Transcriptional Regulation of Multi-Gene Loci: Multi-Level Control.

Recent studies indicate that different levels of control operate within multigene loci. In addition to regulatory sequences immediately flanking the genes, there are also elements that act over long distances on more than one gene. Competition for these elements among genes can influence both the level and timing of gene expression during development

Understanding packet loss for sound monitoring in a smart stadium IoT testbed

The Smart Stadium for Smarter Living project provides an end-to-end testbed for IoT innovation through a collaboration between Croke Park Stadium in Dublin, Ireland and Dublin City University, Intel and Microsoft. This enables practical evaluations of IoT solutions in a controlled environment that is small enough to conduct trials but large enough to prove and challenge the technologies. An evaluation of sound monitoring capabilities during the 2016 sporting finals was used to test the capture, transfer, storage and analysis of decibel level sound monitoring. The purpose of the evaluation was to use existing sound level microphones to measure crowd response to pre-determined events for display on big screens at half-time and to test the end-to-end performance of the testbed. While this is not the specific original purpose of the sound level microphones, it provided a useful test case and produced engaging content for the project. Analysis of the data streams showed significant packet loss during the events and further investigations were conducted to understand where and how this loss occurred. This paper describes the smart stadium testbed configuration using Intel gateways linking with the Azure cloud platform and analyses the performance of the system during the sound monitoring evaluation

National Self-Harm Registry Ireland annual report 2017.

This is the sixteenth annual report from the National Self-Harm Registry Ireland. It is based on data collected on persons presenting to hospital emergency departments following self-harm in 2017 in the Republic of Ireland. The Registry had near complete coverage of the country’s hospitals for the period 2002-2005 and, since 2006, all general hospital and paediatric hospital emergency departments in the Republic of Ireland have contributed data to the Registry. Role of alcohol in self-harm: Alcohol was involved in 31% of all cases. Alcohol was significantly more often involved in male episodes of self-harm than female episodes (33% and 29%, respectively). In line with previous years, misuse or abuse of alcohol is one of the factors associated with the higher rate of self-harm presentations on Sundays, Mondays and public holidays, around the hours of midnight. Recent publications from the Registry data have highlighted the role of alcohol in selfharm. Such complex presentations indicate the need for active consultation and collaboration between the mental health services and addiction treatment services for patients who present with dual diagnoses. In addition, alcohol involvement has been shown to be strongly associated with self-harm presentations out-of-hours, at weekends and on public holidays. The Registry findings related to alcohol provide further support for the full implementation of the Public Health (Alcohol) Bill, which would introduce evidence-based policies to reduce the burden of alcohol harm on our society by improving health, safety and wellbeing. Restricting access to means: …In line with previous years, drug overdose was the most common method of self-harm recorded. Over the years, the Registry has identified the drug types most frequently involved in intentional overdoses. New research has classified the range of drugs recorded by the Registry according to the World Health Organisation’s (WHO) Anatomical Therapeutic Chemical (ATC) classification system. This work has systematically classified the wide range of drugs involved in intentional overdoses, and will be instrumental in facilitating comparative work in this area. This system has allowed for examination of trends in specific drug types, with a recent publication highlighting the increasing involvement of gabapentinoids (prescription-only neuropathic pain medication). Despite a decrease in their involvement in intentional overdose in 2017, minor tranquillisers have been the most frequently used type of drug involved in intentional overdoses. Reducing access to frequently used drugs should be an ongoing priority

The effect of distance on long-range chromatin interactions.

We have used gene competition to distinguish between possible mechanisms of transcriptional activation of the genes of the human beta-globin locus. The insertion of a second beta-globin gene at different points in the locus shows that the more proximal beta gene competes more effectively for activation by the locus control region (LCR). Reducing the relative distance between the genes and the LCR reduces the competitive advantage of the proximal gene, a result that supports activation by direct interaction between the LCR and the genes. Visualization of the primary transcripts shows that the level of transcription is proportional to the frequency of transcriptional periods and that such periods last approximately 8 min in vivo. We also find that the position of the beta-globin gene in the locus is important for correct developmental regulation

Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells.

Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER)-associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non-redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma

Genes in the postgenomic era

We outline three very different concepts of the gene - 'instrumental', 'nominal', and 'postgenomic'. The instrumental gene has a critical role in the construction and interpretation of experiments in which the relationship between genotype and phenotype is explored via hybridization between organisms or directly between nucleic acid molecules. It also plays an important theoretical role in the foundations of disciplines such as quantitative genetics and population genetics. The nominal gene is a critical practical tool, allowing stable communication between bioscientists in a wide range of fields grounded in well-defined sequences of nucleotides, but this concept does not embody major theoretical insights into genome structure or function. The post-genomic gene embodies the continuing project of understanding how genome structure supports genome function, but with a deflationary picture of the gene as a structural unit. This final concept of the gene poses a significant challenge to conventional assumptions about the relationship between genome structure and function, and between genotype and phenotype

Cost and performance of some carbon capture technology options for producing different quality CO₂ product streams

A techno-economic assessment of power plants with CO2 capture technologies with a focus on process scenarios that deliver different grades of CO2 product purity is presented. The three leading CO2 capture technologies are considered, namely; oxyfuel combustion, pre-combustion and post-combustion capture. The study uses a combination of process simulation of flue gas cleaning processes, modelling with a power plant cost and performance calculator and literature values of key performance criteria in order to evaluate the performance, cost and CO2 product purity of the considered CO2 capture options. For oxyfuel combustion capture plants, three raw CO2 flue gas processing strategies of compression and dehydration only, double flash system purification and distillation purification are considered. Analysis of pre-combustion capture options is based on integrated gasification combined cycle plants using physical solvent systems for capturing CO2 and sulfur species via three routes; co-capture of sulfur impurities with the CO2 stream using Selexol™ solvent, separate capture of CO2 and sulfur impurities using Selexol™, and Rectisol® solvent systems for separate capture of sulfur impurities and CO2. Analysis of post-combustion capture plants was made with and without some conventional pollution control devices. The results highlight the wide variation in CO2 product purity for different oxyfuel combustion capture scenarios and the wide cost variation for the pre-combustion capture scenarios. The post-combustion capture plant with conventional pollution control devices offers high CO2 purity (99.99 mol%) for average cost of considered technologies. The calculations performed will be of use in further analyses of whole chain CCS for the safe and economic capture, transport and storage of CO2

Ikaros DNA-Binding Proteins as Integral Components of B Cell Developmental-Stage-Specific Regulatory Circuits

Ikaros DNA-binding proteins are critical for the development of lymphocytes and other hematopoietic lineages, but it remains unclear how they cooperate with other regulators of signaling and transcription to achieve ordered gene expression during development. Here, we show that Ikaros proteins regulate the pre-BCR component λ5 in a stage-specific manner. In pre-BI cells, Ikaros modulated λ5 expression in competition with the transcriptional activator EBF. This required Ikaros binding to the Igll1 (λ5) promoter and was abolished either by mutation of the Ikaros DNA-binding domain or by deletion of a single Ikaros site from the Igll1 promoter. At the transition from the pre-BI to pre-BII stage, the expression of the Ikaros family member Aiolos was upregulated and required for the efficient silencing of Igll1. Aiolos expression was controlled by pre-BCR signals via the adaptor protein SLP-65. Thus, pre-BCR signaling regulates Aiolos and the silencing of Igll1 via a developmental-stage-specific feedback loop

Introduction: Shakespeare's public spheres

Habermas’ sense of a “cultural Public Sphere” is a notoriously complex term and, when applied to Early Modern cultures, needs careful definition. This essay both introduces the variety of methods by which we might approach playtexts with a view to their public – auditory – impact and contributes to a debate about an audience's understanding of Shakespeare's plays. By selecting two words and their spread of use in one play, Twelfth Night, we might appreciate the potential for meaningful ambiguity latent in how we hear the language of live performance. If we search for how certain terms (in this case, the cluster of semes derived from repetitions of “fancy” and “play”), we might find at times incompatible senses, yet we get near to appreciating the range of Early Modern dramatic language

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages