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Neural circuits construct internal 'world-models' to guide behavior. The predictive processing framework posits that neural activity signaling sensory predictions and concurrently computing prediction-errors is a signature of those internal models. Here, to understand how the brain generates predictions for complex sensorimotor signals, we investigate the emergence of high-dimensional, multi-modal predictive representations in recurrent networks. We find that robust predictive processing arises in a network with loose excitatory/inhibitory balance. Contrary to previous proposals of functionally specialized cell-types, the network exhibits desegregation of stimulus and prediction-error representations. We confirmed these model predictions by experimentally probing predictive-coding circuits using a rich stimulus-set to violate learned expectations. When constrained by data, our model further reveals and makes concrete testable experimental predictions for the distinct functional roles of excitatory and inhibitory neurons, and of neurons in different layers along a laminar hierarchy, in computing multi-modal predictions. These results together imply that in natural conditions, neural representations of internal models are highly distributed, yet structured to allow flexible readout of behaviorally-relevant information. The generality of our model advances the understanding of computation of internal models across species, by incorporating different types of predictive computations into a unified framework.
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Analysis of the recall response ex vivo in cattle vaccinated with a Mycobacterium avium subsp. paratuberculosis (Map) rel deletion mutant revealed the immune response was directed toward a 35 kD major membrane protein (MMP) of Map. Antigen presenting cells (APC) primed with MMP elicited expansion of CD8 cytotoxic memory T cells (CTL) with ability to kill intracellular bacteria. Development of CTL was MHC-restricted. The gene MAP2121c, encoding MMP, was modified for expression of MMP (tPA-MMP-2mut) in a mammalian cell line to explore the potential of developing MMP as a vaccine. Ex vivo stimulation of PBMC, from Map free cattle, with APC primed with tPA-MMP-2mut expressed p35 elicited a primary CD8 CTL response comparable to the recall response elicited with PBMC from cattle vaccinated with either the Maprel deletion mutant or MMP. In the present study, the modified gene for MMP, now referred to as p35NN, was placed into a bovine herpes virus-4 (BoHV4) vector to determine the potential use of BoHV-4AΔTK-p35NN as a peptide-based vaccine. Subcutaneous vaccination of healthy cattle with BoHV-4AΔTK-p35NN elicited a CTL recall response, as detected ex vivo. The results show use of a virus vector is an effective way for delivery of MMP as a vaccine. The immunogenic activity of MMP was not lost when modified for expression in mammalian cells. The next step is to conduct a field trial to determine if presence of an immune response to MMP prevents Map from establishing an infection.
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During behavior, the motor cortex sends copies of motor-related signals to sensory cortices. Here, we combine closed-loop behavior with large-scale physiology, projection-pattern-specific recordings, and circuit perturbations to show that neurons in mouse secondary motor cortex (M2) encode sensation and are influenced by expectation. When a movement unexpectedly produces a sound, M2 becomes dominated by sound-evoked activity. Sound responses in M2 are inherited partially from the auditory cortex and are routed back to the auditory cortex, providing a path for the reciprocal exchange of sensory-motor information during behavior. When the acoustic consequences of a movement become predictable, M2 responses to self-generated sounds are selectively gated off. These changes in single-cell responses are reflected in population dynamics, which are influenced by both sensation and expectation. Together, these findings reveal the embedding of sensory and expectation signals in motor cortical activity.
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Córtex Motor , Animais , Córtex Motor/fisiologia , Camundongos , Córtex Auditivo/fisiologia , Estimulação Acústica , Sensação/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , FemininoRESUMO
RNA polymerase I (Pol I) is responsible for synthesizing ribosomal RNA, which is the rate limiting step in ribosome biogenesis. We have reported wide variability in the magnitude of the rate constants defining the rate limiting step in sequential nucleotide additions catalyzed by Pol I. in this study we sought to determine if base identity impacts the rate limiting step of nucleotide addition catalyzed by Pol I. To this end, we report a transient state kinetic interrogation of AMP, CMP, GMP, and UMP incorporations catalyzed by Pol I. We found that Pol I uses one kinetic mechanism to incorporate all nucleotides. However, we found that UMP incorporation is faster than AMP, CMP, and GMP additions. Further, we found that endonucleolytic removal of a dimer from the 3' end was fastest when the 3' terminal base is a UMP. It has been previously shown that both downstream and upstream template sequence identity impacts the kinetics of nucleotide addition. The results reported here show that the incoming base identity also impacts the magnitude of the observed rate limiting step.
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RNA Polimerase I , Cinética , RNA Polimerase I/metabolismo , RNA Polimerase I/química , Nucleotídeos/metabolismo , Nucleotídeos/químicaRESUMO
Chronic wasting disease (CWD) is a fatal prion disease of cervids spreading across North America. More effective mitigation efforts may require expansion of the available toolkit to include new methods that provide earlier antemortem detection, higher throughput, and less expense than current immunohistochemistry (IHC) methods. The rectal mucosa near the rectoanal junction is a site of early accumulation of CWD prions and is safely sampled in living animals by pinch biopsy. A fluorescence-based, 96-well format, protein-aggregation assay-the real-time quaking-induced conversion (RT-QuIC) assay-is capable of ultra-sensitive detection of CWD prions. Notably, the recombinant protein substrate is crucial to the assay's performance and is now commercially available. In this blinded independent study, the preclinical diagnostic performance of a standardized RT-QuIC protocol using a commercially sourced substrate (MNPROtein) and a laboratory-produced substrate was studied using mock biopsy samples of the rectal mucosa from 284 white-tailed deer (Odocoileus virginianus). The samples were from a frozen archive of intact rectoanal junctions collected at depopulations of farmed herds positive for CWD in the United States. All deer were pre-clinical at the time of depopulation and infection status was established from the regulatory record, which evaluated the medial retropharyngeal lymph nodes (MRPLNs) and obex by CWD-IHC. A pre-analytic sample precipitation step was found to enhance the protocol's detection limit. Performance metrics were influenced by the choice of RT-QuIC diagnostic cut points (minimum number of positive wells and assay time) and by deer attributes (preclinical infection stage and prion protein genotype). The peak overall diagnostic sensitivities of the protocol were similar for both substrates (MNPROtein, 76.8%; laboratory-produced, 73.2%), though each was achieved at different cut points. Preclinical infection stage and prion protein genotype at codon 96 (G = glycine, S = serine) were primary predictors of sensitivity. The diagnostic sensitivities in late preclinical infections (CWD-IHC positive MPRLNs and obex) were similar, ranging from 96% in GG96 deer to 80% in xS96 deer (x = G or S). In early preclinical infections (CWD-IHC positive MRPLNs only), the diagnostic sensitivity was 64-71% in GG96 deer but only 25% in xS96 deer. These results demonstrate that this standardized RT-QuIC protocol for rectal biopsy samples using a commercial source of substrate produced stratified diagnostic sensitivities similar to or greater than those reported for CWD-IHC but in less than 30 hours of assay time and in a 96-well format. Notably, the RT-QuIC protocol used herein represents a standardization of protocols from several previous studies. Alignment of the sensitivities across these studies suggests the diagnostic performance of the assay is robust given quality reagents, optimized diagnostic criteria, and experienced staff.
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Cervos , Mucosa Intestinal , Reto , Doença de Emaciação Crônica , Animais , Doença de Emaciação Crônica/diagnóstico , Reto/patologia , Reto/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Príons/metabolismo , Príons/análise , Sensibilidade e EspecificidadeRESUMO
Eukaryotes express at least three nuclear DNA dependent RNA polymerases (Pols). Pols I, II, and III synthesize ribosomal (r) RNA, messenger (m) RNA, and transfer (t) RNA, respectively. Pol I and Pol III have intrinsic nuclease activity conferred by the A12.2 and C11 subunits, respectively. In contrast, Pol II requires the transcription factor (TF) IIS to confer robust nuclease activity. We recently reported that in the absence of the A12.2 subunit Pol I reverses bond formation by pyrophosphorolysis in the absence of added PPi, indicating slow PPi release. Thus, we hypothesized that Pol II, naturally lacking TFIIS, would reverse bond formation through pyrophosphorolysis. Here we report the results of transient-state kinetic experiments to examine the addition of nine nucleotides to a growing RNA chain catalyzed by Pol II. Our results indicate that Pol II reverses bond formation by pyrophosphorolysis in the absence of added PPi. We propose that, in the absence of endonuclease activity, this bond reversal may represent kinetic proofreading. Thus, given the hypothesis that Pol I evolved from Pol II through the incorporation of general transcription factors, pyrophosphorolysis may represent a more ancient form of proofreading that has been evolutionarily replaced with nuclease activity.
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Difosfatos , RNA Polimerase II , Saccharomyces cerevisiae , RNA Polimerase II/metabolismo , RNA Polimerase II/genética , Cinética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Difosfatos/metabolismo , Nucleotídeos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/químicaRESUMO
Animals including humans often react to sounds by involuntarily moving their face and body. A new study shows that facial movements provide a simple and reliable readout of a mouse's hearing ability that is more sensitive than traditional measurements.
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Face , Animais , Camundongos , Face/fisiologia , Percepção Auditiva/fisiologia , Audição/fisiologia , Som , Movimento/fisiologia , HumanosRESUMO
It has been well established that cardiovascular diseases exhibit significant differences between sexes in both preclinical models and humans. In addition, there is growing recognition that disrupted circadian rhythms can contribute to the onset and progression of cardiovascular diseases. However little is known about sex differences between the cardiac circadian clock and circadian transcriptomes in mice. Here, we show that the the core clock genes are expressed in common in both sexes but the circadian transcriptome of the mouse heart is very sex-specific. Hearts from female mice expressed significantly more rhythmically expressed genes (REGs) than male hearts and the temporal pattern of REGs was distinctly different between sexes. We next used a cardiomyocyte-specific knock out of the core clock gene, Bmal1, to investigate its role in sex-specific gene expression in the heart. All sex differences in the circadian transcriptomes were significantly diminished with cardiomyocyte-specific loss of Bmal1. Surprisingly, loss of cardiomyocyte Bmal1 also resulted in a roughly 8-fold reduction in the number of all the differentially expressed genes between male and female hearts. We conclude that cardiomyocyte-specific Bmal1, and potentially the core clock mechanism, is vital in conferring sex-specific gene expression in the adult mouse heart.
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Prions or prion-like aggregates such as those composed of PrP, α-synuclein, and tau are key features of proteinopathies such as prion, Parkinson's and Alzheimer's diseases, respectively. Their presence on solid surfaces may be biohazardous under some circumstances. PrP prions bound to solids are detectable by ultrasensitive real-time quaking-induced conversion (RT-QuIC) assays if the solids can be immersed in assay wells or the prions transferred to pads. Here we show that prion-like seeds can remain detectable on steel wires for at least a year, or even after enzymatic cleaning and sterilization. We also show that contamination of larger objects with pathological seeds of α-synuclein, tau, and PrP can be detected by simply assaying a sampling medium that has been transiently applied to the surface. Human α-synuclein seeds in dementia with Lewy bodies brain tissue were detected by α-synuclein RT-QuIC after drying of tissue dilutions with concentrations as low as 10-6 onto stainless steel. Tau RT-QuIC detected tau seeding activity on steel exposed to Alzheimer's disease brain tissue diluted as much as a billion fold. Prion RT-QuIC assays detected seeding activity on plates exposed to brain dilutions as extreme as 10-5-10-8 from prion-affected humans, sheep, cattle and cervids. Sampling medium collected from surgical instruments used in necropsies of sporadic Creutzfeldt-Jakob disease-infected transgenic mice was positive down to 10-6 dilution. Sensitivity for prion detection was not sacrificed by omitting the recombinant PrP substrate from the sampling medium during its application to a surface and subsequent storage as long as the substrate was added prior to performing the assay reaction. Our findings demonstrate practical prototypic surface RT-QuIC protocols for the highly sensitive detection of pathologic seeds of α-synuclein, tau, and PrP on solid objects.
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Proteínas Priônicas , alfa-Sinucleína , Proteínas tau , Proteínas tau/metabolismo , alfa-Sinucleína/metabolismo , alfa-Sinucleína/análise , Humanos , Proteínas Priônicas/metabolismo , Animais , Camundongos , Encéfalo/metabolismo , Encéfalo/patologia , Príons/metabolismo , Doença por Corpos de Lewy/metabolismoRESUMO
BACKGROUND: Preoperative imaging before parathyroidectomy can localize adenomas and reduce unnecessary bilateral neck explorations. We hypothesized that (1) the utility of preoperative imaging varies substantially depending on the preoperative probability of having adenoma(s) and (2) that a selective imaging approach based on this probability could avoid unnecessary patient costs and radiation. METHODS: We analyzed 3,577 patients who underwent parathyroidectomy for primary hyperparathyroidism from 2001 to 2022. The predicted probability of patients having single or double adenoma versus hyperplasia was estimated using logistic regression. We then estimated the relationship between the predicted probability of single/double adenoma and the likelihood that sestamibi or 4-dimensional computed tomography was helpful for operative planning. Current Medicare costs and published data on radiation dosing were used to calculate costs and radiation exposure from non-helpful imaging. RESULTS: The mean age was 62 ± 13 years; 78% were women. Adenomas were associated with higher mean calcium (11.2 ± 0.74 mg/dL) and parathyroid hormone levels (140.6 ± 94 pg/mL) than hyperplasia (9.8 ± 0.52 mg/dL and 81.4 ± 66 pg/mL). The probability that imaging helped with operative planning increased from 12% to 65%, as the predicted probability of adenoma increased from 30% to 90%. For every 10,000 patients, a selective approach to imaging that considered the preoperative probability of having adenomas could save patients up to $3.4 million and >239,000 millisieverts of radiation. CONCLUSION: Rather than imaging all patients with primary hyperparathyroidism, a selective strategy that considers the probability of having adenomas could reduce costs and avoid excess radiation exposure.
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Adenoma , Hiperparatireoidismo Primário , Neoplasias das Paratireoides , Estados Unidos , Humanos , Feminino , Idoso , Pessoa de Meia-Idade , Masculino , Paratireoidectomia/métodos , Hiperparatireoidismo Primário/diagnóstico por imagem , Hiperparatireoidismo Primário/cirurgia , Neoplasias das Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/cirurgia , Tecnécio Tc 99m Sestamibi , Hiperplasia/diagnóstico por imagem , Medicare , Compostos Radiofarmacêuticos , Hormônio Paratireóideo , Adenoma/diagnóstico por imagem , Adenoma/cirurgiaRESUMO
RNA polymerase I (Pol I) is responsible for synthesizing the three largest eukaryotic ribosomal RNAs (rRNAs), which form the backbone of the ribosome. Transcription by Pol I is required for cell growth and, therefore, is subject to complex and intricate regulatory mechanisms. To accomplish this robust regulation, the cell engages a series of trans-acting transcription factors. One such factor, high mobility group protein 1 (Hmo1), has long been established as a trans-acting factor for Pol I in Saccharomyces cerevisiae; however, the mechanism by which Hmo1 promotes rRNA synthesis has not been defined. Here, we investigated the effect of the deletion of HMO1 on transcription elongation by Pol I in vivo. We determined that Hmo1 is an important activator of transcription elongation, and without this protein, Pol I accumulates across rDNA in a sequence-specific manner. Our results demonstrate that Hmo1 promotes efficient transcription elongation by rendering Pol I less sensitive to pausing in the G-rich regions of rDNA.
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Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , RNA Polimerase I/genética , RNA Polimerase I/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Transcrição Gênica , DNA Ribossômico/genética , DNA Ribossômico/metabolismo , RNA Ribossômico/genética , RNA Ribossômico/metabolismo , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Grupo de Alta Mobilidade/metabolismoRESUMO
OBJECTIVES: FcÉ£RIIa amplifies platelet activation and greater expression increases platelet reactivity. In patients with myocardial infarction (MI), high platelet FcÉ£RIIa identifies patients with an approximately 4-fold greater risk of MI, stroke, and death. We compared platelet FcÉ£RIIa in 2 groups: (1) patients who had not had an MI in the previous year and were undergoing cardiac catheterization and percutaneous coronary intervention (PCI) labeled as stable coronary artery disease (CAD), and (2) previously obtained results in patients with MI (n = 197). METHODS: Patients undergoing cardiac catheterization and PCI were enrolled. FcÉ£RIIa expression was quantified with the use of flow cytometry. Comparisons were made with Mann-Whitney Rank Sum Test and Chi Squared analysis. Significance was defined as P less than .05. RESULTS: Compared to patients with MI, patients with stable CAD (n = 49) were older (70 ± 9 years vs 63 ± 12 years) and were more likely to have had prior MI (43% vs 23%), prior revascularization (62% vs 33%), diabetes (35% vs 24%), and hypertension (98% vs 66%). In patients with stable CAD, platelet FcÉ£RIIa was, on average, lower than that seen in patients with acute MI (9746 ± 4316 vs 11 479 ± 2405 molecules/platelet, P less than .001). Patients with stable CAD exhibited a range of platelet FcÉ£RIIa (~4500 to ~27 000 molecules/platelet) similar to that seen in acute MI patients (~6500 to ~30 000 molecules/platelet). CONCLUSIONS: Compared to patients with MI, patients with stable CAD had, on average, lower platelet FcÉ£RIIa. However, the range of platelet FcÉ£RIIa was similar to that seen in patients with MI. These results support future studies designed to assess the prognostic implications of platelet FcÉ£RIIa in patients with stable CAD.
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Doença da Artéria Coronariana , Infarto do Miocárdio , Intervenção Coronária Percutânea , Receptores de IgG , Humanos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Resultado do Tratamento , Infarto do Miocárdio/diagnósticoRESUMO
Transcription is a tightly regulated, complex, and essential cellular process in all living organisms. Transcription is comprised of three steps, transcription initiation, elongation, and termination. The distinct transcription initiation and termination mechanisms of eukaryotic RNA polymerases I, II, and III (Pols I, II, and III) have long been appreciated. Recent methodological advances have empowered high-resolution investigations of the Pols' transcription elongation mechanisms. Here, we review the kinetic similarities and differences in the individual steps of Pol I-, II-, and III-catalyzed transcription elongation, including NTP binding, bond formation, pyrophosphate release, and translocation. This review serves as an important summation of Saccharomyces cerevisiae (yeast) Pol I, II, and III kinetic investigations which reveal that transcription elongation by the Pols is governed by distinct mechanisms. Further, these studies illustrate how basic, biochemical investigations of the Pols can empower the development of chemotherapeutic compounds.
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Tratamento Farmacológico , RNA Polimerase III , RNA Polimerase II , RNA Polimerase I , Saccharomyces cerevisiae , Elongação da Transcrição Genética , Biocatálise/efeitos dos fármacos , Cinética , RNA Polimerase I/metabolismo , RNA Polimerase II/metabolismo , RNA Polimerase III/metabolismo , Saccharomyces cerevisiae/enzimologia , Elongação da Transcrição Genética/efeitos dos fármacosRESUMO
Ophidiomyces ophidiicola, the fungus causing snake fungal disease (SFD), has been identified in northern pine snakes (Pituophis melanoleucus) in New Jersey. In this paper, we (1) review the positivity rate of SFD on different locations on snakes' bodies, (2) determine the relationship between the sores and quantitative polymerase chain reaction (qPCR) positivity rates, and (3) explore the relationship between the investigators' clinical evaluation of the severity of sores, their evaluation of the likelihood of the sores being positive, and the qPCR positivity of SFD for the sores. Swabbing the sores was more effective at determining whether the snakes tested positive for O. ophidiicola than ventrum swabbing alone. The perception of the severity of the sores did not relate to qPCR positivity for O. ophidiicola. We suggest that the assessment of the rate of SFD among snakes in the wild needs to include the sampling of snakes with no clinical signs, as well as those with sores, and the swabbing of all the sores collectively. Clear terminology for sores, the identification of clinical signs of SFD, and distinguishing the rates of O. ophidiicola by PCR testing should be adopted. Overall, the pine snakes exhibited a higher rate of sores and positivity of O. ophidiicola swabs by PCR testing compared to the other snakes.
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The cortex integrates sound- and movement-related signals to predict the acoustic consequences of behavior and detect violations from expectations. Although expectation- and prediction-related activity has been observed in the auditory cortex of humans, monkeys, and mice during vocal and non-vocal acoustic behaviors, the specific cortical circuitry required for forming memories, recalling expectations, and making predictions remains unknown. By combining closed-loop behavior, electrophysiological recordings, longitudinal pharmacology, and targeted optogenetic circuit activation, we identify a cortical locus for the emergence of expectation and error signals. Movement-related expectation signals and sound-related error signals emerge in parallel in the auditory cortex and are concentrated in largely distinct neurons, consistent with a compartmentalization of different prediction-related computations. On a trial-by-trial basis, expectation and error signals are correlated in auditory cortex, consistent with a local circuit implementation of an internal model. Silencing the auditory cortex during motor-sensory learning prevents the emergence of expectation signals and error signals, revealing the auditory cortex as a necessary node for learning to make predictions. Prediction-like signals can be experimentally induced in the auditory cortex, even in the absence of behavioral experience, by pairing optogenetic motor cortical activation with sound playback, indicating that cortical circuits are sufficient for movement-like predictive processing. Finally, motor-sensory experience realigns the manifold dimensions in which auditory cortical populations encode movement and sound, consistent with predictive processing. These findings show that prediction-related signals reshape auditory cortex dynamics during behavior and reveal a cortical locus for the emergence of expectation and error.
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BACKGROUND: CAR T-cell therapy has transformed the treatment of hematologic malignancies, but it is complex and challenging to convey to patients. Educational video interventions are efficacious for improving patient knowledge about cancer therapeutics and informing their care preferences, yet no educational videos have been evaluated in CAR T-cell therapy. METHODS: We conducted a randomized controlled trial comparing an educational video versus usual care in adults (age ≥18 years) with hematologic malignancies receiving CAR T-cell therapy at Massachusetts General Hospital. Intervention participants watched a 13-minute video depicting how CAR T-cell therapy works, logistics, toxicities, prognosis, recovery, and approaches for dealing with prognostic uncertainty. The primary outcome was feasibility (≥60% enrollment rate). Secondary outcomes included acceptability (≥80% reporting comfort with the video), patients' knowledge about CAR T-cell therapy (10-item test), and self-efficacy (Communication and Attitudinal Self-Efficacy Scale-Cancer), decision satisfaction (Decision Conflict Scale), psychological distress (Hospital Anxiety and Depression Scale), and preference for CAR T-cell therapy. RESULTS: We enrolled 79% (80/101) of eligible patients. Of that group, 91% (30/33) reported being very or somewhat comfortable watching the video, and 94% (31/33) would definitely or probably recommend the video. At 1 month, participants in the video arm reported higher self-efficacy (mean difference [MD], 9.2 [95% CI, -4.0 to 22.3]; Cohen's d, 0.32), decision satisfaction (MD, 2.5 [95% CI, 0.7-4.2]; Cohen's d, 0.67), and lower anxiety (MD, -0.8 [95% CI, -2.5 to 0.7]; Cohen's d, 0.26) compared with participants in the usual care arm. At 1 week, both arms reported high preferences for CAR T-cell therapy (video arm, 94% [33/35]; usual care, 84% [27/32]). CONCLUSIONS: We found that an educational video for patients receiving CAR T-cell therapy was feasible and acceptable. The educational video demonstrated promising preliminary effects on patient self-efficacy and decision satisfaction and warrants further study.
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Neoplasias Hematológicas , Neoplasias , Adulto , Humanos , Adolescente , Projetos Piloto , Imunoterapia Adotiva/efeitos adversos , Ansiedade/etiologia , Ansiedade/terapia , Neoplasias/terapiaRESUMO
Neurons in the mouse auditory cortex are strongly influenced by behavior, including both suppression and enhancement of sound-evoked responses during movement. The mouse auditory cortex comprises multiple fields with different roles in sound processing and distinct connectivity to movement-related centers of the brain. Here, we asked whether movement-related modulation in male mice might differ across auditory cortical fields, thereby contributing to the heterogeneity of movement-related modulation at the single-cell level. We used wide-field calcium imaging to identify distinct cortical fields and cellular-resolution two-photon calcium imaging to visualize the activity of layer 2/3 excitatory neurons within each field. We measured each neuron's responses to three sound categories (pure tones, chirps, and amplitude-modulated white noise) as mice rested and ran on a non-motorized treadmill. We found that individual neurons in each cortical field typically respond to just one sound category. Some neurons are only active during rest and others during locomotion, and those that are responsive across conditions retain their sound-category tuning. The effects of locomotion on sound-evoked responses vary at the single-cell level, with both suppression and enhancement of neural responses, and the net modulatory effect of locomotion is largely conserved across cortical fields. Movement-related modulation in auditory cortex also reflects more complex behavioral patterns, including instantaneous running speed and nonlocomotor movements such as grooming and postural adjustments, with similar patterns seen across all auditory cortical fields. Our findings underscore the complexity of movement-related modulation throughout the mouse auditory cortex and indicate that movement-related modulation is a widespread phenomenon.
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Córtex Auditivo , Masculino , Camundongos , Animais , Córtex Auditivo/fisiologia , Estimulação Acústica , Cálcio , Neurônios/fisiologia , Som , Percepção Auditiva/fisiologiaRESUMO
Diaphanoscopic illumination has the disadvantage that the intraocular spectrum is red-shifted due to transmission properties of the eyewall. This red-shift should be counteracted as well as the retinal risk should be reduced with adjusting the spectral distribution of the illumination light. Likewise, the illumination spectrum has to be adapted to the eye color of the patient. With the further development of a red, green, blue and white light-emitting diode (RGBW-LED) diaphanoscopy pen, the intensities of each color can be varied. The functionality of the LED pen is tested on ex-vivo porcine eyes. By measuring the transmission of the sclera and choroidea, the photochemical and thermal retinal hazard and the maximum exposure time are determined according to the standard DIN EN ISO 15004-2:2007. With this RGBW-LED pen the intraocular space can be illuminated clearly of up to 1.5 h without potential retinal damage according to DIN EN ISO 15004:2-2007. By adjusting the illumination spectrum the red-shift can be compensated and retinal risk can be reduced. By varying the LED intensities, the correlated color temperature in the eye can also be varied from cold white to warm white appearance as comfortable to the ophthalmologist. Additionally, a simple adjustment of the illumination to the eye color of the patient is possible. Using this RGBW-LED pen, the ophthalmologist can set the desired intraocular color appearance, which he prefers for special applications. He could also adjust the illumination to the eye color as this would reduce retinal hazard.