ALBERT

Description: The DOBRE-2 wide-angle reflection and refraction profile was acquired in June 2007 as a direct, southwestwards prolongation of the 1999 DOBREfraction'99 that crossed the Donbas Foldbelt in eastern Ukraine. It crosses the Azov Massif of the East European Craton, the Azov Sea, the Kerch Peninsula (the easternmost part of Crimea) and the northern East Black Sea Basin, thus traversing the entire Crimea–Caucasus compressional zone centred on the Kerch Peninsula. The DOBRE-2 profile recorded a mix of onshore explosive sources as well as airguns at sea. A variety of single-component recorders were used on land and ocean bottom instruments were deployed offshore and recovered by ship. The DOBRE-2 datasets were degraded by a lack of shot-point reversal at the southwestern terminus and by some poor signal registration elsewhere, in particular in the Black Sea. Nevertheless, they allowed a robust velocity model of the upper crust to be constructed along the entire profile as well as through the entire crust beneath the Azov Massif. A less well constrained model was constructed for much of the crust beneath the Azov Sea and the Kerch Peninsula. The results showed that there is a significant change in the upper crustal lithology in the northern Azov Sea, expressed in the near surface as the Main Azov Fault; this boundary can be taken as the boundary between the East European Craton and the Scythian Platform. The upper crustal rocks of the Scythian Platform in this area probably consist of metasedimentary rocks. A narrow unit as shallow as about 5 km and characterized by velocities typical of the crystalline basement bounds the metasedimentary succession on its southern margin and also marks the northern margin of the northern foredeep and the underlying successions of the Crimea–Caucasus compressional zone in the southern part of the Azov Sea. A broader and somewhat deeper basement unit (about 11 km) with an antiformal shape lies beneath the northern East Black Sea Basin and forms the southern margin of the Crimea–Caucasus compressional zone. The depth of the underlying Moho discontinuity increases from 40 km beneath the Azov Massif to 47 km beneath the Crimea–Caucasus compressional zone.

Description: The margin of the northeastern Black Sea is formed by the Crimea and Kerch peninsulas, which separate it from the Azov Sea to the north. The age and architecture of the sedimentary successions in this area are described from exploration reflection seismic profiling acquired in the area, in addition to the regional DOBRE-2 CDP profile acquired in 2007. The sediments range in age from Mesozoic to Quaternary and can be divided into five seismo-stratigraphic complexes linked to the tectono-sedimentological evolution of the area. The present regional basin architecture consists of a series of basement structural highs separating a series of sedimentary depocentres and is mainly a consequence of the compressional tectonic regime affecting the area since the Eocene. This has focused shortening deformation and uplift along the axis of the Crimea–Caucasus Inversion Zone on the Kerch Peninsula and Kerch Shelf of the Black Sea. Two major sedimentary basins that mainly formed during this time – the Sorokin Trough in the Black Sea and the Indolo-Kuban Trough to the north of the Kerch Peninsula in the Azov Sea – formed as marginal troughs to the main inversion zone.

Description: Permian palynostratigraphic schemes are used primarily to correlate coal- and hydrocarbon-bearing rocks within basins and between basins, sometimes at high levels of biostratigraphic resolution. Up to now, their main shortcoming has been the lack of correlation with schemes outside the basins, coalfields and hydrocarbon fields that they serve, and chiefly a lack of correlation with the international Permian scale. This is partly because of phytogeographical provinciality from the Guadalupian onwards, making correlation between regional palynostratigraphic schemes difficult. However, local high-resolution palynostratigraphic schemes for regions are now being linked either by assemblage-level quantitative taxonomic comparison or by the use of single well-characterized palynological taxa that occur across Permian phytogeographical provinces. Such taxa include: Scutasporites spp., Vittatina spp., Weylandites spp., Lueckisporites virkkiae , Otynisporites eotriassicus and Converrucosisporites confluens . These palynological correlations are being facilitated and supplemented with radiometric, magnetostratigraphic, independent faunal and strontium isotopic dating.

Description: For climate services to be relevant and informative for users, scientific data definitions need to match users’ perceptions or beliefs. This study proposes and tests novel yet simple methods to compare beliefs of timing of recurrent climatic events with empirical evidence from multiple historical time series. The methods are tested by applying them to the onset date of the monsoon in Bangladesh, where several scientific monsoon definitions can be applied, yielding different results for monsoon onset dates. It is a challenge to know which monsoon definition compares best with people’s beliefs. Time series from eight different scientific monsoon definitions in six regions are compared with respondent beliefs from a previously completed survey concerning the monsoon onset. Beliefs about the timing of the monsoon onset are represented probabilistically for each respondent by constructing a probability mass function (PMF) from elicited responses about the earliest, normal, and latest dates for the event. A three-parameter circular modified triangular distribution (CMTD) is used to allow for the possibility (albeit small) of the onset at any time of the year. These distributions are then compared to the historical time series using two approaches: likelihood scores, and the mean and standard deviation of time series of dates simulated from each belief distribution. The methods proposed give the basis for further iterative discussion with decision-makers in the development of eventual climate services. This study uses Jessore, Bangladesh, as an example and finds that a rainfall definition, applying a 10 mm day−1 threshold to NCEP–NCAR reanalysis (Reanalyis-1) data, best matches the survey respondents’ beliefs about monsoon onset.

Description: A simple model of an internal wave advected by an oscillating barotropic flow suggests flaws in standard approaches to estimating properties of the internal tide. When the M2 barotropic tidal current amplitude is of similar size to the phase speed of the M2 baroclinic tide, spectral and harmonic analysis techniques lead to erroneous estimates of the amplitude, phase, and energy in the M2 internal tide. In general, harmonic fits and bandpass or low-pass filters that attempt to isolate the lowest M2 harmonic significantly underestimate the strength of M2 baroclinic energy fluxes in shelf seas. Baroclinic energy flux estimates may show artificial spatial variability, giving the illusion of sources and sinks of energy where none are actually present. Analysis of previously published estimates of baroclinic energy fluxes in the Celtic Sea suggests this mechanism may lead to values being 25%–60% too low.

Description: This study describes a systematic approach to selecting optimal statistical recalibration methods and hindcast designs for producing reliable probability forecasts on seasonal-to-decadal time scales. A new recalibration method is introduced that includes adjustments for both unconditional and conditional biases in the mean and variance of the forecast distribution and linear time-dependent bias in the mean. The complexity of the recalibration can be systematically varied by restricting the parameters. Simple recalibration methods may outperform more complex ones given limited training data. A new cross-validation methodology is proposed that allows the comparison of multiple recalibration methods and varying training periods using limited data. Part I considers the effect on forecast skill of varying the recalibration complexity and training period length. The interaction between these factors is analyzed for gridbox forecasts of annual mean near-surface temperature from the CanCM4 model. Recalibration methods that include conditional adjustment of the ensemble mean outperform simple bias correction by issuing climatological forecasts where the model has limited skill. Trend-adjusted forecasts outperform forecasts without trend adjustment at almost 75% of grid boxes. The optimal training period is around 30 yr for trend-adjusted forecasts and around 15 yr otherwise. The optimal training period is strongly related to the length of the optimal climatology. Longer training periods may increase overall performance but at the expense of very poor forecasts where skill is limited.

Description: The inclusion of carbon cycle processes within CMIP5 Earth system models provides the opportunity to explore the relative importance of differences in scenario and climate model representation to future land and ocean carbon fluxes. A two-way analysis of variance (ANOVA) approach was used to quantify the variability owing to differences between scenarios and between climate models at different lead times. For global ocean carbon fluxes, the variance attributed to differences between representative concentration pathway scenarios exceeds the variance attributed to differences between climate models by around 2025, completely dominating by 2100. This contrasts with global land carbon fluxes, where the variance attributed to differences between climate models continues to dominate beyond 2100. This suggests that modeled processes that determine ocean fluxes are currently better constrained than those of land fluxes; thus, one can be more confident in linking different future socioeconomic pathways to consequences of ocean carbon uptake than for land carbon uptake. The contribution of internal variance is negligible for ocean fluxes and small for land fluxes, indicating that there is little dependence on the initial conditions. The apparent agreement in atmosphere–ocean carbon fluxes, globally, masks strong climate model differences at a regional level. The North Atlantic and Southern Ocean are key regions, where differences in modeled processes represent an important source of variability in projected regional fluxes.

Description: Predictability estimates of ensemble prediction systems are uncertain because of limited numbers of past forecasts and observations. To account for such uncertainty, this paper proposes a Bayesian inferential framework that provides a simple 6-parameter representation of ensemble forecasting systems and the corresponding observations. The framework is probabilistic and thus allows for quantifying uncertainty in predictability measures, such as correlation skill and signal-to-noise ratios. It also provides a natural way to produce recalibrated probabilistic predictions from uncalibrated ensembles forecasts. The framework is used to address important questions concerning the skill of winter hindcasts of the North Atlantic Oscillation for 1992–2011 issued by the Met Office Global Seasonal Forecast System, version 5 (GloSea5), climate prediction system. Although there is much uncertainty in the correlation between ensemble mean and observations, there is strong evidence of skill: the 95% credible interval of the correlation coefficient of [0.19, 0.68] does not overlap zero. There is also strong evidence that the forecasts are not exchangeable with the observations: with over 99% certainty, the signal-to-noise ratio of the forecasts is smaller than the signal-to-noise ratio of the observations, which suggests that raw forecasts should not be taken as representative scenarios of the observations. Forecast recalibration is thus required, which can be coherently addressed within the proposed framework.

Description: CD74, also known as HLA-DR-associated invariant chain, is a type II transmembrane glycoprotein highly expressed in many B-cell malignancies. The limited expression of CD74 in normal tissues suggests it may be a suitable ADC target for these tumor types. Accordingly, we engineered an anti-CD74 human IgG1 antibody (SP7219) using novel Fab-based ribosome display methods. The selected Fabs were readily reformatted and directly screened as IgGs using Sutro's unique high-throughput, cell-free protein synthesis platform, Xpress CFTM. We then developed novel, potent ADCs, SP7676 and SP7675 (STRO-001), comprised of our lead antibody (SP7219) conjugated to non-cleavable DBCO-maytansinoid linker-warheads with an average drug-antibody ratios (DAR) of 2. We used site-specific conjugation technology which results in a high degree of homogeneity characterized by the drug linker covalently binding to a single defined site. The sites for conjugation were selected based on highest cell killing activity and stablity in vitro and in vivo. Both ADCs demonstrate potent cell killing activity across multiple B-cell tumor lines in vitro, and anti-tumor activity in preclinical multiple myeloma xenograft models. In vitro cytotoxicity assays show nanomolar potency of STRO-001 in four MM cell lines: Mc/CAR (IC50 0.8 nM), MM.1S (IC50 10-11 nM), U266B1 (IC50 8.5 -9.3 nM), and ARP-1 (IC50 4.3-22 nM). CD74 cell surface expression is required for ADC anti-proliferative effect but the expression level does not seem to correlate with in vitro potency. SP7676 elicited a robust anti-tumor response in the ANBL-6 multiple myeloma xenograft model. Durable regressions were observed in all mice at ≥ 3 mg/kg, with equivalent efficacy (regression) at 3 mg/kg (every 3 days x5) and 10 mg/kg (every 3 days x5 or weekly x3). SP7676 also elicited a clear survival benefit in a disseminated multiple myeloma CAG xenograft model starting at 1mg/kg every 3 days x 5 doses. Similarly, both SP7676 and STRO-001 inhibited the formation of internal visceral tumors in the ARP-1 xenograft model after 3 weekly doses of 3 mg/kg. Evaluation of our lead candidate, STRO-001 in additional MM cell lines and primary patient samples is planned. The tolerability of STRO-001 in non-human primates is under evaluation. STRO-001 was administered to cynomolgous monkeys in an exploratory dose-escalating study up to 30 mg/kg x 2 doses on Day 1 and 15. STRO-001 reduces normal B-cell populations at ≥1 mg/kg after a single dose, providing pharmacodynamic evidence of B-cell targeting while other hematopoietic lineages are mostly affected only at the highest dose studied. Anticipated hematologic toxicities were readily reversible at 1, 3 and 10 mg/kg and target organs of interest were identified. Based on these encouraging data, STRO-001 is advancing to IND-enabling studies for the treatment of CD74 expressing multiple myeloma and other B-cell malignancies. Disclosures Abrahams: Sutro Biopharma: Employment. Li:Sutro Biopharma: Employment. Yu:Sutro Biopharma: Employment. Krimm:Sutro Biopharma: Employment. Kahana:Celgene: Employment. Narla:Celgene: Employment. Schwartz:Celgene: Employment. Boylan:Celgene: Employment. Hoffmann:Sutro Biopharma: Employment. Steiner:Sutro Biopharma: Employment. Zawada:Sutro Biopharma: Employment. Stephenson:Sutro Biopharma: Employment. Bruhns:Sutro Biopharma: Employment. DeAlmeida:Sutro Biopharma: Employment. Matheny:Sutro Biopharma: Employment. Bussell:Sutro Biopharma: Employment. Galan:Sutro Biopharma: Employment. Kline:Sutro Biopharma: Employment. Vasquez:Sutro Biopharma: Employment. Yam:Sutro Biopharma: Employment. Stafford:Sutro Biopharma: Employment. Heinsohn:Sutro Biopharma: Employment. Sato:Sutro Biopharma: Employment. Molina:Sutro Biopharma: Employment. Hallam:Sutro Biopharma: Employment. Lupher:Sutro Biopharma: Employment.