Telemedicine With Wearable Technologies in Patients Undergoing Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapy (TEL-HEMATO Study): Prospective Noninterventional Single-Center Study.

BACKGROUND: Patients with hematological malignancies receiving hematopoietic cell transplantation (HCT) or chimeric antigen receptor (CAR) T-cell therapy are at risk of developing serious clinical complications after discharge. OBJECTIVE: The aim of the TEL-HEMATO study was to improve our telehealth platform for the follow-up of patients undergoing HCT or CAR T-cell therapy during the first 3 months after discharge with the addition of wearable devices. METHODS: Eleven patients who received autologous (n=2) or allogeneic (n=5) HCT or CAR T-cell therapy (n=4) for hematological malignancies were screened from November 2022 to July 2023. Two patients discontinued the study after enrollment. The telehealth platform consisted of the daily collection of vital signs, physical symptoms, and quality of life assessment up to 3 months after hospital discharge. Each patient received a clinically validated smartwatch (ScanWatch) and a digital thermometer, and a dedicated smartphone app was used to collect these data. Daily revision of the data was performed through a web-based platform by a hematologist or a nurse specialized in HCT and CAR T-cell therapy. RESULTS: Vital signs measured through ScanWatch were successfully collected with medium/high adherence: heart rate was recorded in 8/9 (89%) patients, oxygen saturation and daily steps were recorded in 9/9 (100%) patients, and sleeping hours were recorded in 7/9 (78%) patients. However, temperature recorded manually by the patients was associated with lower compliance, which was recorded in 5/9 (55%) patients. Overall, 5/9 (55%) patients reported clinical symptoms in the app. Quality of life assessment was completed by 8/9 (89%) patients at study enrollment, which decreased to 3/9 (33%) at the end of the third month. Usability was considered acceptable through ratings provided on the System Usability Scale. However, technological issues were reported by the patients. CONCLUSIONS: While the addition of wearable devices to a telehealth clinical platform could have potentially synergic benefits for HCT and CAR T-cell therapy patient monitoring, noncomplete automation of the platform and the absence of a dedicated telemedicine team still represent major limitations to be overcome. This is especially true in our real-life setting where the target population generally comprises patients of older age with a low digital education level.

Disconnecting the Golgi ribbon from the centrosome prevents directional cell migration and ciliogenesis.

Mammalian cells exhibit a frequent pericentrosomal Golgi ribbon organization. In this paper, we show that two AKAP450 N-terminal fragments, both containing the Golgi-binding GM130-interacting domain of AKAP450, dissociated endogenous AKAP450 from the Golgi and inhibited microtubule (MT) nucleation at the Golgi without interfering with centrosomal activity. These two fragments had, however, strikingly different effects on both Golgi apparatus (GA) integrity and positioning, whereas the short fragment induced GA circularization and ribbon fragmentation, the large construct that encompasses an additional p150glued/MT-binding domain induced separation of the Golgi ribbon from the centrosome. These distinct phenotypes arose by specific interference of each fragment with either Golgi-dependent or centrosome-dependent stages of Golgi assembly. We could thus demonstrate that breaking the polarity axis by perturbing GA positioning has a more dramatic effect on directional cell migration than disrupting the Golgi ribbon. Both features, however, were required for ciliogenesis. We thus identified AKAP450 as a key determinant of pericentrosomal Golgi ribbon integrity, positioning, and function in mammalian cells.

Brahma is required for proper expression of the floral repressor FLC in Arabidopsis.

BACKGROUND: BRAHMA (BRM) is a member of a family of ATPases of the SWI/SNF chromatin remodeling complexes from Arabidopsis. BRM has been previously shown to be crucial for vegetative and reproductive development. METHODOLOGY/PRINCIPAL FINDINGS: Here we carry out a detailed analysis of the flowering phenotype of brm mutant plants which reveals that, in addition to repressing the flowering promoting genes CONSTANS (CO), FLOWERING LOCUS T (FT) and SUPPRESSOR OF OVEREXPRESSION OF CO1 (SOC1), BRM also represses expression of the general flowering repressor FLOWERING LOCUS C (FLC). Thus, in brm mutant plants FLC expression is elevated, and FLC chromatin exhibits increased levels of histone H3 lysine 4 tri-methylation and decreased levels of H3 lysine 27 tri-methylation, indicating that BRM imposes a repressive chromatin configuration at the FLC locus. However, brm mutants display a normal vernalization response, indicating that BRM is not involved in vernalization-mediated FLC repression. Analysis of double mutants suggests that BRM is partially redundant with the autonomous pathway. Analysis of genetic interactions between BRM and the histone H2A.Z deposition machinery demonstrates that brm mutations overcome a requirement of H2A.Z for FLC activation suggesting that in the absence of BRM, a constitutively open chromatin conformation renders H2A.Z dispensable. CONCLUSIONS/SIGNIFICANCE: BRM is critical for phase transition in Arabidopsis. Thus, BRM represses expression of the flowering promoting genes CO, FT and SOC1 and of the flowering repressor FLC. Our results indicate that BRM controls expression of FLC by creating a repressive chromatin configuration of the locus.

The Arabidopsis BRAHMA chromatin-remodeling ATPase is involved in repression of seed maturation genes in leaves.

Synthesis and accumulation of seed storage proteins (SSPs) is an important aspect of the seed maturation program. Genes encoding SSPs are specifically and highly expressed in the seed during maturation. However, the mechanisms that repress the expression of these genes in leaf tissue are not well understood. To gain insight into the repression mechanisms, we performed a genetic screen for mutants that express SSPs in leaves. Here, we show that mutations affecting BRAHMA (BRM), a SNF2 chromatin-remodeling ATPase, cause ectopic expression of a subset of SSPs and other embryogenesis-related genes in leaf tissue. Consistent with the notion that such SNF2-like ATPases form protein complexes in vivo, we observed similar phenotypes for mutations of AtSWI3C, a BRM-interacting partner, and BSH, a SNF5 homolog and essential SWI/SNF subunit. Chromatin immunoprecipitation experiments show that BRM is recruited to the promoters of a number of embryogenesis genes in wild-type leaves, including the 2S genes, expressed in brm leaves. Consistent with its role in nucleosome remodeling, BRM appears to affect the chromatin structure of the At2S2 promoter. Thus, the BRM-containing chromatin-remodeling ATPase complex involved in many aspects of plant development mediates the repression of SSPs in leaf tissue.

The putative SWI/SNF complex subunit BRAHMA activates flower homeotic genes in Arabidopsis thaliana.

Arabidopsis thaliana BRAHMA (BRM, also called AtBRM) is a SNF2 family protein homolog of Brahma, the ATPase of the Drosophila SWI/SNF complex involved in chromatin remodeling during transcription. Here we show that, in contrast to its Drosophila counterpart, BRM is not an essential gene. Thus, homozygous BRM loss of function mutants are viable but exhibit numerous defects including dwarfism, altered leaf and root development and several reproduction defects. The analysis of the progeny of self-fertilized heterozygous brm plants and reciprocal crosses between heterozygous and wild type plants indicated that disruption of BRM reduced both male and female gametophyte transmission. This was consistent with the presence of aborted ovules in the self-fertilized heterozygous flowers that contained arrested embryos predominantly at the two terminal cells stage. Furthermore, brm homozygous mutants were completely sterile. Flowers of brm loss-of-function mutants have several developmental abnormalities, including homeotic transformations in the second and third floral whorls. In accordance with these results, brm mutants present reduced levels of APETALA2, APETALA3, PISTILLATA and NAC-LIKE, ACTIVATED BY AP3/PI. We have previously shown that BRM strongly interacts with AtSWI3C. Now we extend our interaction studies demonstrating that BRM interacts weakly with AtSWI3B but not with AtSWI3A or AtSWI3D. In agreement with these results, the phenotype described in this study for brm plants is very similar to that previously described for the AtSWI3C mutant plants, suggesting that both proteins participate in the same genetic pathway or form a molecular complex.

The Arabidopsis thaliana SNF2 homolog AtBRM controls shoot development and flowering.

Chromatin remodeling is essential for the reprogramming of transcription associated with development and cell differentiation. The SWI/SNF complex was the first chromatin remodeling complex characterized in yeast and Drosophila. In this work we have characterized an Arabidopsis thaliana homolog of Brahma, the ATPase of the Drosophila SWI/SNF complex. As its Drosophila counterpart, Arabidopsis thaliana BRAHMA (AtBRM) is a nuclear protein present in a high molecular mass complex. Furthermore, the N terminus of AtBRM interacts, in the two-hybrid system, with CHB4 (AtSWI3C), an Arabidopsis homolog of the yeast SWI/SNF complex subunit SWI3. The AtBRM gene is primarily expressed in meristems, organ primordia and tissues with active cell division. Silencing of the expression of the AtBRM gene by RNA interference demonstrated that AtBRM is required for vegetative and reproductive development. The AtBRM silenced plants exhibited a reduction in overall plant size with small and curled leafs, as well as a reduction in the size of the inflorescence meristem. In the absence of AtBRM, Arabidopsis flowers have small petals and stamens, immature anthers, homeotic transformations and reduced fertility. The AtBRM silenced plants flower earlier than wild-type plants both under inductive and non-inductive photoperiods. Furthermore, levels of CO, FT and SOC1 transcripts were up-regulated under non-inductive conditions suggesting that AtBRM is a repressor of the photoperiod-dependent flowering pathway.