The Mediterranean Outflow Water (MOW), modified by paleoceanographic conditions and tectonic processes, played a significant role in the formation of sediments drifts along the Iberian Margin. Using sediment samples from IODP Hole U1387C, we explore the Early Pleistocene history of the upper MOW core above the central Faro Drift in the Gulf of Cadiz. The time series of benthic foraminifer stable isotope and grain size related data have a rigorous stratigraphic framework consisting of nannofossil biostratigraphy and paleomagnetic and delta 18O stratigraphy. The paleoenvironmental records are supplemented by natural gamma ray downhole logging data. Above the hiatus associated with the youngest dolostone, sandy to muddy contourite sedimentation started at 1.946 Ma, i.e., within Marine Isotope Stage (MIS) 74, at IODP Site U1387, slightly younger than at IODP Site U1389. Formation of contourite layers, reflected in the sortable silt and sand percentage records, strongly reacted to precession forcing, including semi- and quarter-precession cycles. The majority of the contourite beds developed during stadial (colder) climate periods, like previous observations from the Early to Late Pleistocene. Formation of contourite layers within MIS 53, MIS 55 and MIS 65, however, appear to be linked to the prevailing atmospheric conditions over North Africa. Periods of poor ventilation in the upper MOW were linked to insolation maxima and reduced ventilation in the Mediterranean Sea. Here, MIS 51 presents a peculiar case as poor ventilation reached from the surface to the lower North Atlantic Deep Water range, reflecting unique interglacial conditions that merit future exploration.

We report preliminary results from the magnetic stratigraphy and the anisotropy of magnetic susceptibility (AMS) of 6 sites drilled from the International Ocean Discovery Program Expeditions 384, 395C and 395 in the North Atlantic Ocean. Five sites were drilled along a transect on the eastern side of the modern Reykjanes Ridge (including Gardar drift and Bjorn drift), and one on its western side, close to Greenland (Eirik drift). The magnetic stratigraphy provides a precise record of geomagnetic reversals that, coupled with biostratigraphic data, was used to build an age model for each site. The resulting age models provide constraints on variations in sedimentation rate, as well as variations in the AMS parameters. The AMS was used to investigate the strength and direction of bottom currents, with implications for oceanic gateway evolution. The AMS data were reoriented using the shipboard mean declination of the cores at 20 mT, assuming a geocentric axial dipole hypothesis, and time-averaged paleosecular variation. The AMS parameters (lineation, foliation, anisotropy factor, and shape parameter) document the onset and change in the strength of bottom currents. The current direction is generally consistent with that of modern instrumental measurements (NNE - SSW), at least in the last 2.5 Myr.

We use the LIMS With LithologY (LILY) database compiled by Childress et al. (https://zenodo.org/records/8408297) to examine relationships between physical properties and the lithology of marine drill cores collected by the International Ocean Discovery Program (IODP) and its precursor program between 2009 and 2019. Within LILY, lithologic information such as the principal lithologic name and the major and minor lithologic modifiers, along with other metadata, have been added to each of the more than 34 million observations from the standard data available in IODP’s LIMS Database, which is accessible through the LIMS Online Reports (LORE) portal (web.iodp.tamu.edu/LORE/). The ability to compare and combine descriptive lithologic information across expeditions and to integrate these descriptions with multisensor track and discrete sample measurements allows for a wealth of scientific investigation not possible under the original data structure. One of the obvious values of LILY is the ability to characterize the basic physical, chemical, and magnetic properties of different lithologies from a very large number of observations. As an example of this, we compute grain densities for all available lithologies using the Moisture and Density (MAD) density data from over 24,000 measurements. Once the grain densities are known, then the bulk densities can be used to determine porosity. This is important because besides the over 24,000 MAD bulk densities, there are 3.7 million gamma ray attenuation (GRA) bulk densities measured by the Whole Round Multi-Sensor Logger (WRMSL). Comparison of MAD and GRA bulk densities permits biases in the GRA density dataset to be corrected. These corrected GRA bulk densities are then used to compute a new high-resolution porosity dataset (https://zenodo.org/records/10001855). We further merge this large bulk density and porosity dataset with the P-wave velocity data from a P-wave Logger that is part of WRMSL, a P-wave Caliper, and P-wave Bayonets to characterize lithologic-dependent relationships between density, porosity, and P-wave velocity.

By studying deep-sea drilled records from the North Atlantic Ocean, several magnetic instabilities of short duration, such as the Iceland Basin (188 ka), the Bj & ouml;rn (1,255 ka) and the Gardar (1,460 ka) excursions, were discovered. These records have contributed to our understanding of Earth's magnetic field and are the foundation of the Geomagnetic Instability Time Scale (GITS) in the Quaternary. Here, we present the magnetostratigraphy from Sites U1555 (0 to similar to 2.7 Ma) and U1563 (0 to similar to 5.2 Ma) drilled during the International Ocean Discovery Program Expedition 395C on the eastern side of the modern Mid-Atlantic Ridge (similar to 60 degrees N, 20-30 degrees W). Shipboard paleomagnetic and microfossil data provided a preliminary age model, extending the regional record to 3.4 Ma. The Virtual Geomagnetic Pole latitudes from archive halves, corroborated with data from discrete samples, were used to build a high-resolution magnetostratigraphy, which contained the expected Brunhes and Matuyama Chrons and their respective Subchrons. We also identified most of the magnetic events reported in the GITS, including the less well-documented ones, such as Osaka, Kamitzukara, Huckleberry Ridge, Reunion, Gardar, Halawa and L4 events. The high-resolution magnetostratigraphy from Sites U1555 and U1563 is compared with two previous legacy sites and contributes toward an increasingly robust GITS, expanding its use as a correlation and dating tool.

This study has developed paleomagnetic secular variation (PSV) records from Sites 1060, 1061, 1062, and 1063 (ODP Leg 172) from the western North Atlantic Ocean during MIS 11-12 (374-478 ka). We have identified 46 inclination features and 49 declination features that can be correlated among the records. We have also developed relative paleointensity records and identified 13 paleointensity features that can be correlated among them. These features can also be dated using the oxygen-isotope dated Global relative-paleointensity record PISO-1500 of Channell et al. (2009). There is one excursion located in these four records. We use the name Levantine/ Bermuda Excursion developed elsewhere by Ryan (1972) and Channell et al. (2017). The Excursion occurred at 408 +/- 4 ka. The excursion is recorded at Sites 1061, 1062, and 1063. The most detailed excursion records occur at Site 1062 where we have both shipboard PSV records and one u-channel PSV record of the excursion. The excursion has two intervals of excursional directions, one short interval (similar to I ky) followed by a long interval (similar to 5 ky). Both intervals have counter-clockwise looping of the excursional directions and the excursion is considered to be a Class I Excursion (Lund et al., 2005). Statistical study of the PSV records after removal of the excursion directions has identified two characteristics of the 'normal' PSV. The first feature is a long-term (>10(4) yrs) deviation in inclination and declination averages from the overall site averages. These deviations suggest some type on long-term memory in the regional dynamo process. The second feature is the variation in PSV angular dispersion (a measure of directional variability). The angular dispersion is quite low (similar to 12 degrees) for most of the 374-478 ka interval. But, there is a short (similar to 8 ky) interval with angular dispersion more than double the amplitude (similar to 25 degrees-30 degrees). This interval has a sharp (<3 ky) onset and termination, This interval contains the Levantine/Bermuda Excursion. Such high-angular dispersion intervals with associated excursions and low paleointensity appear to be regular distinctive features of the Brunhes Chron PSV.

Increases in temperature and pressure caused by rapid burial of sediments seaward of the Sumatra subduction zone have been hypothesized to trigger dehydration reactions that diagenetically strengthen sediments and contribute to the formation of an over-pressured pre-d & eacute;collement, which together facilitate the occurrence of large shallow earthquakes. We present paleomagnetic, rock magnetic, and electron microscopic analyses from drill cores collected offshore Sumatra at Site U1480 during IODP Expedition 362 that support this hypothesis. The older pre-fan units (Late Cretaceous to early Paleocene) were deposited when Site U1480 was moving rapidly northward with the Indian plate from a paleolatitude of 50 degrees to 30 degrees S, which would equate to expected absolute paleomagnetic inclinations of 70 degrees-43 degrees. Most of the older pre-fan sediments, however, have shallow observed inclinations (shallower than +/- 20 degrees), indicating that the sediments were overprinted when Site U1480 was located near the paleoequator, as it has been since the early Oligocene. Electron microscopic observations reveal that the pre-existing detrital magnetite grains have undergone pervasive dissolution and alteration by hydrothermal fluids. The diagenesis observed is consistent with mineral dehydration, possibly driven by rapid burial of pelagic sediments by the similar to 1250 m thick Nicobar Fan sequence. In addition, the elevated burial temperature also facilitated the smectite to illite conversion reaction. We hypothesize that chemical reactions resulted in the formation of fine-grained magnetite that records a chemical remanent magnetization overprint. This overprint is consistent with the alteration occurring after burial by the thick Nicobar Fan sequence sometime in the past few million years. Sediments and rocks commonly contain magnetic minerals that record the direction and intensity of Earth's magnetic field as they are being emplaced, thus preserving an ancient record of the geomagnetic field. Subsequent alteration of the magnetic minerals caused by heating and/or fluid circulation can result in the acquisition of secondary magnetizations (i.e., remagnetization) that may overprint or completely reset the primary ancient magnetization. Such remagnetization provides evidence of the physical and chemical changes that have occurred. Here through paleomagnetic, rock magnetic, and microscopic analyses of the deeper older (pre-fan) stratigraphic sequence cored offshore Sumatra, we find that hydrothermal fluids, resulting from mineral dehydration driven by rapid burial of this sequence by younger, thick Nicobar Fan sediments, led to pervasive secondary remagnetization. Consequently, the newly formed magnetite recorded a much younger paleomagnetic field, leaving a shallow overprint that probably occurred sometime in the past few million years. The dehydration reactions also increased the strength of the sediments entering the subduction zone and aided in the formation of slip surfaces (called d & eacute;collements), possibly contributing to the shallow, large earthquakes that have generated tsunamis off Sumatra. The 60-67 Ma pre-fan sediments offshore Sumatra were most likely remagnetized since deposition of the Nicobar Fan sediments, which began at similar to 9 Ma Remagnetization of pre-fan sediments caused by mineral dehydration may be linked to shallow seismogenic slip off Sumatra Magnetic properties of input sediments in the subduction margin record conditions that may have facilitated the generation of earthquakes

Abstract During each expedition of the International Ocean Discovery Program and its precursor, the Integrated Ocean Drilling Program (jointly referred to as IODP), vast arrays of data are collected from drill cores. These data, which are accessible from the IODP LIMS (Laboratory Information Management System) database, include physical, chemical, and magnetic properties collected semi‐continuously along cores using automated track systems, as well as a variety of analyses conducted on discrete subsamples taken from the cores. In addition, the lithology of all cores is described based on visual characteristics of the surface of split cores, visual examination of smear slides and thin sections, and compositional or mineralogical information derived from geochemical analyses. We extract basic lithologic information from this complex array of descriptive information and then tie that information to all other measurements. This new database is referred to as LIMS with Lithology (LILY). LILY currently contains over 34 million data from 89 km of core recovered on 42 expeditions conducted 2009–2019. Some uses of LILY include identifying the abundance of different lithologies, finding data from core intervals with a specific lithology, assessing the efficacy of coring systems in different lithologies, or characterizing and analyzing physical, chemical, and magnetic properties based on lithology. We illustrate the use of LILY by computing the grain density by lithology from over 24,000 moisture and density measurements and then use those grain densities, along with the large IODP bulk density dataset, to compute a new high‐resolution porosity dataset with over 3.7 million new porosity estimates.

Supplementary Table 1. Summary of pharmacodynamic changes observed in paired skin punch biopsies. Skin punch biopsies were optional until a dose limiting toxicity was found (11.5 mg/m2/day) when they were mandated. Inhibition of pHH3 (substrate for Aurora kinase B) can be observed in the majority of patients from the 11.5 mg/m2/day dose level. Decreases in Ki67 can be observed from the 18.5 mg/m2/day dose level.

Supplementary Figure 1. Examples of changes observed in M30/M65 profiles as a function of dosing of AT9283 in two selected patients. Pt. 58/032 from cohort 4 (14.5 mg/m2/day) and Pt. 31/030 from cohort 6 (23 mg/m2/day).

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies 1–3 . Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity 4,5 , its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (T reg ) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on T reg cells. Accordingly, in mouse models, PI3Kδi decreased the number of T reg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 T reg cells, accompanied by expansion of pathogenic T helper 17 (T H 17) and type 17 CD8 + T (T C 17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

This paper summarizes paleomagnetic secular variation (PSV) and excursions recorded from MIS 9-10 (300-374 ka) shipboard measurements of sediments from the western North Atlantic Ocean at ODP Sites 1060, 1061, 1062, and 1063. We have identified 33 inclination features, 31 declination features, and 12 paleointensity features that are reproducible among the four ODP Sites. We have dated these records based on estimates of Milankovich carbonate cyclicity in Grutzner et al. (2002). We also dated these records by comparison with the PISO-1500 global paleointensity record (Channel et al., 2009). The two methods give comparable age estimates for this time interval.. We have also recovered a 9-m PSV record from u-channel studies of Hole 1062H. This record is almost identical to the shipboard paleomagnetic results from Site 1062. All records show evidence for the Calabrian Ridge Excursion (329 +/- 3 ka); Sites 1062 and 1063 contain the most consistent and high-resolution paleomagnetic records of the excursion. The Calabrian Ridge excursion is associated with a narrow (similar to 12 ky) interval of high angular dispersion and low paleointensity. We have also carried out a statistical study of the PSV records after removing all true excursional directions (Lund, 2018). There is significant PSV directional variability over 104 yr time scales that is common to all four sites. The pattern of angular dispersion variability is bimodal with most time spent with low (similar to 10 degrees) dispersion, with two shorter intervals of high (similar to 25) dispersion. The high-dispersion intervals are associated with low intensity intervals and excursions.

During each International Ocean Discovery Program (IODP) expedition a vast array of data, typically amounting to hundreds of gigabytes to several terabytes of information, are collected from drill cores. These data include physical, chemical, and magnetic properties and digital images collected continuously or every few centimeters along the cores using automated track systems, as well as a variety of analyses conducted on discrete subsamples taken from the cores. Coring just since the start of Expedition 349 in January 2014 has recovered over 50 km of core, resulting in a very large amount of data, most of which are accessible from the IODP LIMS database. Some of the properties typically measured include P-wave velocity, density, magnetic susceptibility, natural remanent magnetization, natural gamma radiation, and visible spectral reflectance. In addition, the lithology of all cores is described based mainly on visual characteristics of the surface of the split cores, visual examination of smear slides and thin sections, and compositional or mineralogical information derived from geochemical analyses. Our goal in this study is to mine these data for interrelationships that would otherwise be difficult to assess given the way the data are partitioned by specific property within the database. In particular, we extract basic lithologic information from the complex array of descriptive information and then tie that information to all other observations in order to characterize the physical, chemical, and magnetic properties of a myriad of lithologies.

Logging data are measurements of physical properties of the formation surrounding a borehole, acquired in situ after completion of coring (wireline logging) or during drilling (Logging-While-Drilling, LWD). The range of data (resistivity, gamma radiation, velocity, density, borehole images,…) in any hole depends on the scientific objectives and operational constraints.

SUMMARY Palaeomagnetic secular variation (PSV) and excursion data obtained across MIS 8 (243–300 ka) from the western North Atlantic Ocean ODP (Ocean Drilling Program) sites 1060–1063 show composite high-resolution PSV records (both directions and relative palaeointensity) developed for each site and intercompared. Two methods of chronostratigraphy allow us to date these records. First, we used published results that compared the calcium carbonate records of ODP Leg 172 sediments and tuned them with Milankovich cyclicity. We also compared our palaeointensity records with the PISO-1500 global palaeointensity record that was dated with oxygen isotope stratigraphy. We prefer the PISO-1500 record to date our cores. Two excursions are preserved in our PSV records—Excursions 8α and 9α. Our revised age estimates for both excursions are 8α (236.7–239.8 ka) and 9α (283.7–286.9 ka). We have compared shipboard measurements of the two excursions with u-channel measurements of selected excursion intervals. Excursion 8α is interpreted as a ‘Class II’ excursion (local reversal) with in-phase inclination and declination changes; Excursion 9α is a ‘Class I’ excursion with 90° out-of-phase inclination and declination changes. Averaged directions (after removal of true excursional directions) and relative palaeointensity in 3 and 9 ka overlapping intervals show significant PSV directional variability over 104 yr timescales that is regionally correlatable among the four sites. A notable pattern of angular dispersion variability involves most time spent with low (∼10°) dispersion, with three shorter intervals of high (∼25°) dispersion. The relative palaeointensity variability also shows significant variability over 104 yr timescales with three notable intervals of low palaeointensity in all four records and a direct correspondence between the three low-palaeointensity intervals and the three intervals of high angular dispersion. The two magnetic field excursions occur in two of the three low-palaeointensity/high-dispersion intervals. This suggests that the geomagnetic field operates in two states between reversals, one with regular to high palaeointensity and low directional variability and one with low palaeointensity and significantly higher directional variability and excursions.

Logging data are measurements of physical properties of the formation surrounding a borehole, acquired in situ after completion of coring (wireline logging) or during drilling (Logging-While-Drilling, LWD). The range of data (resistivity, gamma radiation, velocity, density, borehole images,…) in any hole depends on the scientific objectives and operational constraints.

Phase Ib dose-escalation study of the selective, noncovalent, reversible Bruton's tyrosine kinase

Phosphoinositide 3-kinase δ (PI3Kδ) plays a key role in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While studies in hematological and solid tumor models in mice have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi on solid tumors in humans remains unclear. Here, we assessed the effects of the PI3Kδi AMG319 in patients with resectable head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating immunosuppressive TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG tissue retention and maintenance. At the tested AMG319 doses, immune-related adverse events caused treatment discontinuation in 12/21 of AMG319-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi decreased TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality. Our data demonstrate the cancer-immunotherapy potential of PI3Kδ inhibition in humans, but its modulation will need to be carefully balanced to harness its anti-tumor capacity while minimizing immune related toxicity.

This paper summarizes the pattern of paleomagnetic secular variation (PSV) and excursions within MIS 6-7 (130-243 ka) from the western North Atlantic Ocean - ODP Sites 1060-1063. Composite high-resolution PSV records (both directions and relative paleointensity) have been developed for each site and inter-compared. There are 65 correlatable inclination features, 67 correlatable declination features, and 15 correlatable paleointensity features in the four PSV records. We have used the results of Grutzner et al. (2002), who compared the calcium carbonate records of ODP Leg 172 sediments and tuned them with Milankovich cyclicity, to date our records. We also dated our PSV records by comparing our paleointensity variability with the study the PISO-1500 global paleointensity record. The two methods agree well. We use the Grutzner phase-shifted chronology to date and analyse our cores because it has lower age uncertainties (-+/- 2 ka). We noted two excursions in our PSV records - Excursions 7 alpha and 7 beta. These are equivalent to the Iceland Basin and Pringle Falls Excursions. Our revised age estimate for the Iceland Basin Excursion is 196 +/- 3 ka. Our revised age estimate for the Pringle Falls Excursion is 215 +/- 2 ka. Both are Class I excursions noted by 2-3 cycles of high-amplitude oscillatory inclinations and declinations. We note a strong similarity in the oscillatory kinematic pattern of the two excursions. We also note evidence for similar but lower amplitude directional PSV between and after the excursions. This complex pattern suggests that the dynamics of the regional dynamo process responsible for these excursions is a continuing process for more than 35 ky. We have carried out a statistical study of the PSV records over the interval 120-250 ka after removing all true excursional directions. We have averaged directions and paleointensity in 3 ka and 9 ka overlapping intervals to evaluate the space/time character of PSV and its geodynamo cause(s). We see significant PSV directional variability over 104 yr time scales that is regionally correlatable among the four sites. There is a notable pattern of angular dispersion variability with most time spent with low (-10 degrees) dispersion, with four shorter intervals of high (-25 degrees) dispersion. There are also four notable intervals of low paleointensity in all four records. There is a one-to-one correspondence between the four low paleointensity intervals and the four intervals of high angular dispersion. The Blake Event (123 +/- 3 ka) and Excursion 8a (238 +/- 2 ka) occur in two of the low intensity/high dispersion intervals that bound MIS 6/7. The two magnetic field excursions within MIS 7 (Iceland Basin and Pringle Falls Excursions) occur in one distinctive long (-35 ka) interval of low paleointensity/high dispersion interval.

Logging data are measurements of physical properties of the formation surrounding a borehole, acquired in situ after completion of coring (wireline logging) or during drilling (Logging-While-Drilling, LWD). The range of data (resistivity, gamma radiation, velocity, density, borehole images,…) in any hole depends on the scientific objectives and operational constraints.