Working Memory Cells' Behavior May Be Explained by Cross-Regional Networks with Synaptic Facilitation

Neurons in the cortex exhibit a number of patterns that correlate with working memory. Specifically, averaged across trials of working memory tasks, neurons exhibit different firing rate patterns during the delay of those tasks. These patterns include: 1) persistent fixed-frequency elevated rates above baseline, 2) elevated rates that decay throughout the tasks memory period, 3) rates that accelerate throughout the delay, and 4) patterns of inhibited firing (below baseline) analogous to each of the preceding excitatory patterns. Persistent elevated rate patterns are believed to be the neural correlate of working memory retention and preparation for execution of behavioral/motor responses as required in working memory tasks. Models have proposed that such activity corresponds to stable attractors in cortical neural networks with fixed synaptic weights. However, the variability in patterned behavior and the firing statistics of real neurons across the entire range of those behaviors across and within trials of working memory tasks are typical not reproduced. Here we examine the effect of dynamic synapses and network architectures with multiple cortical areas on the states and dynamics of working memory networks. The analysis indicates that the multiple pattern types exhibited by cells in working memory networks are inherent in networks with dynamic synapses, and that the variability and firing statistics in such networks with distributed architectures agree with that observed in the cortex

Cetuximab potentiates oxaliplatin cytotoxic effect through a defect in NER and DNA replication initiation

Preclinical studies have demonstrated that the chemotherapeutic action of oxaliplatin, a third generation platinum derivative, is improved when combined with cetuximab, a monoclonal antibody inhibitor of epidermal growth factor receptors. To explore the mechanism of this synergistic benefit, we used HCT-8 and HCT-116, two human colon cancer cell lines, respectively, responsive and non-responsive to the oxaliplatin/cetuximab combination. We examined the effect of drug exposure on glutathione-S-transferase-mediated oxaliplatin detoxification, DNA–platinum adducts formation, cell cycle distribution, apoptosis, and the expression of multiple targets involved in DNA replication, recombination, and repair. The major changes we found in HCT-8 were a stimulation of oxaliplatin–DNA adduct formation associated with reduced expression of the key enzyme (excision repair cross complementation group1: ERCC1) in the key repair process of oxaliplatin–DNA platinum adduct, the nucleotide excision repair (NER), both at the mRNA and protein levels. We also observed a reduced expression of factors involved in DNA replication initiation, which correlates with an enrichment of cells in the G1 phase of the cell cycle as well as an acceleration of apoptosis. None of these changes occurred in the non-responsive HCT-116 cell that we used as a negative control. These findings support the fact that cetuximab potentiates the oxaliplatin-mediated cytotoxic effect as the result of inhibition of NER and also DNA replication initiation

International perspectives on backwards vertical integration

International audienceThis chapter provides a broad understanding of the motivations and debates related to vertical integration backwards, through concrete examples or practical cases. Vertical integration backwards in the wine industry was extensively discussed in the literature (see, e.g. Sidlovits and Kator 2007). However, those contributions focus on one region or country or a particular type of firm (e.g. wine co-operatives). Without pretending to cover all the dimensions of vertical integration, we introduce hereafter, through several examples, the causes or consequences that lead firms to practice vertical integration

Habitat preferences of <i>Phoebetria</i> albatrosses in sympatry and allopatry

Publication status: PublishedFunder: Natural Environment Research Council; doi: http://dx.doi.org/10.13039/501100000270Funder: Gates Cambridge Trust; doi: http://dx.doi.org/10.13039/501100005370Funder: Prince Albert II of Monaco Foundation; doi: http://dx.doi.org/10.13039/501100011592Funder: Institut Polaire Français Paul Emile Victor; doi: http://dx.doi.org/10.13039/501100004796AbstractAimCompetition is often proposed to drive niche segregation along multiple axes in speciose communities. Understanding spatial partitioning of foraging areas is particularly important in species that are constrained to a central place. We present a natural experiment examining variation in habitat preferences of congeneric Southern Ocean predators in sympatry and allopatry. Our aim was to ascertain consistency of habitat preferences within species, and to test whether preferences changed in the presence of the congener.LocationSouthern Hemisphere.TaxonMultiple colonies of both species within the genus Phoebetria (sooty albatrosses).MethodsThe two Phoebetria albatrosses breed on islands located from ~37–55°S – sooty albatrosses (P. fusca) in the north and light‐mantled albatrosses (P. palpebrata) in the south – with sympatric overlap at locations ~46–49°S. We analysed GPS and PTT tracks from 87 individuals and multiple remotely sensed environmental variables using GAMs, to determine and compare the key factors influencing habitat preference for each species at each breeding colony.ResultsWhile foraging habitat preferences are consistent in light‐mantled albatrosses, there is divergence of preferences in sooty albatrosses depending on whether they are in sympatry with their congener or in allopatry.Main ConclusionsThis study represents the most comprehensive work on this genus to date and highlights how habitat preferences and behavioural plasticity may influence species distributions under different competitive conditions.</jats:sec

Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial

PURPOSE: Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. PATIENTS AND METHODS: Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus-negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. RESULTS: Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. CONCLUSION: The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population