Series Compensation to Increase Power Flow: a Case Study on the Irish Transmission System

Ireland presents an interesting case study for transmission network strengthening. The majority of load in the country is located at the nation\u27s capital, Dublin, in the East, while most of the new conventional generation and renewable generation are found in the South-West. Power is transferred between the two via a 400 kV network. This leads to large cross- country power flows. This power distribution disparity is due to increase. A large thermal generating station which is connected to the 400 kV system in the West, will close by 2025. This generation will be replaced partially with wind generation in the South West, which is connected at 110 kV and 220 kV. This can cause power flow to avoid the 400 kV network, leading to less efficiency, overloading and other issues associated with power flow on lower voltage networks.In this paper, the application of series compensation on the 400 kV transmission network in Ireland for increasing power transfer capability is investigated and a viable solution is found. The lower voltage network is modelled to investigate the effects of 400 kV series compensation on the rest of the network. With our series compensation solution on the 400 kV network, power flows are successfully reduced on the 110 kV network as the lower reactance of the 400 kV network now attracts power to flow through the more stable and less lossy 400 kV network

Rationality and Group Decision-Making in Practical Healthcare

In this paper, a view of non-compliance in practical healthcare is provided that identifies certain non-compliant behaviours as rational. This view of rational non-compliance is used to update a current form of doctor patient relationships with the aim of reducing non-compliance. In addition to reforming one standard doctor patient relationship model, the normative implications of understanding non-compliance as a rational form of human behaviour are described

Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse

SMARCB1 regulates the hypoxic stress response in sickle cell trait during the pathogenesis of renal medullary carcinoma.

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Collagen Gene Polymorphisms Previously Associated with Resistance to Soft-Tissue Injury Are More Common in Competitive Runners Than Nonathletes

Dines, HR, Nixon, J, Lockey, SJ, Herbert, AJ, Kipps, C, Pedlar, CR, Day, SH, Heffernan, SM, Antrobus, MR, Brazier, J, Erskine, RM, Stebbings, GK, Hall, ECR, and Williams, AG. Collagen gene polymorphisms previously associated with resistance to soft-tissue injury are more common in competitive runners than nonathletes. J Strength Cond Res XX(X): 000-000, 2022-Single-nucleotide polymorphisms (SNPs) of collagen genes have been associated with soft-tissue injury and running performance. However, their combined contribution to running performance is unknown. We investigated the association of 2 collagen gene SNPs with athlete status and performance in 1,429 Caucasian subjects, including 597 competitive runners (354 men and 243 women) and 832 nonathletes (490 men and 342 women). Genotyping for COL1A1 rs1800012 (C > A) and COL5A1 rs12722 (C > T) SNPs was performed by a real-time polymerase chain reaction. The numbers of "injury-resistant" alleles from each SNP, based on previous literature (rs1800012 A allele and rs12722 C allele), were combined as an injury-resistance score (RScore, 0-4; higher scores indicate injury resistance). Genotype frequencies, individually and combined as an RScore, were compared between cohorts and investigated for associations with performance using official race times. Runners had 1.34 times greater odds of being rs12722 CC homozygotes than nonathletes (19.7% vs. 15.5%, p = 0.020) with no difference in the rs1800012 genotype distribution (p = 0.659). Fewer runners had an RScore 0 of (18.5% vs. 24.7%) and more had an RScore of 4 (0.6% vs. 0.3%) than nonathletes (p < 0.001). Competitive performance was not associated with the COL1A1 genotype (p = 0.933), COL5A1 genotype (p = 0.613), or RScore (p = 0.477). Although not associated directly with running performance among competitive runners, a higher combined frequency of injury-resistant COL1A1 rs1800012 A and COL5A1 rs12722 C alleles in competitive runners than nonathletes suggests these SNPs may be advantageous through a mechanism that supports, but does not directly enhance, running performance

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (\u3e4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies

The brain of binge drinkers at rest: alterations in theta and beta oscillations in first-year college students with a binge drinking pattern

Background: Previous studies have reported anomalous resting brain activity in the electroencephalogram (EEG) of alcoholics, often reflected as increased power in the beta and theta frequency bands. The effects of binge drinking, the most common pattern of excessive alcohol consumption during adolescence and youth, on brain activity at rest is still poorly known. In this study, we sought to assess the pattern of resting-state EEG oscillations in college-aged binge drinkers (BDs). Methods: Resting-state brain activity during eyes-open and eyes-closed conditions was recorded from 60 channels in 80 first-year undergraduate students (40 controls and 40 BDs). Cortical sources activity of EEG rhythms was estimated using exact Low-Resolution Electromagnetic Tomography (eLORETA) analysis. Results: EEG-source localization analysis revealed that BDs showed, in comparison with controls, significantly higher intracranial current density in the beta frequency band over the right temporal lobe (parahippocampal and fusiform gyri) during eyes-open resting state as well as higher intracranial current density in the theta band over the bilateral occipital cortex (cuneus and lingual gyrus) during eyes-closed resting condition. Conclusions: These findings are in line with previous results observing increased beta and/or theta power following chronic or heavy alcohol drinking in alcohol-dependent subjects and BDs. Increased tonic beta and theta oscillations are suggestive of an augmented cortical excitability and of potential difficulties in the information processing capacity in young BDs. Furthermore, enhanced EEG power in these frequency bands may respond to a neuromaturational delay as a result of excessive alcohol consumption during this critical brain developmental period.This study was supported by the projects SPI/2010/134 and SPI/2010/051 from the Spanish Ministry of Health and Social Politics (National Plan on Drugs), and the project PSI2015- 70525-P from the Spanish Ministry of Science and Innovation co-financed by European Regional Development Found. EL and AlC were supported by the Postdoctoral Fellowship of the Portuguese Foundation for Science and Technology SFRH/BPD/109750/2015 and SFRH/BPD/91440/2012 respectively, as well as by the Psychology Research Centre (UID/PSI/01662/2013), co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007653)