julilili42/papers huggingface dataset:
Bcl‐xL as prognostic marker and potential therapeutic target in cholangiocarcinoma
2022-08-19

Abstract Intrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti‐apoptotic Bcl‐2 proteins (Bcl‐2, Bcl‐x L , Mcl‐1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl‐2 proteins were analysed in a pan‐cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial ( n = 1140, CCA n = 72) via RNA‐sequencing and transcriptome‐based protein activity interference revealing high ranks of CCA for Bcl‐x L and Mcl‐1. Expression of Bcl‐x L , Mcl‐1, and Bcl‐2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative‐RT‐PCR. Immunohistochemistry confirmed the upregulation of Bcl‐x L and Mcl‐1 in iCCA tissues. Cell death of CCA cell lines upon treatment with specific small molecule inhibitors of Bcl‐x L (Wehi‐539), of Mcl‐1 (S63845), and Bcl‐2 (ABT‐199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl‐x L induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl‐x L and Mcl‐1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl‐2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl‐x L in CCA depending on the CCA subtype. Collectively, these observations identify Bcl‐x L as a key protein in cell death resistance of CCA and may pave the way for clinical application.
Latest Pleistocene and Holocene Floodplain Evolution in Central Europe—Insights from the Upper Unstrut Catchment (NW-Thuringia/Germany)
2022-08-19

The upper Unstrut River is located in Germany at the modern Central European climate boundary of Cfb and Dfb climate. The river drains a loess landscape, which has experienced important environmental changes throughout the last 12,000 years. To evaluate the impacts of these changes on floodplain evolution, a multi-proxy research program, consisting of 2D electrical resistivity tomography profiling (ERT), vibracoring, and sedimentological investigations, 14C and OSL dating were applied. From base to top the investigations the following fluvial deposits were revealed: (1) gravels embedded in a fine-grained sediment matrix (interpreted as fluvial bedload deposits); (2) silty sediment with pedogenic features (interpreted as overbank floodplain deposits); (3) peat and tufa deposits (interpreted as wetland deposits) intercalated by pedogenetically influenced silty sediments (interpreted as overbank deposits); (4) humic silty sediment with some pedogenic features (interpreted as overbank floodplain deposits); and (5) silty sediments (interpreted as overbank deposits). Radiocarbon and luminescence dates yielded the following periods for sediment formation: (1) Younger Dryas to Preboreal period (around 11.6 cal ka BP); (2) Preboreal to early Atlantic period (approx. 11.6 to 7.0 cal ka BP); (3) early Atlantic to late Subboreal period (approx. 7.3 to 3.4 cal ka BP); (4) late Subboreal to early Subatlantic period (2.9 to 2.3 cal ka BP); and (5) late Subatlantic period (approx. 1.0 to 0.6 cal ka BP). The results suggest that floodplain development during the latest Pleistocene and early Holocene (approx. 11.6 to 7.0 cal ka BP) was considerably controlled by climatic conditions and short-term climate variabilities, which caused gravel deposition and overbank sedimentation. Afterwards floodplain conditions varied between rather stable (peat and tufa development, initial soil formation) and active periods (deposition of overbank fines). In this context, active periods with increased sediment input prevailed from approx. 5.1 to 3.4 cal ka BP, 2.9 to 2.3 cal ka, and 1.0 to 0.6 cal ka BP, temporally corresponding well with increased land-use phases of the past. In conclusion this study demonstrates that the investigated Unstrut catchment has reacted very sensitively to natural and human-induced changes during the latest Pleistocene and Holocene. Consequently, this high vulnerability to external changes should be considered in future river predictions or river management.
Single-cell RNA sequencing highlights a reduced function of natural killer and cytotoxic T cell in recovered COVID-19 pregnant women
2022-08-19

Abstract Pregnancy is a complex phenomenon during which women undergo immense immunological change throughout this period. Having an infection with the SARS-CoV-2 virus leads to an additional burden on the highly stretched immune response. Some studies suggest that age-matched pregnant women are more prone to SARS-CoV-2 infection compared with normal healthy (non-pregnant) women, while alternative evidence proposed that pregnant women are neither susceptible nor develop severe symptoms. This discrepancy in different findings regarding the immune responses of pregnant women infected with SARS-CoV-2 virus is not well understood. In this study, we investigated how SARS-CoV-2 viral infection could modulate the immune landscape during the active infection phase and recovery in pregnant females. Using flow cytometry, we identified that intermediate effector CD8 + T cells were increased in pregnant women who had recovered from COVID-19 as opposed to those currently infected. Similarly, an increase in CD4 + T helper cells (early or late) during the recovered phase was observed during the recovery phase compared with infected pregnant women or healthy pregnant women, whilst infected pregnant women had a reduced number of late effector CD4 + T cells. CD3 + CD4 - CD8 - NKT cells that diminished during active infection in contrast to healthy pregnant women were significant increase in recovered COVID-19 recovered pregnant women. Further, our single-cell RNA sequencing data revealed that infection of SARS-CoV-2 had changed the gene expression profile of monocytes, CD4 + effector cells and antibody producing B cells in convalescent as opposed to healthy pregnant women. Additionally, several genes with cytotoxic function, interferon signalling type I &amp; II, and pro- and anti-inflammatory functions in natural killer cells and CD8 + cytotoxic T cells were compromised in recovered patients compared with healthy pregnant women. Overall, our study highlights that SARS-CoV-2 infection deranged the adaptive immune response in pregnant women and could be implicated in pregnancy complications in ongoing pregnancies.
Protocol to visualize CD11c+ cells in atherosclerosis using LacZ reporter mice
2022-08-19

Here, we describe an <i>in vivo</i> approach to visualize CD11c<sup>+</sup> cells in atherosclerosis. In particular, we use a protocol for X-Gal staining of immune cells within atherosclerotic plaques, which can be used as an alternative to analyze plaque composition and cell-specific molecules in atherogenesis. LacZ knockin mice have to be bred to mice carrying the CD11c<sup>cre</sup> recombinase-both brought onto an ApoE<sup>-/-</sup> background-to be able to visualize this cell type of interest in the plaques by X-Gal staining. With this approach, different immune cells in atherogenesis can be examined. For complete details on the use and execution of this protocol, please refer to Sauter et al. (2021).
Meeting the Need for a Discussion of Unmet Medical Need
2022-08-19

As Europe and the world continue to battle against COVID, the customary complacency of society over future threats is clearly on display. Just 30 months ago, such a massive disruption to global lives, livelihoods and quality of life seemed unimaginable. Some remedial European Union action is now emerging, and more is proposed, including in relation to tackling “unmet medical need” (UMN). This initiative—directing attention to the future of treating disease and contemplating incentives to stimulate research and development—is welcome in principle. But the current approach being considered by EU officials merits further discussion, because it may prove counter-productive, impeding rather than promoting innovation. This paper aims to feed into these ongoing policy discussions, and rather than presenting research in the classical sense, it discusses the key elements from a multistakeholder perspective. Its central concern is over the risk that the envisaged support will fail to generate valuable new treatments if the legislation is phrased in a rigidly linear manner that does not reflect the serpentine realities of the innovation process, or if the definition placed on unmet medical need is too restrictive. It cautions that such an approach presumes that “unmet need” can be precisely and comprehensively defined in advance on the basis of the past. It cautions that such an approach can reinforce the comfortable delusion that the future is totally predictable—the delusion that left the world as easy prey to COVID. Instead, the paper urges reflection on how the legislation that will shortly enter the pipeline can be phrased so as to allow for the flourishing of a culture capable of rapid adaptation to the unexpected.
Discovery and Development of first-in-class ACKR3/CXCR7 Superagonists for Platelet Degranulation Modulation
2022-08-19

Molecular Dynamics trajectories of ACKR3 bound to compound 27. Desmond MD engine was used for the MD simulation with OPLS4 force field. The system was solvated in an orthorhombic box (minimum distance of 12 Å to the edges from the protein). The POPC (1-palmitoyl-2- oleylphosphatidylcholine) lipid bilayer was the membrane of choice for MD. The membrane was placed automatically on helices with further manual validation of transmembrane atoms. A temperature of 300 K was used for membrane patch pre-equilibration. The water was described with the TIP3P model. The final systems comprised ~44 k atoms. All simulations were run in the NpT ensemble (T = 310 K, Nosé-Hoover method; p = 1.01325 bar, Martyna-Tobias-Klein method) with default Desmond settings. Reversible reference system propagator algorithms (RESPA) integrator with 2 fs, 2 fs, and 6 fs timesteps were used for bonded/non-bonded interactions, near and far, respectively. The default value of 9 Å was used for the Coulombic cut-off. The system was relaxed using the default Desmond protocol before the production simulation. Five replicas of production simulations for the ACKR3–<strong>27</strong> were carried out with the same settings as mentioned above. Each system was simulated for 500 ns (5 × 500 ns = 2.5 μs). For each replica, a random seed was used. Replica names are allocated as following: 110 . replica 1 110r1 - replica 2 110r2 - replica 3 110r3 - replica 4 110r4 - replica 5 Figure 5 Pymol session attached.
Is the urgency message encoded in heterospecific alarm calls perceived by domestic chickens?
2022-08-20

Abstract Vertebrate alarm calls can signal danger, and often encode information about predator proximity. Some species of birds alter the number of notes of their alarm calls to reflect urgency, with high‐urgency alarm calls having more notes than low‐urgency calls. Not only do individuals perceive the urgency message encoded in the alarm calls of conspecifics, but also in the alarm calls given by heterospecifics (sympatric and allopatric species). Yet, although well studied in wild species, the capacity to use heterospecific graded alarm call systems has not been investigated in domestic animals. Domestication may have altered the perceptual and communicative abilities of domestic species because they are less threatened by predators. Using playbacks conducted on domestic naked neck chickens ( Gallus gallus domesticus ) in France, we tested whether this species is able to decode information about urgency in alarm calls produced by a sympatric species; the common chaffinch ( Fringilla coelebs ), and by an allopatric species; the Australian magpie ( Cracticus tibicen ). We found the latency to resume foraging behaviour was higher after the high‐urgency call playbacks than the low‐urgency call playbacks, suggesting that the urgency encoded in heterospecific calls was perceived by chickens. However, results seem to indicate that the chickens are not able to discriminate between alarm and control (songs) sounds, but simply respond to specific sound characteristics of each playback stimulus. Our results raise some questions about how animals perceive and attend to information provided by heterospecific alarms. We hope this study will encourage future work with domesticated and nondomesticated animals.
Neural circuits underpinning face tuning in male depression
2022-08-20

Abstract Reading bodies and faces is essential for efficient social interactions, though it may be thought-provoking for individuals with depression. Yet aberrations in the face sensitivity and underwriting neural circuits are not well understood, in particular, in male depression. Here, we use cutting-edge analyses of time course and dynamic topography of gamma oscillatory neuromagnetic cortical activity during administration of a task with Arcimboldo-like images. No difference in face tuning was found between individuals with depression and their neurotypical peers. Furthermore, this behavioral outcome nicely dovetails with magnetoencephalographic data: at early processing stages, the gamma oscillatory response to images resembling a face was rather similar in patients and controls. These bursts originated primarily from the right medioventral occipital cortex and lateral occipital cortex. At later processing stages, however, its topography altered remarkably in depression with profound engagement of the frontal circuits. Yet the primary difference in depressive individuals as compared with their neurotypical peers occurred over the left middle temporal cortices, a part of the social brain, engaged in feature integration and meaning retrieval. The outcome suggests compensatory recruitment of neural resources in male depression.
Selective Cytotoxicity and Changes in Protein Expression of T24 BladderCarcinoma Permanent Cell Line after Treatment with Hemocyanins
2022-08-20

Background: Some molluscan hemocyanins (Hcs) have significant immunological and antitumor potential, enabling their application in oncology. The antitumor activity of Hcs from marine snails Rapana venosa (RvH), giant keyhole limpet Megathura crenulata (KLH) and garden snails Helix lucorum (HlH), as well as their different derivatives, were studied in vitro on a permanent T24 cell line of bladder cancer and normal urothelial cell line HL 10/29 compared to doxorubicin. Methods: The antiproliferative activity of the tested Hcs was determined using WST-1 assay and BrdU ELISA assay. Morphological changes in both urothelial cell lines were confirmed by fluorescence microscopy. The proteomic analysis of a cell line of bladder cancer before and after treatment with functional unit (FU) βc-HlH-h using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry revealed differences in the expression of some proteins. Results: Studies prove that the T24 tumor cell line is dose- and time-dependent, sensitive to the action of the tested isoforms and the glycosylated FU of these hemocyanins. Selective inhibition of T24 cell growth was observed after incubation with structural subunits (βc-HlH, RvHI and RvHII) and FUs (βc-HlH-h and RvHII-e). Fluorescent microphotographs did not show apoptotic or necrotic alterations in the normal urothelial cell line HL 10/29. The FU βc-HlH-h demonstrated the highest antiproliferative effect (similarly to doxorubicin), in which predominantly apoptotic and less late apoptotic or necrotic changes in the tumor cells were observed. Several down- and up-regulated proteins identified by proteome analysis may be associated with the apoptosis pathway. Conclusions: The present study illustrated the selectivity of the cytotoxic effect of Hcs against the Т24 cancer cell line. This is the first report of protein expression in T24 human bladder cancer cells under the influence of FU βc-HlH-h. That is probably due to the specific oligosaccharide structures rich in methylated hexoses exposed on the surface of βc-HlH-h.
Leveraging Synthetic Data in Object Detection on Unmanned Aerial Vehicles
2022-08-21

Acquiring data to train deep learning-based object detectors on Unmanned Aerial Vehicles (UAVs) is expensive, time-consuming and may even be prohibited by law in specific environments. On the other hand, synthetic data is fast and cheap to access. In this work, we explore the potential use of synthetic data in object detection from UAVs across various application environments. For that, we extend the open-source framework DeepGTAV to work for UAV scenarios. We capture various large-scale high-resolution synthetic data sets in several domains to demonstrate their use in real-world object detection from UAVs by analyzing multiple training strategies across several models. Furthermore, we analyze several different data generation and sampling parameters to provide actionable engineering advice for further scientific research. The DeepGTAV framework is available at https://git.io/Jyf5j.
Findings and Outcome of Transcatheter Right Ventricular Endomyocardial Biopsy and Hemodynamic Assessment in Children with Suspected Myocarditis or Cardiomyopathy
2022-08-21

Objective: The study objective is assessing findings and outcome in children with suspected cardiomyopathy (CMP) or myocarditis undergoing cardiac catheterization with transcatheter right ventricular endomyocardial biopsy (RV-EMB). Methods: All consecutive children undergoing cardiac catheterization with RV-EMB for suspected CMP/myocarditis between 2002–2021 were analysed regarding clinical presentation, cardiac biomarkers, periprocedural management, hemodynamic, histological/immunohistological findings, and outcome. Results: Eighty-five RV-EMBs were performed in 81 patients at a median age of 6.8 (IQR 9.9) years and a bodyweight of 20 (32.2) kg. Histological/immunohistological findings of RV-EMB revealed dilated CMP in 10 (12%), chronic myocarditis in 28 (33%), healing myocarditis in 5 (6%), acute myocarditis in 9 (11%), other heart muscle diseases in 23 (27%) (7 restrictive CMP, 5 hypertrophic CMP, 4 toxic/anthracycline-induced CMP, 4 endocardfibroelastosis, 1 arrhythmogenic right ventricular CMP, 1 laminin CMP, 1 haemangioma), no conclusive histology in 7 (8%), and normal histology in 3 (4%) patients. Median LVEDP was 17 mmHg (IQR 9), LAP 15 mmHg (10), and PVR 1.83 (1.87) Wood Units/m2. There were 3 major complications (3%), all patients recovered without any sequelae. At follow-up (median 1153, IQR 1799 days) 47 (59%) patients were alive, 11 (13%) dead, 15 (18%) underwent cardiac transplantation, and 8 (9%) were lost to follow-up. Death/cardiac transplantation occurred within 3 years from RV-EMB. All patients with an acute myocarditis survived. NT-pro-BNP, echo parameters, and invasive hemodynamics correlate independently with death/cardiac transplant. Conclusion: Hemodynamic invasive data and morphological findings in RV-EMB complete clinical diagnosis in children with suspected CMP/myocarditis and provide important information for further clinical management.
Challenges and opportunities associated with rare-variant pharmacogenomics
2022-08-22

Recent advances in next-generation sequencing (NGS) have resulted in the identification of tens of thousands of rare pharmacogenetic variations with unknown functional effects. However, although such pharmacogenetic variations have been estimated to account for a considerable amount of the heritable variability in drug response and toxicity, accurate interpretation at the level of the individual patient remains challenging. We discuss emerging strategies and concepts to close this translational gap. We illustrate how massively parallel experimental assays, artificial intelligence (AI), and machine learning can synergize with population-scale biobank projects to facilitate the interpretation of NGS data to individualize clinical decision-making and personalized medicine.
Performance of a deep learning tool to detect missed aortic dilatation in a large chest CT cohort
2022-08-22

Purpose Thoracic aortic (TA) dilatation (TAD) is a risk factor for acute aortic syndrome and must therefore be reported in every CT report. However, the complex anatomy of the thoracic aorta impedes TAD detection. We investigated the performance of a deep learning (DL) prototype as a secondary reading tool built to measure TA diameters in a large-scale cohort. Material and methods Consecutive contrast-enhanced (CE) and non-CE chest CT exams with “normal” TA diameters according to their radiology reports were included. The DL-prototype (AIRad, Siemens Healthineers, Germany) measured the TA at nine locations according to AHA guidelines. Dilatation was defined as &amp;gt;45 mm at aortic sinus, sinotubular junction (STJ), ascending aorta (AA) and proximal arch and &amp;gt;40 mm from mid arch to abdominal aorta. A cardiovascular radiologist reviewed all cases with TAD according to AIRad. Multivariable logistic regression (MLR) was used to identify factors (demographics and scan parameters) associated with TAD classification by AIRad. Results 18,243 CT scans (45.7% female) were successfully analyzed by AIRad. Mean age was 62.3 ± 15.9 years and 12,092 (66.3%) were CE scans. AIRad confirmed normal diameters in 17,239 exams (94.5%) and reported TAD in 1,004/18,243 exams (5.5%). Review confirmed TAD classification in 452/1,004 exams (45.0%, 2.5% total), 552 cases were false-positive but identification was easily possible using visual outputs by AIRad. MLR revealed that the following factors were significantly associated with correct TAD classification by AIRad: TAD reported at AA [odds ratio (OR): 1.12, p &amp;lt; 0.001] and STJ (OR: 1.09, p = 0.002), TAD found at &amp;gt;1 location (OR: 1.42, p = 0.008), in CE exams (OR: 2.1–3.1, p &amp;lt; 0.05), men (OR: 2.4, p = 0.003) and patients presenting with higher BMI (OR: 1.05, p = 0.01). Overall, 17,691/18,243 (97.0%) exams were correctly classified. Conclusions AIRad correctly assessed the presence or absence of TAD in 17,691 exams (97%), including 452 cases with previously missed TAD independent from contrast protocol. These findings suggest its usefulness as a secondary reading tool by improving report quality and efficiency.
Using Daily Creativity Planning to Promote Creative Behavior
2022-08-22

ABSTRACT Research has demonstrated that on the path from a creative idea to a creative outcome, high creativity motivation and self‐efficacy do not necessarily lead to creative behavior. The present study proposed and examined the notion that daily creativity planning could promote creative behavior and contribute to the cultivation of creativity. A total of 77 middle school students (39 students in the experimental group and 38 in the control group) participated in this study, for which a quasi‐experimental design was administered. The experimental group conducted a two‐week daily planning for creative activities, while the control group did not conduct any intervention. The results showed that students' creativity motivation and creative self‐efficacy were at relatively high levels overall and were positively and moderately correlated with creative behavior. Daily planning could effectively facilitate students' creative behavior. These findings point to a promising and simple creativity enhancement strategy for cultivating students to develop the habit of making creative plans in their daily lives.