julilili42/papers huggingface dataset:
PB1759: RETAINED FUNCTIONAL NORMAL AND/OR PRE-LEUKEMIC HSCS IN THE BONE MARROW ARE ASSOCIATED TO GOOD PROGNOSIS IN DNMT3AMUTNPM1MUT AML PATIENTS
2023-08-01

Topic: 3. Acute myeloid leukemia - Biology & Translational Research Background: Acute Myeloid Leukemia (AML) is a highly aggressive adult leukemia with a high incidence of relapse and mortality. AML hijacked the hierarchical organization of normal hematopoiesis with Leukemia Stem Cells (LSCs) at the top of the differentiation tree and differentiated and highly proliferating myeloid blast at the bottom. Similar to normal hematopoietic stem cells (HSCs), LSCs have been originally identified as CD34+CD38- cells. However, this strategy to isolate LSCs is particularly challenging in NPM1 mutated AMLs, since expression of CD34 on leukemic cells is low or absent altogether. Aims: In this study, we aimed to establish a novel sorting strategy to isolate LSCs independently of CD34 surface marker in both CD34positive and CD34negative AMLs. Methods: Using a genetically highly homogeneous cohort of 46 AML patients carrying DNMT3A and NPM1 mutations, we established a novel isolation strategy to enrich for LSCs even in CD34negative AMLs by additionally including a positive selection for GPR56 and a negative selection for mature markers such as NKG2DLigandss. Results: By combining functional in vivo data, mutational analyses on xenografts and transcriptomic data, we found that CD34+GPR56+NKG2DL- subpopulations can contain along with LSCs also normal and/or pre-leukemic (HSCs). In contrast, no such residual normal or pre-leukemic HSCs were detected in CD34-GPR56+NKG2DL- subpopulations. Finally, we show that naïve AML patients who retain a relevant reserve of normal and/or preleukemic HSCs, able to reconstitute immunocompromised mice at time of diagnosis, have significant longer relapse-free and overall survival compared to patients without engrafting HSCs. Summary/Conclusion: These data suggest that the presence of normal and/or preleukemic HSCs with multilineage engrafting potential in the bone marrow of naïve patients is associated with good response to standard chemotherapy, providing a basis for the development of novel predictive biomarkers for standard chemotherapy regime. Keywords: DNMT3A, AML, Leukemic stem cell, Stem cell marker
Measuring lightness constancy with varying realism
2023-08-01

In everyday life, surface colours typically appear constant under different lighting despite the (potentially) dramatic changes in luminance—human observers are (nearly) colour constant. Failures of colour constancy using simple artificial stimuli are often explicable in terms of luminance normalization and color adaptation, but not in realistic scenes with multiple light sources in which the perceiver ought to separate all illuminants from the surface reflectances. What remains to be established, however, is the link between lightness constancy using simple artificial stimuli versus realistic scenes. Here we present a lightness scaling experiment to investigate the impact of realism on lightness perception. Observers see physically accurate renderings of indoor scenes that contain three target patches of varying illumination and luminance; the observers have to judge which lateral target patch appears more similar to the center target. Based on these triad judgments, we estimated 1D and 2D lightness scales for different manipulations of scene realism with an ordinal embedding algorithm, a modern variant of multidimensional scaling. Preliminary results show a mixed picture of lightness constancy's dependence on scene realism. Scene realism per se appears not critical; instead, we observe lightness constancy if the scene contains spotlights with clearly visible, sharp light cones. Targets in a scene without sharp light cones—but still clearly visible illuminants, e.g. a ceiling window—were judged based on the brightness both in the full and reduced realism conditions. Our results may indicate that it is not realism per se that is crucial for lightness constancy but the ease with which individual illuminants be identified through the local context.
Is edge sensitivity more than contrast sensitivity?
2023-08-01

How does the human visual system extract relevant information from the pattern of light on the retinae? The psychophysical study of early vision has led to important insights in the initial processing characteristics of human vision, and we have image-computable models which quantitatively account for relevant psychophysical findings. Many of these findings come from experiments with sinusoidal gratings and Gabor patches, which, due to their narrow spectra, are thought to be ideal to isolate and test mechanisms of early vision. However, during natural viewing relevant stimulus features such as object boundaries involve sharp luminance discontinuities (i.e. edges) and thus broad spectra. Here we explore whether the computational mechanisms which account for the perception of sinusoidal gratings can also predict psychophysical sensitivity to (isolated) edges. Psychophysically, we probe human edge sensitivity (2-AFC, position of edge) in the presence of different types of noise. Edges were Cornsweet edges with peak frequencies at 0.5, 3 and 9 cpd, and noise types were white, pink, and brown as well as three narrowband noises with center frequencies at 0.5, 3 and 9 cpd. Computationally, we implemented several edge models using standard components of existing edge models (single or multiple odd-symmetric log-Gabor filters) and standard components from spatial vision models (divisive contrast gain control, signal-detection-theory based decoders of varying complexity). We find that several different models can reasonably account for the data and thus conclude that human contrast and edge sensitivity are likely employing similar computational mechanisms - results from narrowband sinusoidal gratings thus generalize to more natural, broadband stimuli. Finally, we discuss the assumptions and design choices involved in our computational modeling and make both explicit to foster their critical examination.
Feature Visualizations do not sufficiently explain hidden units of Artificial Neural Networks
2023-08-01

Artificial Neural Networks (ANNs) have been proposed as computational models of the primate ventral stream, because their performance on tasks such as image classification rivals or exceeds human baselines. But useful models should not only predict data well, but also offer insights into the systems they represent, which remains a challenge for ANNs. We here investigate a specific method that has been proposed to shed light on the representations learned by ANNs: Feature Visualizations (FVs), that is, synthetic images specifically designed to excite individual units ("neurons") of the target network. Theoretically, these images should visualize the features that a unit is sensitive to, like receptive fields in neurophysiology. We conduct a psychophysical experiment to establish an upper bound on the interpretability afforded by FVs, in which participants need to match five sets of exemplars (natural images that highly activate certain units) to five sets of FVs of the same units---a task that should be trivial if FVs were informative. Extending earlier work that has cast doubts on the utility of this method, we show that (1) even human experts perform hardly better than chance when trying to match a unit's FVs to its exemplars and that (2) matching exemplars to each other is much easier, even if only a single exemplar is shown per set. Presumably, this difficulty is not caused by so-called polysemantic units (neurons that code for multiple unrelated features, possibly mixing them in their visualizations) but by the unnatural visual appearance of FVs themselves. We also investigate the effect of visualizing units from different layers and find that the interpretability of FVs declines in later layers---contrary to what one might expect, since later layers should represent semantic concepts. These findings highlight the need for better interpretability-techniques, if ANNs are ever to become useful models of human vision.
Relating trial-to-trial variability in superior colliculus visual responses to saccadic reaction time variability
2023-08-01

Reflexive saccades towards the same appearing stimulus vary substantially in their reaction times (RT’s). While several cognitive processes, like target selection and decision making, contribute to such variability, none of these processes can begin before sensory detection of stimulus occurrence. Consistent with this, variability in the time at which primary visual cortex (V1) neurons first detect stimulus onset is significantly correlated with RT variability (Lee et al., 2010). We asked how trial-to-trial variability in the visual responses of the superior colliculus (SC), a structure with both visual sensitivity and direct projections to oculomotor control circuitry, behaves. We analyzed recordings of 188 SC neurons from two macaque monkeys that performed a reflexive visually-guided saccade task. After 550-800 ms of initial fixation, a 0.51-deg radius disc of 10-100% contrast appeared within the response field of a neuron; the fixation spot was extinguished simultaneously. We estimated the first-spike latency of visual responses using a similar method to (Lee et al., 2010). We also calculated spike likelihood across trials in 2-ms running time bins. Within a given contrast level, we observed a significant positive correlation between trial-to-trial first-spike latency and RT, like in V1. However, numerically, the correlations were surprisingly weaker than in the V1 data of Lee et al. (2010). We then analyzed spike likelihood in the SC visual responses. In this case, and unlike in V1, trial-to-trial variability in firing rate, again within a given contrast level, exhibited stronger correlations with RT (which were now negative: lower spike rates implying longer RT’s). These results suggest that a rate, rather than temporal, code dominates the relationship between trial-to-trial SC visual response variability and RT’s. We hypothesize that relying on a rate code, necessitating temporal integration, can reduce sensitivity to noise, which can erroneously trigger movements through the SC’s descending brainstem projections.
Peri-saccadic mislocalization in a rhesus macaque monkey depends on the visual appearance of the saccade target
2023-08-01

Briefly presented high contrast stimuli are strongly mislocalized peri-saccadically. This phenomenon is likely a consequence, at least partially, of saccade vector information being internally relayed (via corollary discharge) to the visual system. Indeed, thalamic relaying of superior colliculus (SC) saccade-related motor bursts to the frontal cortex is necessary for peri-saccadic response field remapping in the latter (Sommer & Wurtz, 2006). Given recent evidence that SC motor bursts contain a visual sensory representation of the saccade target appearance (Baumann et al., 2022), we hypothesize that SC-sourced corollary discharge may transmit more than just vector information to the cortex. However, neuronally testing such a hypothesis requires a means to assess peri-saccadic visual mislocalization in non-human primates, and to ask whether such mislocalization depends on saccade target visual appearance. We trained a male monkey to repeatedly generate the same saccade within a session, but to two different possible targets (100% contrast grating of 1.5 deg radius and either 0.5 or 8 cycles/deg spatial frequency). After online saccade detection, we presented a flash (~10 ms; black; 0.45 by 0.45 deg) at one of three possible locations ahead of the saccade target center (10.6 deg; directly ahead or with +/- 45 deg deviation from saccade direction); flash onset occurred immediately or after 40 or 100 ms from saccade detection. After 500-800 ms from saccade end, we removed the grating, instructing the monkey to look towards where it previously saw the flash. Across 13735 trials from multiple sessions and different saccade directions, the monkey consistently exhibited robust mislocalization towards the saccade target location, like in classic human studies, and there was recovery with delayed post-saccadic flashes. Importantly, mislocalization strength depended on saccade target appearance. Thus, we established a suitable model for neuronally testing predictions regarding the functional role of sensory tuning in SC neuronal movement commands.
Psychophysical scale of optical distortions of multifocal spectacle lenses
2023-08-01

Multifocal lenses have regions of different optical power, correcting far and near vision for presbyopes with one pair of glasses. Optical distortions are an unavoidable side effect of those lenses. From previous research and reports of spectacle wearers we know that such distortions cause unnatural and often discomforting motion percepts. Depending on design choices and the intended refractive correction, the strength and shape of distortions vary between lenses. For the design of spectacle lenses it is important to understand how perceived distortions depend on different parameters of the spectacle lens. In this work we analyze physical distortions induced by multifocal glasses with varying correction on a subjective, psychophysical scale of distortions. To measure the internal scale we performed a psychophysical experiment in virtual reality (VR). The image in VR was transformed to replicate the distortions of ten simulated lenses. Subjects looked around freely in a virtual indoor environment while three different distortions were presented consecutively in each trial; they were asked for the pair of distortions that appeared more similar: first to second, or second to third. We estimated the scale as a coordinate for every lens with an ordinal embedding algorithm, so that the distances in the scale maximally agree with the subjects' perceived similarities. The fit is best with a single coordinate dimension for the perceived distortions, even though we varied multiple lens parameters, resulting in complex transformations of the images. This perceived distortion is increasing with the optical power in the far vision area of the lens and the additional power in the near vision area of the lens. Distortions for lenses with negative optical power in the far area appear closer to undistorted vision with increasing power in the near area, suggesting a compensation of distortions for negative lenses.
Modeling internal state changes in free-viewing and visual search scanpaths with gain control in DeepGaze III
2023-08-01

The DeepGaze III model currently sets the state-of-the-art in predicting free-viewing human scanpaths on natural images by predicting future fixations from the observed image and recent fixation locations. Inspired by gain control mechanisms in Neuroscience, we introduce gain control layers into the network architecture which can modulate the activity in certain channels of the network depending on additional factors, such as observer biases or search targets. By comparing the prediction performance of the baseline model with the performance of such an extended model in terms of information gain, we can quantify the amount of information that additional factors contribute to fixation placement. Due to the modular DeepGaze III architecture, we can decompose the information gain into different components: (1) a first component affecting only the modulation amplitude of the fixation distribution, (2) a second component modulating which image features are salient, and (3) a third component affecting the scanpath dynamics. Applying this approach, we quantify how much a fixation’s index in a scanpath, subject identity and search targets affect scanpaths in free-viewing and visual search. For free-viewing, we find that fixation index and subject identity contribute to a similar degree to fixation placement. In the case of fixation index, this information is equally split into a part making the fixation density more uniform over time, and a part changing which image features are salient. The contribution of subject identity is mostly due to different subjects preferring different image features. For visual search on the COCO Search18 dataset, the search target increases the explained information by 18% compared to just the presented image, suggesting substantial similarities in fixation behavior across targets. Our work demonstrates how contrast gain control can be used as a very general and sample-efficient mechanism to flexibly modify neural network computation to account for additional factors of interest.
Corrigendum to “Co-reduction of Fe(III) and S0 drives Fe-S biomineral formation and phosphate mobilisation” by Bronner et al., 2023
2023-08-01

In the third paragraph of 'Mineralogical analyses' (Materials and Methods) in the Supplementary Information, "hexamethyldisilazane" was incorrectly written as "hexamethyldisiloxane" in the following sentence:"After the final ethanol dehydration, a mixture of 100 % ethanol (250 μL) and hexamethyldisiloxane (HMDS, 250 μL) was added to each well and the sample were incubated for 30 min."This has now been corrected to "hexamethyldisilazane" in the Supplementary Information, appearing as: "After the final ethanol dehydration, a mixture of 100 % ethanol (250 μL) and hexamethyldisilazane (HMDS, 250 μL) was added to each well and the sample were incubated for 30 min."
Pathophysiology of Red Blood Cell Dysfunction in Diabetes and Its Complications
2023-08-02

Diabetes Mellitus (DM) is a complex metabolic disorder associated with multiple microvascular complications leading to nephropathy, retinopathy, and neuropathy. Mounting evidence suggests that red blood cell (RBC) alterations are both a cause and consequence of disturbances related to DM-associated complications. Importantly, a significant proportion of DM patients develop varying degrees of anemia of confounding etiology, leading to increased morbidity. In chronic hyperglycemia, RBCs display morphological, enzymatic, and biophysical changes, which in turn prime them for swift phagocytic clearance from circulation. A multitude of endogenous factors, such as oxidative and dicarbonyl stress, uremic toxins, extracellular hypertonicity, sorbitol accumulation, and deranged nitric oxide metabolism, have been implicated in pathological RBC changes in DM. This review collates clinical laboratory findings of changes in hematology indices in DM patients and discusses recent reports on the putative mechanisms underpinning shortened RBC survival and disturbed cell membrane architecture within the diabetic milieu. Specifically, RBC cell death signaling, RBC metabolism, procoagulant RBC phenotype, RBC-triggered endothelial cell dysfunction, and changes in RBC deformability and aggregation in the context of DM are discussed. Understanding the mechanisms of RBC alterations in DM provides valuable insights into the clinical significance of the crosstalk between RBCs and microangiopathy in DM.
Reactivity of Acrylamides Causes Cytotoxicity and Activates Oxidative Stress Response
2023-08-02

Acrylamides are widely used industrial chemicals that cause adverse effects in humans or animals, such as carcinogenicity or neurotoxicity. The excess toxicity of these reactive electrophilic chemicals is especially interesting, as it is mostly triggered by covalent reactions with biological nucleophiles, such as DNA bases, proteins, or peptides. The cytotoxicity and activation of oxidative stress response of 10 (meth)acrylamides measured in three reporter gene cell lines occurred at similar concentrations. Most acrylamides exhibited high excess toxicity, while methacrylamides acted as baseline toxicants. The (meth)acrylamides showed no reactivity toward the hard biological nucleophile 2-deoxyguanosine (2DG) within 24 h, and only acrylamides reacted with the soft nucleophile glutathione (GSH). Second-order degradation rate constants (<i>k</i><sub>GSH</sub>) were measured for all acrylamides with <i>N</i>,<i>N</i>'-methylenebis(acrylamide) (NMBA) showing the highest <i>k</i><sub>GSH</sub> (134.800 M<sup>-1</sup> h<sup>-1</sup>) and <i>N</i>,<i>N</i>-diethylacrylamide (NDA) the lowest <i>k</i><sub>GSH</sub> (2.574 M<sup>-1</sup> h<sup>-1</sup>). Liquid chromatography coupled to high-resolution mass spectrometry was used to confirm the GSH conjugates of the acrylamides with a double conjugate formed for NMBA. The differences in reactivity between acrylamides and methacrylamides could be explained by the charge density of the carbon atoms because the electron-donating inductive effect of the methyl group of the methacrylamides lowered their electrophilicity and thus their reactivity. The differences in reactivity within the group of acrylamides could be explained by the energy of the lowest unoccupied molecular orbital and steric hindrance. Cytotoxicity and activation of oxidative stress response were linearly correlated with the second-order reaction rate constants of the acrylamides with GSH. The reaction of the acrylamides with GSH is hence not only a detoxification mechanism but also leads to disturbances of the redox balance, making the cells more vulnerable to reactive oxygen species. The reactivity of acrylamides explained the oxidative stress response and cytotoxicity in the cells, and the lack of reactivity of the methacrylamides led to baseline toxicity.
Autotrophic growth of Escherichia coli is achieved by a small number of genetic changes
2023-08-02

Synthetic autotrophy is a promising avenue to sustainable bioproduction from CO 2 . Here, we use iterative laboratory evolution to generate several distinct autotrophic strains. Utilising this genetic diversity, we identify that just three mutations are sufficient for Escherichia coli to grow autotrophically, when introduced alongside non-native energy (formate dehydrogenase) and carbon-fixing (RuBisCO, phosphoribulokinase, carbonic anhydrase) modules. The mutated genes are involved in glycolysis ( pgi ), central-carbon regulation ( crp ), and RNA transcription ( rpoB ). The pgi mutation reduces the enzyme’s activity, thereby stabilising the carbon-fixing cycle by capping a major branching flux. For the other two mutations, we observe down-regulation of several metabolic pathways and increased expression of native genes associated with the carbon-fixing module ( rpiB ) and the energy module ( fdoGH ), as well as an increased ratio of NADH/NAD + - the cycle’s electron-donor. This study demonstrates the malleability of metabolism and its capacity to switch trophic modes using only a small number of genetic changes and could facilitate transforming other heterotrophic organisms into autotrophs.