TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia

While research on T cell exhaustion in context of cancer particularly focuses on CD8C cytotoxic T cells, the role of inhibitory receptors on CD4C T-helper cells have remained largely unexplored. TIGIT is a recently identified inhibitory receptor on T cells and natural killer (NK) cells. In this study, we examined TIGIT expression on T cell subsets from CLL patients. While we did not observe any differences in TIGIT expression in CD8C T cells of healthy controls and CLL cells, we found an enrichment of TIGITC T cells in the CD4C T cell compartment in CLL. Intriguingly, CLL patients with an advanced disease stage displayed elevated numbers of CD4C TIGITC T cells compared to low risk patients. Autologous CLL-T cell co-culture assays revealed that depleting CD4C TIGITC expressing T cells from co-cultures significantly decreased CLL viability. Accordingly, a supportive effect of TIGITCCD4C T cells on CLL cells in vitro could be recapitulated by blocking the interaction of TIGIT with its ligands using TIGIT-Fc molecules, which also impeded the T cell specific production of CLL-prosurvival cytokines. Our data reveal that TIGITCCD4CT cells provide a supportive microenvironment for CLL cells, representing a potential therapeutic target for CLL treatment

Static and dynamic 68Ga-FAPI PET/CT for the detection of malignant transformation of intraductal papillary mucinous neoplasia of the pancreas.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) may arise from intraductal papillary-mucinous neoplasms (IPMN) with malignant transformation, but a significant portion of IPMN remains to show benign behavior. Therefore, it is important to differentiate between benign IPMN and IPMN lesions undergoing malignant transformation. However, non-operative differentiation by ultrasound, CT, MRI and carbohydrate antigen 19-9 (CA19-9) is still unsatisfactory. Here, we assessed the clinical feasibility of additional assessment of malignancy by positron emission tomography using 68Gallium-labeled Fibroblast Activation Protein Inhibitors (68Ga-FAPI-PET) in 25 patients with magnetic resonance imaging (MRI) - or computed tomography (CT) - proven cystic pancreatic lesions. Methods: 25 patients with cystic pancreatic lesions who were followed up in the European Pancreas Center of Heidelberg University hospital and who were led to surgical resection or fine needle aspiration (FNA) due to suspicious clinical, laboratory chemistry or radiological findings were examined by static (all patients) and dynamic (20 patients) 68Ga-FAPI-PET. Cystic pancreatic lesions were delineated and maximum and mean standardized uptake values (SUVmax / SUVmean) were determined. Time activity curves and dynamic parameters (time to peak, K1, k2, K3, k4) were extracted from dynamic PET data. Receiver operating curves (ROC) of static and dynamic PET parameters were calculated. Results: 11 of the patients suffered from menacing IPMN (high grade IPMN with (6 cases) or without (5 cases) progression into PDAC) and 11 from low grade IPMN, 3 patients from other benign entities. Menacing IMPN showed significantly elevated 68Ga-FAPI uptake compared to low grade IPMN and other benign cystic lesions. In dynamic imaging, menacing IPMN showed increasing time activity curves (TAC) followed by slow decrease afterwards, TAC of low grade IPMN showed an immediate peak followed by rapid decrease for about 10 minutes and slower decrease for the rest of the time. ROC curves showed high sensitivity and specificity (area under the curve (AUC) greater than 80%) of static and dynamic PET parameters for the differentiation of IPMN subtypes. Conclusion: 68Ga-FAPI-PET is a helpful new tool for the differentiation of menacing and low grade IPMN and shows the potential to avoid unnecessary surgery for non-malignant pancreatic IPMN

Functional Conservation of the Drosophila gooseberry Gene and Its Evolutionary Alleles

The Drosophila Pax gene gooseberry (gsb) is required for development of the larval cuticle and CNS, survival to adulthood, and male fertility. These functions can be rescued in gsb mutants by two gsb evolutionary alleles, gsb-Prd and gsb-Pax3, which express the Drosophila Paired and mouse Pax3 proteins under the control of gooseberry cis-regulatory region. Therefore, both Paired and Pax3 proteins have conserved all the Gsb functions that are required for survival of embryos to fertile adults, despite the divergent primary sequences in their C-terminal halves. As gsb-Prd and gsb-Pax3 uncover a gsb function involved in male fertility, construction of evolutionary alleles may provide a powerful strategy to dissect hitherto unknown gene functions. Our results provide further evidence for the essential role of cis-regulatory regions in the functional diversification of duplicated genes during evolution

Measurement of the diffractive structure function in deep inelastic scattering at HERA

This paper presents an analysis of the inclusive properties of diffractive deep inelastic scattering events produced in $ep$ interactions at HERA. The events are characterised by a rapidity gap between the outgoing proton system and the remaining hadronic system. Inclusive distributions are presented and compared with Monte Carlo models for diffractive processes. The data are consistent with models where the pomeron structure function has a hard and a soft contribution. The diffractive structure function is measured as a function of \xpom, the momentum fraction lost by the proton, of $\beta$, the momentum fraction of the struck quark with respect to \xpom, and of $Q^2$. The \xpom dependence is consistent with the form \xpoma where $a~=~1.30~\pm~0.08~(stat)~^{+~0.08}_{-~0.14}~(sys)$ in all bins of $\beta$ and $Q^2$. In the measured $Q^2$ range, the diffractive structure function approximately scales with $Q^2$ at fixed $\beta$. In an Ingelman-Schlein type model, where commonly used pomeron flux factor normalisations are assumed, it is found that the quarks within the pomeron do not saturate the momentum sum rule.Comment: 36 pages, latex, 11 figures appended as uuencoded fil

Observation of hard scattering in photoproduction events with a large rapidity gap at HERA

Events with a large rapidity gap and total transverse energy greater than 5 GeV have been observed in quasi-real photoproduction at HERA with the ZEUS detector. The distribution of these events as a function of the $\gamma p$ centre of mass energy is consistent with diffractive scattering. For total transverse energies above 12 GeV, the hadronic final states show predominantly a two-jet structure with each jet having a transverse energy greater than 4 GeV. For the two-jet events, little energy flow is found outside the jets. This observation is consistent with the hard scattering of a quasi-real photon with a colourless object in the proton.Comment: 19 pages, latex, 4 figures appended as uuencoded fil

Expedition 382 Preliminary Report: Iceberg Alley and Subantarctic Ice and Ocean Dynamics

This is the final version. Available from International Ocean Discovery Program via the DOI in this record. International Ocean Discovery Program (IODP) Expedition 382, Iceberg Alley and Subantarctic Ice and Ocean Dynamics, investigated the long-term climate history of Antarctica, seeking to understand how polar ice sheets responded to changes in insolation and atmospheric CO2 in the past and how ice sheet evolution influenced global sea level and vice versa. Five sites (U1534–U1538) were drilled east of the Drake Passage: two sites at 53.2°S at the northern edge of the Scotia Sea and three sites at 57.4°–59.4°S in the southern Scotia Sea. We recovered continuously deposited late Neogene sediment to reconstruct the past history and variability in Antarctic Ice Sheet (AIS) mass loss and associated changes in oceanic and atmospheric circulation. The sites from the southern Scotia Sea (Sites U1536–U1538) will be used to study the Neogene flux of icebergs through “Iceberg Alley,” the main pathway along which icebergs calved from the mar- gin of the AIS travel as they move equatorward into the warmer wa- ters of the Antarctic Circumpolar Current (ACC). In particular, sediments from this area will allow us to assess the magnitude of iceberg flux during key times of AIS evolution, including the following: • The middle Miocene glacial intensification of the East Antarctic Ice Sheet, • The mid-Pliocene warm period, • The late Pliocene glacial expansion of the West Antarctic Ice Sheet, • The mid-Pleistocene transition (MPT), and • The “warm interglacials” and glacial terminations of the last 800 ky. We will use the geochemical provenance of iceberg-rafted detritus and other glacially eroded material to determine regional sources of AIS mass loss. We will also address interhemispheric phasing of ice sheet growth and decay, study the distribution and history of land-based versus marine-based ice sheets around the continent over time, and explore the links between AIS variability and global sea level. By comparing north–south variations across the Scotia Sea be- tween the Pirie Basin (Site U1538) and the Dove Basin (Sites U1536 and U1537), Expedition 382 will also deliver critical information on how climate changes in the Southern Ocean affect ocean circulation through the Drake Passage, meridional overturning in the region, water mass production, ocean–atmosphere CO2 transfer by wind- induced upwelling, sea ice variability, bottom water outflow from the Weddell Sea, Antarctic weathering inputs, and changes in oceanic and atmospheric fronts in the vicinity of the ACC. Comparing changes in dust proxy records between the Scotia Sea and Antarctic ice cores will also provide a detailed reconstruction of changes in the Southern Hemisphere westerlies on millennial and orbital timescales for the last 800 ky. Extending the ocean dust record beyond the last 800 ky will help to evaluate dust-climate couplings since the Pliocene, the potential role of dust in iron fertilization and atmospheric CO2 drawdown during glacials, and whether dust input to Antarctica played a role in the MPT. The principal scientific objective of Subantarctic Front Sites U1534 and U1535 at the northern limit of the Scotia Sea is to recon- struct and understand how ocean circulation and intermediate water formation responds to changes in climate with a special focus on the connectivity between the Atlantic and Pacific basins, the “cold water route.” The Subantarctic Front contourite drift, deposited between 400 and 2000 m water depth on the northern flank of an east–west trending trough off the Chilean continental shelf, is ideally situated to monitor millennial- to orbital-scale variability in the export of Antarctic Intermediate Water beneath the Subantarctic Front. During Expedition 382, we recovered continuously deposited sediments from this drift spanning the late Pleistocene (from ~0.78 Ma to recent) and from the late Pliocene (~3.1–2.6 Ma). These sites are expected to yield a wide array of paleoceanographic records that can be used to interpret past changes in the density structure of the Atlantic sector of the Southern Ocean, track migrations of the Sub- antarctic Front, and give insights into the role and evolution of the cold water route over significant climate episodes, including the following: • The most recent warm interglacials of the late Pleistocene and • The intensification of Northern Hemisphere glaciation.National Science Foundatio

A Concerted Action of Engrailed and Gooseberry-Neuro in Neuroblast 6-4 Is Triggering the Formation of Embryonic Posterior Commissure Bundles

One challenging question in neurogenesis concerns the identification of cues that trigger axonal growth and pathfinding to form stereotypic neuronal networks during the construction of a nervous system. Here, we show that in Drosophila, Engrailed (EN) and Gooseberry-Neuro (GsbN) act together as cofactors to build the posterior commissures (PCs), which shapes the ventral nerve cord. Indeed, we show that these two proteins are acting together in axon growth and midline crossing, and that this concerted action occurs at early development, in neuroblasts. More precisely, we identified that their expressions in NB 6-4 are necessary and sufficient to trigger the formation of the PCs, demonstrating that segmentation genes such as EN and GsbN play a crucial role in the determination of NB 6-4 in a way that will later influence growth and guidance of all the axons that form the PCs. We also demonstrate a more specific function of GsbN in differentiated neurons, leading to fasciculations between axons, which might be required to obtain PC mature axon bundles

Neodymium isotope constraints on provenance, dispersal, and climate-driven supply of Zambezi sediments along the Mozambique Margin during the past ∼45,000 years

Marine sediments deposited off the Zambezi River that drains a considerable part of the southeast African continent provide continuous records of the continental climatic and environmental conditions. Here we present time series of neodymium (Nd) isotope signatures of the detrital sediment fraction during the past ~45,000 years, to reconstruct climate-driven changes in the provenance of clays deposited along the Mozambique Margin. Coherent with the surface current regime, the Nd isotope distribution in surface sediments reveals mixing of the alongshore flowing Zambezi suspension load with sediments supplied by smaller rivers located further north. To reconstruct past changes in sediment provenances, Nd isotope signatures of clays that are not significantly fractionated during weathering processes have been obtained from core 64PE304-80, which was recovered just north of the Zambezi mouth at 1329 m water depth. Distinctly unradiogenic clay signatures (ENd values <214.2) are found during the Last Glacial Maximum, Heinrich Stadial 1, and Younger Dryas. In contrast, the Nd isotope record shows higher, more radiogenic isotope signatures during Marine Isotope Stage 3 and between ~15 and ~5 ka BP, the latter coinciding with the timing of the northern hemisphere African Humid Period. The clay-sized sediment fraction with the least radiogenic Nd isotope signatures was deposited during the Holocene, when the adjacent Mozambique Shelf became completely flooded. In general, the contribution of the distinctly unradiogenic Zambezi suspension load has followed the intensity of precession-forced monsoonal precipitation and enhanced during periods of increased southern hemisphere insolation and high-latitude northern hemispheric climate variability

Equine post-breeding endometritis: A review

The deposition of semen, bacteria and debris in the uterus of the mare after breeding normally induces a self-limiting endometritis. The resultant fluid and inflammatory products are cleared by 48 hours post cover. Mares that are susceptible to persistent post-breeding endometritis (PPBEM) have impaired uterine defence and clearance mechanisms, making them unable to resolve this inflammation within the normal time. This persists beyond 48 hours post-breeding and causes persistent fluid accumulation within the uterus. Mares with PPBEM have an increased rate of embryonic loss and a lower overall pregnancy rate than those without the condition. To enhance conception rates, mares at high risk need optimal breeding management as well as early diagnosis, followed by the most appropriate treatment. This article reviews the pathogenesis, diagnosis and treatment of PPBEM and the management of affected mares

Observation of direct processes in photoproduction at HERA

Jets in photoproduction events have been studied with the ZEUS detector for gammap centre-of-mass energies ranging from 130 to 2 50 GeV. The inclusive jet distributions give evidence for the dominance of resolved photon interactions. In the di-jet sample the direct processes are for the first time clearly isolated. Di-jet cross sections for the resolved and direct processes are given in a restricted kinematic range