Phase 1 Clinical Trial of Trametes versicolor in Women with Breast Cancer

Introduction. Orally administered preparations from the Trametes versicolor (Tv) mushroom have been hypothesized to improve immune response in women with breast cancer after standard chemotherapy and radiotherapy. Methods. A phase I, two-center, dose escalation study was done to determine the maximum tolerated dose of a Tv preparation when taken daily in divided doses for 6 weeks after recent completion of radiotherapy. Eleven participants were recruited and nine women completed the study. Each cohort was comprised of three participants given one of three doses of Tv (3, 6, or 9 grams). Immune data was collected pre- and postradiation, at 3 on-treatment time points and after a 3-week washout. Results. Nine adverse events were reported (7 mild, 1 moderate, and 1 severe), suggesting that Tv was well tolerated. Immunological results indicated trends in (1) increased lymphocyte counts at 6 and 9 grams/day; (2) increased natural killer cell functional activity at 6 grams/day; (3) dose-related increases in CD8+ T cells and CD19+ B cells , but not CD4+ T cells or CD16+56+ NK cells. Conclusion. These findings show that up to 9 grams/day of a Tv preparation is safe and tolerable in women with breast cancer in the postprimary treatment setting. This Tv preparation may improve immune status in immunocompromised breast cancer patients following standard primary oncologic treatment

“Early intervention isn't an option, it's a necessity”: learning from implementation facilitators and challenges from the rapid scaling of an early intervention eating disorders programme in England

IntroductionThe First Episode Rapid Early Intervention for Eating Disorders (FREED) service has shown promising outcomes for young people with an eating disorder, leading to national scaling and implementation across England. Between 2020 and 2023, the national implementation of FREED was supported by the Academic Health Science Networks (AHSNs), which are publicly funded organisations with the mission to spread innovations at scale and pace. This study aimed to investigate the views and experiences of AHSN programme leads on the national roll-out of FREED and the perceived sustainability of the model.Methods and resultsSemi-structured interviews were conducted with 13 programme leads across the AHSNs with direct experience supporting the national implementation of FREED. Thematic analysis was adopted using a critical realist approach. Initial sub-themes were inductively generated and then organised under seven larger themes representing the domains of the Non-adoption, Abandonment, and Challenges to Scale-Up, Spread and Sustainability (NASSS) framework. Each sub-theme was classified as a facilitator and/or barrier and then each larger theme/domain was assessed for its complexity (simple, complicated, complex). Data analysis revealed 28 sub-themes, 10 identified as facilitators, 13 as barriers, and five as both. Two domains were classed as simple, three as complicated, and two as complex. Sub-themes ranged from illness-related complexities to organisational pressures. Key facilitators included a high-value proposition for FREED and a supportive network. Key barriers included staffing issues and illness-related factors that challenge early intervention.DiscussionParticipants described broad support for FREED but desired sustained investment for continued provision and improving implementation fidelity. Future development areas raised by participants included enlarging the evidence base for early intervention, increasing associated training opportunities, and widening the reach of FREED. Results offer learning for early intervention in eating disorders and the scaling of new health initiatives

A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex.

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain1-3. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigenomes from more than 500,000 individual cells in the mouse primary motor cortex, a structure that has an evolutionarily conserved role in locomotion. We developed computational and statistical methods to integrate multimodal data and quantitatively validate cell-type reproducibility. The resulting reference atlas-containing over 56 neuronal cell types that are highly replicable across analysis methods, sequencing technologies and modalities-is a comprehensive molecular and genomic account of the diverse neuronal and non-neuronal cell types in the mouse primary motor cortex. The atlas includes a population of excitatory neurons that resemble pyramidal cells in layer 4 in other cortical regions4. We further discovered thousands of concordant marker genes and gene regulatory elements for these cell types. Our results highlight the complex molecular regulation of cell types in the brain and will directly enable the design of reagents to target specific cell types in the mouse primary motor cortex for functional analysis

Comparative cellular analysis of motor cortex in human, marmoset and mouse

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations

A multimodal cell census and atlas of the mammalian primary motor cortex

ABSTRACT We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. Together, our results advance the collective knowledge and understanding of brain cell type organization: First, our study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. Together, our results establish a unified and mechanistic framework of neuronal cell type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties

Datasheet1_“Early intervention isn't an option, it's a necessity”: learning from implementation facilitators and challenges from the rapid scaling of an early intervention eating disorders programme in England.pdf

IntroductionThe First Episode Rapid Early Intervention for Eating Disorders (FREED) service has shown promising outcomes for young people with an eating disorder, leading to national scaling and implementation across England. Between 2020 and 2023, the national implementation of FREED was supported by the Academic Health Science Networks (AHSNs), which are publicly funded organisations with the mission to spread innovations at scale and pace. This study aimed to investigate the views and experiences of AHSN programme leads on the national roll-out of FREED and the perceived sustainability of the model.Methods and resultsSemi-structured interviews were conducted with 13 programme leads across the AHSNs with direct experience supporting the national implementation of FREED. Thematic analysis was adopted using a critical realist approach. Initial sub-themes were inductively generated and then organised under seven larger themes representing the domains of the Non-adoption, Abandonment, and Challenges to Scale-Up, Spread and Sustainability (NASSS) framework. Each sub-theme was classified as a facilitator and/or barrier and then each larger theme/domain was assessed for its complexity (simple, complicated, complex). Data analysis revealed 28 sub-themes, 10 identified as facilitators, 13 as barriers, and five as both. Two domains were classed as simple, three as complicated, and two as complex. Sub-themes ranged from illness-related complexities to organisational pressures. Key facilitators included a high-value proposition for FREED and a supportive network. Key barriers included staffing issues and illness-related factors that challenge early intervention.DiscussionParticipants described broad support for FREED but desired sustained investment for continued provision and improving implementation fidelity. Future development areas raised by participants included enlarging the evidence base for early intervention, increasing associated training opportunities, and widening the reach of FREED. Results offer learning for early intervention in eating disorders and the scaling of new health initiatives.</p

Site Environmental Report for 2021

The annual Site Environmental Report documents Lawrence Berkeley National Laboratory’s performance in reducing its environmental impacts, progress toward cleaning up groundwater contamination, and compliance with applicable Department of Energy, federal, state, and local environmental regulations