THE EVOLUTIONARY RELATIONSHIPS OF THE ENZYMES INVOLVED IN BLOOD COAGULATION AND HEMOSTASIS *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73621/1/j.1749-6632.1981.tb29759.x.pd

Synthesis of Diverse β-Quaternary Ketones via Palladium-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to Cyclic Enones

The development and optimization of a palladium-catalyzed asymmetric conjugate addition of arylboronic acids to cyclic enone conjugate acceptors is described. These reactions employ air-stable and readily-available reagents in an operationally simple and robust transformation that yields β-quaternary ketones in high yields and enantioselectivities. Notably, the reaction itself is highly tolerant of atmospheric oxygen and moisture and therefore does not require the use of dry or deoxygenated solvents, specially purified reagents, or an inert atmosphere. The ring size and β-substituent of the enone are highly variable, and a wide variety of β-quaternary ketones can be synthesized. More recently, the use of NH_4PF_6 has further expanded the substrate scope to include heteroatom-containing arylboronic acids and β-acyl enone substrates

Agricultural Turns, Geographical Turns: Retrospect and Prospect.

It is accepted that British rural geography has actively engaged with the ‘cultural turn’, leading to a resurgence of research within the sub-discipline. However, a reading of recent reviews suggests that the cultural turn has largely, if not completely, bypassed those geographers interested in the agricultural sector. Farming centred engagements with notions of culture have been relatively limited compared with those concerned with the non-agricultural aspects of rural space. Indeed, agricultural geography represents something of an awkward case in the context of the disciplinary turn to culture, a situation that demands further exposition. In seeking explanation, it becomes evident that research on the farm sector is more culturally informed than initially appears. This paper argues that there have been both interesting and important engagements between agricultural geography and cultural perspectives over the past decade. The paper elaborates four specific areas of research which provide evidence for concern about the ‘culture’ within agriculture. The future contribution that culturally informed perspectives in geographical research can bring to agricultural issues is outlined by way of conclusion

Templated encapsulation of platinum-based catalysts promotes high-temperature stability to 1,100 °C

Stable catalysts are essential to address energy and environmental challenges, especially for applications in harsh environments (for example, high temperature, oxidizing atmosphere and steam). In such conditions, supported metal catalysts deactivate due to sintering-a process where initially small nanoparticles grow into larger ones with reduced active surface area-but strategies to stabilize them can lead to decreased performance. Here we report stable catalysts prepared through the encapsulation of platinum nanoparticles inside an alumina framework, which was formed by depositing an alumina precursor within a separately prepared porous organic framework impregnated with platinum nanoparticles. These catalysts do not sinter at 800 °C in the presence of oxygen and steam, conditions in which conventional catalysts sinter to a large extent, while showing similar reaction rates. Extending this approach to Pd-Pt bimetallic catalysts led to the small particle size being maintained at temperatures as high as 1,100 °C in air and 10% steam. This strategy can be broadly applied to other metal and metal oxides for applications where sintering is a major cause of material deactivation

DataPerf: Benchmarks for Data-Centric AI Development

Machine learning research has long focused on models rather than datasets, and prominent datasets are used for common ML tasks without regard to the breadth, difficulty, and faithfulness of the underlying problems. Neglecting the fundamental importance of data has given rise to inaccuracy, bias, and fragility in real-world applications, and research is hindered by saturation across existing dataset benchmarks. In response, we present DataPerf, a community-led benchmark suite for evaluating ML datasets and data-centric algorithms. We aim to foster innovation in data-centric AI through competition, comparability, and reproducibility. We enable the ML community to iterate on datasets, instead of just architectures, and we provide an open, online platform with multiple rounds of challenges to support this iterative development. The first iteration of DataPerf contains five benchmarks covering a wide spectrum of data-centric techniques, tasks, and modalities in vision, speech, acquisition, debugging, and diffusion prompting, and we support hosting new contributed benchmarks from the community. The benchmarks, online evaluation platform, and baseline implementations are open source, and the MLCommons Association will maintain DataPerf to ensure long-term benefits to academia and industry.Comment: NeurIPS 2023 Datasets and Benchmarks Trac

Artificial Adaptive Systems and predictive medicine: a revolutionary paradigm shift

An individual patient is not the average representative of the population. Rather he or she is a person with unique characteristics. An intervention may be effective for a population but not necessarily for the individual patient. The recommendation of a guideline may not be right for a particular patient because it is not what he or she wants, and implementing the recommendation will not necessarily mean a favourable outcome

Poundbury Camp in context – a new perspective on the lives of children from urban and rural Roman England

Objectives The current understanding of child morbidity in Roman England is dominated by studies of single sites/regions. Much of the data are derived from third to fifth century AD Poundbury Camp, Dorchester, Dorset, considered an unusual site due to high levels of non-adult morbidity. There is little understanding of children in rural areas, and whether Poundbury Camp was representative of Romano-British childhood. Materials and methods The study provides the first large scale analysis of child health in urban and rural Roman England, adding to the previously published intra-site analysis of non-adult paleopathology at Poundbury Camp. Age-at-death and pathology prevalence rates were reassessed for 953 non-adults (0–17 years) from five major urban, six minor urban, and four rural sites (first to fifth century AD). The data were compared to the results from 364 non-adults from Poundbury Camp. Results Rural sites demonstrated higher levels of infant burials, and greater prevalence of cribra orbitalia in the 1.1–2.5 year (TPR 64.3%), and 6.6–10.5 year cohorts (TPR 66.7%). Endocranial lesions were more frequent in the minor urban sample (TPR 15.9%). Three new cases of tuberculosis were identified in urban contexts. Vitamin D deficiency was most prevalent at Poundbury Camp (CPR 18.8%), vitamin C deficiency was identified more frequently in rural settlements (CPR 5.9%). Discussion The Poundbury Camp data on morbidity and mortality are not representative of patterns in Roman England and other major urban sites. Rural children suffered from a distinct set of pathologies described as diseases of deprivation, prompting reconsideration of how Romano-British land management affected those at the bottom of the social hierarchy

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival