julilili42/papers huggingface dataset:
Neural circuits in the mouse retina support color vision in the upper visual field
2019-08-24

ABSTRACT Color vision is essential to the survival of most animals. Its neural basis lies in the retina, where chromatic signals from different photoreceptor types sensitive to distinct wavelengths are locally compared by neural circuits. Mice, like most mammals, are generally dichromatic and have two cone photoreceptor types. However, in the ventral retina most cones display the same spectral preference, impairing spectral comparisons necessary for color vision. This conflicts with behavioral evidence showing that mice can discriminate colors only in the corresponding upper visual field. Here, we systematically investigated the neural circuits underlying mouse color vision across three processing stages of the retina by recording the output of cones, bipolar and ganglion cells using two-photon imaging. Surprisingly, we found that across all retinal layers most color-opponent cells were located in the ventral retina. This started at the level of the cone output, where color-opponency was mediated by horizontal cells and likely involving rod photoreceptors. Next, bipolar cells relayed the chromatic information to ganglion cells in the inner retina, where type-specific, non-linear center-surround interactions resulted in specific color-opponent output channels to the brain. This suggests that neural circuits in the mouse retina are specifically tuned to extract color information from the upper visual field, aiding robust detection of aerial predators and ensuring the animal’s survival.
PGRMC1 phosphorylation and cell plasticity 1: glycolysis, mitochondria, tumor growth
2019-08-24

SUMMARY Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. Here, we demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with increased PI3K/Akt activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/Akt activation. Mutation of Y180F strongly attenuated mouse xenograft tumor growth. An accompanying paper demonstrates altered metabolism, mutation incidence, and epigenetic status in these cells, indicating that PGRMC1 phosphorylation strongly influences cancer biology.
On the Economics of Refugee Flows
2019-08-24

Although the phenomenon of refugee flows is not devoid of economic connotations, it has so far been investigated primarily by political scientists and sociologists. The analytical tools of economic inquiry have not yet been applied to this subject, although it stands to reason that such a study will contribute to our understanding of why refugee flows occur and will guide the policy response. This note illustrates how economic analysis can be brought to bear on three key aspects of refugee flows: fear, poverty, and group movement.
Why would some migrants choose to engage in degrading work?
2019-08-24

This paper develops a model of voluntary migration into degrading work. The essence of the model is a tension between two “bads:” that which arises from being relatively deprived at home, and that which arises from engaging in humiliating work away from home. Balancing between these two “bads” can give rise to an explicit, voluntary choice to engage in humiliating work. The paper identifies conditions under which a migrant will choose to engage in degrading work rather than being forced into it, to work abroad as a prostitute, say, rather than on a farm. The paper delineates the possible equilibria and finds that greater relative deprivation will make it more likely that the equilibrium outcome will be “engagement in prostitution.” It is shown that under well specified conditions, every individual will work as a prostitute, yet every individual would be better off working on a farm. Put differently, when specific conditions are satisfied, there is a possibility of a “coordination failure:” if individuals believe that everyone else will choose to be a prostitute, this belief will be self-fulfilling. In this case, all the individuals choose to engage in prostitution, which renders each of them worse off. The paper discusses various policy implications. It is shown that a policy intervention (a crackdown on migrants’ engagement in prostitution), if implemented strictly, can increase everyone’s welfare, but when the policy is implemented loosely, cracking down on prostitution will only reduce individuals’ welfare without reducing their engagement in prostitution.
PGRMC1 phosphorylation status and cell plasticity 1: glucose metabolism, mitochondria, and mouse xenograft tumorigenesis
2019-08-24

ABSTRACT Background Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. Multiple different functions and cellular locations have been attributed to PGRMC1 in a variety of contexts, however the mechanisms underlying PGRMC1 biology remain obscure. The protein contains several phosphorylated residues including tyrosines which were acquired in animal evolution prior to bilateral symmetry, and could be involved with animal cell differentiation mechanisms. Results Here we demonstrate that mutagenic manipulation of PGRMC1 phosphorylation status in MIA PaCa-2 pancreatic cells exerts broad pleiotropic effects, influencing cell plasticity and tumorigenicity, as assayed by cell biological and proteomics measurements. Relative to parental cells over-expressing hemagglutinin-tagged wild-type PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with Rho-kinase inhibitor-sensitive changes including altered cell shape, motility, increased PI3K/Akt activity, and fragmented mitochondrial morphology. An S57A/Y180F/S181A triple mutant reduced PI3K/Akt activity, indicating involvement of Y180 in PI3K/Akt induction. Both triple mutant and Y180F single mutant cells exhibited attenuated mouse xenograft tumor growth. Conclusions Phosphorylation status of the PGRMC1 tyrosine 180 regulatory motif exerts dramatic influence over cancer cell biology, including Warburg effect-like glucose metabolism. In accompanying papers we show that: 1) the cells examined here exhibit dramatically altered metabolism and epigenetic status, with the triple mutant inducing hypermethylation similar to that of embryonic stem cells, and that 2) Y180 was acquired in evolution concurrently with appearance of the organizer that induces animal gastrulation. Taken together, these results indicate that the undescribed mechanisms regulating PGRMC1 phosphorylation may be of great disease relevance and merit urgent investigation.
Germline genome editing versus preimplantation genetic diagnosis: Is there a case in favour of germline interventions?
2019-08-25

Abstract CRISPR is widely considered to be a disruptive technology. However, when it comes to the most controversial topic, germline genome editing (GGE), there is no consensus on whether this technology has any substantial advantages over existing procedures such as embryo selection after in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD). Answering this question, however, is crucial for evaluating whether the pursuit of further research and development on GGE is justified. This paper explores the question from both a clinical and a moral viewpoint, namely whether GGE has any advantages over existing technologies of selective reproduction and whether GGE could complement or even replace them. In a first step, I review an argument of extended applicability. The paper confirms that there are some scenarios in which only germline intervention allows couples to have (biologically related) healthy offspring, because selection will not avoid disease. In a second step, I examine possible moral arguments in favour of genetic modification, namely that GGE could save some embryos and that GGE would provide certain benefits for a future person that PGD does not. Both arguments for GGE have limitations. With regard to the extended applicability of GGE, however, a weak case in favour of GGE should still be made.
Diagnostic Performance of a Support Vector Machine for Dermatofluoroscopic Melanoma Recognition: The Results of the Retrospective Clinical Study on 214 Pigmented Skin Lesions
2019-08-25

The need for diagnosing malignant melanoma in its earliest stages results in an increasing number of unnecessary excisions. Objective criteria beyond the visual inspection are needed to distinguish between benign and malignant melanocytic tumors in vivo. Fluorescence spectra collected during the prospective, multicenter observational study (“FLIMMA”) were retrospectively analyzed by the newly developed machine learning algorithm. The formalin-fixed paraffin-embedded (FFPE) tissue samples of 214 pigmented skin lesions (PSLs) from 144 patients were examined by two independent pathologists in addition to the first diagnosis from the FLIMMA study, resulting in three histopathological results per sample. The support vector machine classifier was trained on 17,918 fluorescence spectra from 49 lesions labeled as malignant (1) and benign (0) by three histopathologists. A scoring system that scales linearly with the number of the “malignant spectra” was designed to classify the lesion as malignant melanoma (score &gt; 28) or non-melanoma (score ≤ 28). Finally, the scoring algorithm was validated on 165 lesions to ensure model prediction power and to estimate the diagnostic accuracy of dermatofluoroscopy in melanoma detection. The scoring algorithm revealed a sensitivity of 91.7% and a specificity of 83.0% in diagnosing malignant melanoma. Using additionally the image segmentation for normalization of lesions’ region of interest, a further improvement of sensitivity of 95.8% was achieved, with a corresponding specificity of 80.9%.
A NanoLuc luciferase-based assay enabling the real-time analysis of protein secretion and injection by bacterial type III secretion systems
2019-08-25

Abstract The elucidation of the molecular mechanisms of secretion through bacterial protein secretion systems is impeded by a lack of assays to quantitatively assess secretion kinetics. Also the analysis of the biological role of these secretion systems as well as the identification of inhibitors targeting these systems would greatly benefit from the availability of a simple, quick and quantitative assay to monitor principle secretion and injection into host cells. Here we present a versatile solution to this need, utilizing the small and very bright NanoLuc luciferase to assess secretion and injection through the type III secretion system encoded by Salmonella pathogenicity island 1. The NanoLuc-based secretion assay features a very high signal-to-noise ratio and sensitivity down to the nanoliter scale. The assay enables monitoring of secretion kinetics and is adaptable to a high throughput screening format in 384-well microplates. We further developed NanoLuc and split-NanoLuc-based assays that enable the monitoring of type III secretion-dependent injection of effector proteins into host cells. Importance The ability to secrete proteins to the bacterial cell surface, to the extracellular environment, or even into target cells is one of the foundations of interbacterial as well as pathogen-host interaction. While great progress has been made in elucidating assembly and structure of secretion systems, our understanding of their secretion mechanism often lags behind, not last because of the challenge to quantitatively assess secretion function. Here, we developed a luciferase-based assay to enable the simple, quick, quantitative, and high throughput-compatible assessment of secretion and injection through virulence-associated type III secretion systems. The assay allows detection of minute amounts of secreted substrate proteins either in the supernatant of the bacterial culture or within eukaryotic host cells. It thus provides an enabling technology to elucidate the mechanisms of secretion and injection of type III secretion systems and is likely adaptable to assay secretion through other bacterial secretion systems.
Alterations in Blood Monocyte Functions in Parkinson's Disease
2019-08-26

Abstract Background PD is a multisystem disease where both central and peripheral nervous systems are affected. This systemic involvement also includes the immune response in PD, which implicates not only microglia in the brain, but also peripheral immune cells, such as monocytes; however, this aspect has been understudied. Objectives The purpose of this study was to investigate the PD‐related changes in peripheral immune cells, their responsiveness to stimulation, and their ability to release immunomodulatory molecules that might have consequences for the disease progression. Methods Using flow cytometry, we investigated the monocytic population in peripheral blood mononuclear cells from PD patients and healthy individuals. We also evaluated the in vitro response to inflammogen lipopolysaccharides and to fibrillar α‐synuclein by measuring the expression of CD14, CD163, and HLA‐DR and by analysis of soluble immune‐related molecules in the supernatant. Results Peripheral blood immune cells from PD patients had lower survival in culture, but showed a higher monocytic proliferative ability than control cells, which was correlated with shorter disease duration and late disease onset. In addition, PD patients’ cells were less responsive to stimulation, as shown by the lack of changes in CD163 and CD14 expression, and by the absence of significant upregulation of anti‐inflammatory cytokines in culture. Moreover, PD peripheral immune cells shed lower in vitro levels of soluble CD163, which suggests a less responsive monocytic population and/or an activation status different from control cells. Interestingly, some of the results were sex associated, supporting a differential immune response in females versus males. Conclusions Our data suggest that PD involves monocytic changes in blood. These cells show reduced viability and are unresponsive to specific stimuli, which might have a relevant consequence for disease progression. © 2019 International Parkinson and Movement Disorder Society
Pyridinylimidazoles as GSK3β Inhibitors: The Impact of Tautomerism on Compound Activity via Water Networks
2019-08-26

Glycogen synthase kinase-3β (GSK3β) is involved in many pathological conditions and represents an attractive drug target. We previously reported dual GSK3β/p38α mitogen-activated protein kinase inhibitors and identified <i>N</i>-(4-(4-(4-fluorophenyl)-2-methyl-1<i>H</i>-imidazol-5-yl)pyridin-2-yl)cyclopropanecarboxamide (<b>1</b>) as a potent dual inhibitor of both target kinases. In this study, we aimed to design selective GSK3β inhibitors based on our pyridinylimidazole scaffold. Our efforts resulted in several novel and potent GSK3β inhibitors with IC<sub>50</sub> values in the low nanomolar range. 5-(2-(Cyclopropanecarboxamido)pyridin-4-yl)-4-cyclopropyl-1<i>H</i>-imidazole-2-carboxamide (<b>6g</b>) displayed very good kinase selectivity as well as metabolical stability and inhibited GSK3β activity in neuronal SH-SY5Y cells. Interestingly, we observed the importance of the 2-methylimidazole's tautomeric state for the compound activity. Finally, we reveal how this crucial tautomerism effect is surmounted by imidazole-2-carboxamides, which are able to stabilize the binding via enhanced water network interactions, regardless of their tautomeric state.
Direct modeling of foveal pit morphology from distortion-corrected OCT images
2019-08-26

Inherent distortions affect the spatial geometry of optical coherence tomography (OCT) images and consequently the foveal pit dimensions. Distortion correction provides an accurate anatomical representation of the retinal shape. A novel approach that automatically extracts foveal pit metrics from distortion-corrected OCT images using a sum of Gaussian function is presented. Foveal width, depth and slope were determined in 292 eyes with low fitting errors and high repeatability. Comparisons to undistorted scans revealed significant differences. To conclude, the internal OCT distortions affect the measurements of the foveal pit with their correction providing further insights into the role of foveal morphology in retinal pathologies and refractive development.
A topological approach to non-uniform complexity
2019-08-26

We investigate the feasibility of a topological method for proving separations of non-uniform circuit classes. Thereto, we chose a rather simple class of circuits: non-uniform constant size circuit classes with gate types underlying certain restrictions. In particular, we consider gate types admitting for a description through regular and commutative varieties of languages. Given a variety of regular languages V describing the gate types, we proceed by giving an alternative characterisation of the class of languages recognised by constant size circuits with the respective gates. This alternative description mainly relies on the block product principle (or substitution principle), which we extend to work with non-regular languages. The extended version of the block product principle is then used as the main tool to derive ultrafilter equations for the languages recognised by non-uniform constant size circuits with gates described by V, depending on the profinite equations that define the variety of regular languages V.
Mathematical General Relativity
2019-08-26

General Relativity is one of the triumphs of twentieth century physics. Its spectacular predictions include gravitational waves, black holes, and spacetime singularities. The mathematical study of this theory leads to deep problems connecting the areas of partial differential equations, geometry and topology with physics. The talks of the workshop illustrated the rapid progress in this subject over the last few years.
Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform
2019-08-27

The devastating effects and incurable nature of hereditary and sporadic retinal diseases such as Stargardt disease, age-related macular degeneration or retinitis pigmentosa urgently require the development of new therapeutic strategies. Additionally, a high prevalence of retinal toxicities is becoming more and more an issue of novel targeted therapeutic agents. Ophthalmologic drug development, to date, largely relies on animal models, which often do not provide results that are translatable to human patients. Hence, the establishment of sophisticated human tissue-based in vitro models is of upmost importance. The discovery of self-forming retinal organoids (ROs) derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) is a promising approach to model the complex stratified retinal tissue. Yet, ROs lack vascularization and cannot recapitulate the important physiological interactions of matured photoreceptors and the retinal pigment epithelium (RPE). In this study, we present the retina-on-a-chip (RoC), a novel microphysiological model of the human retina integrating more than seven different essential retinal cell types derived from hiPSCs. It provides vasculature-like perfusion and enables, for the first time, the recapitulation of the interaction of mature photoreceptor segments with RPE in vitro. We show that this interaction enhances the formation of outer segment-like structures and the establishment of in vivo-like physiological processes such as outer segment phagocytosis and calcium dynamics. In addition, we demonstrate the applicability of the RoC for drug testing, by reproducing the retinopathic side-effects of the anti-malaria drug chloroquine and the antibiotic gentamicin. The developed hiPSC-based RoC has the potential to promote drug development and provide new insights into the underlying pathology of retinal diseases.
Volitional control of vocalizations in corvid songbirds
2019-08-27

Songbirds are renowned for their acoustically elaborate songs. However, it is unclear whether songbirds can cognitively control their vocal output. Here, we show that crows, songbirds of the corvid family, can be trained to exert control over their vocalizations. In a detection task, three male carrion crows rapidly learned to emit vocalizations in response to a visual cue with no inherent meaning (go trials) and to withhold vocalizations in response to another cue (catch trials). Two of these crows were then trained on a go/nogo task, with the cue colors reversed, in addition to being rewarded for withholding vocalizations to yet another cue (nogo trials). Vocalizations in response to the detection of the go cue were temporally precise and highly reliable in all three crows. Crows also quickly learned to withhold vocal output in nogo trials, showing that vocalizations were not produced by an anticipation of a food reward in correct trials. The results demonstrate that corvids can volitionally control the release and onset of their vocalizations, suggesting that songbird vocalizations are under cognitive control and can be decoupled from affective states.
Local translation of yeast ERG4 mRNA at the endoplasmic reticulum requires the brefeldin A resistance protein Bfr1
2019-08-27

Brefeldin A resistance factor 1 (Bfr1p) is a nonessential RNA-binding protein and multicopy suppressor of brefeldin A sensitivity in Saccharomyces cerevisiae . Deletion of BFR1 leads to multiple defects, including altered cell shape and size, change in ploidy, induction of P-bodies and chromosomal missegregation. Bfr1p has been shown to associate with polysomes, binds to several hundred mRNAs, and can target some of them to P-bodies. Although this implies a role of Bfr1p in translational control of mRNAs, its molecular function remains elusive. In the present study, we show that mutations in RNA-binding residues of Bfr1p impede its RNA-dependent colocalization with ER, yet do not mimic the known cellular defects seen upon BFR1 deletion. However, a Bfr1 RNA-binding mutant is impaired in binding to ERG4 mRNA, which encodes an enzyme required for the final step of ergosterol biosynthesis. Consistently, bfr1 Δ strains show a strong reduction in Erg4p protein levels, most likely because of degradation of misfolded Erg4p. Polysome profiling of bfr1Δ or bfr1 mutant strains reveals a strong shift of ERG4 mRNA to polysomes, consistent with a function of Bfr1p in elongation or increased ribosome loading. Collectively, our data reveal that Bfr1 has at least two separable functions: one in RNA binding and cotranslational protein translocation into the ER and one in ploidy control or chromosome segregation.