Narrow Time Interval Research Articles

Abstract PD9-08: Modeling clonal structure over narrow time frames via circulating tumor DNA in metastatic breast cancer

Abstract Introduction: Circulating tumor DNA (ctDNA) offers the ability to repeatedly interrogate tumor genomic information, providing an opportunity for real-time monitoring of tumor genomic dynamics. In this study, we deeply analyzed multiple ctDNA samples collected over narrow time frames (days-to-weeks) from seven patients with metastatic triple-negative breast cancer (mTNBC), a cancer type known to have high ctDNA content. Methods: Patients with mTNBC were enrolled in a clinical trial of multi-kinase inhibitor cabozantinib, providing uniform and targeted treatment, and samples were collected day 1, day 8, then every 21 to 42 days on study. ctDNA was extracted from each plasma sample and underwent ultra-low pass whole genome sequencing (ULP-WGS; average depth 0.1x; n=42 samples), deep targeted panel sequencing (TPS) of 402 cancer-related genes with unique molecular identifier indexing (depth 10,000x; n=42 samples), and samples with tumor fraction (TFx) >10% underwent whole exome sequencing (WES; depth 200x; n=31 samples), with whole blood germline sequencing of both TPS and WES for subsequent analyses. Somatic copy number alterations (SCNAs) were identified from ULP-WGS and WES. PyClone with TPS was employed for clonal dynamic analyses. Predicted neoantigens were determined from WES using HLAthena. Results: A total of 42 total plasma samples from 7 patients (range 4-8 samples per patient) were collected at narrow time intervals, median 21 days (range 6 to 42 days) between samples. The median TFx across all samples was 18.1% (range 2.5% to 44.3%). TFx estimates were concordant when comparing orthogonal sequencing approaches (ULP-WGS, WES) and tumor fraction estimation algorithms (ichorCNA, FACETS). Despite all seven patients having ‘stable disease’ as best objective response, TFx dynamics were widely variable with TFx declining to lower limit of detection in three of seven patients. Of all samples, 31/42 (73.8%) had tumor fraction >10% and underwent WES; each patient had at least 3 samples that underwent both WES and TPS. There was strong agreement between TPS and WES: across all 31 shared samples, mutation recall in TPS versus WES (gold standard) was 95.5%. Variant allele frequency across all mutations detected in both TPS and WES was highly concordant (Pearson’s r=0.949). Clonal mutations were consistently detected across multiple samples within patients. When comparing genome-wide copy number from last to first available sample within each patient, copy number log ratios were largely stable within patients (union Pearson’s r=0.924) and there were not recurrent shifts in SCNAs across patients. Through statistical modeling of TPS data, we tracked distinct clonal populations for each patient over their sampling windows. Modeled clonal architecture in most patients revealed stable, polyclonal profiles, with important breast cancer driver alterations (e.g. TP53 and PIK3CA) recurrently presenting at high prevalence. Infrequently, we also detected emergence and expansion of clones over narrow time frames (weeks) containing acquired alterations poorly annotated in the breast cancer literature. We successfully predicted neoantigens from ctDNA WES at multiple time points in each patient, with evidence that patients acquired new mutations predicted to be ‘strong binder’ neoantigens over time on therapy. Conclusions: Analysis of serial ctDNA samples collected at narrow time intervals (days-to-weeks) provides unique insight into the dynamics of ctDNA. We demonstrate strong concordance across ctDNA sequencing appraoches. Evolving genomic features of tumor populations can be identified via ctDNA while on treatment, potentially providing real time insight for clinical decision-making. Citation Format: Daniel G Stover, Katharine A Collier, David Tallman, Juliet Forman, Sachet Shukla, Sarah Asad, Justin Rhoades, Samuel Freeman, Mathew Cherian, Sagar Sardesai, Romualdo Barroso-Sousa, Carrie Cibulskis, Niall Lennon, Gavin Ha, Sara M Tolaney, Viktor A Adalsteinsson, Zachary Weber. Modeling clonal structure over narrow time frames via circulating tumor DNA in metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD9-08.

Dating the Bushveld Complex: Timing of Crystallization, Duration of Magmatism, and Cooling of the World’s Largest Layered Intrusion and Related Rocks

Abstract The Paleoproterozoic Bushveld Complex, including the world’s largest layered intrusion and host to world-class stratiform chromium, platinum group element, and vanadium deposits, is a remarkable natural laboratory for investigating the timescales of magmatic processes in the Earth’s crust. A framework for the emplacement, crystallization, and cooling of the Bushveld Complex based on integrated U–Pb zircon–baddeleyite–titanite–rutile geochronology is presented for samples of different rock types from the Bushveld Complex, including ultramafic and mafic cumulates, mineralized horizons, granitic rocks from the roof, and a carbonatite from the nearby alkaline Phalaborwa Complex. The results indicate that (1) the Bushveld Complex was built incrementally over an ∼5 Myr interval from 2060 to 2055 Ma with a peak in magma flux at c. 2055–2056 Ma, (2) U–Pb zircon crystallization ages do not decrease in an uninterrupted systematic manner from the base to the top of the intrusion, indicating that the Bushveld Complex does not represent the crystallized products of a single progressively filled and cooled magma chamber, and (3) U–Pb rutile dates constrain cooling of the intrusion at the level of the Critical Zone through ∼500 °C by 2053 Ma. The c. 2060 Ma Phalaborwa Complex (pyroxenite, syenite, carbonatite + Cu–Fe-phosphate–vermiculite deposits) represents one of the earliest manifestations of widespread Bushveld-related magmatism in the northern Kaapvaal craton. The extended range and out-of-sequence U–Pb zircon dates determined for a harzburgite from the Lower Zone (c. 2056 Ma), an orthopyroxenite from the Lower Critical Zone (c. 2057 Ma), and orthopyroxenites from the Upper Critical Zone (c. 2057–2060 Ma) are interpreted to indicate that the lower part of the Bushveld Complex developed through successive intrusions and accretion of sheet-like intrusions (sills), some intruded at different stratigraphic levels. Crystallization of the main volume of the Bushveld Complex, as represented by the thick gabbroic sequences of the Main Zone and Upper Zone, is constrained to a relatively narrow interval of time (∼1 Myr) at c. 2055–2056 Ma. Granites and granophyres in the roof, and a diorite in the uppermost Upper Zone, constitute the youngest igneous activity in the Bushveld Complex at c. 2055 Ma. Collectively, these results contribute to an emerging paradigm shift for the assembly of some ultramafic–mafic magmatic systems from the conventional ‘big tank’ model to an ‘amalgamated sill’ model. The volume–duration relationship determined for magmatism in the Bushveld Complex, when compared with timescales established for the assembly of other layered intrusions and more silica-rich plutonic–volcanic systems worldwide, is distinct and equivalent to those determined for Phanerozoic continental and oceanic flood basalts that constitute large igneous provinces. Emplacement of the 2055–2060 Ma Bushveld Complex corresponds to the end of the Lomagundi–Jatuli Event, the largest magnitude positive carbon isotope excursion in Earth history, and this temporal correlation suggests that there may have been a contribution from voluminous Bushveld ultramafic–mafic–silicic magmatism to disruptions in the global paleoenvironment.

A γ-Ray Detector of the INES Setup for Measuring Neutron Cross Sections

A liquid-scintillator γ-ray detector has been investigated. The electronics, which consists of a preamplifier and a shaping amplifier of the detector signals, is described. A method for determining the start pulse for the time-of-flight technique has been developed based on the detection of several (three or more) γ rays from a neutron source in a narrow time interval. This method is insensitive to the timing instability of the sync pulse of the proton beam. The energy resolution of the γ-detector section is compared to the simulation results for the γ-ray detection. The potential of the γ detector for measuring cross sections for radiative neutron capture by a nucleus is shown.

Serum of Mice Immunized with Mt1-MMP Metalloproteinase Reduces Migration Potential of Pancreatic Cancer Cells

Expression levels of matrix metalloproteinases, in particular MT1-MMP, are elevated in pancreatic cancer (PC) cells, and this is associated with increased tumor proliferation, invasion, and migration. MT1-MMP is considered a promising target for drug therapy of PC, but the use of inhibitors and therapeutic antibodies to MT1-MMP is limited because maximal efficiency is only observed in a narrow time interval, at the early asymptomatic stages of the disease. This problem could be solved by immunization to MPs at the moment of detection of the primary tumor. This therapeutic effect could be provided by specific antibodies that can be re-produced in case of relapses. Here, we selected the optimal mode for immunization of mice with MT1-MMP fragments that allows us to obtain a high titer of specific antibodies in the blood serum. The obtained antiserums effectively inhibited MT1-MMP enzymatic activity, migration of PANC-02 PC cells through the collagen matrix, and activation of the main inducers of epithelial -mesenchymal transition, TGF-β and MMP-2. These results maybe useful in the development of drugs for PC treatment, and the approach we propose might form the basis for design of antitumor drugs with prolonged action.

The state dynamics of Scots pine communities under conditions of a decrease in airborne industrial pollution

This work examines the changes in the life state of Scots pine communities located in the immediate vicinity of the source of aerial anthropogenic emission with a clear decrease in its level in the time interval 2015-2018. It is shown that due to the physiological and ontogenetic characteristics of woody forms of plants, the response to changes in the level of pollution by the tree layer will be insignificant in a relatively narrow time interval (within the limit of statistical error). However, this response to the reduction of pollution will still manifest itself. Also, one of the reasons for such a slow response can be considered the accumulation of heavy metals in the organic horizons of the soil, where heavy metals form complex compounds (chylates) that are inactive for eluvial processes. The most probable way of development of these communities, while maintaining the current level of emission, will be a gradual increase in the life state of the tree layer to a certain value.

New Caledonia Ophiolite, Marginal Rifting to Fore‐arc Evolution

AbstractThe New Caledonia Ophiolite (Peridotite Nappe), represents about one third of the island's surface (i.e. 5 500 km2). The ophiolite is composed of harzburgites, dunites, lherzolites, minor mafic‐ultramafic cumulates, and various dykes and sills. The mantle section underwent a polyphase evolution, which involved prominent depletion and re‐fertilization.The oldest events are probably recorded by abyssal‐type lherzolites of the northern massifs, which bear traces of moderate partial melting. Plagioclase lherzolites were formed by shallow entrapment of highly depleted MORB melt in residual spinel lherzolites. Nd isotope compositions are consistent with derivation from an asthenospheric mantle source that experienced a recent MORB‐producing depletion. This evolution was most likely accomplished during the late Cretaceous breakup of the eastern Australian margin.The harzburgite‐dunite association, which forms the bulk of Peridotite Nappe was probably formed through a multistage magma‐producing process. Harzburgites composition may have be obtained by a first phase of ∼15% dry fractional melting, followed by 15%–18% hydrous melting in a supra‐subduction zone setting. Variable ∊Nd negatively correlate with 87Sr/86Sr, while Pb isotopes cover a wide range, trending from depleted mantle towards enriched, sediment‐like, compositions. Such signatures likely reflect the evolution of a highly depleted fore‐arc mantle wedge variably modified by different fluid and melt inputs during Eocene subduction.The harzburgite‐dunite set is overlain by a dunite transition zone ∼300m thick, in turn discontinuously covered by cumulate lenses consisting of layered pyroxenites, dunites, and wherlites at the base and gabbronorites/websterites on top. The mafic cumulates crystallized from primitive, ultra‐depleted melts in the nascent lower fore‐arc crust. In particular, FME enrichments and Nd‐Pb isotopes support an origin from a refractory mantle source modified by slab fluids for the gabbronorite‐forming melts.The Peridotite Nappe has been extensively serpentinized (40% to 100%) with extremely scarce occurrences of unserpentinized rocks. Lizardite, brucite, magnetite and minor chrysotile developed from joints and intra‐granular cooling cracks in a near‐static environment. Serpentine‐coated joints and peridotite foliation have been thereafter reopened and injected by various felsic, mafic and ultramafic supra‐subduction melts emplaced within a narrow time interval (55–50 Ma), immediately after subduction inception at 56 Ma, i.e. the age of granulite‐facies metamorphic sole. The youngest magmatic event is represented by island‐arc tholeiite dykes dated at 50 Ma.A widespread set of antigorite and tremolite‐bearing veins crosscut all previous structures in a progressively cooling fore‐arc environment. The former are synkinematic crack seals, which display highly radiogenic, sediment‐like 87Sr/86Sr ratios suggesting direct derivation of fluids from the subduction zone, while the latter bear mantle‐like isotopic signatures and probably originated from the interaction of wall rocks with Ca‐rich fluids released by Eocene dykes or fluids that leached them.Finally, continental subduction and obduction occurred during the 44–34 Ma interval and were accompanied by the development of the HP‐LT metamorphic belt of northern New Caledonia, which constrains the polarity of subduction.

Dynamic discretization discovery for the service network design problem with mixed autonomous fleets

We consider a service network design problem for the tactical planning of parcel delivery in a city logistics setting. A logistics service provider seeks a repeatable plan to transport commodities from distribution centers on the periphery to inner-city satellites. In a heterogeneous infrastructure, autonomous vehicles in level 4 may only drive in feasible streets but need to be pulled elsewhere by manually operated vehicles in platoons. We formulate an integer program to determine the fleet mix, schedule transportation services, and decide on the routing or outsourcing of commodities. Platooning requires a high level of synchronization between vehicles which demands the time-expanded networks to contain narrow time intervals. Thus, we develop an algorithm based on the dynamic discretization discovery scheme which refines partially time-expanded networks iteratively without having to enumerate the fully time-expanded network a priori. We introduce valid inequalities and provide two enhanced versions of the algorithm that exploit linear relaxations of the problem. Further, we propose heuristic ideas to speed up the search for high-quality solutions. In a computational study, we analyze the efficacy of the algorithm in different versions and observe improvements of computational performance in comparison to a commercial solver. Finally, we solve a case study on a real-world based network to obtain insights into the deployment of a mixed autonomous fleet in an existing heterogeneous infrastructure.

Winter is coming: Pathogen emergence in seasonal environments.

Many infectious diseases exhibit seasonal dynamics driven by periodic fluctuations of the environment. Predicting the risk of pathogen emergence at different points in time is key for the development of effective public health strategies. Here we study the impact of seasonality on the probability of emergence of directly transmitted pathogens under different epidemiological scenarios. We show that when the period of the fluctuation is large relative to the duration of the infection, the probability of emergence varies dramatically with the time at which the pathogen is introduced in the host population. In particular, we identify a new effect of seasonality (the winter is coming effect) where the probability of emergence is vanishingly small even though pathogen transmission is high. We use this theoretical framework to compare the impact of different preventive control strategies on the average probability of emergence. We show that, when pathogen eradication is not attainable, the optimal strategy is to act intensively in a narrow time interval. Interestingly, the optimal control strategy is not always the strategy minimizing R0, the basic reproduction ratio of the pathogen. This theoretical framework is extended to study the probability of emergence of vector borne diseases in seasonal environments and we show how it can be used to improve risk maps of Zika virus emergence.

Abstract PR06: Clonal evolution over narrow time frames via circulating tumor DNA in metastatic breast cancer

Abstract Introduction: Circulating tumor DNA (ctDNA) offers the ability to serially interrogate tumor genomic information, providing an opportunity for real-time monitoring of tumor genomic shifts. In this study, we deeply analyzed multiple ctDNA samples collected over narrow time frames (days-to-weeks) from seven patients with metastatic triple-negative breast cancer (mTNBC), a cancer type known to have high ctDNA content. Methods: Patients were enrolled in a clinical trial of the multikinase inhibitor cabozantinib, providing uniform and targeted treatment, and samples were collected at study entry, then every 21 to 42 days on study. ctDNA was extracted from each plasma sample and underwent ultra-low pass whole-genome sequencing (ULP-WGS; average depth 0.1x; n=42 samples), deep targeted panel sequencing of 402 cancer-related genes with unique molecular identifier indexing (depth 10,000x; n=42 samples), and samples with tumor fraction >10% underwent whole-exome sequencing (WES; depth 200x; n=31 samples), with germline sequencing of both targeted panel and WES for downstream analyses. SCNAs were identified from ULP-WGS and WES. PyClone with targeted panel sequencing data was employed for clonal evolution analyses. Predicted neoantigens were determined from WES. Results: 42 total plasma samples were analyzed (range 4-8 samples per patient) collected at narrow time intervals, ranging from 6 to 42 days (median 21 days) between samples. The median tumor fraction across all samples was 18.1% (range 2.5% to 44.3%). Tumor fraction/purity estimates were largely concordant when comparing orthogonal sequencing approaches (ULP-WGS, WES) and tumor fraction estimation algorithms (ichorCNA and FACETS, respectively). Of all samples, 31/42 (73.8%) had tumor fraction >10% and underwent WES; each patient had at least 3 samples that underwent WES. SCNAs were largely concordant between ULP-WGS and WES (all Cohen’s kappa >0.8). When comparing first and last available sample, there were not recurrent shifts in SCNAs. At lower tumor fractions, fewer mutations were detected, yet clonal alterations were consistently identified across multiple samples within patients. Through statistical modeling, we tracked distinct clonal populations for each patient and found diverse clonal architectures and dynamics through treatment. Additionally, several emergent somatic alterations were discovered at late time points, including alterations found in coding regions, proximal regulatory sites, and introns of key drug targets, underscoring the speed at which tumors can adapt to therapeutic agents. Conclusions: Analysis of serial ctDNA samples collected at narrow time intervals (days-to-weeks) provides unique insight into the dynamics of ctDNA as well as clonal evolution. We show that despite low tumor content, evolving genomic features of tumor populations can be identified while on treatment, potentially providing real-time insight for clinical decision-making. This abstract is also being presented as Poster A27. Citation Format: Zachary Weber, David Tallman, Sinclair Stockaard, Katharine Collier, Sarah Asad, Justin Rhoades, Samuel Freeman, Heather A. Parsons, Sara M. Tolaney, Gavin Ha, Viktor A. Adalsteinsson, Daniel G. Stover. Clonal evolution over narrow time frames via circulating tumor DNA in metastatic breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR06.

Two phases of Paleoproterozoic orogenesis in the Tarim Craton: Implications for Columbia assembly

Paleoproterozoic orogenic pulses associated magmatism and metamorphism provide important constraints on the assembly of Columbia. New zircon UPb ages and whole-rock geochemistry results are reported from the Tarim craton, an externally positioned landmass within the Columbia supercontinent. Two samples of low-grade metagranites collected from borehole samples yielded crystallization ages of 1851 ± 9 Ma and 1850.4 ± 9.1 Ma. High-grade metamorphosed granites yielded discordia with upper intercept ages of 1822 ± 52 Ma and 1843 ± 58 Ma, and amphibolitic rocks yielded a concordant age of 1915 ± 30 Ma from the outcrops in southwestern Tarim. Together with previously published data, we propose the following sequence of events in Tarim. Magmatism in the Tarim craton took place during two narrow time intervals. The first phase of magmatism occurred between 1.96 and 1.90 Ga and was followed by a slightly younger magmatic pulse between 1.86 and 1.80 Ga. The latter intrusive phase was followed immediately by ca. 1.8 Ga metamorphism, which is widespread throughout the Tarim craton. We are unable to discriminate any regional age differences between the northern and southern regions of the Tarim Craton. Elemental and zircon Hf isotopes suggest that the magmatic sources were mainly derived from partial melting of the Paleoproterozoic-Neoarchean reworked crust, while variable mantle-derived magma involved in the earliest 1.96–1.90 Ga igneous rocks. The earliest magmatic phase is geodynamically related to subduction setting, whereas the younger phase (1.86–1.80) formed in a continental collisional setting. This process suggests an orogeny at ca. 1.96–1.90 Ga with the amalgamation between the southern and northern terranes, and a collisional orogeny between 1.86 and 1.80 Ga as Tarim becomes a peripheral part of the Columbia supercontinent. The two stages of orogenic activities argue for the amalgamation of the Tarim craton followed by the assembly of Columbia.

Ovarian follicular response to oestrous synchronisation and induction of ovulation in Norwegian Red cattle

BackgroundOestrous synchronisation of cattle has been widely applied to accomplish simultaneous ovulation in animals and facilitate timed artificial insemination. The main aim of this study was to investigate the ovarian follicular growth and ovulatory response to oestrus and ovulation synchronisation in Norwegian Red heifers and cows. Oestrous cycles in 34 heifers and 10 cows from 4 herds were synchronised with two PGF2α analogue treatments 11 days apart, followed by GnRH analogue treatment for induction of ovulation. Thereafter, the ovaries were examined by ultrasonography at 3 h intervals until ovulation.ResultsThe luteolytic effect of the PGF2α analogue was verified in 9 of 10 cows by progesterone contents in milk. Maximum physical activity of the cows occurred on average 69 h after PGF2α analogue treatment. An ovulatory response was recorded in 95.5% (42/44) of the animals. A significant difference in follicle size at ovulation was found between 2 of the herds. Animals with medium sized and large follicles and heifers aged > 16 months ovulated earlier than other animals.ConclusionsThe applied sequence of treatments in the study was shown to be effective in synchronizing and inducing ovulation within a relatively narrow time interval in the Norwegian Red heifers and cows, consistent with findings in other cattle breeds.

A linear equation based on signal increments to predict disruptive behaviours and the time to disruption on JET

This article describes the development of a generic disruption predictor that is also used as basic system to provide an estimation of the time to disruption at the alarm times. The mode lock signal normalised to the plasma current is used as input feature. The recognition of disruptive/non-disruptive behaviours is not based on a simple threshold of this quantity but on the evolution of the amplitudes between consecutive samples taken periodically. The separation frontier between plasma behaviours (disruptive/non-disruptive) is linear in such parameter space. The percentages of recognised and false alarms are 98% and 4%, respectively. The recognised alarms can be split into valid alarms (90%) and late detections (8%). The experimental distribution of warning times follows an exponential model with average warning time of 443 ms. On the other hand, the prediction of the time to the disruption has been fitted to a Weibull model that relates this predicted time to the distance of the points to the diagonal in the parameter space of consecutive samples. The model shows a very good agreement between predicted times and warning times in narrow time intervals (between 0.01 s and 0.06 s) before the disruption.

Turtles Protestudo bessarabica from the Late Miocene of Ukraine

The paper describes three incomplete shells of terrestrial turtle Protestudo bessarabica (Testudinidae) from the Late Miocene (Maeotian, biozone MN 12) of the Belka locality (Ukraine). This is the first description of this species from Ukraine. Materials from Belka add to the data on morphology and variation of the P. bessarabica shell in the formula of the neural plates, the shape of the precentral scale and the gular projection. Additionally, materials from Belka confirm the previously known variation of the shell of P. bessarabica in other characters. This species had a wide geographic distribution in Eastern Europe (Moldova, Russia, and Ukraine) in a rather narrow time interval of the Late Sarmatian–Maeotian and may be important for biostratigraphic correlation.

Achievable simultaneous time and frequency domain energy concentration for finite length sequences

For numerous applications in the field of signal processing, it is desired to design a compact window that can simultaneously concentrate maximum energy in finite time interval and frequency band. Although zero-order discrete prolate spheroidal sequence (DPSS) meets this requirement, it is of infinite support. Limiting this sequence to finite support no longer guarantees the optimality property. This study aims at designing a discrete finite length window that can maximise the energy simultaneously in narrow time interval and frequency band. A multi-objective optimisation approach is adopted to obtain the upper bound of maximum achievable time and frequency domain energy concentrations for finite length sequences. The optimal sequence thus obtained is termed as the optimal window with finite support (OWFS), and its various associated properties are discussed. It is shown analytically that as the support of OWFS approaches infinity, it converges to zero-order DPSS. In order to illustrate its optimality, the compactness of the proposed OWFS is compared with those of various window functions. Extending the proposed OWFS, this study also discusses the formulation and associated properties of the zero-order periodic DPSS. Further, the closed form expression for the upper bound of achievable time and frequency domain energy concentrations is also derived.

Spiral wave unpinning facilitated by wave emitting sites in cardiac monolayers.

Rotating spiral waves of electrical activity in the heart can anchor to unexcitable tissue (an obstacle) and become stable pinned waves. A pinned rotating wave can be unpinned either by a local electrical stimulus applied close to the spiral core, or by an electric field pulse that excites the core of a pinned wave independently of its localization. The wave will be unpinned only when the pulse is delivered inside a narrow time interval called the unpinning window (UW) of the spiral. In experiments with cardiac monolayers, we found that other obstacles situated near the pinning centre of the spiral can facilitate unpinning. In numerical simulations, we found increasing or decreasing of the UW depending on the location, orientation and distance between the pinning centre and an obstacle. Our study indicates that multiple obstacles could contribute to unpinning in experiments with intact hearts.

ОЛІСТОСТРОМА В ОЛІГОЦЕНІ КРОСНЕНСЬКОГО (ТУРКІВСЬКИЙ СУБПОКРИВ) І ДУКЛЯНСЬКО-ЧОРНОГОРСЬКОГО ПОКРИВІВ УКРАЇНСЬКИХ КАРПАТ

Olistostrome horizons in the Oligocene deposits of the south-western part in the Bytlya-Svydovets subcover of the Krosno nappe or in so-called Pre-Duklya folds are described in a number of works. There is not enough information about olistostrome in the northern part of the Krosno nappe in its Turka subcover and in the outer part of the Duklya-Chornohora nappe (Stavniany subcover). In the mentioned tectonic units olistostrome is localized in the Lower Verkhovynian deposits of Oligocene above the marker bed of stripped limestones in the region of the Smozhe populated area of the Skole district of the Lviv Region, Torun and Lopushna of the Mizhgirria region of the Transcarpathian Region as well as near Lyuta Village of the same region. Matrix is mainly composed by the grey carbonate flysh of the Krosno lithotype. Olistostrome horizons are presented by strongly crumped chaotic non-sorted formations. In its composition also are present more ancient rocks than matrix, olistolites of the Upper Cretaceous-Lower Oligocene age as well as redeposited rocks formed as a result of washout of more ancient deposits. Some geologists consider, according, to M. G. Leonov hypothesis (1978), that olistolites came off the front part of the Duklya nappe during its overthrusting to the north-east. Materials collected during geological surveys and later observations deny such a mechanism. This is proved by the following: a) overthrust of the Duklya nappe couldn’t cause the formation of the Krosno olistostrome. Because olistostrome is also fixed in Oligocene of the Stavniany subcover of the given nappe of the Lyuta Village and the Mlaky ravine in the section of the Lyuta River. b) Olistostrome is traced at the strathigraphic level at a relatively narrow time interval. It means that sources of removal of olistolites were functioning not so long that contradicts the thesis on the permanent overthrusting movement. c) If olistostrome was caused by the given overthrust, so it would (and olistolites) be observed continuously, but not discretely. d) In sandstones of-the Lower Verkhovynian subsuite the presence of nummulites was fixed, and in argillites of Oligocene the microfauna of Cretaceous-Eocene age – this in the evidence of the washout event. e) Over olistostrome are developed normal bedded high sections of-the Lower Verkhovynian subsuite, thus the overthrusting of the scales in Oligocene was absent. f) In the composition of the Bytlya olistostrome are present rocks that are absent in the composition of Duklya-Chornohora nappe. In the light of data mentioned above, the alternative thesis about cordillera as a source of removal of olistolites is rather grounded and non-alternative. It is possible that as sources of removal was a number of islands that were uplifted higher that sea level at the beginning of the Upper Verkhovynian time. In places the tongues of olistostromes into the Turka sub cove olistolites in the Smozhe and Torun Village possibly due to the presence of long alluvial fans. It is probable that cordillera occurred at the boundary between the Krosno and Dusynian basins of sedimentation that differed by the conditions of sediment forming that was manifested by the presence of two lithotypes of Oligocene of Krosno and Dusynian.

Late Mesozoic carbonatite provinces in Central Asia: Their compositions, sources and genetic settings

Identification of the Late Mesozoic carbonatite province in Central Asia is herein discussed. Its regional extent and distribution is investigated, and the areas with manifestations of carbonatite magmatism are described. It is shown that they were developed in terranes with heterogeneous and heterochronous basements: Siberian (Aldan Shield) and North China cratons; Early Paleozoic (Caledonian) and Middle–Late Paleozoic (Hercynian) structures of the Central Asian fold belt (Transbaikal and Tuva zones in Russia; Mongolia). Irrespective of the structural position, the carbonatites were generated within a relatively narrow time interval (150–118 Ma). The geochemical (Sr, LREE, Ba, F and P) specialization of carbonatites of the province is reflected in their mineral composition. Some rocks of the carbonatite complexes always include one or more distinctive minerals: fluorite, Ba–Sr sulfates, Ba–Sr–Ca carbonates, LREE fluorocarbonates, or apatite. Compared to counterparts from other age groups (for example, Maimecha–Kotui group in North Asia), these carbonatites are depleted in Ti, Nb, Ta, Zr and Hf. It is shown that the Sr and Nd isotope composition of carbonatites correlates with the geological age of the host crust. Rocks of carbonatite complexes associated with cratons are characterized by the lowest εNd(T) and highest ISr(T) values, indicating that their formation involved an ancient lithospheric material. Carbonatite magmatism occurred simultaneously with the largest plateau basalts 130–120 Ma ago in rift zones in the Late Mesozoic intraplate volcanic province of Central Asia. This interval corresponds to timing of global activation of intraplate magmatism processes, suggesting a link of the carbonatite province with these processes. It is shown that fields with the carbonatite magmatism were controlled by small mantle plumes (“hot fingers”) responsible for the Central Asian mantle plume events.

ГЕОЛОГИЯ И СТРАТИГРАФИЯ ПОЛУОСТРОВА ПОСЬЕТ (ЮЖНОЕ ПРИМОРЬЕ) С МИНЕРАЛОГИЧЕСКОЙ ТОЧКИ ЗРЕНИЯ

Authigenic minerals were studied in volcanogenic-sedimentary rocks of the Posyet Peninsular (Southern Primorye). They are sensitive indicators of sedimentation conditions, and indicate changes in the paleogeographic environment and the nature of diagenetic transformations in sedimentary material. The revealed minerals are corrensite, rektorite, highly ordered mixed-layer differences such as chlorite-smectite (corrensite-like), illite-smectite (rectorite-like), illite and chlorite are typical for the Paleogene and Cretaceous rocks, widely developed in the zone of transition from the Asian continent to the Pacific. Previous studies have shown that highly ordered formations such as smectite-chlorite (corrensite), smectite-illite (rectorite) have a rather narrow time interval (Cretaceous – Paleogene) and important marking significance. The author made an attempt to clarify stratigraphic constructions using mineralogical data, and also proposed to expand the age range of the tested deposits from the Posyet area from the Early Cretaceous to the Oligocene.

U-Pb-dated flowstones restrict South African early hominin record to dry climate phases.

The Cradle of Humankind (Cradle) in South Africa preserves a rich collection of fossil hominins representing Australopithecus, Paranthropus and Homo1. The ages of these fossils are contentious2-4 and have compromised the degree to which the South African hominin record can be used to test hypotheses of human evolution. However, uranium-lead (U-Pb) analyses of horizontally bedded layers of calcium carbonate (flowstone) provide a potential opportunity to obtain a robust chronology5. Flowstones are ubiquitous cave features and provide a palaeoclimatic context, because they grow only during phases of increased effective precipitation6,7, ideally in closed caves. Here we show that flowstones from eight Cradle caves date to six narrow time intervals between 3.2 and 1.3 million years ago. We use a kernel density estimate to combine 29 U-Pb ages into a single record of flowstone growth intervals. We interpret these as major wet phases, when an increased water supply, more extensive vegetation cover and at least partially closed caves allowed for undisturbed, semi-continuous growth of the flowstones. The intervening times represent substantially drier phases, during which fossils of hominins and other fossils accumulated in open caves. Fossil preservation, restricted to drier intervals, thus biases the view of hominin evolutionary history and behaviour, and places the hominins in a community of comparatively dry-adapted fauna. Although the periods of cave closure leave temporal gaps in the South African fossil record, the flowstones themselves provide valuable insights into both local and pan-African climate variability.

The association of nocturnal hypoxia and an echocardiographic measure of pulmonary hypertension in children with sickle cell disease.

Pulmonary hypertension (PH) is multifactorial in origin and may develop early in children with sickle cell disease (C-SCD). Potential etiologies are hemolysis-induced endothelial dysfunction, left ventricular (LV) dysfunction, and chronic hypoxia. Nocturnal hypoxia (NH) in C-SCD is known to be a sequela of obstructive sleep apnea (OSA). The primary objective of this study is to correlate polysomnographic evidence NH with echocardiographic measures of PH in C-SCD. We performed a retrospective chart review of 20 C-SCD (Hemoglobin SS), who had polysomnography and echocardiogram performed within a narrow time interval, and 31% of them had pre-existing cardiac conditions. Tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/s was considered as an indicator of PH. Twenty-five percent of the subjects had NH. Forty percent of C-SCD, predominantly male, had evidence of PH based on an elevated TRJV. Children with NH compared to non-NH had significantly worse baseline hypoxemia (p < 0.001), higher TRJV (p = 0.005), and higher LV end-diastolic diameters (p = 0.009). The severity of NH was influenced by OSA. However, PH was not associated with OSA or duration of hydroxyurea therapy. Our study indicates that NH is associated with PH in C-SCD, and that screening for NH may help to identify C-SCD with higher morbidity risk.