Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. ...We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with ∼19,000 basal transcript levels across 823 different human cancer cell lines and identified selective outlier transcripts. This process yielded many novel mechanistic insights, including the identification of activation mechanisms, cellular transporters and direct protein targets. We found that ML239, originally identified in a phenotypic screen for selective cytotoxicity in breast cancer stem-like cells, most likely acts through activation of fatty acid desaturase 2 (FADS2). These data and analytical tools are available to the research community through the Cancer Therapeutics Response Portal.
Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of ...small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset. This analysis reveals insights into small-molecule mechanisms of action, and genomic features that associate with CCL response to small-molecule treatment. We are able to recapitulate known relationships between FDA-approved therapies and cancer dependencies and to uncover new relationships, including for KRAS-mutant cancers and neuroblastoma. To enable the cancer community to explore these data, and to generate novel hypotheses, we created an updated version of the Cancer Therapeutic Response Portal (CTRP v2).
We present the largest CCL sensitivity dataset yet available, and an analysis method integrating information from multiple CCLs and multiple small molecules to identify CCL response predictors robustly. We updated the CTRP to enable the cancer research community to leverage these data and analyses.
Hydroides elegans is an indirectly developing polychaete with equal spiral cleavage, gastrulation by invagination, and a feeding trochophore. Expression of several transcription factors and ...differentiation genes has been characterized. Comparative analysis reveals evolutionarily conserved roles. For example, the synexpression of transcription factors FoxA and Brachyury suggests homology of primary and secondary gut openings in protostomes and deuterostomes, and the expression of Sall suggests similar regulatory controls in the posterior growth zone of bilaterians. Differences in gene expression suggest regulatory differences control gastrulation by invagination in polychaetes with a feeding trochophore and gastrulation by epiboly in polychaetes without a feeding trochophore. Association of histone variant H2A.Z with transcriptional potency and its expression suggest a developmental role during both embryogenesis and the larva-to-adult transformation. Methods are being developed for experimental exploration of the gene regulatory networks involved in trochophore development in Hydroides. It is unknown if polychaete feeding trochophores evolved from a larval stage already present in the life cycle of the last common ancestor of protostomes and deuterostomes. Previous evolutionary scenarios about larval origins overemphasize the discontinuity between larval and adult development and require the early evolution of undifferentiated and transcriptionally potent "set aside" cells. Indirect development may proceed by developmental remodeling of differentiated cells and could have evolved after gradual transformation of juveniles into larvae; undifferentiated and transcriptionally potent cells would have evolved secondarily. Comprehensive characterization of gene regulatory networks for feeding trochophore development may help resolve these major evolutionary questions.
Abstract A rapid and sensitive LC/MS method was developed for the simultaneous analysis of N , N -dimethylamphetamine (DMA), N , N -dimethylamphetamine N -oxide (DMANO), methylamphetamine (MA) and ...amphetamine (A) in urine samples. Employing an Alltech C18 column for solid phase extraction followed by LC/MS analysis using an Alltech Platinum EPS C18 column with a mixture of ammonium formate (0.01 M, pH 3) and acetonitrile (77:23, v/v) as mobile phase at a flow rate of 0.2 mL/min, simultaneous identification and quantitation of A, MA, DMA and DMANO in urine can be achieved using a 5-min chromatographic run. The calibration ranges were 0.10–3.0 μg/mL for DMANO, 0.05–3.0 μg/mL for DMA and 0.05–5.0 μg/mL for both MA and A. The intra-, inter-day precision and accuracy for all analytes, spiked at three different concentrations in quality control samples, were in the ranges of 1.7–8.6, 4.1–10.0, −11.6 to 12.9%, respectively. The newly developed method was applied to the analysis of urine samples obtained from 118 suspected MA/DMA abusers, with the presence of MA confirmed in their urine samples under the drug-use surveillance program. Of these 118 samples, 43 were found to contain DMANO and 11 with both DMANO and DMA.
The crystal quality of GaN based light emitting diodes (LEDs) with sputtered physical vapor deposition (PVD) aluminum nitride (AlN) nucleation layers were investigated. It was found that the crystal ...quality in terms of defect density and X-ray diffraction linewidth was greatly improved. The light output power and reverse bias voltage of leakage current were increased on LEDs with PVD AlN nucleation layers.
Ultrathin ferroelectric materials could potentially enable low-power perovskite ferroelectric tetragonality logic and nonvolatile memories
. As ferroelectric materials are made thinner, however, the ...ferroelectricity is usually suppressed. Size effects in ferroelectrics have been thoroughly investigated in perovskite oxides-the archetypal ferroelectric system
. Perovskites, however, have so far proved unsuitable for thickness scaling and integration with modern semiconductor processes
. Here we report ferroelectricity in ultrathin doped hafnium oxide (HfO
), a fluorite-structure oxide grown by atomic layer deposition on silicon. We demonstrate the persistence of inversion symmetry breaking and spontaneous, switchable polarization down to a thickness of one nanometre. Our results indicate not only the absence of a ferroelectric critical thickness but also enhanced polar distortions as film thickness is reduced, unlike in perovskite ferroelectrics. This approach to enhancing ferroelectricity in ultrathin layers could provide a route towards polarization-driven memories and ferroelectric-based advanced transistors. This work shifts the search for the fundamental limits of ferroelectricity to simpler transition-metal oxide systems-that is, from perovskite-derived complex oxides to fluorite-structure binary oxides-in which 'reverse' size effects counterintuitively stabilize polar symmetry in the ultrathin regime.
Cross-species comparison of transcriptomes is important for elucidating evolutionary molecular mechanisms underpinning phenotypic variation between and within species, yet to date it has been ...essentially limited to model organisms with relatively small sample sizes.
Here, we systematically analyze and compare 10,830 and 4866 publicly available RNA-seq samples in humans and cattle, respectively, representing 20 common tissues. Focusing on 17,315 orthologous genes, we demonstrate that mean/median gene expression, inter-individual variation of expression, expression quantitative trait loci, and gene co-expression networks are generally conserved between humans and cattle. By examining large-scale genome-wide association studies for 46 human traits (average n = 327,973) and 45 cattle traits (average n = 24,635), we reveal that the heritability of complex traits in both species is significantly more enriched in transcriptionally conserved than diverged genes across tissues.
In summary, our study provides a comprehensive comparison of transcriptomes between humans and cattle, which might help decipher the genetic and evolutionary basis of complex traits in both species.
Ferroelectric field-effect transistors (FeFETs) based on HfO 2 are promising for low-power and high-speed non-volatile memory devices. However, most reported FeFETs show limited write endurance and ...significant read-after-write delay due to parasitic charge trapping. Here we show that n-type FeFETs with SiN x interfacial layer and high write endurance also exhibit immediate read-after-write behavior due to negligible charge trapping. This overcomes one of the major challenges faced by FeFET technologies today.
N6-methyl-adenosine (m(6)A) is the most abundant modification on messenger RNAs and is linked to human diseases, but its functions in mammalian development are poorly understood. Here we reveal the ...evolutionary conservation and function of m(6)A by mapping the m(6)A methylome in mouse and human embryonic stem cells. Thousands of messenger and long noncoding RNAs show conserved m(6)A modification, including transcripts encoding core pluripotency transcription factors. m(6)A is enriched over 3' untranslated regions at defined sequence motifs and marks unstable transcripts, including transcripts turned over upon differentiation. Genetic inactivation or depletion of mouse and human Mettl3, one of the m(6)A methylases, led to m(6)A erasure on select target genes, prolonged Nanog expression upon differentiation, and impaired ESC exit from self-renewal toward differentiation into several lineages in vitro and in vivo. Thus, m(6)A is a mark of transcriptome flexibility required for stem cells to differentiate to specific lineages.
Telerehabilitation for people with low vision Bittner, Ava K; Yoshinaga, Patrick D; Rittiphairoj, Thanitsara ...
Cochrane database of systematic reviews,
01/2023, Letnik:
1
Journal Article
Recenzirano
Odprti dostop
Low vision affects over 300 million people worldwide and can compromise both activities of daily living and quality of life. Rehabilitative training and vision assistive equipment (VAE) may help, but ...some visually impaired people have limited resources to attend in-person visits to rehabilitation clinics to be trained to learn to use VAE. These people may be able to overcome barriers to care through access to remote, internet-based consultation (telerehabilitation).
To compare the effects of telerehabilitation with face-to-face (e.g. in-office or inpatient) vision rehabilitation services for improving vision-related quality of life and near reading ability in people with visual function loss due to any ocular condition. Secondary objectives were to evaluate compliance with scheduled rehabilitation sessions, abandonment rates for VAE devices, and patient satisfaction ratings.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register) (2021, Issue 9); Ovid MEDLINE; Embase.com; PubMed; ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any language restriction or study design filter in the electronic searches; however, we restricted the searches from 1980 onwards because the internet was not introduced to the public until 1982. We last searched CENTRAL, MEDLINE Ovid, Embase, and PubMed on 14 September 2021, and the trial registries on 16 March 2022.
We included randomized controlled trials (RCTs) or controlled clinical trials (CCTs) in which participants diagnosed with low vision had received vision rehabilitation services remotely from a human provider using internet, web-based technology compared with an approach involving in-person consultations.
Two review authors independently screened titles and abstracts retrieved by the searches of the electronic databases and then full-text articles for eligible studies. Two review authors independently abstracted data from the included studies. Any discrepancies were resolved by discussion.
We identified one RCT/CCT that indirectly met our inclusion criteria, and two ongoing trials that met our inclusion criteria. The included trial had an overall high risk of bias. We did not conduct a quantitative analysis since multiple controlled trials were not identified. The single included trial of 57 participants utilized a parallel-group design. It compared 30 hours of either personalized low vision training through telerehabilitation with a low vision therapist (the experimental group) with the self-training standard provided by eSight using the eSkills User Guide that was self-administered by the participants at home for one hour per day for 30 days (the comparison group). The trial investigators found a similar direction of effects for both groups for vision-related quality of life and satisfaction at two weeks, three months, and six months. A greater proportion of participants in the comparison group had abandoned or discontinued use of the eSight Eyewear at two weeks than those in the telerehabilitation group, but discontinuance rates were similar between groups at one month and three months. We rated the certainty of the evidence for all outcomes as very low due to high risk of bias in randomization processes and missing outcome data and imprecision. AUTHORS' CONCLUSIONS: The included trial found similar efficacy between telerehabilitation with a therapist and an active control intervention of self-guided training in mostly younger to middle-aged adults with low vision who received a new wearable electronic aid. Given the disease burden and the growing interest in telemedicine, the two ongoing studies, when completed, may provide further evidence of the potential for telerehabilitation as a platform for providing services to people with low vision.
PDF
