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Nature Methods Nov 2023Engineered transactivation domains (TADs) combined with programmable DNA binding platforms have revolutionized synthetic transcriptional control. Despite recent progress...
Engineered transactivation domains (TADs) combined with programmable DNA binding platforms have revolutionized synthetic transcriptional control. Despite recent progress in programmable CRISPR-Cas-based transactivation (CRISPRa) technologies, the TADs used in these systems often contain poorly tolerated elements and/or are prohibitively large for many applications. Here, we defined and optimized minimal TADs built from human mechanosensitive transcription factors. We used these components to construct potent and compact multipartite transactivation modules (MSN, NMS and eN3x9) and to build the CRISPR-dCas9 recruited enhanced activation module (CRISPR-DREAM) platform. We found that CRISPR-DREAM was specific and robust across mammalian cell types, and efficiently stimulated transcription from diverse regulatory loci. We also showed that MSN and NMS were portable across Type I, II and V CRISPR systems, transcription activator-like effectors and zinc finger proteins. Further, as proofs of concept, we used dCas9-NMS to efficiently reprogram human fibroblasts into induced pluripotent stem cells and demonstrated that mechanosensitive transcription factor TADs are efficacious and well tolerated in therapeutically important primary human cell types. Finally, we leveraged the compact and potent features of these engineered TADs to build dual and all-in-one CRISPRa AAV systems. Altogether, these compact human TADs, fusion modules and delivery architectures should be valuable for synthetic transcriptional control in biomedical applications.
Topics: Animals; Humans; Transcriptional Activation; CRISPR-Cas Systems; Gene Expression Regulation; Transcription Factors; Fibroblasts; Mammals
PubMed: 37813990
DOI: 10.1038/s41592-023-02036-1 -
Sleep Dec 2023
Topics: Memory Consolidation; Dreams; Surveys and Questionnaires
PubMed: 37170861
DOI: 10.1093/sleep/zsad139 -
Journal of Cardiovascular... Sep 2023
Topics: Humans; Atrial Fibrillation; Treatment Outcome; Catheter Ablation
PubMed: 37579220
DOI: 10.1111/jce.16040 -
Current Opinion in Oncology Nov 2023Therapeutic advancements in multiple myeloma have led to increasingly deeper and more durable responses, creating a need for highly sensitive and applicable techniques...
PURPOSE OF REVIEW
Therapeutic advancements in multiple myeloma have led to increasingly deeper and more durable responses, creating a need for highly sensitive and applicable techniques for measurable residual disease (MRD) assessment. Bone marrow assays can deeply assess for MRD, but it is not conducive to performing frequent and dynamic evaluations, which may be needed for MRD-adapted treatment approaches. Recently, numerous techniques for MRD assessment in peripheral blood have come under investigation, and their integration into routine clinical practice is eagerly anticipated.
RECENT FINDINGS
The identification of circulating tumor cells (CTCs), evaluation of cell-free DNA, and measuring monoclonal protein concentration with mass spectrometry are promising research areas for assessing myeloma in peripheral blood. CTCs assessment and cell-free DNA may carry prognostic significance, but they lack the sensitivity of bone marrow-based techniques. Mass spectrometry has already been implemented in clinical practice in certain centers, but its full potential has yet to be fully realized. This review focuses on recent developments in these fields, emphasizing the potential future roles of these assessments.
SUMMARY
MRD assessment in peripheral blood is still in the development stage but holds promise for not only complementing bone marrow based evaluations but also potential for improving sensitivity.
PubMed: 37621165
DOI: 10.1097/CCO.0000000000000987 -
Biomedicines Jun 2024It is generally assumed that all estrogen-receptor-positive (ER+) breast cancers proliferate in response to estrogen and, therefore, examples of the estrogen-induced... (Review)
Review
It is generally assumed that all estrogen-receptor-positive (ER+) breast cancers proliferate in response to estrogen and, therefore, examples of the estrogen-induced regression of ER+ cancers are paradoxical. This review re-examines the estrogen regression paradox for the Luminal A subtype of ER+ breast cancers. The proliferative response to estrogen is shown to depend on the level of ER. Mechanistically, a window of opportunity study of pre-operative estradiol suggested that with higher levels of ER, estradiol could activate the DREAM-MMB (Dimerization partner, Retinoblastoma-like proteins, E2F4, and MuvB-MYB-MuvB) pathway to decrease proliferation. The response of breast epithelium and the incidence of breast cancers during hormonal variations that occur during the menstrual cycle and at the menopausal transition, respectively, suggest that a single hormone, either estrogen, progesterone or androgen, could activate the DREAM pathway, leading to reversible cell cycle arrest. Conversely, the presence of two hormones could switch the DREAM-MMB complex to a pro-proliferative pathway. Using publicly available data, we examine the gene expression changes after aromatase inhibitors and ICI 182,780 to provide support for the hypothesis. This review suggests that it might be possible to integrate all current hormonal therapies for Luminal A tumors within a single theoretical schema.
PubMed: 38927507
DOI: 10.3390/biomedicines12061300 -
Consciousness and Cognition Jul 2024Some dissociative experiences may be related, in part, to REM intrusion into waking consciousness. If so, some aspects of dream content may be associated with daytime...
Some dissociative experiences may be related, in part, to REM intrusion into waking consciousness. If so, some aspects of dream content may be associated with daytime dissociative experiences. We tested the hypothesis that some types of dream content would predict daytime dissociative symptomology. As part of a longitudinal study of the impact of dreams on everyday behavior we administered a battery of survey instruments to 219 volunteers. Assessments included the Dissociative Experiences Scale (DES), along with other measures known to be related to either REM intrusion effects or dissociative experiences. We also collected dream reports and sleep measures across a two-week period from a subgroup of the individuals in the baseline group. Of this subgroup we analyzed two different subsamples; 24 individuals with dream recall for at least half the nights in the two-week period; and 30 individuals who wore the DREEM Headband which captured measures of sleep architecture. In addition to using multiple regression analyses to quantify associations between DES and REM intrusion and dream content variables we used a split half procedure to create high vs low DES groups and then compared groups across all measures. Participants in the high DES group evidenced significantly greater nightmare distress scores, REM Behavior Disorder scores, paranormal beliefs, lucid dreams, and sleep onset times. Validated measures of dreamed first person perspective and overall dream coherence in a time series significantly predicted overall DES score accounting for 26% of the variance in dissociation. Dream phenomenology and coherence of the dreamed self significantly predicts dissociative symptomology as an individual trait. REM intrusion may be one source of dissociative experiences. Attempts to ameliorate dissociative symptoms or to treat nightmare distress should consider the stability of dream content as a viable indicator of dissociative tendencies.
Topics: Humans; Dreams; Dissociative Disorders; Adult; Female; Male; Young Adult; Longitudinal Studies; Middle Aged; Sleep, REM; Adolescent
PubMed: 38821030
DOI: 10.1016/j.concog.2024.103708 -
Brain Sciences May 2024Dreaming, a widely researched aspect of sleep, often mirrors waking-life experiences. Despite the prevalence of sensory perception during wakefulness, sensory...
Dreaming, a widely researched aspect of sleep, often mirrors waking-life experiences. Despite the prevalence of sensory perception during wakefulness, sensory experiences in dreams remain relatively unexplored. Free recall dream reports, where individuals describe their dreams freely, may not fully capture sensory dream experiences. In this study, we developed a dream diary with direct questions about sensory dream experiences. Participants reported sensory experiences in their dreams upon awakening, over multiple days, in a home-based setting (n = 3476 diaries). Our findings show that vision was the most common sensory dream experience, followed by audition and touch. Olfaction and gustation were reported at equally low rates. Multisensory dreams were far more prevalent than unisensory dreams. Additionally, the prevalence of sensory dream experiences varied across emotionally positive and negative dreams. A positive relationship was found between on the one hand sensory richness and, on the other emotional intensity of dreams and clarity of dream recall, for both positive and negative dreams. These results underscore the variety of dream experiences and suggest a link between sensory richness, emotional content and dream recall clarity. Systematic registration of sensory dream experiences offers valuable insights into dream manifestation, aiding the understanding of sleep-related memory consolidation and other aspects of sleep-related information processing.
PubMed: 38928535
DOI: 10.3390/brainsci14060533 -
JAAPA : Official Journal of the... Dec 2023Physician associates/assistants (PAs) are poised to be excellent grant writers for local projects that can improve access to quality care and improve the finances of...
Physician associates/assistants (PAs) are poised to be excellent grant writers for local projects that can improve access to quality care and improve the finances of historically underserved, urban, and rural healthcare communities. Because grant writing focuses on the dream of what is possible with funding, it contrasts with other forms of medical writing, which focus on past findings. This article aims to introduce PAs to six steps that can help them with grant writing, with a goal of improving patient care or starting community outreach projects.
Topics: Humans; Writing; Quality of Health Care
PubMed: 37989168
DOI: 10.1097/01.JAA.0000991356.86042.d1 -
Research Involvement and Engagement Sep 2023Promoting wellbeing of persons with dementia and their families is a priority of research and practice. Engaging diverse partners, including persons with dementia and...
Promoting wellbeing of persons with dementia and their families is a priority of research and practice. Engaging diverse partners, including persons with dementia and their families, to co-develop interventions promotes relevant and impactful solutions. We describe the process, output, and lessons learned from the dementia resources for eating, activity, and meaningful inclusion (DREAM) project, which co-developed tools/resources with persons with dementia, care partners, community service providers, health care professionals, and researchers with the aim of increasing supports for physical activity, healthy eating, and wellbeing of persons with dementia. Our process included: (1) Engaging and maintaining the DREAM Steering Team; (2) Setting and navigating ways of engagement; (3) Selecting the priority audience and content; (4) Drafting the toolkit; (5) Iterative co-development of tools and resources; (6) Usability testing; and (7) Implementation and evaluation. In virtual meetings, the DREAM Steering Team confirmed the toolkit audiences (primary: community service providers; secondary: persons with dementia and care partners) and identified and evolved content areas. An environmental scan identified few existing, high-quality resources aligned with content areas. The Steering Team, additional multi-perspective partners, and external contractors iteratively co-developed new tools/resources to meet gaps over a 4-month virtual process that included virtual meetings, email exchange of documents and feedback, and one-on-one calls by telephone or email. The final DREAM toolkit includes a website with seven learning modules (on the diversity of dementia, rights and inclusion of persons living with dementia, physical activity, healthy eating, dementia-inclusive practices), a learning manual, six videos, nine handouts, and four wallet cards ( www.dementiawellness.ca ). Our co-development participants rated the process highly in relation to the principles and enablers of authentic partnership even though all engagement was virtual. Through use of the co-developed DREAM toolkit, we anticipate community service providers will gain the knowledge and confidence needed to provide dementia-inclusive wellness programs and services that benefit persons with dementia and their families.
PubMed: 37775790
DOI: 10.1186/s40900-023-00497-4 -
The Lancet. Neurology Aug 2023
Topics: Humans; Sleep; Dreams
PubMed: 37271156
DOI: 10.1016/S1474-4422(23)00208-9