julilili42/papers huggingface dataset:
An inactivating human TRPC6 channel mutation without focal segmental glomerulosclerosis
2023-08-24

Abstract Transient receptor potential cation channel-6 ( TRPC6 ) gene mutations cause familial focal segmental glomerulosclerosis (FSGS), which is inherited as an autosomal dominant disease. In patients with TRPC6 -related FSGS, all mutations map to the N- or C-terminal TRPC6 protein domains. Thus far, the majority of TRPC6 mutations are missense resulting in increased or decreased calcium influx; however, the fundamental molecular mechanisms causing cell injury and kidney pathology are unclear. We report a novel heterozygous TRPC6 mutation (V691Kfs*) in a large kindred with no signs of FSGS despite a largely truncated TRPC6 protein. We studied the molecular effects of V691Kfs* TRPC6 mutant using the tridimensional cryo-EM structure of the tetrameric TRPC6 protein. The results indicated that V691 is localized at the pore-forming transmembrane region affecting the ion conduction pathway, and predicted that V691Kfs* causes closure of the ion-conducting pathway leading to channel inactivation. We assessed the impact of V691Kfs* and two previously reported TRPC6 disease mutants (P112Q and G757D) on calcium influx in cells. Our data show that the V691Kfs* fully inactivated the TRCP6 channel-specific calcium influx consistent with a complete loss-of-function phenotype. Furthermore, the V691Kfs* truncation exerted a dominant negative effect on the full-length TRPC6 proteins. In conclusion, the V691Kfs* non-functional truncated TRPC6 is not sufficient to cause FSGS. Our data corroborate recently characterized TRPC6 loss-of-function and gain-of-function mutants suggesting that one defective TRPC6 gene copy is not sufficient to cause FSGS. We underscore the importance of increased rather than reduced calcium influx through TRPC6 for podocyte cell death.
Autumn migration of the migrant hawker (Aeshna mixta) at the Baltic coast
2023-08-24

Abstract Background Migratory insects are important for the provision of ecosystem services both at the origin and destination sites but – apart from some iconic species – the migration routes of many insect species have not been assessed. Coastlines serve as a funnel where migrating animals including insects accumulate. Migratory behaviour and captures of dragonflies in bird traps suggest autumn migration of dragonflies along coastlines while the origin and regularity of this migration remain unclear. Methods Dragonfly species were caught at the bird observatory Kabli at the Baltic coast in Estonia in 2009, 2010 and 2015. For the 2015 data set, we used a stable hydrogen (H) approach to trace the potential natal origin of the migrant hawker ( Aeshna mixta ). Results 1079 (2009), 701 (2010) and 88 (2015) A. mixta individuals were caught during the study periods (35, 37 and 11 days in 2009, 2010 and 2015, respectively). The migration period lasted from end of August to end of September. Based on the results from our stable isotope analysis, we identified two populations of A. mixta : One (range of isotope signatures of non-exchangeable H [δ 2 H n wing ]: −78‰ to −112‰) had a local likely origin while the other (δ 2 H n wing : −113‰ to −147‰) migrated from northerly directions even in headwind from the South. The former showed an even sex ratio whereas the actively migrating population was dominated by males. Conclusions Our results suggest a regular southbound autumn migration of A. mixta along the Baltic coast. However, nearly half of the sampled individuals originated from the surroundings suggesting either no, partial or “leap-frog” migration. Contrary to our expectation, A. mixta did not select favourable wind conditions but continued the southbound autumn migration in the flight boundary layer even in case of headwinds. The dominance of males might indicate migration as a result of competition for resources. Further repeated, large-scale studies along the Baltic coast are necessary to pinpoint the migratory pattern and the reason for migration of A. mixta . Such studies should also comprise locations north of the known species range of A. mixta because of the rapid climate-change induced range expansion.
Memory for abstract control states does not decay with increasing retrieval delays
2023-08-24

Abstract Recent studies have suggested that abstract control states (i.e., internal attentional states independent from concrete stimuli and responses) can be stored in episodic memory and retrieved subsequently. However, the duration of such a control state memory remains unclear. Previous research has found a quick and complete decay for stimulus–response bindings after 2000–5000 ms. Here, we tested a possible decay of control state bindings with retrieval delays of 2000, 3000, or 5000 ms. Five preregistered experiments used a confound-minimized prime-target task to measure the congruency sequence effect (CSE) separately for trials in which a nominally irrelevant context feature changed or repeated across trials. Analyses of the individual experiments did not result in conclusive evidence. A mega-analysis integrating the data of all experiments ( N total = 326) replicated evidence for binding and retrieval of control states, in that larger CSEs were found for context repetition trials. Importantly, Bayesian analysis indicated that this effect was not modulated by the length of retrieval delay. While this finding suggests that bindings of abstract control states can be relatively robust, we also discuss possible limitations of the present research.
Value of Magnetic Resonance Imaging for Skeletal Bone Age Assessment in Healthy Male Children
2023-08-24

Abstract Background: Skeletal bone age assessment for medical reasons is usually performed by conventional x-ray with use of ionizing radiation. Few pilot studies have shown the possible use of magnetic resonance imaging (MRI). Purpose: To comprehensively evaluate feasibility and value of MRI for skeletal bone age (SBA) assessment in healthy male children. Materials and Methods: In this prospective cross-sectional study, 63 male soccer athletes with mean age of 12.35 ± 1.1 years were examined. All participants underwent 3.0 Tesla MRI with coronal T1-weighted turbo spin echo (TSE), coronal proton density (PD)–weighted turbo spin echo (TSE), and T1-weighted three-dimensional (3D) volume interpolated breath-hold examination (VIBE) sequence. Subsequently, SBA was assessed by 3 independent blinded radiologists with different levels of experience using the common Greulich-Pyle (GP) atlas and the Tanner-Whitehouse (TW2) method. Results: In a mean total acquisition time of 5:04 ± 0:47 min, MR image quality was sufficient in all cases. MRI appraisal was significantly faster ( P &lt; 0.0001) by GP with mean duration of 1:22 ± 0:08 min vs. 7:39 ± 0:28 min by TW. SBA assessment by GP resulted in mean age of 12.8 ± 1.2 years, by TW 13.0 ± 1.4 years. Interrater reliabilities were excellent for both GP (ICC = 0.912 (95% confidence interval [CI] = 0.868–0.944) and TW (ICC = 0.988 (95% CI = 0.980–0.992) and showed statistical significance ( P &lt; 0.001). Subdivided, for GP, ICCs were 0.822 (95% CI = 0.680–0.907) and 0.843 (95% CI = 0.713–0.919) in Under 12 and Under 14 group. For TW, ICCs were 0.978 (95% CI = 0.958–0.989) in Under 12 and 0.979 (95% CI = 0.961–0.989) in Under 14 group. Conclusion: MRI is a clinically feasible, rapidly evaluable method to assess skeletal bone age of healthy male children. Using the Greulich-Pyle (GP) atlas or the Tanner-Whitehouse (TW2) method, reliable results are obtained independent of the radiologist's experience level.
Pitfalls and considerations in determining the potency and mutant selectivity of covalent epidermal growth factor receptor inhibitors
2023-08-24

Pursuing enzyme inhibitors with molecules that form covalent bonds with the desired target is an attractive focus in drug development that is increasing in prevalence. However, challenges arise when carrying out assessments of their time-dependent inhibitory properties as well as making correlations with values reported in the literature. Given the prominent focus on the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase in oncology, and the diverse structures and binding modes of covalent EGFR inhibitors, this perspective seeks to explore various broadly relevant factors that arise in the measurement of kinetic parameters within this class of drugs. A review of several studies indicates that variable literature potency values require investigators to include appropriate reference molecules and consistent substrate conditions for experimental consistency and proper benchmarks. The impact on covalent inhibitor potency with respect to common buffer conditions and compound liquid handling is surveyed highlighting the importance of multiple experimental variables when conducting these assays. Additionally, when assessing the potency for inhibitor selectivity in targeting EGFR mutants over wild-type (WT), it is ideal to consider ratios of true potency due to the variable ATP substrate binding affinities. The overview presented here, although most directly applicable to the tyrosine kinase inhibitor field, serves inhibitor assessments broadly by providing guided insights into conducting biochemical assays for designing and validating next-generation covalent inhibitors.
ATG8 delipidation is not universally critical for autophagy in plants
2023-08-24

Abstract Intracellular recycling via autophagy is governed by post-translational modifications of the autophagy-related (ATG) proteins. One notable example is ATG4-dependent delipidation of ATG8, a process that plays critical but distinct roles in autophagosome formation in yeast and mammals. Here, we aimed to elucidate the specific contribution of this process to autophagosome formation in species representative of evolutionary distant green plant lineages: unicellular green alga Chlamydomonas reinhardtii , with a relatively simple set of ATG genes, and a vascular plant Arabidopsis thaliana , harboring expanded ATG gene families. Remarkably, the more complex autophagy machinery of Arabidopsis rendered ATG8 delipidation entirely dispensable for the maturation of autophagosomes, autophagic flux and related stress tolerance; whereas autophagy in Chlamydomonas strictly depended on the ATG4-mediated delipidation of ATG8. Importantly, we uncovered the distinct impact of different Arabidopsis ATG8 orthologs on autophagosome formation, especially prevalent under nitrogen depletion, providing a new insight into potential drivers behind the expansion of the ATG8 family in higher plants. Our findings underscore the evolutionary diversification of the molecular mechanism governing the maturation of autophagosomes in eukaryotic lineages and highlight how this conserved pathway is tailored to diverse organisms.
Nonequilibrium transition between dissipative time crystals
2023-08-24

We show a dissipative phase transition in a driven nonlinear quantum oscillator in which a discrete time-translation symmetry is spontaneously broken in two different ways. The corresponding regimes display either discrete or incommensurate time-crystal order, which we analyze numerically and analytically beyond the classical limit addressing observable dynamics, phenomenology in different (laboratory and rotating) frames, Liouvillian spectral features, and quantum fluctuations. Via an effective semiclassical description, we show that phase diffusion dominates in the incommensurate time crystal (or continuous time crystal in the rotating frame), which manifests as a band of eigenmodes with a lifetime growing linearly with the mean-field excitation number. Instead, in the discrete time crystal phase, the leading fluctuation process corresponds to quantum activation with a single mode that has an exponentially growing lifetime. Interestingly, the transition between these two regimes manifests itself already in the quantum regime as a spectral singularity, namely as an exceptional point mediating between phase diffusion and quantum activation. Finally, we discuss this transition between different time-crystal orders in the context of synchronization phenomena.
Human REM sleep recalibrates neural activity in support of memory formation
2023-08-25

The proposed mechanisms of sleep-dependent memory consolidation involve the overnight regulation of neural activity at both synaptic and whole-network levels. Now, there is a lack of in vivo data in humans elucidating if, and how, sleep and its varied stages balance neural activity, and if such recalibration benefits memory. We combined electrophysiology with in vivo two-photon calcium imaging in rodents as well as intracranial and scalp electroencephalography (EEG) in humans to reveal a key role for non-oscillatory brain activity during rapid eye movement (REM) sleep to mediate sleep-dependent recalibration of neural population dynamics. The extent of this REM sleep recalibration predicted the success of overnight memory consolidation, expressly the modulation of hippocampal—neocortical activity, favoring remembering rather than forgetting. The findings describe a non-oscillatory mechanism how human REM sleep modulates neural population activity to enhance long-term memory.
Modular architecture facilitates noise-driven control of synchrony in neuronal networks
2023-08-25

High-level information processing in the mammalian cortex requires both segregated processing in specialized circuits and integration across multiple circuits. One possible way to implement these seemingly opposing demands is by flexibly switching between states with different levels of synchrony. However, the mechanisms behind the control of complex synchronization patterns in neuronal networks remain elusive. Here, we use precision neuroengineering to manipulate and stimulate networks of cortical neurons in vitro, in combination with an in silico model of spiking neurons and a mesoscopic model of stochastically coupled modules to show that (i) a modular architecture enhances the sensitivity of the network to noise delivered as external asynchronous stimulation and that (ii) the persistent depletion of synaptic resources in stimulated neurons is the underlying mechanism for this effect. Together, our results demonstrate that the inherent dynamical state in structured networks of excitable units is determined by both its modular architecture and the properties of the external inputs.
IXPE and XMM-Newton Observations of the Soft Gamma Repeater SGR 1806–20
2023-08-25

Abstract Recent observations with the Imaging X-ray Polarimetry Explorer (IXPE) of two anomalous X-ray pulsars provided evidence that X-ray emission from magnetar sources is strongly polarized. Here we report on the joint IXPE and XMM-Newton observations of the soft γ -repeater SGR 1806–20. The spectral and timing properties of SGR 1806–20 derived from XMM-Newton data are in broad agreement with previous measurements; however, we found the source at an all-time low persistent flux level. No significant polarization was measured apart from the 4–5 keV energy range, where a probable detection with PD = 31.6% ± 10.5% and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mi>PA</mml:mi> <mml:mo>=</mml:mo> <mml:mo>−</mml:mo> <mml:mn>17</mml:mn> <mml:mrow> <mml:mo>.°</mml:mo> </mml:mrow> <mml:msubsup> <mml:mrow> <mml:mn>6</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>15</mml:mn> <mml:mrow> <mml:mo>.°</mml:mo> </mml:mrow> <mml:mn>0</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>+</mml:mo> <mml:mn>15</mml:mn> <mml:mrow> <mml:mo>.°</mml:mo> </mml:mrow> <mml:mn>5</mml:mn> </mml:mrow> </mml:msubsup> </mml:math> was obtained. The resulting polarization signal, together with the upper limits we derive at lower and higher energies (2–4 and 5–8 keV, respectively), is compatible with a picture in which thermal radiation from the condensed star surface is reprocessed by resonant Compton scattering in the magnetosphere, similar to what was proposed for the bright magnetar 4U 0142+61.
Tacrine First-Phase Biotransformation and Associated Hepatotoxicity: A Possible Way to Avoid Quinone Methide Formation
2023-08-25

Tacrine was withdrawn from clinical use as a drug against Alzheimer's disease in 2013, mainly due to drug-induced liver injury. The culprit of tacrine-associated hepatotoxicity is believed to be the 7-OH-tacrine metabolite, a possible precursor of quinone methide (Q<sub>meth</sub>), which binds to intracellular -SH proteins. In our study, several different animal and human models (liver microsomes, primary hepatocytes, and liver slices) were used to investigate the biotransformation and hepatotoxicity of tacrine and its 7-substituted analogues (7-methoxy-, 7-phenoxy-, and 7-OH-tacrine). Our goal was to find the most appropriate <i>in vitro</i> model for studying tacrine hepatotoxicity and, through rational structure modifications, to develop derivatives of tacrine that are less prone to Q<sub>meth</sub> formation. Our results show that none of animal models tested accurately mimic human tacrine biotransformation; however, the murine model seems to be more suitable than the rat model. Tacrine metabolism was overall most accurately mimicked in three-dimensional (3D) spheroid cultures of primary human hepatocytes (PHHs). In this system, tacrine and 7-methoxytacrine were hydroxylated to 7-OH-tacrine, whereas 7-phenoxytacrine formed, as expected, only trace amounts. Surprisingly, however, our study showed that 7-OH-tacrine was the least hepatotoxic (7-OH-tacrine < tacrine < 7-methoxytacrine < 7-phenoxytacrine) even after doses had been adjusted to achieve the same intracellular concentrations. The formation of Q<sub>meth</sub>-cysteine and Q<sub>meth</sub>-glutathione adducts after human liver microsome incubation was confirmed by all of the studied tacrine derivatives, but these findings were not confirmed after incubation with 3D PHH spheroids. Therefore, the presented data call into question the suggested previously hypothesized mechanism of toxicity, and the results open new avenues for chemical modifications to improve the safety of novel tacrine derivatives.
(R)evolution of the Standard Addition Procedure for Immunoassays
2023-08-25

A new method to transfer the standard addition procedure for concentration determination to immunoassays with non-linear calibration curves was developed. The new method was successfully applied to simulated data and benchmarked against a state-of-the-art algorithm, showing a significantly improved performance with improvement factors between 2 and 192. The logit function was used to transform the immunoassay signal response of test samples spiked with known analyte concentrations. The relationship between logit(signal) and log-transformed estimated total analyte concentration is linear if the estimated total analyte concentration is correct. Finally, the new method was validated experimentally using different assays in varying, relevant complex matrices, such as serum, saliva, and milk. Different concentrations of testosterone and amitriptyline between 0.05 and 3.0 μg L−1 were quantified using a binding inhibition assay in combination with reflectometric interference spectroscopy (RIfS) as the transduction principle. The sample concentration was calculated using a numerical method. Samples could be quantified with recoveries between 70 and 118%. The standard addition method accounts for individual matrix interference on the immunoassay by spiking the test sample itself. Although the experiments were carried out using RIfS, the method can be applied to any immunoassay that meets the analytical requirements.
BLASTphylo: An Interactive Web Tool for Taxonomic and Phylogenetic Analysis of Prokaryotic Genes
2023-08-25

Identifying a protein's function is crucial to reveal its role in the cellular complex. Computationally, the most common approach is to search for homologous proteins in a large database of proteins of known function using BLAST. One goal of such an analysis is the identification and visualization of the protein in the taxonomy of interest. Another goal is the reconstruction of the phylogenetic history of the protein. However, the BLAST result provides information about the occurrence of the protein in the taxonomy and its putative function mainly in a tabular format. This requires manual interventions and makes the taxonomic identification laborious. Although various tools exist to visualize and annotate large-scale trees, none of them intuitively and interactively visualizes the protein's occurrence in the taxonomy for different taxonomic ranks. To target this gap, we developed BLASTphylo, a web tool that combines BLAST with automatic taxonomic mapping and phylogenetic analysis and provides the results in interactive visualizations. We demonstrate the functionalities of BLASTphylo in two case studies.
Pulse Profile Modelling of Thermonuclear Burst Oscillations II: Handling variability
2023-08-25

Pulse profile modelling is a relativistic ray-tracing technique that can be used to infer masses, radii and geometric parameters of neutron stars. In a previous study, we looked at the performance of this technique when applied to thermonuclear burst oscillations from accreting neutron stars. That study showed that ignoring the variability associated with burst oscillation sources resulted in significant biases in the inferred mass and radius, particularly for the high count rates that are nominally required to obtain meaningful constraints. In this follow-on study, we show that the bias can be mitigated by slicing the bursts into shorter segments where variability can be neglected, and jointly fitting the segments. Using this approach, the systematic uncertainties on the mass and radius are brought within the range of the statistical uncertainty. With about 10 source counts, this yields uncertainties of approximately 10% for both the mass and radius. However, this modelling strategy requires substantial computational resources. We also confirm that the posterior distributions of the mass and radius obtained from multiple bursts of the same source can be merged to produce outcomes comparable to that of a single burst with an equivalent total number of counts.
The latest freshwater giants: a new Peltocephalus (Pleurodira: Podocnemididae) turtle from the Late Pleistocene of the Brazilian Amazon
2023-08-25

Dataset related to the publication "The latest freshwater giants: a new &lt;i&gt;Peltocephalus&lt;/i&gt; (Pleurodira: Podocnemididae) turtle from the Late Pleistocene of the Brazilian Amazon". This dataset contains a file with detailed description of methodology, materials and results obtained in this publication, as well as original raw and processed data, and R scripts used for the analyses.
The latest freshwater giants: a new Peltocephalus (Pleurodira: Podocnemididae) turtle from the Late Pleistocene of the Brazilian Amazon
2023-08-25

&lt;p&gt;Dataset related to the publication &quot;The latest freshwater giants: a new &lt;i&gt;Peltocephalus&lt;/i&gt; (Pleurodira: Podocnemididae) turtle from the Late Pleistocene of the Brazilian Amazon&quot;. This dataset contains a file with detailed description of methodology, materials and results obtained in this publication, as well as original raw and processed data, and R scripts used for the analyses.&lt;/p&gt;
Report on scipost_202304_00007v1
2023-08-26

We calculate the quantum Fisher information for a generic many-body fermionic system in a pure state depending on a parameter.We discuss the situations where the parameter is imprinted in the basis states, in the state coefficients, or both.In the case where the parameter dependence of coefficients results from a Hamiltonian evolution, we derive a particularly simple expression for the quantum Fisher information.We apply our findings to the quantum Hall effect, and evaluate the quantum Fisher information associated with the optimal measurement of the magnetic field for a system in the ground state of the effective Hamiltonian.The occupation of electron states with high momentum enforced by the Pauli principle leads to a super-Heisenberg scaling of the sensitivity with a power law that depends on the geometry of the sensor.