Multivariate word properties in fluency tasks reveal markers of Alzheimer’s dementia

Version of Record online: 12 October 2023INTRODUCTION Verbal fluency tasks are common in Alzheimer's disease (AD) assessments. Yet, standard valid response counts fail to reveal disease-specific semantic memory patterns. Here, we leveraged automated word-property analysis to capture neurocognitive markers of AD vis-à-vis behavioral variant frontotemporal dementia (bvFTD). METHODS Patients and healthy controls completed two fluency tasks. We counted valid responses and computed each word's frequency, granularity, neighborhood, length, familiarity, and imageability. These features were used for group-level discrimination, patient-level identification, and correlations with executive and neural (magnetic resonanance imaging [MRI], functional MRI [fMRI], electroencephalography [EEG]) patterns. RESULTS Valid responses revealed deficits in both disorders. Conversely, frequency, granularity, and neighborhood yielded robust group- and subject-level discrimination only in AD, also predicting executive outcomes. Disease-specific cortical thickness patterns were predicted by frequency in both disorders. Default-mode and salience network hypoconnectivity, and EEG beta hypoconnectivity, were predicted by frequency and granularity only in AD. DISCUSSION Word-property analysis of fluency can boost AD characterization and diagnosis. Highlights We report novel word-property analyses of verbal fluency in AD and bvFTD. Standard valid response counts captured deficits and brain patterns in both groups. Specific word properties (e.g., frequency, granularity) were altered only in AD. Such properties predicted cognitive and neural (MRI, fMRI, EEG) patterns in AD. Word-property analysis of fluency can boost AD characterization and diagnosis.National Institutes of Health, National Institutes of Aging, Grant/Award Numbers: R01AG057234, R01AG075775; ANID: FONDECYT Regular, Grant/Award Numbers: 1210176, 1210195, 1220995; FONDAP, Grant/Award Number: 15150012; PIA/ANILLOS, Grant/Award Number: ACT210096; FONDEF, Grant/Award Number: ID20I10152; GBHI, Alzheimer’s Association, and Alzheimer’s Society: Alzheimer’s Association GBHI, Grant/Award Number: ALZ UK-22-865742; Alzheimer’s Association, Grant/Award Number: SG-20-725707; Latin American Brain Health Institute (BrainLat), Universidad Adolfo Ibáñez, Santiago, Chile, Grant/Award Number: #BL-SRGP2021-01; Programa Interdisciplinario de Investigación Experimental en Comunicación y Cognición (PIIECC), Facultad de Humanidades, USACH; Takeda, Grant/Award Number: CW2680521; Rainwater Charitable Foundation; Tau Consortium; European Commission: H2020-MSCA-IF-GFMULTI-LAND, Grant/Award Number: 10102581

Metaheuristic Design Patterns: New Perspectives for Larger-Scale Search Architectures

Design patterns capture the essentials of recurring best practice in an abstract form. Their merits are well established in domains as diverse as architecture and software development. They offer significant benefits, not least a common conceptual vocabulary for designers, enabling greater communication of high-level concerns and increased software reuse. Inspired by the success of software design patterns, this chapter seeks to promote the merits of a pattern-based method to the development of metaheuristic search software components. To achieve this, a catalog of patterns is presented, organized into the families of structural, behavioral, methodological and component-based patterns. As an alternative to the increasing specialization associated with individual metaheuristic search components, the authors encourage computer scientists to embrace the ‘cross cutting' benefits of a pattern-based perspective to optimization algorithms. Some ways in which the patterns might form the basis of further larger-scale metaheuristic component design automation are also discussed

Immunosuppressive niche engineering at the onset of human colorectal cancer

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune “cold” ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC

Immunosuppressive niche engineering at the onset of human colorectal cancer

The evolutionary dynamics of tumor initiation remain undetermined, and the interplay between neoplastic cells and the immune system is hypothesized to be critical in transformation. Colorectal cancer (CRC) presents a unique opportunity to study the transition to malignancy as pre-cancers (adenomas) and early-stage cancers are frequently resected. Here, we examine tumor-immune eco-evolutionary dynamics from pre-cancer to carcinoma using a computational model, ecological analysis of digital pathology data, and neoantigen prediction in 62 patient samples. Modeling predicted recruitment of immunosuppressive cells would be the most common driver of transformation. As predicted, ecological analysis reveals that progressed adenomas co-localized with immunosuppressive cells and cytokines, while benign adenomas co-localized with a mixed immune response. Carcinomas converge to a common immune “cold” ecology, relaxing selection against immunogenicity and high neoantigen burdens, with little evidence for PD-L1 overexpression driving tumor initiation. These findings suggest re-engineering the immunosuppressive niche may prove an effective immunotherapy in CRC

SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation

Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ~6000 drugs and \u3e30 spike variants. Together with quantitative cell biology approaches, the screen reveals an essential role for biophysical aspects of the membrane, particularly cholesterol-rich regions, in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings potentially provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses