26 research outputs found
On the interaction of replication and transcriptional regulation
No full textDNA replication introduces a gradient of gene copy numbers, and in Bacteria it affects gene expression accordingly. In E. coli and other species, the slope of the gradient averaged over the population can be predicted on the basis of its relationship with growth rate. In this work we integrated this growth- and position-dependent gradient into a classical transcriptional regulation model, to highlight their interaction. The theoretical treatment of our model highlights that the sensitivity to transcription factor-mediated regulations acquires an additional dimension related to the position of a locus on the oriter axis and to division time. This reinforces the idea of replication as an additional layer in gene regulation. We highlight here that replication- and transcription factor-mediated regulations can in theory work in concert or counteract each other, and we discuss why this is important from an evolutionary point of view with respect to both steady state transcript abundance and its variance across conditions. Finally, we note that this treatment may improve the estimation of kinetic parameters for transcription factor activity using RNA-seq data, and the estimation of the dispersion factor in differential gene expression analysis when division time across conditions changes significantly
A new selective force driving metabolic gene clustering
No full textABSTRACT The evolution of operons has puzzled evolutionary biologists since their discovery, and many theories exist to explain their emergence, spreading, and evolutionary conservation. In this work, we suggest that DNA replication introduces a selective force for the clustering of functionally related genes on chromosomes, which we interpret as a preliminary and necessary step in operon formation. Our reasoning starts from the observation that DNA replication produces copy number variations of genomic regions, and we propose that such changes perturb metabolism. The formalization of this effect by exploiting concepts from metabolic control analysis suggests that the minimization of such perturbations during evolution could be achieved through the formation of gene clusters and operons. We support our theoretical derivations with simulations based on a realistic metabolic network, and we confirm that present-day genomes have a degree of compaction of functionally related genes, which is significantly correlated to the proposed perturbations introduced by replication. The formation of clusters of functionally related genes in microbial genomes has puzzled microbiologists since their first discovery. Here, we suggest that replication, and the copy number variations due to the replisome passage, might play a role in the process through a perturbation in metabolite homeostasis. We provide theoretical support to this hypothesis, and we found that both simulations and genomic analysis support our hypothesis.IMPORTANCEThe formation of clusters of functionally related genes in microbial genomes has puzzled microbiologists since their discovery. Here, we suggest that replication, and the copy number variations due to the replisome passage, might play a role in the process through a perturbation in metabolite homeostasis. We provide theoretical support to this hypothesis, and we found that both simulations and genomic analysis support our hypothesis
Emotional reactivity in referred youth with disruptive behavior disorders: the role of the callous-unemotional traits
No full textDeficits in emotional reactivity are frequently reported in Disruptive Behavior Disorders (DBDs). A deficit in
prosocial emotions, namely the callous unemotional traits (CU), may be a mediator of emotional reactivity.
Our aim is to investigate subjective emotional reactivity towards visual stimuli with different affective
valence in youths with DBDs and healthy controls. The clinical sample included 62 youths with DBDs (51
males, 8 to16 years, mean 11.372.1 years), the control group 53subjects (36 males,8 to 16 years, mean
10.871.5 years). The groups were compared using the Child Behavior Checklist (CBCL), the Inventory of
Callous-Unemotional Traits (ICU),and the International Affective Picture System (IAPS),which explores the
affective(pleasant/unpleasant emotional reaction) and arousal (low/high intensity of emotion) dimen-
sions.The DBD group presented higher scores in externalizing and internalizing CBCL scores, and in ICU
callous and indifferent subscales. At the IAPS,DBD patients differed from controls in the affective valence
of the images, rating less unpleasant neutral and negative images. The CU traits were the only predictor of
emotional reactivity in the DBD sample. A less aversive way to interpret neutral and negatives timuli may
explain why DBD patients are less responsive to negative reinforcements
Effectiveness and Satisfaction with Telemedicine in Geriatric Patients at High Risk of Fragility Fractures
No full textBackground: Telemedicine has increasingly widespread to improve the monitoring of patients with chronic diseases. Secondary prevention of fragility fractures is an urgent matter to be addressed by means of available technology, although supported by little evidence so far. We investigated the feasibility, efficacy, and satisfaction of managing older adults at high risk of fragility fractures during the COVID-19 lockdown. Methods: During the period January to July 2021, a prospective observational study for safety and adherence purposes was conducted among older adults (n = 407) with ongoing treatments for secondary prevention of fragility fractures. The study procedures comply with national and regional resolutions related to telemedicine service (TS), including equipment, staff behaviors, and patient reports. Results: A majority (86.48% [n = 352]) of the eligible patients joined the remote visits, mainly women (88.2%), 81.4 +/- 8.8 years of age, 49.6% independent in 5 out of 6 BADL, despite high comorbidity (4.9 +/- 1.5), and polypharmacy (4.9 +/- 3.1). Almost all were on second-line antifracture treatments (95.58%) due to previous major (84.03%) and minor (42.5%) fragility fractures. About 58% reported good and very good reliability of the internet network, allowing easy access to the TS platform, and 54% declared the degree of satisfaction with TS as good and very good. About 75% of clinicians acknowledged the efficacy of TS and expressed willingness to recommend the use of TS to colleagues. Ultimately, 68% of specialists defined the time allocated for patients' remote visits as acceptable. Conclusion: TS may be an opportunity to improve the availability of appropriate health care services to satisfy patients' needs and optimize health care resource allocation
Song Literature I Renaissance and Baroque Music, December 1, 1992
No full textThis is the concert program of the Song Literature I Renaissance and Baroque Music performance on Wednesday, December 1, 1992 at 8:00 p.m., at the Concert Hall, 855 Commonwealth Avenue. Works performed were Eau vive, source d'amour by Gabrielle Bataille, Deh, dove son fuggiti by Giulio Caccini, O miei giorni fugaci by Jacopo Peri, Come Away, Come Sweet Love by John Dowland,"Addio Corindo" from "I casti amori d'Orontea" by Pietro Antonio Cesti, "Itorno all'ido mio" from "I casti amori d'Orontea" by P. A. Cesti, "Seek not to know" from "The Indian Queen" by Henry Purcell, Sento nel core by Alessandro Scarlatti, Vieni, vieni, o mio diletto by Antonio Vivaldi, Piango gemo by A. Vivaldi, The Timely Admonition by Thomas Arne, "Aria di Buona fede" from "Il mondo della luna" by Franz Joseph Haydn, "Oh had I jubal's lyre" from "Joshua" by George Frideric Handel, "O Numi eterni" from "Lucretia" by G. F. Handel, "I know that my Redeemer liveth" from "Messiah" by G. F. Handel, "Và godendo" from "Serse" by G. F. Handel, and "Let the Bright Seraphim" from "Samson" by G. F. Handel. Digitization for Boston University Concert Programs was supported by the Boston University Humanities Library Endowed Fund
A plasmonic route towards the energy scaling of on-chip integrated all-photonic phase-change memories
No full textThis is the author accepted manuscript.Phase-change photonic memory devices, conventionally implemented as a thin layer of phase-change material deposited on the top of an integrated Si or SiN waveguide, have the flexibility to be applied in a widely diverse context, as a pure memory device, a logic gate, an arithmetic processing unit and for biologically inspired computing. In all such applications increasing the speed, and reducing the power consumption, of the phase-switching process is most desirable. In this work, therefore, we investigate, via simulation, a novel integrated photonic device architecture that exploits plasmonic effects to enhance the light-matter interaction. Our device comprises a dimer nanoantenna fabricated on top of a SiN waveguide and with a phase-change material deposited into the gap between the two nanoantenna halves. We observed very considerably increased device speeds and reduced energy requirements, of up to two orders of magnitude, when compared to the conventional structure.Engineering and Physical Sciences Research Council (EPSRC
A behavioural model for integrated phase-change photonics
No full textThis is the author accepted manuscript. The final version is available from the European Phase Change and Ovonics Symposium via the link in this recordThe use of phase-change materials in integrated photonics applications has enabled the development
of new types of all-optical devices, including multilevel photonic memories, arithmetic and logic
processors and synaptic and neuron mimics. In order to design, optimise and understand the
performance of large-scale systems, fast and accurate material and device models are needed. Here we
present a behavioural model for phase-change photonic devices that can simulate the write, erase and
readout operations in timespans compatible with system level performance evaluation.European Union Horizon 2020Engineering and Physical Sciences Research Council (EPSRC
Clinical and genetic Rett syndrome variants are defined by stable electrophysiological profiles
No full textAbstract Background Rett Syndrome (RTT) is a complex neurodevelopmental disorder, frequently associated with epilepsy. Despite increasing recognition of the clinical heterogeneity of RTT and its variants (e.g Classical, Hanefeld and PSV(Preserved Speech Variant)), the link between causative mutations and observed clinical phenotypes remains unclear. Quantitative analysis of electroencephalogram (EEG) recordings may further elucidate important differences between the different clinical and genetic forms of RTT. Methods Using a large cohort (n = 42) of RTT patients, we analysed the electrophysiological profiles of RTT variants (genetic and clinical) in addition to epilepsy status (no epilepsy/treatment-responsive epilepsy/treatment-resistant epilepsy). The distribution of spectral power and inter-electrode coherence measures were derived from continuous resting-state EEG recordings. Results RTT genetic variants (MeCP2/CDLK5) were characterised by significant differences in network architecture on comparing first principal components of inter-electrode coherence across all frequency bands (p < 0.0001). Greater coherence in occipital and temporal pairs were seen in MeCP2 vs CDLK5 variants, the main drivers in between group differences. Similarly, clinical phenotypes (Classical RTT/Hanefeld/PSV) demonstrated significant differences in network architecture (p < 0.0001). Right tempero-parietal connectivity was found to differ between groups (p = 0.04), with greatest coherence in the Classical RTT phenotype. PSV demonstrated a significant difference in left-sided parieto-occipital coherence (p = 0.026). Whilst overall power decreased over time, there were no difference in asymmetry and inter-electrode coherence profiles over time. There was a significant difference in asymmetry in the overall power spectra between epilepsy groups (p = 0.04) in addition to occipital asymmetry across all frequency bands. Significant differences in network architecture were also seen across epilepsy groups (p = 0.044). Conclusions Genetic and clinical variants of RTT are characterised by discrete patterns of inter-electrode coherence and network architecture which remain stable over time. Further, hemispheric distribution of spectral power and measures of network dysfunction are associated with epilepsy status and treatment responsiveness. These findings support the role of discrete EEG profiles as non-invasive biomarkers in RTT and its genetic/clinical variants
Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
No full textThe contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers. © 2022. The Author(s)
The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant
No full textPurpose: To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making. © 2021, The Author(s)
