided exploration of the capsid sequence space. Notably, during our validation process, we determined that nearly all published AAV capsids that were selected for their ability to cross the BBB in mice leverage either the LY6A or LY6C1 protein, which are not present in primates. This work demonstrates that AAV capsids can be directly targeted to specific proteins to generate potent gene delivery vectors with known mechanisms of action and predictable tropisms.

Health, the environment, and animal rights represent the three main reasons people cite for vegetarian diet in Western societies. However, it has not been shown that these motives can be distinguished empirically, and little is known about what kind of people are likely to be compelled by these different motives. This study had three goals. First, we aimed to use construct validation to test whether develop health, environmental, and animal rights motives for a vegetarian diet could be distinguished. Second, we evaluated whether these motivations were associated with different demographic, behavioral, and personality profiles in three diverse samples. Third, we examined whether peoples' motivations were related to responses to vegetarian advocacy materials. We created the Vegetarian Eating Motives Inventory, a 15-item measure whose structure was invariant across three samples (N = 1006, 1004, 5478) and two languages (English and Dutch). Using this measure, we found that health was the most common motive for non-vegetarians to consider vegetarian diets and it had the broadest array of correlates, which primarily involved communal and agentic values. Correlates of environmental and animal rights motives were limited, but these motives were strong and specific predictors of advocacy materials in a fourth sample (N = 739). These results provide researchers with a useful tool for identifying vegetarian motives among both vegetarian and non-vegetarian respondents, offer useful insights into the nomological net of vegetarian motivations, and provide advocates with guidance about how to best target campaigns promoting a vegetarian diet.