julilili42/papers huggingface dataset:
Dissociation between red and white stimulus perception: A perimetric quantification of protanopic color vision deficiencies
2021-12-20

Significance Horizontal visual field extension was assessed for red and white stimuli in subjects with protanopia using semi-automated kinetic perimetry. In contrast to a conventional anomaloscope, the “red/white dissociation ratio” (RWR) allows to describe protanopia numerically. For the majority of subjects with protanopia a restriction for faint red stimuli was found. Purpose Comparing the horizontal visual field extensions for red and white stimuli in subjects with protanopia and those with normal trichromacy and assessing the related intra-subject intra-session repeatability. Methods The subjects were divided into groups with protanopia and with normal trichromacy, based on color vision testing (HMC anomaloscope, Oculus, Wetzlar/FRG). Two stimulus characteristics, III4e and III1e, according to the Goldmann-classification, were presented with semi-automated kinetic perimetry (Octopus 900 perimeter, Haag-Streit, Köniz/CH). They moved along the horizontal meridian, with an angular velocity of 3°/s towards the visual field center, starting from either the temporal or nasal periphery. If necessary, a 20° nasal fixation point offset was chosen to capture the temporal periphery of the visual field. For each condition the red/white dissociation ratio (RWR); Pat Appl . DPMA DRN 43200082D) between the extent of the isopter for red (RG610, Schott, Mainz/ FRG) and white stimuli along the horizontal meridian was determined. Results All data are listed as median/interquartile range: Five males with protanopia (age 22.1/4.5 years) and six males with normal trichromacy (control group, age 30.5/15.2 years) were enrolled. The RWR is listed for the right eye, as no clinically relevant difference between right and left eye occurred. Protanopes’ RWR for mark III4e (in brackets: control group) was 0.941/0.013 (0.977/0.019) and for mark III1e 0.496/0.062 (0.805/0.051), respectively. Conclusions In this exploratory “proof-of-concept study” red/white dissociation ratio perimetry is introduced as a novel technique aiming at assessing and quantifying the severity of protanopia. Further effort is needed to understand the magnitude of the observed red-/white dissociation and to extend this methodology to a wider age range of the sample and to anomalous trichromacies (protanomalia) with varying magnitude.
Disruption of amygdalaTsc2in adolescence leads to changed prelimbic cellular activity and generalized fear responses at adulthood in rats
2021-12-20

Abstract Adolescence constitutes a period of vulnerability in the emergence of fear-related disorders (FRD), as a massive reorganization occurs in the amygdala-prefrontal cortex network, critical to regulate fear behavior. Genetic and environmental factors during development may predispose to the emergence of FRD at the adult age, but the underlying mechanisms are poorly understood. In the present study, we tested whether a partial knock-down of tuberous sclerosis complex 2 (Tsc2, Tuberin), a risk gene for neurodevelopmental disorders, in the basolateral amygdala (BLA) from adolescence could alter fear-network functionality and create a vulnerability ground to FRD appearance at adulthood. Using bilateral injection of a lentiviral vector expressing a miRNA against Tsc2 in the BLA of early (PN25) or late adolescent (PN50) rats, we show that alteration induced specifically from PN25 resulted in an increased c-Fos activity at adulthood in specific layers of the prelimbic cortex, a resistance to fear extinction and an overgeneralization of fear to a safe, novel stimulus. A developmental dysfunction of the amygdala could thus play a role in the vulnerability to FRD emergence at adulthood. We propose our methodology as an alternative to model the developmental vulnerability to FRD, especially in its comorbidity with TSC2-related autism syndrome.
Enantioselective UHPLC Screening Combined with In Silico Modeling for Streamlined Development of Ultrafast Enantiopurity Assays
2021-12-21

Enantioselective chromatography has been the preferred technique for the determination of enantiomeric excess across academia and industry. Although sequential multicolumn enantioselective supercritical fluid chromatography screenings are widespread, access to automated ultra-high-performance liquid chromatography (UHPLC) platforms using state-of-the-art small particle size chiral stationary phases (CSPs) is an underdeveloped area. Herein, we introduce a multicolumn UHPLC screening workflow capable of combining 14 columns (packed with sub-2 μm fully porous and sub-3 μm superficially porous particles) with nine mobile phase eluent choices. This automated setup operates under a vast selection of reversed-phase liquid chromatography, hydrophilic interaction liquid chromatography, polar-organic mode, and polar-ionic mode conditions with minimal manual intervention and high success rate. Examples of highly efficient enantioseparations are illustrated from the integration of chiral screening conditions and computer-assisted modeling. Furthermore, we describe the nuances of <i>in silico</i> method development for chiral separations <i>via</i> second-degree polynomial regression fit using LC simulator (ACD/Labs) software. The retention models were found to be very accurate for chiral resolution of single and multicomponent mixtures of enantiomeric species across different types of CSPs, with differences between experimental and simulated retention times of less than 0.5%. Finally, we illustrate how this approach lays the foundation for a streamlined development of ultrafast enantioseparations applied to high-throughput enantiopurity analysis and its use in the second dimension of two-dimensional liquid chromatography experiments.
Lipidome profiling with Raman microspectroscopy identifies macrophage response to surface topographies of implant materials
2021-12-21

Significance Macrophage plasticity and activation dynamics are under intense investigation because their full complexity cannot be captured by the few predefined markers that are commonly used. Macrophages are highly adherent and respond to surface microstructures in a sensitive manner. Here, we use Raman microspectroscopy and Raman imaging to study the macrophage response to defined activation stimuli and transfer these findings to macrophages cultured on titanium with varying surface roughness. We show that Raman-based methods can discriminate between macrophage phenotypes noninvasively and without the need to use antibody-based cell markers.
Personal Perspectives on Plant Ribosomal RNA Genes Research: From Precursor-rRNA to Molecular Evolution
2021-12-21

The history of rDNA research started almost 90 years ago when the geneticist, Barbara McClintock observed that in interphase nuclei of maize the nucleolus was formed in association with a specific region normally located near the end of a chromosome, which she called the nucleolar organizer region (NOR). Cytologists in the twentieth century recognized the nucleolus as a common structure in all eukaryotic cells, using both light and electron microscopy and biochemical and genetic studies identified ribosomes as the subcellular sites of protein synthesis. In the mid- to late 1960s, the synthesis of nuclear-encoded rRNA was the only system in multicellular organisms where transcripts of known function could be isolated, and their synthesis and processing could be studied. Cytogenetic observations of NOR regions with altered structure in plant interspecific hybrids and detailed knowledge of structure and function of rDNA were prerequisites for studies of nucleolar dominance, epistatic interactions of rDNA loci, and epigenetic silencing. In this article, we focus on the early rDNA research in plants, performed mainly at the dawn of molecular biology in the 60 to 80-ties of the last century which presented a prequel to the modern genomic era. We discuss – from a personal view – the topics such as synthesis of rRNA precursor (35S pre-rRNA in plants), processing, and the organization of 35S and 5S rDNA. Cloning and sequencing led to the observation that the transcribed and processed regions of the rRNA genes vary enormously, even between populations and species, in comparison with the more conserved regions coding for the mature rRNAs. Epigenetic phenomena and the impact of hybridization and allopolyploidy on rDNA expression and homogenization are discussed. This historical view of scientific progress and achievements sets the scene for the other articles highlighting the immense progress in rDNA research published in this special issue of Frontiers in Plant Science on “Molecular organization, evolution, and function of ribosomal DNA.”
Pharmacokinetics of Pullulan–Dexamethasone Conjugates in Retinal Drug Delivery
2021-12-21

The treatment of retinal diseases by intravitreal injections requires frequent administration unless drug delivery systems with long retention and controlled release are used. In this work, we focused on pullulan (≈67 kDa) conjugates of dexamethasone as therapeutic systems for intravitreal administration. The pullulan–dexamethasone conjugates self-assemble into negatively charged nanoparticles (average size 326 ± 29 nm). Intravitreal injections of pullulan and pullulan–dexamethasone were safe in mouse, rat and rabbit eyes. Fluorescently labeled pullulan particles showed prolonged retention in the vitreous and they were almost completely eliminated via aqueous humor outflow. Pullulan conjugates also distributed to the retina via Müller glial cells when tested in ex vivo retina explants and in vivo. Pharmacokinetic simulations showed that pullulan–dexamethasone conjugates may release free and active dexamethasone in the vitreous humor for over 16 days, even though a large fraction of dexamethasone may be eliminated from the eye as bound pullulan–dexamethasone. We conclude that pullulan based drug conjugates are promising intravitreal drug delivery systems as they may reduce injection frequency and deliver drugs into the retinal cells.
Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations
2021-12-21

Abstract SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection. The novel variant of concern (VoC) Omicron (B.1.1.529) has the largest number of amino acid alterations in its Spike protein to date. Thus, it may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (93-100%) towards SARS-CoV-2 wild-type, but some reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination or vector-based AZD1222 or Ad26.CoV2.S performed less well with peak responder rates of 33%, 50% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argues for urgent booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based immunization scheme.
Developing formalin‐based fixative agents for post mortem brain MRI at 9.4 T
2021-12-21

Abstract Purpose To develop fixative agents for high‐field MRI with suitable dielectric properties and measure MR properties in immersion‐fixed brain tissue. Methods Dielectric properties of formalin‐based agents were assessed (100 MHz–4.5 GHz), and four candidate fixatives with/without polyvinylpyrrolidone (PVP) and different salt concentrations were formulated. B 1 field and MR properties ( T 1 , , R 2 , , and magnetic susceptibility [QSM]) were observed in white and gray matter of pig brain samples during 0.5–35 days of immersion fixation. The kinetics were fitted using exponential functions. The immersion time required to reach maximum values at different tissue depths was used to estimate the Medawar coefficient for fixative penetration. The effect of replacing the fixatives with Fluoroinert and phosphate‐buffered saline as embedding media was also evaluated. Results The dielectric properties of formalin were nonlinearly modified by increasing amounts of additives. With 5% PVP and 0.04% NaCl, the dielectric properties and B 1 field reflected in vivo conditions. The highest B 1 values were found in white matter with PVP and varied significantly with tissue depth and embedding media, but not with immersion time. The MR properties depended on PVP yielding lower T 1 , higher , more paramagnetic QSM values, and a lower Medawar coefficient (0.9 ; without PVP: 1.5). Regardless of fixative, switching to phosphate‐buffered saline as embedder caused a paramagnetic shift in QSM and decreased that progressed during 1 month of storage, whereas no differences were found with Fluorinert. Conclusion In vivo–like B 1 fields can be achieved in formalin fixatives using PVP and a low salt concentration, yielding lower T 1 , higher , and more paramagnetic QSM than without additives. The kinetics of allowed estimation of fixative tissue penetration.
Even under majority influence, great apes fail to copy novel actions
2021-12-21

It remains unclear when and why the ability to copy actions evolved and also its uniqueness to humans. Thus far, a lack of valid evidence for spontaneous action copying by other apes supports the view that only humans spontaneously copy actions. However, wild apes have access to multiple demonstrators and have been demonstrated to be affected by majority influences, thus raising the possibility that ape action copying might require a majority ratio of demonstrators to observers. We tested for spontaneous ape action copying across all four non-human great ape species using a demonstrator majority. Nineteen captive mother-reared apes (across 4 species) were tested (Raage=9-52; Mage=18.63; ♀=14; ♂=5). All failed to copy the demonstrated actions, despite observing it in a majority influence condition. We conclude that culture in non-human great apes is more likely supported by variants of social learning which regulate frequencies, rather than forms, of observed behaviours.
Global Change Modulated Asian Inland Climate Since 7.3 Ma: Carbonate Manganese Records in the Western Qaidam Basin
2021-12-21

Late Cenozoic drying of the Asian inland has not only exerted a profound impact on the regional environment but also affected global climate as an important source of global atmospheric dust. Continuous and accurately dated sediment records from the Asian interior are pivotal to a better understanding of the evolutionary history of Asian inland drying and the associated driving mechanisms. In this study, we present a continuous record of climate change in the Asian interior spanning the past 7.3 Myr, reconstructed by the redox evolution of a paleolake in the western Qaidam Basin, NE Tibetan Plateau. The paleolake redox conditions are linked to the oxygen concentration of lake bottom water and lake level, and were revealed by the manganese (Mn) concentration in the carbonate fraction (leached by the diluted acetic acid) of the carbonate-rich lacustrine sediments retrieved from two drill-cores (SG-1 and SG-1b). The reconstructed regional climate in the western Qaidam Basin shows long-term fluctuations, consistent with the secular evolution of the coeval global climate, especially the sea surface temperature variation in the high latitude North Atlantic. Three transitions of the paleolake hydrochemical system occurred at 6.2, 5.3, and 2.6 Ma, with a short drying stage at 6.2–5.3 Ma and prolonged Quaternary drying since 2.6 Ma. We argue that drying of the Asia interior has been dominantly forced by global cooling, in particular, the high-latitude cooling of the Northern Hemisphere.
Luminescence Sensitivity of Rhine Valley Loess: Indicators of Source Variability?
2021-12-21

Loess provides a valuable terrestrial record of past environmental conditions, including the dynamics and trajectories of air mass circulation responsible for dust transport. Here we explore variations in the luminescence sensitivity characteristics of sedimentary quartz and feldspar as possible tools for identifying changes in source down a loess-palaeosol sequence (LPS). Luminescence sensitivity is a rapidly measurable index which is the product of interplay between source lithology and the history of the quartz or feldspar clasts. Variations in sensitivity of down profile may therefore reflect changes in sediment provenance as well as other factors such as weathering through pedogenesis. We undertake an empirical investigation of the luminescence sensitivity of quartz and feldspar from different grain-size fractions from the Schwalbenberg LPS in the German Rhine valley. We compare samples from a 30 m core spanning the last full glacial cycle with samples of oxygen isotope stage (OIS) 3–2 age exposed within nearby profile. We find an overall inverse relationship between quartz and feldspar sensitivity, as well as variability in sensitivity between different quartz grain sizes. Statistical analyses yield a significant correlation between IR50 sensitivity from unprocessed sediments and clay content, and feldspar sensitivity and Si/Al ratios down the core. Since Si/Al ratios may indicate changes in provenance, the latter correlation suggests that IR50 measurements on unprocessed samples may be used to provide a reliable, rapid scan of source variability over millennial timescales.
Characterization of GPVI- or GPVI-CD39-Coated Nanoparticles and Their Impact on In Vitro Thrombus Formation
2021-12-21

Traditional antithrombotic agents commonly share a therapy-limiting side effect, as they increase the overall systemic bleeding risk. A novel approach for targeted antithrombotic therapy is nanoparticles. In other therapeutic fields, nanoparticles have enabled site-specific delivery with low levels of toxicity and side effects. Here, we paired nanotechnology with an established dimeric glycoprotein VI-Fc (GPVI-Fc) and a GPVI-CD39 fusion protein, thereby combining site-specific delivery and new antithrombotic drugs. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles, NP-BSA, NP-GPVI and NP-GPVI-CD39 were characterized through electron microscopy, atomic force measurements and flow cytometry. Light transmission aggregometry enabled analysis of platelet aggregation. Thrombus formation was observed through flow chamber experiments. NP-GPVI and NP-GPVI-CD39 displayed a characteristic surface coating pattern. Fluorescence properties were identical amongst all samples. NP-GPVI and NP-GPVI-CD39 significantly impaired platelet aggregation. Thrombus formation was significantly impaired by NP-GPVI and was particularly impaired by NP-GPVI-CD39. The receptor-coated nanoparticles NP-GPVI and the bifunctional molecule NP-GPVI-CD39 demonstrated significant inhibition of in vitro thrombus formation. Consequently, the nanoparticle-mediated antithrombotic effect of GPVI-Fc, as well as GPVI-CD39, and an additive impact of CD39 was confirmed. In conclusion, NP-GPVI and NP-GPVI-CD39 may serve as a promising foundation for a novel therapeutic approach regarding targeted antithrombotic therapy.
Scellseg: a style-aware cell instance segmentation tool with pre-training and contrastive fine-tuning
2021-12-21

Abstract Deep learning-based cell segmentation is increasingly utilized in cell biology and molecular pathology, due to massive accumulation of diverse large-scale datasets and excellent progress in cell representation. However, the development of specialized algorithms has long been hampered by a paucity of annotated training data, whereas the performance of generalist algorithm was limited without experiment-specific calibration. Here, we present a deep learning-based tool called Scellseg consisted of novel pre-trained network architecture and contrastive fine-tuning strategy. In comparison to four commonly used algorithms, Scellseg outperformed others in average precision and Aggregated Jaccard Index on three disparate datasets. Interestingly, we found that eight images are sufficient for model tuning to achieve satisfied performance based on a shot data scale experiment. We also developed a graphical user interface integrated with functions of annotation, fine-tuning and inference, that allows biologists to easily specialize their self-adaptive segmentation model for analyzing images at the single-cell level.
Regulating the Poor through Internal Borders: The EU in Historical and International Perspectives
2021-12-21

Tensions surrounding internal migrants’ access to welfare and the associated politicisations about who should shoulder the ‘fiscal burden’ are not unique to the European Union (EU). Based on a Most Different Systems Design and following an institutionalist approach, this article analyses the developments associated with freedom of movement and access to poor relief/social assistance in four economically and politically diverse jurisdictions. It also considers the implications of these developments for the EU. The four cases analysed are industrialising England, contemporary China, Germany, and the United States. Although economic integration was a necessary, it was not a sufficient condition for the abolishment of residence requirements for internal migrants in all four jurisdictions. Moreover, it took political power, various coalitions, or the leadership of actors to overcome the barriers and hurdles on the path to social citizenship in the wider territorial jurisdictions. Solidarity as a precondition did not play a significant role.
Nazugum, a new 4000 year old rockshelter site in the Ili Alatau, Tien Shan
2021-12-21

The PALAEOSILKROAD project has been conducting field surveys in Kazakhstan to explore the regional Palaeolithic record by targeting primarily caves and rockshelters. However, the survey also discovered numerous sites that were occupied during the Holocene. In this paper, we present our preliminary findings from the Nazugum rockshelter, a new archaeological site located in south-eastern Kazakhstan (Almaty region). The stratigraphic sequence demonstrates the transition from fluvial channel deposits without artifacts to aeolian loess deposits with lithics, charcoal remnants, and fragments of animal bones. The lithics recovered from the sediment wall are dominated by bladelet technology, characteristic for Holocene assemblages. Radiocarbon dates from adjacent charcoal samples yielded an age of 2461-2347 cal. years BC attributing the human occupation to the transitional period of late Eneolithic and early Bronze Age. Our study provides new data for the use of rockshelters in Kazakhstan during the late Holocene and lays the groundwork for future salvage work in Nazugum rockshelter due to the active erosion of the archaeological record.
Trial of Spesolimab for Generalized Pustular Psoriasis
2021-12-22

In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).