julilili42/papers huggingface dataset:
Reoperation for recurrent glioblastomas: What to expect?
2021-02-03

Background: The current standard treatment for glioblastoma (GBM) is maximal safe surgical resection followed by radiation and chemotherapy. Unfortunately, the disease will invariably recur even with the best treatment. Although the literature suggests some advantages in reoperating patients harboring GBM, controversy remains. Here, we asked whether reoperation is an efficacious treatment strategy for GBM, and under which circumstances, it confers a better prognosis. Methods: We retrospectively reviewed 286 consecutive cases of newly diagnosed GBM in a single university hospital from 2008 to 2015. We evaluated clinical and epidemiological parameters possibly influencing overall survival (OS) by multivariate Cox regression analysis. OS was calculated using the Kaplan–Meier method in patients submitted to one or two surgical procedures. Finally, the survival curves were fitted with the Weibull model, and survival rates at 6, 12, and 24 months were estimated. Results: The reoperated group survived significantly longer ( n = 63, OS = 20.0 ± 2.3 vs. 11.4 ± 1.0 months, P &lt; 0.0001). Second, the multivariate analysis revealed an association between survival and number of surgeries, initial Karnofsky Performance Status, and age (all P &lt; 0.001). Survival estimates according to the Weibull regression model revealed higher survival probabilities for reoperation compared with one operation at 6 months (83.74 ± 3.42 vs. 63.56 ± 3.59, respectively), 12 months (64.00 ± 4.85 vs. 37.53 ± 3.52), and 24 months (32.53 ± 4.78 vs. 12.02 ± 2.36). Conclusion: Our data support the indication of reoperation for GBM, especially for younger patients with good functional status. Under these circumstances, survival can be doubled at 12 and 24 months.
Specialization and selective social attention establishes the balance between individual and social learning
2021-02-03

Abstract A key question individuals face in any social learning environment is when to innovate alone and when to imitate others. Previous simulation results have found that the best performing groups exhibit an intermediate balance, yet it is still largely unknown how individuals collectively negotiate this balance. We use an immersive collective foraging experiment, implemented in the Minecraft game engine, facilitating unprecedented access to spatial trajectories and visual field data. The virtual environment imposes a limited field of view, creating a natural trade-off between allocating visual attention towards individual search or to look towards peers for social imitation. By analyzing foraging patterns, social interactions (visual and spatial), and social influence, we shine new light on how groups collectively adapt to the fluctuating demands of the environment through specialization and selective imitation, rather than homogeneity and indiscriminate copying of others.
Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies
2021-02-03

Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (CSS,min ENDX) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target CSS,min ENDX applying conventional tamoxifen dosing. Moreover, 4–75% of patients are non-adherent, resulting in worse disease outcomes. Assuming complete adherence, we previously showed model-informed precision dosing (MIPD) to be superior to conventional and CYP2D6-guided dosing in minimising the proportion of patients with subtarget CSS,min ENDX. Given the high non-adherence rate in long-term tamoxifen therapy, this study investigated the impact of non-adherence on CSS,min ENDX target attainment in different dosing strategies. We show that MIPD allows to account for the expected level of non-adherence (here: up to 2 missed doses/week): increasing the MIPD target threshold from 5.97 ng/mL to 9 ng/mL (the lowest reported CSS,min ENDX in CYP2D6 normal metabolisers) as a safeguard resulted in the lowest interindividual variability and proportion of patients with subtarget CSS,min ENDX even in non-adherent patients. This is a significant improvement to conventional and CYP2D6-guided dosing. Adding a fixed increment to the originally selected dose is not recommended, since it inflates interindividual variability.
The flavin monooxygenase Bs3 triggers cell death in plants, impairs growth in yeast and produces H2O2in vitro
2021-02-03

ABSTRACT The pepper resistance gene Bs3 triggers a hypersensitive response (HR) upon transcriptional activation by the corresponding transcription activator-like effector AvrBs3 from the bacterial pathogen Xanthomonas . Bs3 is homologous to flavin monooxygenases (FMOs), an enzyme class that has NADPH oxidase activity and can produce H 2 O 2 , a hallmark metabolite in plant immune reactions. Histochemical staining of infected pepper leaves and a translational fusion of Bs3 to the redox reporter roGFP2 both indicated that the Bs3-dependent HR induces a local increase in H 2 O 2 levels in planta . Moreover, our in vitro studies with recombinant Bs3 protein confirmed its NADPH oxidase activity. To test if the NADPH oxidation of Bs3 induces HR, we adapted previous studies which have uncovered mutations in fungal FMOs that result in higher NADPH oxidase activity. We replicated one of these mutations and demonstrated that the generated recombinant Bs3 S211A protein has twofold higher NADPH oxidase activity than wildtype Bs3 in vitro . Translational fusions to roGFP2 showed that Bs3 S211A also had increased NADPH oxidase activity in planta . Interestingly, while the mutant derivative Bs3 S211A had an increase in NADPH oxidase capacity, it did not trigger HR in planta . Ultimately, this reveals that Bs3 produces H 2 O 2 in planta , but that the H 2 O 2 produced by Bs3 on its own is not sufficient to trigger HR. We also demonstrated that expression of Bs3 not only triggered HR in plants, but also inhibited proliferation of yeast, which lends this model system to be utilized for the genetic dissection of Bs3 function in future studies. One sentence summary The executor-type resistance protein Bs3 from pepper ( Capsicum annuum ) acts as an NADPH oxidase but reactive oxygen species produced by Bs3 are not sufficient to trigger plant cell death
Marker-free imaging of α-Synuclein aggregates in a rat model of Parkinson’s disease using Raman microspectroscopy
2021-02-03

Abstract A hallmark of Parkinson’s disease (PD) is the formation of Lewy bodies in the brain. Lewy bodies are rich in the aggregated form of misfolded α-Synuclein (α-Syn). The brain from PD patients can only be analysed after post-mortem, limiting the diagnosis of PD to the manifestation of motor symptoms. In PD patients and animal models phosphorylated α-Syn was detected in the gut, thus, raising the hypothesizes that early-stage PD could be diagnosed based on colon tissues biopsies. Non-invasive marker-free technologies represent an ideal method to potentially detect aggregated α-Syn in vivo. Raman microspectroscopy has been established for the detection of molecular changes such as alterations of protein structures. Here, the olfactory bulb in the brain and the muscularis mucosae of colon tissue sections of a human BAC-SNCA transgenic (TG) rat model was analysed using Raman imaging and microspectroscopy. Raman images from TG and WT rats were investigated using spectral, principal component and true component analysis. Spectral components indicated protein aggregates (spheroidal oligomers) in TG rat brain and colon tissues even at a young age but not in WT. In summary, we have demonstrated that Raman imaging is capable to detect α-Syn aggregates in colon tissues of a PD rat model and making it a promising tool for future use in PD pathology.
cGMP signaling: probing antagonistic cyclic nucleotide platelet signals by modeling and experiment
2021-02-03

Abstract Background The cyclic nucleotides cAMP and cGMP inhibit platelet activation. Results We extended an older model and systematically integrated drugs as external stimuli. Data driven modeling allowed us to design models that provide a quantitative output for quantitative input information. This relies on condensed information about involved regulation and modeling of pharmacological interventions by systematic optimization methods. By multi-experiment fitting, we validated our model optimizing the parameters of the model. In addition, we show how the output of the developed cGMP model can be used as input for a modular model of VASP phosphorylation and for the activity of cAMP and cGMP pathways in platelets. Conclusions We present a model for cGMP signaling and VASP phosphorylation, that allows to estimate drug action on any of the inhibitory cyclic nucleotide pathways (cGMP, cAMP) and has been validated by experimental data.
Fingerprints of the Local Moment Formation and its Kondo Screening in the Generalized Susceptibilities of Many-Electron Problems
2021-02-04

We identify the precise hallmarks of the local magnetic moment formation and its Kondo screening in the frequency structure of the generalized charge susceptibility. The sharpness of our identification even pinpoints an alternative criterion to determine the Kondo temperature of strongly correlated systems on the two-particle level, which only requires calculations at the lowest Matsubara frequency. We showcase its strength by applying it to the single impurity and the periodic Anderson model as well as to the Hubbard model. Our results represent a significant progress for the general understanding of quantum field theory at the two-particle level and allow for tracing the limits of the physics captured by perturbative approaches for correlated systems.
Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia
2021-02-04

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.
Mir-1, miR-122, miR-132, and miR-133 Are Related to Subclinical Aortic Atherosclerosis Associated with Metabolic Syndrome
2021-02-04

Previously, miR-1, miR-122, miR-126, miR-132, miR-133, and miR-370 were found to be related to coronary artery disease (CAD) progression. However, their relationship with subclinical atherosclerosis, especially in subjects with metabolic syndrome, is unknown. Therefore, our aim was to determine their relationship with arterial markers of subclinical atherosclerosis. Metabolic syndrome subjects (n = 182) with high cardiovascular risk but without overt cardiovascular disease (CVD) were recruited from the Lithuanian High Cardiovascular Risk (LitHiR) primary prevention program. The ardio-ankle vascular index (CAVI), augmentation index normalized to a heart rate of 75 bpm (AIxHR75), aortic pulse wave velocity (AoPWV), and carotid artery stiffness were assessed. MicroRNAs (miRs) were analyzed in serum. Pearson correlation and a univariate linear regression t-test showed that miR-1, miR-133b, and miR-133a were negatively associated with CAVI mean, whereas miR-122 was positively associated. MiR-1, miR-133b and miR-133a, and miR-145 were negatively associated with AIxHR75. MiR-122 correlated negatively with AoPWV. In multivariate linear regression models, miR-133b and miR-122 predicted CAVImean, miR-133 predicted AIxHR75, and miR-122 predicted AoPWV. MiR-132 predicted right carotid artery stiffness, and miR-1 predicted left carotid artery stiffness. The addition of smoking to miR-133b and miR-122 enhanced the prediction of CAVI. Age and triglycerides enhanced the prediction of AoPWV by miR-122. A cluster of four miRs are related to subclinical atherosclerosis in subjects with metabolic syndrome. Combined, they may have a more substantial diagnostic or prognostic value than any single miR. Future follow-up studies are needed to establish their clinical relevance.
Platelet-expressed immune checkpoint regulator GITRL in breast cancer
2021-02-04

Abstract Owing to their key role in several diseases including cancer, activating and inhibitory immune checkpoint molecules are increasingly exploited as targets for immunotherapy. Recently, we demonstrated that platelets, which largely influence tumor progression and immune evasion, functionally express the ligand of the checkpoint molecule GITR. This immunoreceptor modulates effector functions of T cells and NK cells with its function varying dependent on cellular context and activation state. Here, we provide a comparative analysis of platelet-derived GITRL (pGITRL) in breast cancer patients and healthy volunteers. The levels of pGITRL were found to be higher on platelets derived from cancer patients and appeared to be specifically regulated during tumor progression as exemplified by several clinical parameters including tumor stage/grade, the occurrence of metastases and tumor proliferation (Ki67) index. In addition, we report that pGITRL is upregulated during platelet maturation and particularly induced upon exposure to tumor-derived soluble factors. Our data indicate that platelets modulate the GITR/GITRL immune checkpoint in the context of malignant disease and provide a rationale to further study the GITR/GITRL axis for exploitation for immunotherapeutic intervention in cancer patients.
Corneal Penetration of Low-Dose Atropine Eye Drops
2021-02-04

Major studies demonstrating the inhibition of myopia in children and juveniles by low-dose atropine eye drops provide little information on the manufacturing process and the exact composition of the atropine dilutions. However, corneal penetration might significantly vary depending on preservatives, such as benzalkonium chloride (BAC), and the atropine concentration. Since there is a trade-off between side effects, stability, and optimal effects of atropine on myopia, it is important to gain better knowledge about intraocular atropine concentrations. We performed an ex vivo study to determine corneal penetration for different formulations. Atropine drops (0.01%) of different formulations were obtained from pharmacies and applied to the cornea of freshly enucleated pig eyes. After 10 min, a sample of aqueous humor was taken and atropine concentrations were determined after liquid–liquid extraction followed by high-performance liquid chromatography–tandem mass spectrometry (LC-MS/MS). The variability that originated from variations in applied drop size exceeded the differences between preserved and preservative-free formulations. The atropine concentration in the anterior chamber measured after 10 min was only 3.8 × 10−8 of its concentration in the applied eye drops, corresponding to 502.4 pM. Obviously, the preservative did not facilitate corneal penetration, at least ex vivo. In the aqueous humor of children’s eyes, similar concentrations, including higher variability, may be expected in the lower therapeutic window of pharmacodynamic action.
Retrospective Comparison of Minimally Invasive and Open Monosegmental Lumbar Fusion, and Impact of Virtual Reality on Surgical Planning and Strategy
2021-02-04

Abstract Background and Study Aims Spinal fusion for symptomatic lumbar spondylolisthesis can be accomplished using an open or minimally invasive surgical (MIS) technique. Evaluation of segmental spondylolisthesis and instabilities and review of their therapies are inseparably connected with lumbar tomographic imaging. We analyzed a cohort of patients who underwent MIS or open monosegmental dorsal fusion and compared surgical outcomes along with complication rates. We furthermore evaluated the influence of virtual reality (VR) visualization on surgical planning in lumbar fusion. Material and Methods Patient files were retrospectively analyzed regarding patient- and disease-related data, operative performance, surgical outcomes, and perioperative surgical complications. Preoperative computed tomography (CT) and magnetic resonance imaging (MRI) scans were retrospectively visualized via VR software. A questionnaire evaluated the influence of three-dimensional (3D) VR images versus two-dimensional CT and MRI scans on therapy planning, fusion method, and surgical technique and procedure. Results Overall, 171 patients were included (MIS/open: 90/81). MIS was associated with less blood loss, shorter surgery time and hospital stay, lower complication rates, equivalent long-term patient-reported outcomes, but lower fusion rates and higher late reoperation rates than open surgery. Image presentation using VR significantly influenced the recommended surgical therapies (decompression only/decompression and fusion; p = 0.02), had no significant influence on the recommended fusion method (rigid/dynamic/stand-alone; p = 0.77), and, in cases of rigid fusion, a significant influence on the recommended technique (MIS/open; p = 0.03) and fusion procedure (p = 0.02). Conclusion In patients with monosegmental degenerative or isthmic spondylolisthesis, MIS fusion was advantageous concerning perioperative complication rates and perioperative surgical outcomes, but disadvantageous regarding fusion and reoperation rates compared to open fusion. 3D-VR-based analysis of sectional images significantly influenced the recommended surgical planning.
(No) variation in the grammar of alternatives
2021-02-04

Abstract The paper reports the results of an in-depth crosslinguistic study of intervention effects and the grammar of alternatives in a typologically diverse sample of five languages: Palestinian Arabic (Afro-Asiatic, Semitic), Russian (Indo-European, Slavic), Samoan (Austronesian, Oceanic), Turkish (Altaic, Turkic), and Yoruba (Niger-Congo, Defoid). In all of these languages, we find an interesting asymmetry in that focus evaluation interrupts question evaluation and causes an intervention effect, but not vice versa. We take our data to inform the crosslinguistic analysis of two alternative-evaluating operators, the squiggle operator and the question operator. To capture the observed absence of variation, we propose two semantic universals: The squiggle operator unselectively evaluates all alternatives in its scope. The question operator, on the other hand, is selective.
Interaction Styles in Context: Comparing Drag-and-Drop, Point-and-Touch, and Touch in a Mobile Spelling Game
2021-02-04

The choice of appropriate interaction style for children's application has been a divisive subject of debate. For example, drag-and-drop is often said to perform worse than point-and-click in educational applications – and vice versa. In this article, we argue for the need to choose the interaction style in context, considering a range of factors. We compare drag-and-drop, point-and-touch, and simple touch for selecting letters to form words in a spelling line as part of an educational spelling game. We evaluate the perceived workload, user experience, preference, and writing times of twenty-five children (8–11 years), eight of whom were dyslexic. We found that touch received better ratings and was ranked highest most often on all subscales compared to drag-and-drop and point-and-touch. Children needed less time using touch and 68% chose it as their favorite interaction style. We also found small advantages for drag-and-drop over point-and-touch, which runs counter to some recent recommendations. This becomes particularly clear when using ranking responses, which support a particularly fine-grained picture.
A protein-based biosensor for detecting calcium by magnetic resonance imaging
2021-02-04

ABSTRACT Calcium-responsive contrast agents for magnetic resonance imaging (MRI) offer an attractive approach to noninvasively image neural activity with wide coverage in deep brain regions. However, current MRI sensors for calcium are based on synthetic architectures fundamentally incompatible with genetic technologies for in vivo delivery and targeting. Here, we present a protein-based MRI sensor for calcium, derived from a calcium-binding protein known as calprotectin. Calcium-binding causes calprotectin to sequester manganese. We demonstrate that this mechanism allows calprotectin to alter T 1 and T 2 weighted contrast in response to biologically relevant calcium concentrations. Corresponding changes in relaxation times are comparable to synthetic calcium sensors and exceed those of previous protein-based MRI sensors for other neurochemical targets. The biological applicability of calprotectin was established by detecting calcium in lysates prepared from a neuronal cell line. Calprotectin thus represents a promising path towards imaging neural activity by combining the benefits of MRI and protein sensors.
Electrocommunication signals indicate motivation to compete during dyadic interactions of an electric fish
2021-02-04

Abstract Animals across species compete for limited resources. While in some species competition behavior is solely based on own abilities, others assess their opponents to facilitate these interactions. Using cues and communication signals, contestants gather information about their opponent, adjust their behavior accordingly, and can thereby avoid high costs of escalating fights. We tracked electrocommunication signals, in particular “rises”, and agonistic behaviors of the gymnotiform electric fish Apteronotus leptorhynchus in staged competition experiments. A larger body size relative to the opponent was the sole significant predictor for winners. Sex and the frequency of the continuously emitted electric field were only mildly influencing competition outcome. In males, correlations of body-size and winning were stronger than in females and, especially when losing against females, communication and agonistic interactions were enhanced, hinting towards males being more motivated to compete. Fish that lost competitions emitted the majority of rises in dependence on the competitors’ relative size and sex. The emission of rises was costly since it provoked ritualized biting or chasing behaviors by the other fish. Despite winners being accurately predictable based on rise numbers already after the initial 25 minutes, losers continued to emit rises. The number of rises emitted by losers and the duration of chasing behaviors depended in similar ways on physical attributes of contestants. The detailed evaluation of these correlations hint towards A. leptorhynchus adjusting their competition behavior according to mutual assessment, where rises could signal a loser’s motivation to continue assessment through ritualized fighting.