julilili42/papers huggingface dataset:
Npm1 haploinsufficiency in collaboration with MEIS1 is sufficient to induce AML in mice
2022-04-25

Abstract NPM1 is among the most frequently mutated genes in acute myeloid leukemia (AML). Mutations in the NPM1 gene result in the increased export of NPM1 to the cytoplasm (NPM1c) and are associated with multiple transforming events including the aberrant upregulation of MEIS1 that maintains stem cell and cell cycle–associated pathways in NPM1c AML. However, another consequence of the NPM1c mutation is the inadequate levels of NPM1 wild-type in the nucleus and nucleolus, caused by the loss of one wild-type allele in addition to enforced NPM1 nuclear export. The contribution of NPM1 haploinsufficiency independently of the NPM1 mutation to AML development and its relationship with MEIS1 function is poorly understood. Using mouse models, our study shows that NPM1 haploinsufficiency paired with MEIS1 overexpression is sufficient to induce a fully penetrant AML in mice that transcriptionally resembles human NPM1c AML. NPM1 haploinsufficiency alters MEIS1-binding occupancies such that it binds the promoter of the oncogene structural maintenance of chromosome protein 4 (SMC4) in NPM1 haploinsufficient AML cells but not in NPM1 wild-type–harboring Hoxa9/Meis1-transformed cells. SMC4 is higher expressed in haploinsufficient and NPM1c+ AML cells, which are more vulnerable to the disruption of the MEIS1-SMC4 axis compared with AML cells with nonmutated NPM1. Taken together, our study underlines that NPM1 haploinsufficiency on its own is a key factor of myeloid leukemogenesis and characterizes the MEIS1-SMC4 axis as a potential therapeutic target in this AML subtype.
Plasma Inflammatory Markers and Ventriculostomy-Related Infection in Patients With Hemorrhagic Stroke: A Retrospective and Descriptive Study
2022-04-25

Background Diagnosis of ventriculostomy-related infection (VRI) remains difficult due to the various existing definitions. In patients with hemorrhagic stroke, its diagnosis might be further complicated by the presence of intraventricular blood. Furthermore, hemorrhagic stroke per se may cause symptoms compatible with VRI. This study aimed to evaluate the benefit of plasma inflammatory markers for the diagnosis of VRI and its differentiation from patients with non-cerebral infection and patients without infection in a cohort of patients with hemorrhagic stroke. Methods A total of 329 patients with hemorrhagic stroke and an external ventricular drain (EVD) in situ were admitted to the Neurocritical Care Unit, University Hospital Zurich over a period of 6 years. Of those patients, 187 with subarachnoid hemorrhage and 76 with spontaneous intracerebral hemorrhage were included. Patients with VRI were compared to patients without any infection and to patients with non-cerebral infection, with regards to their clinical characteristics, as well as their inflammatory plasma and cerebrospinal fluid (CSF) markers. For the analysis, peak values were considered. Results The VRI was diagnosed in 36% of patients with subarachnoid and in 17% of patients with intracerebral hemorrhage. The VRI was diagnosed on an average day 9±6.2 after EVD insertion, one day after the white blood cell count (WBC) peaked in CSF (8 ± 6.3). Plasma inflammatory markers (WBC, C-reactive protein “CRP” and procalcitonin “PCT”) did not differ among patients with VRI compared to patients without infection. The CRP and PCT, however, were higher in patients with non-cerebral infection than in patients with VRI. The WBC in CSF was generally higher in patients with VRI compared to both patients without any infection and patients with non-cerebral infection. Conclusions No differences in plasma inflammatory markers could be found between patients with VRI and patients without any infection. Conversely, CRP/PCT were higher in patients with non-cerebral infection than in patients with VRI. Altogether, CRP, PCT, and WBC are not suitable parameters for VRI diagnosis in neurocritical care unit patients.
How not to decide whether inner speech is speech: Two common mistakes
2022-04-25

Abstract Philosophical interest in inner speech has grown in recent years. In seeking to understand the phenomenon, many philosophers have drawn heavily on two theories from neighbouring disciplines: Lev Vygotsky’s theory on the development of inner speech in children and a cognitive-scientific theory about speech production. I argue that they have been too uncritical in their acceptance of these theories, which has prevented a proper analysis of inner speech.
Expression Patterns and Corepressor Function of Retinoic Acid-induced 2 in Prostate Cancer
2022-04-25

Abstract Background Revealing molecular mechanisms linked to androgen receptor activity can help to improve diagnosis and treatment of prostate cancer. Retinoic acid-induced 2 (RAI2) protein is thought to act as a transcriptional coregulator involved in hormonal responses and epithelial differentiation. We evaluated the clinical relevance and biological function of the RAI2 protein in prostate cancer. Methods We assessed RAI2 gene expression in the Cancer Genome Atlas prostate adenocarcinoma PanCancer cohort and protein expression in primary tumors (n = 199) by immunohistochemistry. We studied RAI2 gene expression as part of a multimarker panel in an enriched circulating tumor cell population isolated from blood samples (n = 38) of patients with metastatic prostate cancer. In prostate cancer cell lines, we analyzed the consequences of androgen receptor inhibition on RAI2 protein expression and the consequences of RAI2 depletion on the expression of the androgen receptor and selected target genes. Results Abundance of the RAI2 protein in adenocarcinomas correlated with the androgen receptor; keratins 8, 18, and 19; and E-cadherin as well as with an early biochemical recurrence. In circulating tumor cells, detection of RAI2 mRNA significantly correlated with gene expression of FOLH1, KLK3, RAI2, AR, and AR-V7. In VCaP and LNCaP cell lines, sustained inhibition of hormone receptor activity induced the RAI2 protein, whereas RAI2 depletion augmented the expression of MME, STEAP4, and WIPI1. Conclusions The RAI2 protein functions as a transcriptional coregulator of the androgen response in prostate cancer cells. Detection of RAI2 gene expression in blood samples from patients with metastatic prostate cancer indicated the presence of circulating tumor cells.
2,2,2‐Trifluoroethanol‐mediated hydroarylation of fluorinated alkynes with indoles: Application to diindolylmethanes
2022-04-25

Abstract A new mild and practically simple alkyne hydroarylation protocol for the synthesis of 3‐(indol‐3‐yl)‐3‐(trifluoromethyl)acrylic acid esters by the reaction of indole derivatives with ethyl/methyl 4,4,4‐trifluoro‐3‐(indol‐3‐yl)but‐2‐enoates in trifluoroethanol was developed. This method has the following advantages: no catalyst, atom economy, high yields, broad substrate scope, and large‐scale synthesis. The potential application of this protocol was further demonstrated by the synthesis of a variety of CF 3 ‐substituted synthons and a new class of (un)symmetrical 3,3ʹ‐diindolylmethanes with a quaternary carbon core that might be biologically active.
How previous treatment changes the metabolomic profile in patients with metastatic breast cancer
2022-04-25

Abstract Purpose Metabolites are in the spotlight of attention as promising novel breast cancer biomarkers. However, no study has been conducted concerning changes in the metabolomics profile of metastatic breast cancer patients according to previous therapy. Methods We performed a retrospective, single-center, nonrandomized, partially blinded, treatment-based study. Metastatic breast cancer (MBC) patients were enrolled between 03/2010 and 09/2016 at the beginning of a new systemic therapy. The endogenous metabolites in the plasma samples were analyzed using the AbsoluteIDQ ® p180 Kit (Biocrates Life Sciences AG, Innsbruck) a targeted, quality and quantitative-controlled metabolomics approach. The statistical analysis was performed using R package, version 3.3.1. ANOVA was used to statistically assess age differences within groups. Furthermore, we analyzed the CTC status of the patients using the CellSearch TM assay. Results We included 178 patients in our study. Upon dividing the study population according to therapy before study inclusion, we found the following: 4 patients had received no therapy, 165 chemotherapy, and 135 anti-hormonal therapy, 30 with anti-Her2 therapy and 38 had received treatment with bevacizumab. Two metabolites were found to be significantly different, depending on the further therapy of the patients: methionine and serine. Whereas methionine levels were higher in the blood of patients who received an anti-Her2-therapy, serine was lower in patients with endocrine therapy only. Conclusion We identified two metabolites for which concentrations differed significantly depending on previous therapies, which could help to choose the next therapy in patients who have already received numerous different treatments.
Drilling predation on spatangoid echinoids from the Miocene of Sardinia: a taphonomic and paleoecological perspective
2022-04-25

Abstract Predation is of great importance in understanding the diversification of spatangoid echinoids as well as their preservation in the fossil record. Herein, the spatangoid-dominated Miocene carbonate succession of Punta Foghe (Montiferru area, central-western Sardinia, Italy) is studied with the aim of reconstructing paleoenvironmental conditions and investigating abiotic and biotic factors, including predation, that influence the paleoecology and preservation potential of spatangoid echinoids. The echinoid fauna is dominated by the spatangoid Agassizia and, to a lesser extent, the clypeasteroid Clypeaster . The fauna also includes both regular (undetermined diadematoids and camarodonts) and irregular ( Plagiobrissus, Echinocyamus , and Koehleraster ) forms. Echinoids and associated fossil content, along with taphonomic and sedimentological signatures, indicate an inner sublittoral environment with moderate energy conditions affected by high-energy events. Agassizia remains, which consist mainly of complete and well-preserved tests, commonly bear subcircular drill holes that are interpreted as the result of cassid gastropod predation and investigated with respect to size selectivity and stereotypy of attack sites. Potential biases related to drilling predation and biostratinomy on the preservation potential of spatangoid tests are discussed. Agassizia lacks any morphological adaptation to minimize high predation risk, including defensive spines and the ability to burrow deeply into the sediment. An antipredator behavior possibly relied on a gregarious life-history strategy, reducing the frequency of attacks on specific individuals by cassid predators.
Representing the Tramp in British Interwar Social Exploration Literature: Frank Jennings, Frank Gray and George Orwell
2022-04-25

This paper focuses upon representations of the figure of the tramp in interwar social exploration literature. It begins by exploring disciplinary attempts to highlight the apparent failure of the homeless to contribute within early social exploration literature, offering James Greenwood as an example. It then investigates Mark Freeman's claims regarding a tendency in later pre-war texts within the genre towards greater levels of personal identification – before using the example of Mary Higgs to suggest that the disciplinary impulse nonetheless remained in such works. In then looking at interwar social exploration texts by Frank Jennings, Frank Gray and George Orwell, an argument is developed that during the interwar period the tendency noted by Freeman was significantly heightened, as authors went to much greater lengths to understand the experience of being homeless. Ultimately, however, this development is seen to have done little to alter the disciplinary outlook of these authors. On the contrary, it is argued that in broadcasting their allegiance to the poor their texts can be seen to indicate the emergence of a survival strategy that enabled the perpetuation of a productivist agenda in the face of working-class enfranchisement and political representation – a strategy that this essay terms disciplinary subterfuge.
DeepGaze III: Modeling free-viewing human scanpaths with deep learning
2022-04-26

Humans typically move their eyes in "scanpaths" of fixations linked by saccades. Here we present DeepGaze III, a new model that predicts the spatial location of consecutive fixations in a free-viewing scanpath over static images. DeepGaze III is a deep learning-based model that combines image information with information about the previous fixation history to predict where a participant might fixate next. As a high-capacity and flexible model, DeepGaze III captures many relevant patterns in the human scanpath data, setting a new state of the art in the MIT300 dataset and thereby providing insight into how much information in scanpaths across observers exists in the first place. We use this insight to assess the importance of mechanisms implemented in simpler, interpretable models for fixation selection. Due to its architecture, DeepGaze III allows us to disentangle several factors that play an important role in fixation selection, such as the interplay of scene content and scanpath history. The modular nature of DeepGaze III allows us to conduct ablation studies, which show that scene content has a stronger effect on fixation selection than previous scanpath history in our main dataset. In addition, we can use the model to identify scenes for which the relative importance of these sources of information differs most. These data-driven insights would be difficult to accomplish with simpler models that do not have the computational capacity to capture such patterns, demonstrating an example of how deep learning advances can be used to contribute to scientific understanding.
Plate tectonic–like cycles since the Hadean: Initiated or inherited?
2022-04-26

Abstract Interpretation of Earth's oldest preserved crustal archive, the Jack Hills zircon of Western Australia, has been controversial in terms of the onset of plate tectonics. We conduct time-series analysis on hafnium isotopes of the Jack Hills zircon and reveal an array of statistically significant cycles that are reminiscent of plate-tectonic subduction. At face value, such cycles may suggest early Earth conditions similar to those of today—the uniformitarian hypothesis that plate tectonics was essentially operational since “day one”. On the other hand, in the context of expected secular changes due to planetary evolution and geological observations, the cycles could instead imply that modern plate-tectonic subduction inherited mantle convective harmonics already facilitated by an early phase of stagnant-lid delamination—the “lid-to-plates” hypothesis. Either way, any model for the nature of plate tectonics must incorporate conditions operating during Hadean time, either by initiation of plate tectonics then or by later inheritance of preexisting cycles of mantle convection.
The prodromal phase of hereditary spastic paraplegia type 4: the preSPG4 cohort study
2022-04-26

Abstract This cohort study aimed to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) using biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities. Fifty-six first-degree relatives at risk of developing SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analysed for neurofilament light chain (NfL), tau, and amyloid-β (Aβ). Thirty participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski's sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of 2 points or more, only two non-mutation carriers reached more than 1 point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or Aβ to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers. This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.
Ataxin-3, The Spinocerebellar Ataxia Type 3 Neurodegenerative Disorder Protein, Affects Mast Cell Functions
2022-04-26

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease, is a progressive neurodegenerative disorder characterized by loss of neuronal matter due to the expansion of the CAG repeat in the ATXN3/MJD1 gene and subsequent ataxin-3 protein. Although the underlying pathogenic protein expansion has been known for more than 20 years, the complexity of its effects is still under exploration. The ataxin-3 protein in its expanded form is known to aggregate and disrupt cellular processes in neuronal tissue but the role of the protein on populations of immune cells is unknown. Recently, mast cells have emerged as potential key players in neuroinflammation and neurodegeneration. Here, we examined the mast cell-related effects of ataxin-3 expansion in the brain tissues of 304Q ataxin-3 knock-in mice and SCA3 patients. We also established cultures of mast cells from the 304Q knock-in mice and examined the effects of 304Q ataxin-3 knock-in on the immune responses of these cells and on markers involved in mast cell growth, development and function. Specifically, our results point to a role for expanded ataxin-3 in suppression of mast cell marker CD117/c-Kit, pro-inflammatory cytokine TNF-α and NF-κB inhibitor IκBα along with an increased expression of the granulocyte-attracting chemokine CXCL1. These results are the beginning of a more holistic understanding of ataxin-3 and could point to the development of novel therapeutic targets which act on inflammation to mitigate symptoms of SCA3.
Fluorescent Microscopy-Based Detection of Chitin in Intact Drosophila melanogaster
2022-04-26

Chitin is the major scaffolding component of the insect cuticle. Ultrastructural analyses revealed that chitin adopts a quasi-crystalline structure building sheets of parallel running microfibrils. These sheets called laminae are stacked either helicoidally or with a preferred orientation of the microfibrils. Precise control of chitin synthesis is mandatory to ensure the correct chitin assembly and in turn proper function of cuticular structures. Thus, evaluation of chitin-metabolism deficient phenotypes is a key to our understanding of the function of the proteins and enzymes involved in cuticle architecture and more generally in cuticle biology in insects. Usually, these phenotypes have been assessed using electron microscopy, which is time-consuming and labor intensive. This stresses the need for rapid and straightforward histological methods to visualize chitin at the whole tissue level. Here, we propose a simple method of chitin staining using the common polysaccharide marker Fluorescent brightener 28 (FB28) in whole-mount Drosophila melanogaster . To overcome the physical barrier of FB28 penetration into the cuticle, staining is performed at 65°C without affecting intactness. We quantify FB28 fluorescence in three functionally different cuticular structures namely wings, dorsal abdomens and forelegs by fluorescence microscopy. We find that, as expected, cuticle pigmentation may interfere with FB28 staining. Down-regulation of critical genes involved in chitin metabolism, including those coding for chitin synthase or chitinases, show that FB28 fluorescence reflects chitin content in these organs. We think that this simple method could be easily applied to a large variety of intact insects.
Evidence for γ-ray emission from the remnant of Kepler’s supernova based on deep H.E.S.S. observations
2022-04-26

Observations with imaging atmospheric Cherenkov telescopes (IACTs) have enhanced our knowledge of nearby supernova (SN) remnants with ages younger than 500 yr by establishing Cassiopeia A and the remnant of Tycho’s SN as very-high-energy (VHE) γ -ray sources. The remnant of Kepler’s SN, which is the product of the most recent naked-eye SN in our Galaxy, is comparable in age to the other two, but is significantly more distant. If the γ -ray luminosities of the remnants of Tycho’s and Kepler’s SNe are similar, then the latter is expected to be one of the faintest γ -ray sources within reach of the current generation IACT arrays. Here we report evidence at a statistical level of 4.6 σ for a VHE signal from the remnant of Kepler’s SN based on deep observations by the High Energy Stereoscopic System (H.E.S.S.) with an exposure of 152 h. The measured integral flux above an energy of 226 GeV is ∼0.3% of the flux of the Crab Nebula. The spectral energy distribution (SED) reveals a γ -ray emitting component connecting the VHE emission observed with H.E.S.S. to the emission observed at GeV energies with Fermi -LAT. The overall SED is similar to that of the remnant of Tycho’s SN, possibly indicating the same nonthermal emission processes acting in both these young remnants of thermonuclear SNe.
The Staphylococcus epidermidis Transcriptional Profile During Carriage
2022-04-26

The virulence factors of the opportunistic human pathogen Staphylococcus epidermidis have been a main subject of research. In contrast, limited information is available on the mechanisms that allow the bacterium to accommodate to the conditions during carriage, a prerequisite for pathogenicity. Here, we tested the hypothesis that the adaptation of S. epidermidis at different anatomical sites is reflected by differential gene regulation. We used qPCR to profile S. epidermidis gene expression in vivo in nose and skin swabs of 11 healthy individuals. Despite some heterogeneity between individuals, significant site-specific differences were detected. For example, expression of the S. epidermidis regulator sar A was found similarly in the nose and on the skin of all individuals. Also, genes encoding colonization and immune evasion factors ( sdr G, cap C, and dlt A), as well as the sphingomyelinase encoding gene sph , were expressed at both anatomical sites. In contrast, expression of the global regulator agr was almost inactive in the nose but readily present on the skin. A similar site-specific expression profile was also identified for the putative chitinase-encoding SE0760. In contrast, expression of the autolysine-encoding gene sce D and the wall teichoic acid (WTA) biosynthesis gene tag B were more pronounced in the nose as compared to the skin. In summary, our analysis identifies site-specific gene expression patterns of S. epidermidis during colonization. In addition, the observed expression signature was significantly different from growth in vitro . Interestingly, the strong transcription of sphingomyelinase together with the low expression of genes encoding the tricarboxylic acid cycle (TCA) suggests very good nutrient supply in both anatomical niches, even on the skin where one might have suspected a rather lower nutrient supply compared to the nose.