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•This study reveals a novel recurrent genetic variant (TRB::NOTCH1) with significant prognostic relevance in T-LBL.•TRB::NOTCH1is absent in the analyzed T-ALL cohort.

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is a powerful imaging method for generating molecular maps of biological samples and has numerous applications in biomedical research. A key challenge in MALDI MSI is to reliably map observed mass peaks to theoretical masses, which can be difficult due to mass shifts that occur during the measurement process. In this paper, we propose MassShiftNet, a novel self-supervised learning framework for mass recalibration. We train a neural network on a data dependent and specifically augmented training data set to directly estimate and correct the mass shift in the observed spectra. In our evaluation, we show that this method is both able to reduce the absolute mass error and to increase the relative mass alignment between peptide MSI spectra acquired from FFPE-fixated tissue using a MALDI time-of-flight (TOF) instrument.

Nosocomial-associated diarrhea due to Clostridioides difficileinfection (CDI) is diagnosed after sample precultivation by the detection of the toxins in enzyme immunoassays or via toxin gene nucleic acid amplification. Rapid and direct diagnosis is important for targeted treatment to prevent severe cases and recurrence. We developed two singleplex and a one-pot duplex fluorescent 15 min isothermal recombinase polymerase amplification (RPA) assays targeting the toxin genes A and B (tcdAand tcdB). Furthermore, we adapted the singleplex RPA to a 3D-printed microreactor device. Analytical sensitivity was determined using a DNA standard and DNA extracts of 20 C. difficilestrains with different toxinotypes. Nineteen clostridial and gastrointestinal bacteria strains were used to determine analytical specificity. Adaptation of singleplex assays to duplex assays in a 50 μL volume required optimized primer and probe concentrations. A volume reduction by one-fourth (12.4 μL) was established for the 3D-printed microreactor. Mixing of RPA was confirmed as essential for optimal analytical sensitivity. Detection limits (LOD) ranging from 119 to 1411 DNA molecules detected were similar in the duplex tube format and in the singleplex 3D-printed microreactor format. The duplex RPA allows the simultaneous detection of both toxins important for the timely and reliable diagnosis of CDI. The 3D-printed reaction chamber can be developed into a microfluidic lab-on-a-chip system use at the point of care.

IEC 60270 is the horizontal standard covering conventional, charge-based partial discharge measurement and has just undergone substantial updates and revision throughout. This article presents a detailed summary of the changes made, together with some of the technical background behind them.

A class of light-activated proteins in the eyes of birds, called cryptochromes, are thought to act as the primary magnetic sensors allowing night-migratory songbirds to navigate over thousands of kilometers using the earth’s magnetic field. Having evolved from DNA-repairing photolyases, cryptochromes have redirected the energy from light to fuel a variety of other functions: as photoreceptors, as regulators of the circadian clock – and, in some species, most likely as sensors of the magnetic field. While the quantum effects of magnetic fields on cryptochromes are already being studied in detail, almost nothing is known about the signaling cascade involving cryptochrome as the primary receptor protein. Two different screening methods have identified potential interaction partners that suggest an involvement of the visual phototransduction pathway, the visual cycle, potassium channels or glutamate receptors, but more pioneering research is needed to unravel the signaling cascade responsible for transducing the magnetic signal.

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For children with medication‐resistant epilepsy who undergo multilobar or hemispheric surgery, the goal of achieving seizure freedom is met with a variety of potential functional consequences, both favorable and unfavorable. However, there is a paucity of literature that comprehensively addresses the cognitive, medical, behavioral, orthopedic, and sensory outcomes across the lifespan following large epilepsy surgeries in childhood, leaving all stakeholders underinformed with regard to counseling and expectations. Through collaboration between clinicians, researchers, and patient/caregiver stakeholders, the “Functional Impacts of Large Resective or Disconnective Pediatric Epilepsy Surgery: Identifying Gaps and Setting PCOR Priorities” meeting was convened on July 18, 2019, to identify gaps in knowledge and inform various patient‐centered research initiatives. Clinicians and researchers with content expertise presented the best available data in each functional domain which is summarized here. As a result of the meeting, the top three consensus priorities included research focused on postoperative: (1) hydrocephalus; (2) mental health issues; and (3) literacy and other educational outcomes. The proceedings of this meeting mark the first time research on functional outcomes after resective and disconnective pediatric epilepsy surgery has been codified and shared among multidisciplinary stakeholders. This joint initiative promotes continued collaboration in the field and ensures that advancements align with actual patient and family needs and experiences. Collaboration around common objectives will lead to better informed counseling around postoperative expectations and management for children undergoing epilepsy surgery.

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

ABSTRACTThe Gac-rsm pathway is a global regulatory network that governs mayor lifestyle and metabolic changes in gamma-proteobacteria. In a previous study, we uncovered the role of CsrA proteins promoting growth and repressing motility, alginate production and virulence in the model phytopathogen Pseudomonas syringaepv. tomato (Pto) DC3000. Here, we focus on the expression and regulation of the rsmregulatory sRNAs, since Pto DC3000 exceptionally has seven variants (rsmX1-5, rsmYand rsmZ). The presented results offer further insights into the functioning of the complex Gac-rsm pathway and the interplay among its components. Overall, rsmexpressions reach maximum levels at high cell densities, are unaffected by surface detection, and require GacA for full expression. The rsmlevels of expression and GacA-dependence are determined by the sequences found in their −35/-10 promoter regions and GacA binding boxes, respectively. rsmX5stands out for being the only rsmin Pto DC3000 whose high expression does not require GacA, constituting the main component of the total rsmpool in a gacAmutant. The deletion of rsmYand rsmZhad minor effects on Pto DC3000 motility and virulence phenotypes, indicating that rsmX1-5can functionally replace them. On the other hand, rsmYor rsmZoverexpression in a gacAmutant did not revert its phenotype. Additionally, a negative feedback regulatory loop in which the CsrA3 protein promotes its own titration by increasing the levels of several rsmRNAs in a GacA-dependent manner has been disclosed as part of this work.

In March 2020, the SARS-CoV-2 virus outbreak was declared as a world pandemic by the World Health Organization (WHO). The only measures for controlling the outbreak are testing and isolation of infected cases. Molecular real-time polymerase chain reaction (PCR) assays are very sensitive but require highly equipped laboratories and well-trained personnel. In this study, a rapid point-of-need detection method was developed to detect the RNA-dependent RNA polymerase (RdRP), envelope protein (E), and nucleocapsid protein (N) genes of SARS-CoV-2 based on the reverse transcription recombinase polymerase amplification (RT-RPA) assay. RdRP, E, and N RT-RPA assays required approximately 15 min to amplify 2, 15, and 15 RNA molecules of molecular standard/reaction, respectively. RdRP and E RT-RPA assays detected SARS-CoV-1 and 2 genomic RNA, whereas the N RT-RPA assay identified only SARS-CoV-2 RNA. All established assays did not cross-react with nucleic acids of other respiratory pathogens. The RT-RPA assay’s clinical sensitivity and specificity in comparison to real-time RT-PCR (n= 36) were 94 and 100% for RdRP; 65 and 77% for E; and 83 and 94% for the N RT-RPA assay. The assays were deployed to the field, where the RdRP RT-RPA assays confirmed to produce the most accurate results in three different laboratories in Africa (n= 89). The RPA assays were run in a mobile suitcase laboratory to facilitate the deployment at point of need. The assays can contribute to speed up the control measures as well as assist in the detection of COVID-19 cases in low-resource settings.

Recent findings suggest that both dorsal and ventral visual pathways process shape information. Nevertheless, a lesion to the ventral pathway alone can result in visual agnosia, an impairment in shape perception. Here, we explored the neural basis of shape processing in a patient with visual agnosia following a circumscribed right hemisphere ventral lesion and evaluated longitudinal changes in the neural profile of shape representations. The results revealed a reduction of shape sensitivity slopes along the patient's right ventral pathway and a similar reduction in the contralesional left ventral pathway. Remarkably, posterior parts of the dorsal pathway bilaterally also evinced a reduction in shape sensitivity. These findings were similar over a two-year interval, revealing that a focal cortical lesion can lead to persistent large-scale alterations of the two visual pathways. These alterations are consistent with the view that a distributed network of regions contributes to shape perception.

ABSTRACTIntroduction: Myeloid malignancies are caused by uncontrolled proliferation of neoplastic cells and lack of mature hematopoietic cells. Beside intrinsic genetic and epigenetic alterations within the neoplastic population, abnormal function of the bone marrow stroma promotes the neoplastic process. To overcome the supportive action of the microenvironment, recent research focuses on the development of targeted therapies, inhibiting the interaction of malignant cells and niche cells.Areas covered: This review covers regulatory networks and potential druggable pathways within the hematopoietic stem cell niche. Recent insights into the cell-to-cell interactions in the bone marrow microenvironment are presented. We performed literature searches using PubMed Database from 2000 to the present.Expert opinion: Future therapy of myeloid malignancies must focus on targeted, personalized treatment addressing specific alterations within the malignant and the supporting niche cells. This includes treatments to overcome resistance mechanisms against chemotherapeutic agents mediated by supporting microenvironment. Novel techniques employing sequencing approaches, Crisp/Cas9, or transgenic mouse models are required to elucidate specific interactions between components of the bone marrow niche to identify new therapeutic targets.

Here we conducted a systematic review and meta-analysis to reach a consensus on whether infected and uninfected mosquitoes respond differently to repellents. After screening 2,316 published studies, theses, and conference abstracts, we identified 18 studies that tested whether infection status modulated the effectiveness of repellents. Thirteen of these studies had outcomes available for meta-analysis, and overall, seven repellents were tested (typically DEET with 62% of outcomes), six mosquito species had repellence behaviors measured (typically Aedes aegypti(L.) (Diptera: Culicidae) mosquitoes with 71% of outcomes), and a broad diversity of infections were tested including Sindbis virus (Togaviridae: Alphavirus) (33% of outcomes), Dengue (Flaviviridae: Flavivirus) (31%), malaria (Plasmodium bergheiVincke & Lips (Haemospororida: Plasmodiidae) or P. falciparumWelch (Haemospororida: Plasmodiidae); 25%), Zika (Flaviviridae: Flavivirus) (7%), and microsporidia (4%). Pooling all outcomes with meta-analysis, we found that repellents were less effective against infected mosquitoes—marking an average 62% reduction in protective efficacy relative to uninfected mosquitoes (pooled odds ratio = 0.38, 95% confidence interval = 0.22–0.66; k= 96). Older infected mosquitoes were also more likely to show altered responses and loss of sensitivity to repellents, emphasizing the challenge of distinguishing between age or incubation period effects. Plasmodium- or Dengue-infected mosquitoes also did not show altered responses to repellents; however, Dengue–mosquito systems used inoculation practices that can introduce variability in repellency responses. Given our findings that repellents offer less protection against infected mosquitoes and that these vectors are the most dangerous in terms of disease transmission, then trials on repellent effectiveness should incorporate infected mosquitoes to improve predictability in blocking vector–human contact.

Wnt16is expressed in bone and arteries, and maintains bone mass in mice and humans, but its role in cardiovascular physiology is unknown. We show that Wnt16 protein accumulates in murine and human vascular smooth muscle (VSM). WNT16genotypes that convey risk for bone frailty also convey risk for cardiovascular events in the Dallas Heart Study. Murine Wnt16 deficiency, which causes postnatal bone loss, also reduced systolic blood pressure. Electron microscopy demonstrated abnormal VSM mitochondrial morphology in Wnt16-null mice, with reductions in mitochondrial respiration. Following angiotensin-II (AngII) infusion, thoracic ascending aorta (TAA) dilatation was greater in Wnt16−/−vs Wnt16+/+ mice (LDLR−/−background). Acta2(vascular smooth muscle alpha actin) deficiency has been shown to impair contractile phenotype and worsen TAA aneurysm with concomitant reductions in blood pressure. Wnt16 deficiency reduced expression of Acta2, SM22(transgelin), and other contractile genes, and reduced VSM contraction induced by TGFβ. Acta2 and SM22 proteins were reduced in Wnt16−/−VSM as was Ankrd1, a prototypic contractile target of Yap1 and Taz activation via TEA domain (TEAD)-directed transcription. Wnt16−/−VSM exhibited reduced nuclear Taz and Yap1 protein accumulation. SiRNA targeting Wnt16or Taz,but not Yap1,phenocopied Wnt16 deficiency, and TazsiRNA inhibited contractile gene upregulation by Wnt16. Wnt16 incubation stimulated mitochondrial respiration and contraction (reversed by verteporfin, a Yap/Taz inhibitor). SiRNA targeting Taz inhibitors Ccm2and Lats1/2mimicked Wnt16 treatment. Wnt16 stimulated Taz binding to Acta2chromatin and H3K4me3 methylation. TEAD cognates in the Acta2promoter conveyed transcriptional responses to Wnt16 and Taz. Wnt16 regulates cardiovascular physiology and VSM contractile phenotype, mediated via Taz signaling.

Untersucht wird der empirische Zusammenhang zwischen Aufsichtsratsvergütung und vergütungsbasierten Maßen der Effektivität der Überwachung des Vorstands. Vor diesem Hintergrund verwenden wir einen Datensatz bestehend aus Gesellschaften des deutschen Prime Standard und stellen im Wege des Fixed-Effects-Ansatzes den Erklärungsgehalt der Aufsichtsratsvergütungshöhe und -struktur zur vorstandsvergütungsbezogenen Überwachungseffektivität (übermäßige Vorstandsvergütung und Pay for Performance-Sensitivität) fest. Wir messen einen positiven Zusammenhang zwischen anreizorientierten (insb. leistungsorientierten) Aufsichtsratsvergütungssystemen und übermäßiger Vorstandsvergütung. Weiterhin moderieren anreizorientierte (insb. leistungsorientierte) Vergütungsbestandteile die Pay for Performance-Sensitivität negativ. Wir schlussfolgern daraus einen positiven Zusammenhang zwischen Agency-Kosten und anreizorientierter Aufsichtsratsvergütung und argumentieren, dass entsprechende Aufsichtsratsvergütungsformen aus Sicht der Aktionäre nicht Bestandteil eines optimalen Vergütungskontrakts sein können. Da für langfristig erfolgsorientierte Aufsichtsratsvergütungsstrukturen teilweise gegenteilige Befunde festgestellt werden, schlagen wir die Aufnahme einer unmittelbaren Empfehlung dieser Entlohnungsform in den Deutschen Corporate Governance Kodex (DCGK) vor.

Patients with visual agnosia show severe deficits in recognizing two-dimensional (2-D) images of objects, despite the fact that early visual processes such as figure-ground segmentation, and stereopsis, are largely intact. Strikingly, however, these patients can nevertheless show a preservation in their ability to recognize real-world objects –a phenomenon known as the ‘real-object advantage’ (ROA) in agnosia. To uncover the mechanisms that support the ROA, patients were asked to identify objects whose size was congruent or incongruent with typical real-world size, presented in different display formats (real objects, 2-D and 3-D images). While recognition of images was extremely poor, real object recognition was surprisingly preserved, but only when physical size matched real-world size. Analogous display format and size manipulations did not influence the recognition of common geometric shapes that lacked real-world size associations. These neuropsychological data provide evidence for a surprising preservation of size-coding of real-world-sized tangible objects in patients for whom ventral contributions to image processing are severely disrupted. We propose that object size information is largely mediated by dorsal visual cortex and that this information, together with detailed representation of object shape which is also subserved by dorsal cortex, serve as the basis of the ROA.

The recording of megalithic art on menhirs in Western Iberia used to be performed through direct tracing. The use of photographic techniques represented an important advance in the interpretation of some of the most important prehistoric sites in this wide region, and also in the structuring of archaeological narratives. With the development of photogrammetry, the possibilities have improved considerably, enabling the recording of decorations not visible to the naked eye. In this paper, we present a new protocol to highlight the engravings on eroded surfaces, based on High Performance Computing and advanced algorithms for 3D mesh calculation. This tailored protocol has rendered expressive visual results that have succeeded in recording one of the most exceptional cromlechs in Western Europe: Almendres (Portugal). The results have proved the efficiency of the method and the need to revisit the classic megalithic sites.

Lenalidomide is an immunomodulatory drug fundamental in treating and managing patients with multiple myeloma (MM). It works through various pathways to induce T-cell proliferation and activation of natural killer (NK) cells. This mechanism of T-cell activation is hypothesized to be one of the mechanisms that cause lenalidomide-related skin reactions. Skin reactions are a well-known adverse effect of lenalidomide treatment, with some studies showing that 44% of patients developed a rash while receiving treatment. Rash development has been associated with improved outcomes with other chemotherapy agents in patients with solid tumors. Initial investigation demonstrated that lenalidomide-induced rashes in myeloma patients were associated with improved survival. Other immune-mediated adverse reactions, such as lenalidomide-related diarrhea (LRD), have also been associated with improved patient outcomes. Lenalidomide-related diarrhea and rash likely stem from the same pathways involving the activation of Th2 and NK cells.

New multibeam bathymetry allows an unprecedented view of the tectonic regime and its along‐strike heterogeneity of the North Chilean marine forearc and the oceanic Nazca Plate between 19 and 22.75°S. Combining bathymetric and backscatter information from the multibeam data with subbottom profiler and published and previously unpublished legacy seismic reflection lines, we derive a tectonic map. The new map reveals a middle and upper slope configuration dominated by pervasive extensional faulting, with some faults outlining a >500‐km‐long ridge that may represent the remnants of a Jurassic or pre‐Jurassic magmatic arc. Lower slope deformation is more variable and includes slope‐failures, normal faulting, re‐entrant embayments, and NW‐SE trending anticlines and synclines. This complex pattern likely results from the combination of subducting lower‐plate topography, gravitational forearc collapse, and the accumulation of permanent deformation over multiple earthquake cycles. We find little evidence for widespread fluid seepage despite a highly faulted upper‐plate. An explanation could be a lack of fluid sources due to the sediment starved nature of the trench and most of the upper‐plate in vicinity of the hyperarid Atacama Desert. Changes in forearc architecture partly correlate to structural variations of the oceanic Nazca Plate, which is dominated by the spreading‐related abyssal hill fabric and is regionally overprinted by the Iquique Ridge. The ridge collides with the forearc around 20–21°S. South of the ridge‐forearc intersection, bending‐related horst‐and‐grabens result in vertical seafloor offsets of hundreds of meters. To the north, plate‐bending is accommodated by reactivation of the paleo‐spreading fabric and new horst‐and‐grabens do not develop. Multibeam bathymetric and seismic reflection data image the structure of the North Chilean marine forearc and the oceanic Nazca plateThe structural character and tectonic configuration of the offshore forearc and the oceanic plate change significantly along the marginThe derived pattern of permanent deformation may hold information for studying seismicity or other types of short term deformation

Interleukin‐6 (IL‐6)‐type cytokines play important roles in liver (patho‐)biology. For instance, they regulate the acute phase response to inflammatory signals and are involved in hepatocarcinogenesis. Much is known about the regulation of protein‐coding genes by cytokines whereas their effects on the miRNome is less well understood. We performed a microarray screen to identify microRNAs (miRNAs) in human hepatocytes which are modulated by IL‐6‐type cytokines. Using samples of 2 donors, 27 and 68 miRNAs (out of 1,733) were found to be differentially expressed upon stimulation with hyper‐IL‐6 (HIL‐6) for up to 72 h, with an overlap of 15 commonly regulated miRNAs. qPCR validation revealed that miR‐146b‐5p was also consistently up‐regulated in hepatocytes derived from 2 other donors. Interestingly, miR‐146b‐5p (but not miR‐146a‐5p) was induced by IL‐6‐type cytokines (HIL‐6 and OSM) in non‐transformed liver‐derived PH5CH8 and THLE2 cells and in Huh‐7 hepatoma cells, but not in HepG2 or Hep3B hepatoma cells. We did not find evidence for a differential regulation of miR‐146b‐5p expression by promoter methylation, also when analyzing the TCGA data set on liver cancer samples. Inducible overexpression of miR‐146b‐5p in PH5CH8 cells followed by RNA‐Seq analysis revealed effects on multiple mRNAs, including those encoding IRAK1 and TRAF6 crucial for Toll‐like receptor signaling. Indeed, LPS‐mediated signaling was attenuated upon overexpression of miR‐146b‐5p, suggesting a regulatory loop to modulate inflammatory signaling in hepatocytes. Further validation experiments suggest DNAJC6, MAGEE1, MPHOSPH6, PPP2R1B, SLC10A3, SNRNP27, and TIMM17B to be novel targets for miR‐146b‐5p (and miR‐146a‐5p). IL‐6‐type cytokines up‐regulate miR‐146b‐5p expression in liver cells, an anti‐inflammatory miRNA with multiple targets shared with miR‐146a‐5p.

Interleukin‐27 (IL27) is a type‐I cytokine of the IL6/IL12 family and is predominantly secreted by activated macrophages and dendritic cells. We show that IL27 induces STAT factor phosphorylation in cancerous cell lines of different tissue origin. IL27 leads to STAT1 phosphorylation and recapitulates an IFN‐γ‐like response in the microarray analyses, with up‐regulation of genes involved in antiviral defense, antigen presentation, and immune suppression. Like IFN‐γ, IL27 leads to an up‐regulation of TAP2 and MHC‐I proteins, which mediate increased tumor immune clearance. However, both cytokines also upregulate proteins such as PD‐L1 (CD274) and IDO‐1, which are associated with immune escape of cancer. Interestingly, differential expression of these genes was observed within the different cell lines and when comparing IL27 to IFN‐γ. In coculture experiments of hepatocellular carcinoma (HCC) cells with peripheral blood mononuclear cells, pre‐treatment of the HCC cells with IL27 resulted in lowered IL2 production by anti‐CD3/‐CD28 activated T‐lymphocytes. Addition of anti‐PD‐L1 antibody, however, restored IL2 secretion. The levels of other TH1 cytokines were also enhanced or restored upon administration of anti‐PD‐L1. In addition, we show that the suppression of IL27 signaling by IL6‐type cytokine pre‐stimulation—mimicking a situation occurring, for example, in IL6‐secreting tumors or in tumor inflammation–induced cachexia—can be antagonized by antibodies against IL6‐type cytokines or their receptors. Therapeutically, the antitumor effects of IL27 (mediated, e.g., by increased antigen presentation) might thus be increased by combining IL27 with blocking antibodies against PD‐L1 or/and IL6‐type cytokines. Anti‐IL6 or anti‐PD‐L1 influence IL27 signaling effects in HCC cells by preventing IL6 mediated inhibition of IL27 or by mediating an increase in immunogenicity, respectively.

Receptor tyrosine kinase (RTK)-dependent signaling has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL) of childhood. However, the RTK-dependent signaling state and its interpretation with regard to biological behavior are often elusive. To decipher signaling circuits that link RTK activity with biological output in vivo, we established patient-derived xenograft ALL (PDX-ALL) models with dependencies on fms-like tyrosine kinase 3 (FLT3) and platelet-derived growth factor receptor β (PDGFRB), which were interrogated by phosphoproteomics using iTRAQ mass spectrometry. Signaling circuits were determined by receptor type and cellular context with few generic features, among which we identified group I p21-activated kinases (PAKs) as potential therapeutic targets. Growth factor stimulation markedly increased catalytic activities of PAK1 and PAK2. RNA interference (RNAi)-mediated or pharmacological inhibition of PAKs using allosteric or adenosine triphosphate (ATP)-competitive compounds attenuated cell growth and increased apoptosis in vitro. Notably, PAK1- or PAK2-directed RNAi enhanced the antiproliferative effects of the type III RTK and protein kinase C inhibitor midostaurin. Treatment of FLT3- or PDGFRB-dependent ALLs with ATP-competitive PAK inhibitors markedly decreased catalytic activities of both PAK isoforms. In FLT3-driven ALL, this effect was augmented by coadministration of midostaurin resulting in synergistic effects on growth inhibition and apoptosis. Finally, combined treatment of FLT3D835HPDX-ALL with the ATP-competitive group I PAK inhibitor FRAX486 and midostaurin in vivo significantly prolonged leukemia progression-free survival compared with midostaurin monotherapy or control. Our study establishes PAKs as potential downstream targets in RTK-dependent ALL of childhood, the inhibition of which might help prevent the selection or acquisition of resistance mutations toward tyrosine kinase inhibitors.

Receptor tyrosine kinase (RTK)-dependent signaling has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL) of childhood. However, the RTK-dependent signaling state and its interpretation with regard to biological behavior are often elusive. To decipher signaling circuits that link RTK activity with biological output in vivo, we established patient-derived xenograft ALL (PDX-ALL) models with dependencies on fms-like tyrosine kinase 3 (FLT3) and platelet-derived growth factor receptor ß (PDGFRB), which were interrogated by phosphoproteomics using iTRAQ mass spectrometry. Signaling circuits were determined by receptor type and cellular context with few generic features, among which we identified group I p21-activated kinases (PAKs) as potential therapeutic targets. Growth factor stimulation markedly increased catalytic activities of PAK1 and PAK2. RNA interference (RNAi)-mediated or pharmacological inhibition of PAKs using allosteric or adenosine triphosphate (ATP)-competitive compounds attenuated cell growth and increased apoptosis in vitro. Notably, PAK1- or PAK2-directed RNAi enhanced the antiproliferative effects of the type III RTK and protein kinase C inhibitor midostaurin. Treatment of FLT3- or PDGFRB-dependent ALLs with ATP-competitive PAK inhibitors markedly decreased catalytic activities of both PAK isoforms. In FLT3-driven ALL, this effect was augmented by coadministration of midostaurin resulting in synergistic effects on growth inhibition and apoptosis. Finally, combined treatment of FLT3D835H PDX-ALL with the ATP-competitive group I PAK inhibitor FRAX486 and midostaurin in vivo significantly prolonged leukemia progression-free survival compared with midostaurin monotherapy or control. Our study establishes PAKs as potential downstream targets in RTK-dependent ALL of childhood, the inhibition of which might help prevent the selection or acquisition of resistance mutations toward tyrosine kinase inhibitors.

The spectrum of slip modes occurring along shallow portions of the plate boundary décollement in subduction zones includes aseismic slip, slow slip, and seismogenic slip. The factors that control slip modes directly influence the hazard potential of subduction zones for generating large‐magnitude earthquakes and tsunamis. We conducted an experimental study of the frictional behavior of subduction input sediments, recovered from two Integrated Ocean Drilling Program expeditions to the erosive subduction margin offshore Costa Rica (Expeditions 334 and 344), employing rotary shear under hydrothermal conditions. The velocity dependence of friction was explored, using simulated gouges prepared from all major lithologies, covering a wide range of conditions representative for the initial stages of subduction. Temperature, effective normal stress, and pore fluid pressure were varied systematically up to 140 °C, 110 MPa, and 120 MPa, respectively. Sliding velocities up to 100μm/s, relevant for earthquake rupture nucleation and slow slip, were investigated. The only sediment type that produced frictional instabilities (i.e., laboratory earthquakes) was the calcareous ooze carried by the incoming Cocos Plate, which by virtue of its slip‐weakening behavior is also a likely candidate for triggering slow slip events. We evaluate this mechanism of producing unstable slip and consider alternatives. Therefore, locking and unlocking of plate boundary megathrusts are not only related to variations in pore fluid pressure but may also depend on the presence of pelagic carbonate‐rich lithologies. Subduction systems containing such input are likely low latitude, where extensive deposition of carbonates takes place above the carbonate compensation depth. Fault slip modes at the plate boundary in erosive subduction zones are governed by subducted sediments carried by the incoming plate

Due to the effects of fire on bones, macroscopic observations of burned human remains are often insufficient to completely characterize an individual (age and sex determination). Herein we explore microstructure of bone fragments recovered in a funerary urn from the 1st millennium BC at Lagunita I archaeological site (Cáceres, Spain) in an attempt to determine if histomorphological analysis could complement macroscopic observation in anthropological study. Although histological analysis is a destructive technique, analyses making use of thin-sections has permitted us to unveil different stages of alteration in two pieces of the same bone despite both appearing to have similar major macroscopic alterations due to high temperatures reached by the fire (over 900 °C in some areas). Furthermore, the mid-shaft fragment suggested that the remains belonged to a young individual (between 12 and 20 years old). In light of the results, we conclude that bone histology could support and enhance inferences made from macroscopic observations improving the analysis of archaeological cremated remains.

Der Einfluss der Aktionäre auf die Vergütung des Vorstands wurde infolge des 2010 eingeführten Vergütungsvotums (sog. Say on Pay) erhöht. Die Untersuchung zielt zunächst darauf ab, (1) mithilfe einer logistischen Regression, Determinanten für die fakultative Durchführung einer Abstimmung über das Vergütungssystem sowie (2) mithilfe einer linearen Regression Determinanten für das Abstimmungsverhalten der Aktionäre zu identifizieren. Darüber hinaus wird im Rahmen einer explorativen Analyse untersucht, (3) wie Unternehmen im Falle eines missbilligenden Votums reagieren und (4) Medien im Falle negativer Voten berichten. Die Analyse erfolgt für deutsche DAX-notierte Unternehmen in einem Sechsjahreszeitraum (2010–2015). Die Ergebnisse zeigen, dass die Wahrscheinlichkeit der Aufnahme des Vergütungsvotums auf die Tagesordnung der Hauptversammlung und das entsprechende Abstimmungsverhalten vor allem von der Vergütungshöhe und -struktur, der gezahlten Dividende, der Aktionärsstruktur und dem Offenlegungsverhalten abhängig ist. Im Falle eines missbilligenden Votums kommt es in den meisten Fällen zu Unternehmensreaktionen wie Änderung von Vergütungssystem oder -struktur, Reduktion der Vergütung oder erneutes Votum im Folgejahr. Darüber hinaus zeigt sich, dass die Fachpresse in der Regel über missbilligende bzw. ablehnende Vergütungsvoten berichtet, es sei denn es existieren überlagernde negative Themen bei den betroffenen Unternehmen. Im Falle nicht durchgeführter Abstimmungen erfolgt mit Ausnahme des Jahres 2010 jedoch kaum eine Berichterstattung in den Medien. Since 2010 German shareholders have the option to vote on the compensation system of the Executive Board (say on pay-votes). This study aims (1) to find determinants that influence whether shareholders vote on the compensation system using logistic regressions, if so, (2) how they vote using linear regressions. Moreover, the study examines exploratory, (3) how companies respond in case of a disapproving vote and (4) whether and how the media reports in the event of negative votes. The data consists of the German DAX-listed companies in a six-year period (2010–2015). We find that the likelihood that the shareholders have the option to vote on the compensation system at the Annual General Meeting and the voting behavior depends on the remuneration amount, compensation structure, the dividends, and shareholder structure and disclosure behavior. The companies react in cases of disapproving votes in various ways (e. g., change of compensation system or structure, reduction of compensation or re-vote in the following year). Furthermore, it appears that the media reported in most cases about negative votes, unless there are overlapping negative topics. There was just few media coverage (except of 2010) in the event that the firms did not put say on pay-votes on the agenda of the shareholders meeting.

Prehistoric paintings from the El Reno cave, Guadalajara (Spain) have been studied by μ-Raman spectroscopy. Goethite (α-FeOOH) and haematite (α-Fe2O3) have been used as pigments in this exceptional Palaeolithic site. Dolomite (CaMgCO3), anatase (TiO2), α-quartz (α-SiO2), hydromagnesite and the calcium carbonate (CaCO3) polymorphs calcite and aragonite have also been detected in the studied paint specimens. Clay minerals of the marl supporting the paintings could be the origin the significant spectral background of fluorescence radiation observed in the Raman spectra. The use of a pictorial recipe mixing haematite and amorphous carbon (charcoal or soot) to prepare the paint of a pictograph is proposed.

Many blueschists and eclogites are inferred to have formed from oceanic basalts in subducted slabs. Knowledge of their elastic behavior is essential for reconstructing the internal structure of subduction zones. The Cycladic blueschist unit, exposed on Syros Island (Greece), contains rocks belonging to an exhumed Tertiary subduction complex. They were possibly part of a subduction channel, a shear zone above the subducting slab in which exhumation is possible during subduction. Intense plastic deformation, forming crystallographic preferred orientations (CPO), accompanied blueschist and eclogite metamorphism. CPO of the constituent minerals in the collected samples was determined by time‐of‐flight neutron diffraction. Two samples are foliated fine‐grained blueschists with strong CPO, rich in glaucophane, zoisite, and phengite. Two coarser‐grained eclogite samples rich in omphacite and clinozoisite, or glaucophane, have weaker CPO. Vpand Vsanisotropies were computed from the orientation distribution function and single‐crystal elastic constants. All samples show velocity maxima parallel to the mineral lineation, and minima normal to the foliation, providing important constraints on orientations of seismic anisotropy in subduction channels. Vpanisotropies are up to 3 times higher (6.5–12%) in the blueschists than in the eclogites (3–4%), pointing to a potentially important lithological control of elastic anisotropy in subducted oceanic crust. Blueschists and eclogites are high‐pressure rocks which form when the oceanic crust sinks into higher depths within the Earth at so‐called subduction zones. During this process the rocks are deformed, which causes a preferred orientation of the minerals constituting the rocks. We measured the orientation of these minerals and used these data to calculate physical properties of these rocks. The minerals have direction‐dependent properties; hence, a preferred orientation of these minerals causes direction‐dependent properties of the rocks. In this case we calculate the velocity of seismic waves in different direction of the rocks to determine the properties of the rocks currently located at depth today. This is useful information for the interpretation of geophysical data. Calculation of elastic anisotropy of subducted oceanic crust from single‐crystal elastic constants and textures of eclogite and blueschistDetermination of physical rock properties in subduction zone settings to help the interpretation of seismic dataUnderstanding of subduction zone processes

Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient T cell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. In vivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. Cells surviving LY-2779964 treatment exhibited inhibitor-induced S6K1 phosphorylation due to increased mTOR-S6K1 co-association, which primed the rapid recovery of S6K1 signaling. In contrast, AD80 avoided S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis. Kinome analysis revealed that AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL. TAM suppression by BMS-777607 or genetic knockdown potentiated cytotoxic responses to LY-2779964 in PTEN-deficient glioblastoma cells. These results reveal that combination targeting of S6K1 and TAMs is a potential strategy for treatment of PTEN-deficient malignancy.

BACKGROUND:Thyroid carcinomas represent the most frequent endocrine malignancies. Recent studies were able to distinguish malignant from benign nodules of the thyroid gland with diffusion-weighted imaging (DWI). Although this differentiation is undoubtedly helpful, presurgical discrimination between well-differentiated and undifferentiated carcinomas would be crucial to define the optimal treatment algorithm. Therefore, the aim of this study was to investigate if readout-segmented multishot echo planar DWI is able to differentiate between differentiated and undifferentiated subtypes of thyroid carcinomas. PATIENTS AND METHODS:Fourteen patients with different types of thyroid carcinomas who received preoperative DWI were included in our study. In all lesions, apparent diffusion coefficient (ADC)min, ADCmean, ADCmax, and Dwere estimated on the basis of region of interest measurements after coregistration with T1-weighted, postcontrast images. All tumors were resected and analyzed histopathologically. Ki-67 index, p53 synthesis, cellularity, and total and average nucleic areas were estimated using ImageJ version 1.48. RESULTS:Analysis of variance revealed a statistically significant difference in ADCmean values between differentiated and undifferentiated thyroid carcinomas (P=.022). Spearman Rho calculation identified significant correlations between ADCmax and cell count (r=0.541, P=.046) as well as between ADCmax and total nuclei area (r=0.605, P=.022). CONCLUSION:DWI can distinguish between differentiated and undifferentiated thyroid carcinomas.