julilili42/papers huggingface dataset:
Impact of 18F-FET PET/MRI on Clinical Management of Brain Tumor Patients
2021-08-05

Multiparametric PET/MRI with the amino-acid analog <i>O</i>-(2-<sup>18</sup>F-fluoroethyl)-l-tyrosine (<sup>18</sup>F-FET) enables the simultaneous assessment of molecular, morphologic, and functional brain tumor characteristics. Although it is considered the most accurate noninvasive approach in brain tumors, its relevance for patient management is still under debate. Here, we report the diagnostic performance of <sup>18</sup>F-FET PET/MRI and its impact on clinical management in a retrospective patient cohort. <b>Methods:</b> We retrospectively analyzed brain tumor patients who underwent <sup>18</sup>F-FET PET/MRI between 2017 and 2018. <sup>18</sup>F-FET PET/MRI examinations were indicated clinically because of equivocal standard imaging results or the clinical course. Histologic confirmation or clinical and standard imaging follow-up served as the reference standard. We evaluated <sup>18</sup>F-FET PET/MRI accuracy in identifying malignancy in untreated suspected lesions (category, new diagnosis) and true progression during adjuvant treatment (category, detection of progression) in a clinical setting. Using multiple regression, we also estimated the contribution of single modalities to produce an optimal PET/MRI outcome. We assessed the recommended and applied therapies before and after <sup>18</sup>F-FET PET/MRI and noted whether the treatment changed on the basis of the <sup>18</sup>F-FET PET/MRI outcome. <b>Results:</b> We included 189 patients in the study. <sup>18</sup>F-FET PET/MRI allowed the identification of malignancy at new diagnosis with an accuracy of 85% and identified true progression with an accuracy of 93%. Contrast enhancement, <sup>18</sup>F-FET PET uptake, and tracer kinetics were the major contributors to an optimal PET/MRI outcome. In the previously equivocal patients, <sup>18</sup>F-FET PET/MRI changed the clinical management in 33% of the untreated lesions and 53% of the cases of tumor progression. <b>Conclusion:</b> Our results suggest that <sup>18</sup>F-FET PET/MRI helps clarify equivocal conditions and profoundly supports the clinical management of brain tumor patients. The optimal modality setting for <sup>18</sup>F-FET PET/MRI and the clinical value of a simultaneous examination need further exploration. At a new diagnosis, multiparametric <sup>18</sup>F-FET PET/MRI might help prevent unnecessary invasive procedures by ruling out malignancy; however, adding static <sup>18</sup>F-FET PET to an already existing MRI examination seems to be of equal value. At detection of progression, multiparametric <sup>18</sup>F-FET PET/MRI may increase therapy effectiveness by distinguishing between tumor progression and therapy-related imaging alterations.
Phenotypic plasticity masks range‐wide genetic differentiation for vegetative but not reproductive traits in a short‐lived plant
2021-08-05

Abstract Genetic differentiation and phenotypic plasticity jointly shape intraspecific trait variation, but their roles differ among traits. In short‐lived plants, reproductive traits may be more genetically determined due to their impact on fitness, whereas vegetative traits may show higher plasticity to buffer short‐term perturbations. Combining a multi‐treatment greenhouse experiment with observational field data throughout the range of a widespread short‐lived herb, Plantago lanceolata , we (1) disentangled genetic and plastic responses of functional traits to a set of environmental drivers and (2) assessed how genetic differentiation and plasticity shape observational trait–environment relationships. Reproductive traits showed distinct genetic differentiation that largely determined observational patterns, but only when correcting traits for differences in biomass. Vegetative traits showed higher plasticity and opposite genetic and plastic responses, masking the genetic component underlying field‐observed trait variation. Our study suggests that genetic differentiation may be inferred from observational data only for the traits most closely related to fitness.
Risk Disclosure in Prodromal Parkinson's Disease
2021-08-05

Abstract Background Impressive progress in the understanding of the prodromal phase of Parkinson's disease (PD) in recent years has enabled the generation of disease prediction models. However, a remaining diagnostic uncertainty and lack of therapeutic options for affected individuals has resulted in a variety of ethical issues that have not to date been addressed sufficiently. Moreover, differences in the specificity of prodromal symptoms and possible subtypes of PD, especially the presence of rapid eye movement (REM) sleep behavior disorder (RBD), may have an important impact on prognostic counseling. Objectives To derive a guideline for risk disclosure in prodromal PD based on the current literature and expert opinion. Methods We performed (1) a literature review on prognostic counseling in PD and (2) consulted with international experts on prodromal PD using a semi‐structured questionnaire based on a Delphi approach to evaluate recommendations for risk disclosure in PD. Results The l iterature research revealed only 11 publications addressing prognostic counseling, with only two studies directly addressing affected individuals and most studies focusing on risk disclosure in RBD. The expert survey revealed the importance of distinguishing between individuals with and without RBD in prognostic counseling. Conclusions Based on the current literature and expert recommendations, a guideline for risk disclosure in prodromal PD for clinical care and research could be elaborated. Prognostic counseling should include differentiation between individuals with and without RBD, taking into account the high uncertainty of risk calculation in RBD‐negative prodromal PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort
2021-08-05

Background Therapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD. Methods The CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau ( MAPT) , 187 GRN , 193 C9orf72 ) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72 ) and 145 non-carriers had available longitudinal data at a follow-up time point. Results Cross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 mutation carriers 71.0 (34.0), controls 96.2 (7.7), p&lt;0.001 for all comparisons, while the mean CDR+NACC FTLD Sum of Boxes was significantly higher in all genetic groups: GRN mutation carriers mean 2.6 (5.2), MAPT mutation carriers 3.2 (5.6), C9orf72 mutation carriers 4.2 (6.2), controls 0.2 (0.6), p&lt;0.001 for all comparisons. Mean FRS score decreased and CDR+NACC FTLD Sum of Boxes increased with increasing disease severity within each individual genetic group. FRS and CDR+NACC FTLD Sum of Boxes scores were strongly negatively correlated across all mutation carriers (r s =−0.77, p&lt;0.001) and within each genetic group (r s =−0.67 to −0.81, p&lt;0.001 in each group). Nonetheless, discrepancies in disease staging were seen between the scales, and with each scale and clinician-judged symptomatic status. Longitudinally, annualised change in both FRS and CDR+NACC FTLD Sum of Boxes scores initially increased with disease severity level before decreasing in those with the most severe disease: controls −0.1 (6.0) for FRS, −0.1 (0.4) for CDR+NACC FTLD Sum of Boxes, asymptomatic mutation carriers −0.5 (8.2), 0.2 (0.9), prodromal disease −2.3 (9.9), 0.6 (2.7), mild disease −10.2 (18.6), 3.0 (4.1), moderate disease −9.6 (16.6), 4.4 (4.0), severe disease −2.7 (8.3), 1.7 (3.3). Sample sizes were calculated for a trial of prodromal mutation carriers: over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures, with sample sizes lower for the FRS. Conclusions Both the FRS and CDR+NACC FTLD measure disease severity in genetic FTD mutation carriers throughout the timeline of their disease, although the FRS may be preferable as an outcome measure. However, neither address a number of key symptoms in the FTD spectrum, for example, motor and neuropsychiatric deficits, which future scales will need to incorporate.
Retinal degeneration: Multilevel protection of photoreceptor and ganglion cell viability and function with the novel PKG inhibitor CN238
2021-08-05

Abstract Hereditary retinal degeneration (RD) is often associated with excessive cGMP-signaling in photoreceptors. Previous research has shown that inhibition of cGMP-dependent protein kinase G (PKG) can slow down the loss of photoreceptors in different RD animal models. In this study, we identified a novel PKG inhibitor, the cGMP analogue CN238, with strong protective effects on photoreceptors in retinal degeneration rd1 and rd10 mutant mice. In long-term organotypic retinal explants, CN238 preserved rd1 and rd10 photoreceptor viability and function. Surprisingly, in explanted retinae CN238 also protected retinal ganglion cells from axotomy induced retrograde degeneration and preserved their functionality. Together, these results confirm the strong neuroprotective capacity of PKG inhibitors for both photoreceptors and retinal ganglion cells, thereby significantly broadening their potential applications for the treatment of retinal diseases and possibly neurodegenerative diseases in general.
Human CD4+ T-Cell Clone Expansion Leads to the Expression of the Cysteine Peptidase Inhibitor Cystatin F
2021-08-05

The existence of CD4+ cytotoxic T cells (CTLs) at relatively high levels under different pathological conditions in vivo suggests their role in protective and/or pathogenic immune functions. CD4+ CTLs utilize the fundamental cytotoxic effector mechanisms also utilized by CD8+ CTLs and natural killer cells. During long-term cultivation, CD4+ T cells were also shown to acquire cytotoxic functions. In this study, CD4+ human T-cell clones derived from activated peripheral blood lymphocytes of healthy young adults were examined for the expression of cytotoxic machinery components. Cystatin F is a protein inhibitor of cysteine cathepsins, synthesized by CD8+ CTLs and natural killer cells. Cystatin F affects the cytotoxic efficacy of these cells by inhibiting the major progranzyme convertases cathepsins C and H as well as cathepsin L, which is involved in perforin activation. Here, we show that human CD4+ T-cell clones express the cysteine cathepsins that are involved in the activation of granzymes and perforin. CD4+ T-cell clones contained both the inactive, dimeric form as well as the active, monomeric form of cystatin F. As in CD8+ CTLs, cysteine cathepsins C and H were the major targets of cystatin F in CD4+ T-cell clones. Furthermore, CD4+ T-cell clones expressed the active forms of perforin and granzymes A and B. The levels of the cystatin F decreased with time in culture concomitantly with an increase in the activities of granzymes A and B. Therefore, our results suggest that cystatin F plays a role in regulating CD4+ T cell cytotoxicity. Since cystatin F can be secreted and taken up by bystander cells, our results suggest that CD4+ CTLs may also be involved in regulating immune responses through cystatin F secretion.
Exploring the Effect of Structure-Based Scaffold Hopping on the Inhibition of Coxsackievirus A24v Transduction by Pentavalent N-Acetylneuraminic Acid Conjugates
2021-08-05

Coxsackievirus A24 variant (CVA24v) is the primary causative agent of the highly contagious eye infection designated acute hemorrhagic conjunctivitis (AHC). It is solely responsible for two pandemics and several recurring outbreaks of the disease over the last decades, thus affecting millions of individuals throughout the world. To date, no antiviral agents or vaccines are available for combating this disease, and treatment is mainly supportive. CVA24v utilizes Neu5Ac-containing glycans as attachment receptors facilitating entry into host cells. We have previously reported that pentavalent Neu5Ac conjugates based on a glucose-scaffold inhibit CVA24v infection of human corneal epithelial cells. In this study, we report on the design and synthesis of scaffold-replaced pentavalent Neu5Ac conjugates and their effect on CVA24v cell transduction and the use of cryogenic electron microscopy (cryo-EM) to study the binding of these multivalent conjugates to CVA24v. The results presented here provide insights into the development of Neu5Ac-based inhibitors of CVA24v and, most significantly, the first application of cryo-EM to study the binding of a multivalent ligand to a lectin.
Lowering the Consumption of Animal Products without Sacrificing Consumer Freedom – A Pragmatic Proposal
2021-08-05

It is well-established that policy aiming to change individual consumption patterns for environmental or other ethical reasons faces a trade-off between effectiveness and public acceptance. The more ambitious a policy intervention is, the higher the likelihood of reactionary backlash; the higher the intervention’s public acceptance, the less bite it is likely to have. This paper proposes a package of interventions aiming for a substantial reduction of animal product consumption while circumventing the diagnosed trade-off. It couples stringent industry regulation, which lowers output and raises prices, with a targeted universal income at a level which would allow typical households to maintain their animal product consumption even at the post-regulation price level. The change of opportunity costs of animal products, however, would induce a shift of consumption away from animal products while enhancing – rather than diminishing – consumer freedom and welfare. The policy package, which is further designed to cohere with traditional value orderings rather than relying exclusively on progressive concerns, is politically ambitious, but psychologically pragmatic. It constitutes an attempt to socialize the endeavor of bringing consumption patterns in line with ethical demands by empowering, rather than sanctioning, individuals, and relevant groups.
Genetic evidence reveals the indispensable role of the rseC gene for autotrophy and the importance of a functional electron balance for nitrate reduction in Clostridium ljungdahlii
2021-08-05

Abstract For Clostridium ljungdahlii , the RNF complex plays a key role for energy conversion from gaseous substrates such as hydrogen and carbon dioxide. In a previous study, a disruption of RNF-complex genes led to the loss of autotrophy, while heterotrophy was still possible via glycolysis. Furthermore, it was shown that the energy limitation during autotrophy could be lifted by nitrate supplementation, which resulted in an elevated cellular growth and ATP yield. Here, we used CRISPR-Cas12a to delete: 1) the RNF complex-encoding gene cluster rnfCDGEAB ; 2) the putative RNF regulator gene rseC ; and 3) a gene cluster that encodes for a putative nitrate reductase. The deletion of either rnfCDGEAB or rseC resulted in a complete loss of autotrophy, which could be restored by plasmid-based complementation of the deleted genes. We observed a transcriptional repression of the RNF-gene cluster in the rseC -deletion strain during autotrophy and investigated the distribution of the rseC gene among acetogenic bacteria. To examine nitrate reduction and its connection to the RNF complex, we compared autotrophic and heterotrophic growth of our three deletion strains with either ammonium or nitrate. The rnfCDGEAB - and rseC -deletion strains failed to reduce nitrate as a metabolic activity in non-growing cultures during autotrophy but not during heterotrophy. In contrast, the nitrate reductase deletion strain was able to grow in all tested conditions but lost the ability to reduce nitrate. Our findings highlight the important role of the rseC gene for autotrophy and contribute to understand the connection of nitrate reduction to energy metabolism. Significance Statement Acetogenic bacteria are widely known for their ability to convert gaseous substrates, such as hydrogen, carbon dioxide, and carbon monoxide, into short-chain fatty acids and alcohols, which can be utilized as sustainable platform chemicals and fuels. However, acetogenic bacteria conserve energy at the thermodynamic limit of life during autotrophy, and thus the production of more complex and energy-dense chemicals is limited due to low ATP yields. Therefore, it is key to decipher the interplay of the electron balancing reactions to understand and optimize the acetogenic metabolism. Recent findings with alternative electron acceptors that accelerated the cellular growth and ATP yield during autotrophy, such as nitrate, provide an opportunity to overcome energetic barriers in the acetogenic metabolism. The interrogation of the nitrate metabolism and the interplay between nitrate reduction and energy conservation in C. ljungdahlii , will contribute to fine-tuning of the acetogenic metabolism for biotechnological applications.
Data for "Unravelling the collateral damage of antibiotics on gut bacteria"
2021-08-05

This dataset encompasses all data needed to reproduce the analyses presented in the paper "Unravelling the collateral damage of antibiotics on gut bacteria", available here: https://doi.org/10.1038/s41586-021-03986-2 You can also check the GitLab repository: https://git.embl.de/maier/abxbug/
Uncertainty estimation and explainability in deep learning-based age estimation of the human brain: Results from the German National Cohort MRI study
2021-08-06

Brain ageing is a complex neurobiological process associated with morphological changes that can be assessed on MRI scans. Recently, Deep learning (DL)-based approaches have been proposed for the prediction of chronological brain age from MR images yielding high accuracy. These approaches, however, usually do not address quantification of uncertainty and, therefore, intrinsic physiological variability. Considering uncertainty is essential for the interpretation of the difference between predicted and chronological age. In addition, DL-based models lack in explainability compared to classical approaches like voxel-based morphometry. In this study, we aim to address both, modeling uncertainty and providing visual explanations to explore physiological patterns in brain ageing. T1-weighted brain MRI datasets of 10691 participants of the German National Cohort Study, drawn from the general population, were included in this study (chronological age from 20 to 72 years). A regression model based on a 3D Convolutional Neural Network taking into account aleatoric noise was implemented for global as well as regional brain age estimation. We observed high overall accuracy of global brain age estimation with a mean absolute error of 3.2 ± 2.5 years and mean uncertainty of 2.9 ± 0.6 years. Regional brain age estimation revealed higher estimation accuracy and lower uncertainty in central compared to peripheral brain regions. Visual explanations illustrating the importance of brain sub-regions were generated using Grad-CAM: the derived saliency maps showed a high relevance of the lateral and third ventricles, the insular lobe as well as parts of the basal ganglia and the internal capsule.
Critical Membrane Concentration and Mass-Balance Model to Identify Baseline Cytotoxicity of Hydrophobic and Ionizable Organic Chemicals in Mammalian Cell Lines
2021-08-06

All chemicals can interfere with cellular membranes and this leads to baseline toxicity, which is the minimal toxicity any chemical elicits. The critical membrane burden is constant for all chemicals; that is, the dosing concentrations to trigger baseline toxicity decrease with increasing hydrophobicity of the chemicals. Quantitative structure-activity relationships, based on hydrophobicity of chemicals, have been established to predict nominal concentrations causing baseline toxicity in human and mammalian cell lines. However, their applicability is limited to hydrophilic neutral compounds. To develop a prediction model that includes more hydrophobic and charged organic chemicals, a mass balance model was applied for mammalian cells (AREc32, AhR-CALUX, PPARγ-BLA, and SH-SY5Y) considering different bioassay conditions. The critical membrane burden for baseline toxicity was converted into nominal concentration causing 10% cytotoxicity by baseline toxicity (IC<sub>10,baseline</sub>) using a mass balance model whose main chemical input parameter was the liposome-water partition constants (<i>K</i><sub>lip/w</sub>) for neutral chemicals or the speciation-corrected <i>D</i><sub>lip/w</sub>(pH 7.4) for ionizable chemicals plus the bioassay-specific protein, lipid, and water contents of cells and media. In these bioassay-specific models, log(1/IC<sub>10,baseline</sub>) increased with increasing hydrophobicity, and the relationship started to level off at log <i>D</i><sub>lip/w</sub> around 2. The bioassay-specific models were applied to 392 chemicals covering a broad range of hydrophobicity and speciation. Comparing the predicted IC<sub>10,baseline</sub> and experimental cytotoxicity IC<sub>10</sub>, known baseline toxicants and many additional chemicals were identified as baseline toxicants, while the others were classified based on specificity of their modes of action in the four cell lines, confirming excess toxicity of some fungicides, antibiotics, and uncouplers. Given the similarity of the bioassay-specific models, we propose a generalized baseline-model for adherent human cell lines: log[1/IC<sub>10,baseline</sub> (M)] = 1.23 + 4.97 × (1 - e<sup>-0.236 log <i>D</i><sub>lip/w</sub></sup>). The derived models for baseline toxicity may serve for specificity analysis in reporter gene and neurotoxicity assays as well as for planning the dosing for cell-based assays.
Collectively Encoded Rydberg Qubit
2021-08-06

We demonstrate a collectively encoded qubit based on a single Rydberg excitation stored in an ensemble of N entangled atoms. Qubit rotations are performed by applying microwave fields that drive excitations between Rydberg states. Coherent readout is performed by mapping the excitation into a single photon. Ramsey interferometry is used to probe the coherence of the qubit, as well as to test the robustness to external perturbations. We show that qubit coherence is preserved even as we lose atoms from the polariton mode, preserving Ramsey fringe visibility. We show that dephasing due to electric field noise scales as the fourth power of field amplitude. These results show that robust quantum information processing can be achieved via collective encoding using Rydberg polaritons, and hence this system could provide an attractive alternative coding strategy for quantum computation and networking.