Limiting peaks in the electricity grid. Experiences from the Norwegian market.

Electrification leads to a need for more grid capacity, and at the same time, the grid is underutilized. High demand occurs only during short periods. To reduce these high peaks, utility companies have implemented a new network tariff to incentivize consumers to even out their energy demand throughout the day and shift their demand from peak to off-peak hours. Using hourly meter readings, survey-, weather- and spot price data, we analyze the effect of a new tariff on households’ peak demand. We investigate the causal relationship between peakpricing and each household’s peak demand using a two-way fixed effects model. We further explore the effects of Time-of-Use tariffs by doing a descriptive analysis. We find that households have reduced their daily peak demand by ~2% after implementing the new network tariff. The households with more occupants, more electric vehicles, or high income are among the groups that have responded the strongest. Our descriptive analysis of Time-of-Use shows a shift from peak- to off-peak hours due to this policy. While the results show a clear response to both the peak-pricing and Time-of-Use components in the tariff, the tariff is insufficient to reach the policy’s goal. We suggest shifting more focus to the Time-of-Use component

Limiting peaks in the electricity grid. Experiences from the Norwegian market

Electrification leads to a need for more grid capacity, and at the same time, the grid is underutilized. High demand occurs only during short periods. To reduce these high peaks, utility companies have implemented a new network tariff to incentivize consumers to even out their energy demand throughout the day and shift their demand from peak to off-peak hours. Using hourly meter readings, survey-, weather- and spot price data, we analyze the effect of a new tariff on households’ peak demand. We investigate the causal relationship between peak-pricing and each household’s peak demand using a two-way fixed effects model. We further explore the effects of Time-of-Use tariffs by doing a descriptive analysis. We find that households have reduced their daily peak demand by ~2% after implementing the new network tariff. The households with more occupants, more electric vehicles, or high income are among the groups that have responded the strongest. Our descriptive analysis of Time-of-Use shows a shift from peak- to off-peak hours due to this policy. While the results show a clear response to both the peak-pricing and Time-of-Use components in the tariff, the tariff is insufficient to reach the policy’s goal. We suggest shifting more focus to the Time-of-Use component

DNA supercoiling in bacteria: state of play and challenges from a viewpoint of physics based modeling

DNA supercoiling is central to fundamental processes of living organisms. Its average level along the chromosome and over time reflects the dynamic equilibrium of opposite activities of topoisomerases, which are required to relax mechanical stresses that are inevitably produced during DNA replication and gene transcription. Supercoiling affects all scales of the spatio-temporal organization of bacterial DNA, from the base pair to the large scale chromosome conformation. Highlighted in vitro and in vivo in the 1960s and 1970s, respectively, the first physical models were proposed concomitantly in order to predict the deformation properties of the double helix. About fifteen years later, polymer physics models demonstrated on larger scales the plectonemic nature and the tree-like organization of supercoiled DNA. Since then, many works have tried to establish a better understanding of the multiple structuring and physiological properties of bacterial DNA in thermodynamic equilibrium and far from equilibrium. The purpose of this essay is to address upcoming challenges by thoroughly exploring the relevance, predictive capacity, and limitations of current physical models, with a specific focus on structural properties beyond the scale of the double helix. We discuss more particularly the problem of DNA conformations, the interplay between DNA supercoiling with gene transcription and DNA replication, its role on nucleoid formation and, finally, the problem of scaling up models. Our primary objective is to foster increased collaboration between physicists and biologists. To achieve this, we have reduced the respective jargon to a minimum and we provide some explanatory background material for the two communities.Comment: 11 figure

La cohésion des chromatides sœurs chez Escherichia coli

Chez les bactéries, la ségrégation du chromosome est initiée durant la phase de réplication. Des expériences de time lapse, utilisées pour observer que la dynamique des loci frères durant le cycle cellulaire, montrent que, chez Escherichia coli, les régions sœurs restent colocalisées pour une période significative dans les régions des macrodomaines du chromosome et pour une courte période dans les régions non-structurées. Nous nous sommes posés la question suivante: est ce que l étape de colocalisation révèle une réelle cohésion entre les chromatides sœurs ? Pour y répondre, nous avons développé un outil génétique, alternatif aux outils de biologie cellulaire, permettant de mesurer la distance entre les chromatides sœurs de manière directe. La fréquence de recombinaison intermoléculaire médiée par la recombinase Cre entre les sites loxP positionnés sur les chromatides sœurs est mesurée pour différentes positions. De cette fréquence, nous avons pu déduire la proximité entre les chromatides sœurs. Nous révélons que les loci frères restent proche l un de l autre pour une courte période après la réplication. Nous appelons cette étape la cohésion moléculaire, celle-ci est dépendante du locus considéré. Nous montrons que les facteurs qui favorisent la colocalisation des foci frères n augmentent pas nécessairement l habilité des loci frères à recombiner. En effet, la protéine MatP, un acteur de la colocalisation des macrodomaines Ter, n affecte pas la cohésion entre les deux copies de cette région. La Topoisomérase IV est un facteur essentiel à la ségrégation des chromosomes. En son absence, les chromosomes ne peuvent se ségréger et restent colocalisés dans la cellule. Nous révélons par le test de recombinaison que l absence de Topoisométase IV dans les cellules provoque une augmentation des interactions entre chromatides sœurs. Au final, nous avons montré que l étape de cohésion est différente de la colocalisation, que les mécanismes moléculaires diffèrent d une étape à l autre et que les liens de précaténation moduleraient la cohésion post-réplicative entre chromatides sœurs.In bacteria, the segregation of the chromosome is initiated during the replication phase. Time lapse experiments, used to watch the dynamic of loci during cell cycle, showed, in Escherichia coli, that the sister loci remain colocalized for a significant amount of time in the macrodomain regions of the chromosome and for shorter period in the Non Structured regions. We asked the following question: does this colocalization step reveal a real cohesion between the sister chromatids? To answer, we have developed a genetic tool, alternative to cell biology tools, to measure the distance between sister chromatids directly. The frequency of intermolecular recombination mediated by Cre recombinase loxP sites located on sister chromatids was measured for various loci. From this frequency we were able to deduce the proximity of sister chromatids. We revealed that sister loci remained in close proximity for a short period following replication. We called this step molecular cohesion, it is dependent on the considered locus. We showed that factors that promote colocalisation of sister foci do not necessarily increase the ability of sister loci to recombine. Indeed, the MatP protein, an actor of macrodomain Ter colocalisation, does not affect the cohesion between the two copies of this region. The TopoIV is essential for the segregation of chromosomes. In its absence, the chromosomes can not segregate and remain colocalized in the cell. We reveal by recombinaison assy that the absence of Topoisomerase IV revealed an increase of interactions between sister chromatids. To conclude, we have shown that the cohesion step is different from the colocalisation step, the molecular mechanisms differ from one stage to another and précaténation links take part in the post-replicative cohesion between sister chromatidsPARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Immunotherapies and Future Combination Strategies for Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Nearly 10 years after the approval of cetuximab, anti-PD1/PD-L1 checkpoint inhibitors are the first drugs that have shown any survival benefit for the treatment on platinum-refractory recurrent/metastatic (R/M) HNSCC. Furthermore, checkpoint inhibitors are better tolerated than chemotherapy. The state of the art in the treatment of R/M HNSCC is changing, thanks to improved results for checkpoint inhibitors. Results for these treatments are also awaited in curative settings and for locally advanced HNSCC. Unfortunately, the response rate of immunotherapy is low. Therefore, the identification of predictive biomarkers of response and resistance to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit the most from immunotherapy. Furthermore, the combination of checkpoint inhibitors with various agents is being currently evaluated to improve the response rate, prolong response duration, and even increase the chances for a cure. In this review, we summarize the most important results regarding immune targeting agents for HNSCC, predictive biomarkers for resistance to immune therapies, and future perspectives

Treatment of keratinocyte carcinoma in elderly patients - a review of the current literature

A large percentage of the patients with keratinocyte carcinoma (KC, formerly known as non-melanoma skin cancer) is of advanced age and often too frail for standard therapies. However, no specific treatment recommendations are given for this population. This review aimed to give an overview of the current literature on the best practice for the treatment of elderly patients with KC. A literature search was performed in MEDLINE, using ‘keratinocyte carcinoma’, ‘elderly’, ‘treatment’ and various synonyms. Case reports, reviews, comments, non-English literature and studies with a sample size <15 were excluded. After selection, a total of 47 studies were reviewed. Two types of studies were identified, focusing on (I) the effect of age on treatment outcomes and (II) alternative treatment schedules for elderly patients. Studies on surgery, the gold standard, describe larger lesions and defect size in the elderly population. Recurrence rate, complication rate and disease-specific survival were not affected by age. Depending on the expected morbidity of a suggested (re-)excision and patient preferences, a conservative watchful waiting policy can be agreed upon as a shared decision. Other common treatment modalities, such as adjuvant radiotherapy, photodynamic therapy and systemic therapy for basal cell carcinoma (BCC), show comparable results in the elderly and younger population. Alternative treatment schedules for elderly patients include primary hypofractionated radiotherapy, which seems effective and well-tolerated, although research is limited to case series. Additionally, localized and topical treatments seem safe and effective especially for low-risk tumours. Data are lacking on the efficacy of systemic therapies of metastatic KC in elderly patients. Efficacy of most treatments (with the exception of photodynamic therapy) is not dependent on age. There is need for more research on the efficacy of adjusted treatment modalities, such as hypofractionated radiotherapy and palliative or curative systemic treatment

A Defined Terminal Region of the E. coli Chromosome Shows Late Segregation and High FtsK Activity

Background: The FtsK DNA-translocase controls the last steps of chromosome segregation in E. coli. It translocates sister chromosomes using the KOPS DNA motifs to orient its activity, and controls the resolution of dimeric forms of sister chromosomes by XerCD-mediated recombination at the dif site and their decatenation by TopoIV. Methodology: We have used XerCD/dif recombination as a genetic trap to probe the interaction of FtsK with loci located in different regions of the chromosome. This assay revealed that the activity of FtsK is restricted to a,400 kb terminal region of the chromosome around the natural position of the dif site. Preferential interaction with this region required the tethering of FtsK to the division septum via its N-terminal domain as well as its translocation activity. However, the KOPSrecognition activity of FtsK was not required. Displacement of replication termination outside the FtsK high activity region had no effect on FtsK activity and deletion of a part of this region was not compensated by its extension to neighbouring regions. By observing the fate of fluorescent-tagged loci of the ter region, we found that segregation of the FtsK high activity region is delayed compared to that of its adjacent regions. Significance: Our results show that a restricted terminal region of the chromosome is specifically dedicated to the last step

Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity.

Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1-binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation-induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity

Structuring the bacterial genome: Y1-transposases associated with REP-BIME sequences†

REPs are highly repeated intergenic palindromic sequences often clustered into structures called BIMEs including two individual REPs separated by short linker of variable length. They play a variety of key roles in the cell. REPs also resemble the sub-terminal hairpins of the atypical IS200/605 family of insertion sequences which encode Y1 transposases (TnpAIS200/IS605). These belong to the HUH endonuclease family, carry a single catalytic tyrosine (Y) and promote single strand transposition. Recently, a new clade of Y1 transposases (TnpAREP) was found associated with REP/BIME in structures called REPtrons. It has been suggested that TnpAREP is responsible for REP/BIME proliferation over genomes. We analysed and compared REP distribution and REPtron structure in numerous available E. coli and Shigella strains. Phylogenetic analysis clearly indicated that tnpAREP was acquired early in the species radiation and was lost later in some strains. To understand REP/BIME behaviour within the host genome, we also studied E. coli K12 TnpAREP activity in vitro and demonstrated that it catalyses cleavage and recombination of BIMEs. While TnpAREP shared the same general organization and similar catalytic characteristics with TnpAIS200/IS605 transposases, it exhibited distinct properties potentially important in the creation of BIME variability and in their amplification. TnpAREP may therefore be one of the first examples of transposase domestication in prokaryotes

Asymmetry of Chromosome Replichores Renders the DNA Translocase Activity of FtsK Essential for Cell Division and Cell Shape Maintenance in Escherichia coli

Bacterial chromosomes are organised as two replichores of opposite polarity that coincide with the replication arms from the ori to the ter region. Here, we investigated the effects of asymmetry in replichore organisation in Escherichia coli. We show that large chromosome inversions from the terminal junction of the replichores disturb the ongoing post-replicative events, resulting in inhibition of both cell division and cell elongation. This is accompanied by alterations of the segregation pattern of loci located at the inversion endpoints, particularly of the new replichore junction. None of these defects is suppressed by restoration of termination of replication opposite oriC, indicating that they are more likely due to the asymmetry of replichore polarity than to asymmetric replication. Strikingly, DNA translocation by FtsK, which processes the terminal junction of the replichores during cell division, becomes essential in inversion-carrying strains. Inactivation of the FtsK translocation activity leads to aberrant cell morphology, strongly suggesting that it controls membrane synthesis at the division septum. Our results reveal that FtsK mediates a reciprocal control between processing of the replichore polarity junction and cell division