The first occurrence of a toxodont (Mammalia, Notoungulata) in the United States

This is the publisher's version, also available electronically from http://www.tandfonline.com/doi/abs/10.1080/02724634.2012.711405#.U1qJK4UvDGJ.Toxodonts were a group of large-sized notoungulates of South American origin. They were diverse and widespread in South America in deposits ranging in age from late Oligocene to late Pleistocene. Sparse remains have been found from the Pleistocene of isolated regions of Central America. All of the Central American specimens have been referred to the genus Mixotoxodon (Van Frank, 1950). They were not previously known north of the southern Mexican states of Michoacan and Veracruz, except for an unconfirmed report of an occurrence in Tamaulipas (Arroyo-Cabrales et al., 2010). Here we report the occurrence of a single toxodont tooth, a left upper third molar, from late Pleistocene deposits in Harris County, Texas (30◦N). This is the first record of toxodonts, or any notoungulate, in the United States and extends the geographic range of this group 1600 km north of their previously known localities at Hihuitlán, Michoacan (18◦52' 3"0 N, 103◦24' 14 "W) and La Estribera, Veracruz (18◦07 '01.27" N, 94◦53 '15.59W) (Polaco et al., 2004) to latitude 30◦N

Nuclear power and coastal birds: predicting the ecological consequences of warm-water outflows

Local alteration of species abundance in natural communities due to anthropogenic impacts may have secondary, cascading effects on species at higher trophic levels. Such effects are typically hard to single out due to their ubiquitous nature and, therefore, may render impact assessment exercises difficult to undertake. Here we describe how we used empirical knowledge together with modelling tools to predict the indirect trophic effects of a future warm-water outflow on populations of shorebirds and wildfowl. Of the main potential benthic prey used by the birds in this instance, the clam Macoma balthica was the only species suspected to be adversely affected by a future increase of temperature. Various scenarios of decreases in prey energy content, simulating various degrees of temperature increase, were tested using an individual-based model, MORPH, in order to assess the effects on birds. The survival and body condition of eight of the 10 bird species modelled, dunlin, ringed plover, turnstone, redshank, grey plover, black-tailed godwit, oystercatcher and shelduck were shown to be not influenced even by the most conservative prey reduction scenarios. Most of these species are known to feed primarily on polychaete worms. For the few bivalve-feeding species, the larger size-classes of polychaete worms were predicted to be a sufficient alternative food. Only knot was predicted to have a lower survival under the two worst case scenario of decreased M. balthica energy content. We believe that this is the first time such predicted cascade effects from a future warm-water outflow have been shown

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

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

Electric Conduction in an Oil-Pumped Vacuum System

The leakage of electricity aoross a vacuum space in an electrostatic generator which employs a mixture of Sr/sup 90/ and Y/sup 90/ as the source of charging current was investigated. The vacuum is obtained by means of an oil pump. The leakage was shown to consist of a flow of positive and negative particles between the anode and the cathode. The positive particles were found to be primarily organic ions produced in a layer of oil on the surface of the anode. The negative particles were shown to be mostly electrons. Yields of secondary negative particles and secondary positive particles produced by average positive particles in the energy range from 50 to 200 kev were measured. Yields were found to be dependent on the nature of the target material as well as on the energy of the incident ion. A mass spectrometer was employed to study the nature of the positive ions. Most of these were charged fragments of organic molecules. Neutral particles were attributed to dissociation of a portion of positive ions during their flight from the anode to cathode. Electrons, most of which originate at the beta source, are presumed to be the agent for positive ion production. It is believed that the leakage current at a limiting voltage is primarily due to a positive ion-negative ion exchange mechanism. (A.C.