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BioRxiv : the Preprint Server For... Jun 2024Prostate cancer is a heterogenous disease, but once it becomes metastatic it eventually becomes treatment resistant. One mechanism of resistance to AR-targeting therapy...
BACKGROUND
Prostate cancer is a heterogenous disease, but once it becomes metastatic it eventually becomes treatment resistant. One mechanism of resistance to AR-targeting therapy is lineage plasticity, where the tumor undergoes a transformation to an AR-indifferent phenotype, most studied in the context of neuroendocrine prostate cancer (NEPC). However, activation of additional de- or trans-differentiation programs, including a gastrointestinal (GI) gene expression program, has been suggested as an alternative method of resistance. In this study, we explored the previously identified GI prostate cancer phenotype (PCa-GI) in a large cohort of metastatic castration-resistant prostate cancer (mCRPC) patient biopsy samples.
METHODS
We analyzed a dataset of 634 mCRPC samples with batch effect corrected gene expression data from the West Coast Dream Team (WCDT), the East Coast Dream Team (ECDT), the Fred Hutchinson Cancer Research Center (FHCRC) and the Weill Cornell Medical center (WCM). Survival data was available from the WCDT and ECDT cohorts. We calculated a gene expression GI score using the sum of z-scores of genes from a published set of PCa-GI-defining genes (N=38). Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards regression with endpoint overall survival from time of biopsy to death of any cause.
RESULTS
We found that the PCa-GI score had a bimodal distribution, identifying a distinct set of tumors with an activated GI expression pattern. Approximately 35% of samples were classified as PCa-GI high, which was concordant with prior reports. Liver metastases had the highest median score but after excluding liver samples, 29% of the remaining samples were still classified as PCa-GI high, suggesting a distinct phenotype not exclusive to liver metastases. No correlation was observed between GI score and proliferation, AR signaling, or NEPC scores. Furthermore, the PCa-GI score was not associated with genomic alterations in or However, tumors with amplifications showed significantly higher GI scores (p=0.0001). Patients with PCa-GI tumors had a shorter survival (HR=1.5 [1.1-2.1], p=0.02), but this result was not significant after adjusting for the liver as metastatic site (HR=1.2 [0.82-1.7], p=0.35). Patients with PCa-GI low samples had a better outcome after androgen receptor signaling inhibitors (ASI, abiraterone or enzalutamide) than other therapies (HR=0.37 [0.22-0.61], p=0.0001) while the benefit of ASI was smaller and non-significant for PCa-GI high samples (HR=0.55 [0.29-1.1], p=0.07). A differential pathway analysis identified FOXA2 signaling to be upregulated PCa-GI high tumors (FDR = 3.7 × 10).
CONCLUSIONS
The PCa-GI phenotype is prevalent in clinical mCRPC samples and may represent a distinct biological entity. PCa-GI tumors may respond less to ASI and could offer a strategy to study novel therapeutic targets.
PubMed: 38895460
DOI: 10.1101/2024.06.02.595931 -
The British Journal of Educational... Jun 2024Countries have been implementing inclusive educational practices for children with special educational needs and disabilities (SEND) for at least 30 years.
BACKGROUND
Countries have been implementing inclusive educational practices for children with special educational needs and disabilities (SEND) for at least 30 years.
AIMS
Some issues continue to present as unresolved and will be examined in this paper with possible ways forward suggested. 1. There is still a lack of clarity around the definition of inclusion, its theoretical underpinnings, its implementation in practice and evaluation of success. 2. Teachers often still report the same problems of insufficient resources and express the same concerns about lack of skills and knowledge as reported in the early days. 3. A key question is, do children with SEND achieve better outcomes in inclusive educational settings?
DISCUSSION AND CONCLUSIONS
The paper argues that an overarching executive framework applied to the education of children with SEND is needed to provide a common frame of reference that can be shared by educators, policymakers and researchers. New ways of resourcing inclusion are discussed including supporting collaboration between mainstream and special schools to better utilize the expertise located in special schools. The paper examines the evidence for improved academic and social outcomes for learners with SEND in inclusive schools and proposes that psychological outcomes now need to be measured too. It further suggests that future research needs to drill down to the level of teacher classroom instruction rather than rely on the broader mainstream school-special school comparison.
PubMed: 38890011
DOI: 10.1111/bjep.12701 -
ELife Jun 2024Rapid eye movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically...
Rapid eye movement sleep (REMs) is characterized by activated electroencephalogram (EEG) and muscle atonia, accompanied by vivid dreams. REMs is homeostatically regulated, ensuring that any loss of REMs is compensated by a subsequent increase in its amount. However, the neural mechanisms underlying the homeostatic control of REMs are largely unknown. Here, we show that GABAergic neurons in the preoptic area of the hypothalamus projecting to the tuberomammillary nucleus (POA→TMN neurons) are crucial for the homeostatic regulation of REMs in mice. POA→TMN neurons are most active during REMs, and inhibiting them specifically decreases REMs. REMs restriction leads to an increased number and amplitude of calcium transients in POA→TMN neurons, reflecting the accumulation of REMs pressure. Inhibiting POA→TMN neurons during REMs restriction blocked the subsequent rebound of REMs. Our findings reveal a hypothalamic circuit whose activity mirrors the buildup of homeostatic REMs pressure during restriction and that is required for the ensuing rebound in REMs.
Topics: Animals; Preoptic Area; Sleep, REM; Homeostasis; Mice; GABAergic Neurons; Male; Electroencephalography; Hypothalamic Area, Lateral
PubMed: 38884573
DOI: 10.7554/eLife.92095 -
National Science Review Jul 2024Room-temperature superconductivity has been a long-held dream of mankind and a focus of considerable interest in the research field of superconductivity. Significant... (Review)
Review
Room-temperature superconductivity has been a long-held dream of mankind and a focus of considerable interest in the research field of superconductivity. Significant progress has recently been achieved in hydrogen-based superconductors found in superhydrides (hydrides with unexpectedly high hydrogen contents) that are stabilized under high-pressure conditions and are not capturable at ambient conditions. Of particular interest is the discovery of a class of best-ever-known superconductors in clathrate metal superhydrides that hold the record for high superconductivity (e.g. = 250-260 K for LaH) among known superconductors and have great promise to be those that realize the long-sought room-temperature superconductivity. In these peculiar clathrate superhydrides, hydrogen forms unusual 'clathrate' cages containing encaged metal atoms, of which such a kind was first reported in a calcium hexa-superhydride (CaH) showing a measured high of 215 K under a pressure of 170 GPa. In this review, we aim to offer an overview of the current status of research progress on the clathrate metal superhydride superconductors, discuss the superconducting mechanism and highlight the key features (e.g. structure motifs, bonding features, electronic structure, etc.) that govern the high-temperature superconductivity. Future research direction along this line to find room-temperature superconductors will be discussed.
PubMed: 38883291
DOI: 10.1093/nsr/nwad270 -
ArXiv Jun 2024Electrical waves in the heart form rotating spiral or scroll waves during life-threatening arrhythmias such as atrial or ventricular fibrillation. The wave dynamics are...
Electrical waves in the heart form rotating spiral or scroll waves during life-threatening arrhythmias such as atrial or ventricular fibrillation. The wave dynamics are typically modeled using coupled partial differential equations, which describe reaction-diffusion dynamics in excitable media. More recently, data-driven generative modeling has emerged as an alternative to generate spatio-temporal patterns in physical and biological systems. Here, we explore denoising diffusion probabilistic models for the generative modeling of electrical wave patterns in cardiac tissue. We trained diffusion models with simulated electrical wave patterns to be able to generate such wave patterns in unconditional and conditional generation tasks. For instance, we explored the diffusion-based i) parameter-specific generation, ii) evolution and iii) inpainting of spiral wave dynamics, including reconstructing three-dimensional scroll wave dynamics from superficial two-dimensional measurements. Further, we generated arbitrarily shaped bi-ventricular geometries and simultaneously initiated scroll wave patterns inside these geometries using diffusion. We characterized and compared the diffusion-generated solutions to solutions obtained with corresponding biophysical models and found that diffusion models learn to replicate spiral and scroll waves dynamics so well that they could be used for data-driven modeling of excitation waves in cardiac tissue. For instance, an ensemble of diffusion-generated spiral wave dynamics exhibits similar self-termination statistics as the corresponding ensemble simulated with a biophysical model. However, we also found that diffusion models {produce artifacts if training data is lacking, e.g. during self-termination,} and `hallucinate' wave patterns when insufficiently constrained.
PubMed: 38883235
DOI: No ID Found -
Journal of Clinical Sleep Medicine :... Jun 2024Brunner syndrome is a recessive X-linked disorder characterized by intellectual disability and impulsive aggressiveness associated with Monoamine Oxidase-A (MAOA)...
Brunner syndrome is a recessive X-linked disorder characterized by intellectual disability and impulsive aggressiveness associated with Monoamine Oxidase-A (MAOA) deficiency leading to increased monoaminergic activity. We report the presence of REM sleep behavior disorder (RBD) in a 46-year-old patient with Brunner syndrome due to a c.1438A>G/iVS14-2 A>G mutation of the gene. He suffered from mild intellectual disability and psychotic disturbances. He presented a 15-year history of nightmares (chase, attacks and fights), sleep-related vocalizations and motor behaviors characterized by talking, screaming, crying, gesturing, punching, and kicking. Video-polysomnography showed RBD characterized by excessive tonic and phasic muscle activity in the mentalis and limb muscles with dream enacting behaviors during REM sleep. Clonazepam achieved a significant reduction of RBD symptomatology. We conclude that RBD can be a manifestation of Brunner syndrome probably due to an increased monoaminergic neurotransmission occurring in this rare genetic disorder.
PubMed: 38881510
DOI: 10.5664/jcsm.11230 -
Bulletin of the History of Medicine 2024Jean-Martin Charcot (1825-1893), the leading neurologist of his time, is best remembered for his studies on hysteria presented in clinical lectures at the Paris...
Jean-Martin Charcot (1825-1893), the leading neurologist of his time, is best remembered for his studies on hysteria presented in clinical lectures at the Paris Salpêtrière hospital. Developing the concept of traumatic male hysteria after accidents in which patients suffered slight physical damage led him to advance a psychological explanation for hysteria. Traumatic hysteria is the context for a close reading of Charcot's "last words" based upon a final unpublished lesson in 1893. This case history concerns a seventeen-year-old Parisian artisan whose various signs of hysteria developed following a dream in which he imagined himself the victim of a violent assault. Charcot identifies the dream/nightmare as the "original" feature determining traumatic hysteria. The dream sets in motion an overwhelming consciousness followed by a susceptibility to "autosuggestion" producing somatic signs of hysteria. Charcot's final lesson on dreams thus culminates his study of the psychological basis of traumatic hysteria.
Topics: Hysteria; Dreams; History, 19th Century; Humans; Male; Neurology; Paris; Neurologists; Adolescent
PubMed: 38881468
DOI: 10.1353/bhm.2024.a929782 -
Neuroscience and Biobehavioral Reviews Jun 2024Out-of-body experiences (OBEs) are characterized by the subjective experience of being located outside the physical body. Little is known about the neurophysiology of... (Review)
Review
Out-of-body experiences (OBEs) are characterized by the subjective experience of being located outside the physical body. Little is known about the neurophysiology of spontaneous OBEs, which are often reported by healthy individuals as occurring during states of reduced vigilance, particularly in proximity to or during sleep (sleep-related OBEs). In this paper, we review the current state of research on sleep-related OBEs and hypothesize that maintaining consciousness during transitions from wakefulness to REM sleep (sleep-onset REM periods) may facilitate sleep-related OBEs. Based on this hypothesis, we propose a new conceptual model that potentially describes the relationship between OBEs and sleep states. The model sheds light on the phenomenological differences between sleep-related OBEs and similar states of consciousness, such as lucid dreaming (the realization of being in a dream state) and sleep paralysis (feeling paralyzed while falling asleep or waking up), and explores the potential polysomnographic features underlying sleep-related OBEs. Additionally, we apply the predictive coding framework and suggest a connecting link between sleep-related OBEs and OBEs reported during wakefulness.
PubMed: 38880408
DOI: 10.1016/j.neubiorev.2024.105770 -
Journal of the American Psychoanalytic... Jun 2024In this essay the author describes some of the transformations that occur as one moves from preverbal functioning to verbally symbolic language. In preverbal experience,...
In this essay the author describes some of the transformations that occur as one moves from preverbal functioning to verbally symbolic language. In preverbal experience, there is a direct connection between the sign and what is signified. An infant or child signifies displeasure by throwing his food or other objects to the floor. Much of the emotional tie between mother and infant and patient and analyst is communicated in this way. When a transformation occurs from preverbal to verbally symbolic language, as occurs in early development and as one interprets a dream, meaning is not merely translated, meaning is created. On acquiring verbally symbolic language, a "space" mediated by an interpreting subject opens between the symbol (for instance, the word ) and the symbolized (the experience of guilt) and a new subjectivity is created. On entry into verbally symbolic language, one becomes able to experience oneself in a qualitatively different way; one becomes both subject and object, I and me; one becomes able to experience a far broader range of feelings and types of thinking. Helen Keller's account of her experience of acquiring verbally symbolic language is drawn upon.
PubMed: 38877745
DOI: 10.1177/00030651241257263 -
Nature Cell Biology Jun 2024Transcription factor (TF) proteins regulate gene activity by binding to regulatory regions, most importantly at gene promoters. Many genes have alternative promoters...
Transcription factor (TF) proteins regulate gene activity by binding to regulatory regions, most importantly at gene promoters. Many genes have alternative promoters (APs) bound by distinct TFs. The role of differential TF activity at APs during tumour development is poorly understood. Here we show, using deep RNA sequencing in 274 biopsies of benign prostate tissue, localized prostate tumours and metastatic castration-resistant prostate cancer, that AP usage increases as tumours progress and APs are responsible for a disproportionate amount of tumour transcriptional activity. Expression of the androgen receptor (AR), the key driver of prostate tumour activity, is correlated with elevated AP usage. We identified AR, FOXA1 and MYC as potential drivers of AP activation. DNA methylation is a likely mechanism for AP activation during tumour progression and lineage plasticity. Our data suggest that prostate tumours activate APs to magnify the transcriptional impact of tumour drivers, including AR and MYC.
PubMed: 38871824
DOI: 10.1038/s41556-024-01438-3