julilili42/papers huggingface dataset:
Comparing efficacy and side effects of two systemic chemotherapy regimens for eye‐preserving therapy in children with retinoblastoma
2021-10-04

Abstract Background Eye‐preserving therapy in retinoblastoma comprises systemic chemotherapy, but studies analyzing the efficacy of different chemotherapy regimens are scarce. Methods The efficacy and side effects of two different eye‐preserving chemotherapy regimens containing either vincristine, etoposide, and carboplatin (VEC) or cyclophosphamide, vincristine, etoposide, and carboplatin (CyVEC) were compared in a prospective non‐interventional observational study including children diagnosed with retinoblastoma between 2013 and 2019 in Germany and Austria. Event‐free eye survival (EFES) and overall eye survival (OES) of all 164 eyes treated with both regimens and risk factors were investigated. Results The EFES after VEC (2‐year EFES 72.3%) was higher than after CyVEC (2‐year EFES 50.4%) ( p logrank &lt; .001). The OES did not differ significantly between the two treatment groups ( p logrank = .77; 2‐year OES VEC: 82.1% vs. CyVEC: 84.8%). Advanced International Classification of Retinoblastoma (ICRB) group was prognostic for a lower EFES ( p logrank &lt; .0001; 2‐year EFES ICRB A/B/C 71.3% vs. ICRB D/E 43.0%) and OES ( p logrank &lt; .0001; 2‐year OES ICRB A/B/C 93.1% vs. ICRB D/E 61.5%). The multivariate analysis showed that age at diagnosis older than 12 months and ICRB A/B/C were associated with better EFES. No second malignancies or ototoxicities were reported after a follow‐up of median 3.1 years after diagnosis of retinoblastoma (range 0.1–6.9 years). Conclusions Despite omitting cyclophosphamide, the EFES was higher after VEC chemotherapy that contains higher doses of carboplatin compared to CyVEC. The major risk factor for enucleation was advanced ICRB tumor grouping. Randomized clinical trials on efficacy and side effects of eye‐preserving chemotherapy are required to tailor treatment protocols for retinoblastoma patients.
Evaluating the Distribution of Bacterial Natural Product Biosynthetic Genes across Lake Huron Sediment
2021-10-04

Environmental microorganisms continue to serve as a major source of bioactive natural products (NPs) and as an inspiration for many other scaffolds in the toolbox of modern medicine. Nearly all microbial NP-inspired therapies can be traced to field expeditions to collect samples from the environment. Despite the importance of these expeditions in the search for new drugs, few studies have attempted to document the extent to which NPs or their corresponding production genes are distributed within a given environment. To gain insights into this, the geographic occurrence of NP ketosynthase (KS) and adenylation (A) domains was documented across 53 and 58 surface sediment samples, respectively, covering 59,590 square kilometers of Lake Huron. Overall, no discernible NP geographic distribution patterns were observed for 90,528 NP classes of nonribosomal peptides and polyketides detected in the survey. While each sampling location harbored a similar number of A domain operational biosynthetic units (OBUs), a limited overlap of OBU type was observed, suggesting that at the sequencing depth used in this study, no single location served as a NP "hotspot". These data support the hypothesis that there is ample variation in NP occurrence between sampling sites and suggest that extensive sample collection efforts are required to fully capture the functional chemical diversity of sediment microbial communities on a regional scale.
Characterization of hepatic zonation in mice by mass-spectrometric and antibody-based proteomics approaches
2021-10-04

Abstract Periportal and perivenous hepatocytes show zonal heterogeneity in metabolism and signaling. Here, hepatic zonation in mouse liver was analyzed by non-targeted mass spectrometry (MS) and by the antibody-based DigiWest technique, yielding a comprehensive overview of protein expression in periportal and perivenous hepatocytes. Targeted immunoaffinity-based proteomics were used to substantiate findings related to drug metabolism. 165 (MS) and 82 (DigiWest) zonated proteins were identified based on the selected criteria for statistical significance, including 7 (MS) and 43 (DigiWest) proteins not identified as zonated before. New zonated proteins especially comprised kinases and phosphatases related to growth factor-dependent signaling, with mainly periportal localization. Moreover, the mainly perivenous zonation of a large panel of cytochrome P450 enzymes was characterized. DigiWest data were shown to complement the MS results, substantially improving possibilities to bioinformatically identify zonated biological processes. Data mining revealed key regulators and pathways preferentially active in either periportal or perivenous hepatocytes, with β-catenin signaling and nuclear xeno-sensing receptors as the most prominent perivenous regulators, and several kinase- and G-protein-dependent signaling cascades active mainly in periportal hepatocytes. In summary, the present data substantially broaden our knowledge of hepatic zonation in mouse liver at the protein level.
Neighborhood and Child Development at Age Five: A UK–US Comparison
2021-10-04

Early childhood is a critical period in the life course, setting the foundation for future life. Early life contexts—neighborhoods and families—influence developmental outcomes, especially when children are exposed to economic and social disadvantage. Residential mobility, frequent among families with pre-school children, may reduce or increase exposure to adverse surroundings. We examine children’s cognitive and behavioral outcomes at age five, in relation to neighborhood composition, family circumstances and residential moves, using two longitudinal micro datasets: an urban subsample of the UK Millennium Cohort Study (N up to 7967), and the Fragile Families and Child Wellbeing Study in the US (N up to 1820). Each is linked to an index of neighborhood advantage, created to make UK/US comparisons, based on census and administrative information. A series of estimates indicate a strong association, in both countries, between cognitive scores and neighborhood advantage, attenuated but not eliminated by family circumstances. Children’s behavior problems, on the other hand, show less association with neighborhood advantage. There are minor and mixed differences by residential mobility particularly when neighborhood disadvantage changes. Notwithstanding the primacy of the family in predicting preschool development, the findings support the notion of neighborhood as potentially advantageous at least in relation to cognitive outcomes.
Substrate Effects on the Bandwidth of CdSe Quantum Dot Photodetectors
2021-10-04

We investigate the time-resolved photocurrent response of CdSe quantum dot (QD) thin films sensitized with zinc beta-tetraaminophthalocyanine (Zn4APc) on three different substrates, namely silicon with 230 nm SiO2 dielectric, glass as well as polyimide. While Si/SiO2(230 nm) is not suitable for any transient photocurrent characterization due to an interfering photocurrent response of the buried silicon, we find that polyimide substrates invoke the larger optical bandwidth with 85 kHz vs. 67 kHz for the same quantum dot thin film on glass. Upon evaluation of the transient photocurrent, we find that the photoresponse of the CdSe quantum dot films can be described as a combination of carrier recombination and fast trapping within 2.7 ns, followed by slower multiple trapping events. The latter are less pronounced on polyimide, which leads to the higher bandwidth. We show that all devices are RC-time limited and that improvements of the photoresistance are the key to further increasing the bandwidth.
Modelling the neural code in large populations of correlated neurons
2021-10-05

Neurons respond selectively to stimuli, and thereby define a code that associates stimuli with population response patterns. Certain correlations within population responses (noise correlations) significantly impact the information content of the code, especially in large populations. Understanding the neural code thus necessitates response models that quantify the coding properties of modelled populations, while fitting large-scale neural recordings and capturing noise correlations. In this paper, we propose a class of response model based on mixture models and exponential families. We show how to fit our models with expectation-maximization, and that they capture diverse variability and covariability in recordings of macaque primary visual cortex. We also show how they facilitate accurate Bayesian decoding, provide a closed-form expression for the Fisher information, and are compatible with theories of probabilistic population coding. Our framework could allow researchers to quantitatively validate the predictions of neural coding theories against both large-scale neural recordings and cognitive performance.
Chemotactic and temperature-dependent responses of the Strongyloidoidea superfamily of nematodes
2021-10-05

Abstract Host-seeking behaviour and how a parasite identifies the correct host to infect remains a poorly understood area of parasitology. What is currently known is that host sensation and seeking behaviour is formed from a complex mixture of chemo-, thermo- and mechanosensory behaviours, of which chemosensation is the best studied. Previous studies of olfaction in parasitic nematodes suggested that this behaviour appears to be more closely related to target host and infection mode than phylogeny. However, there has not yet been a study comparing the chemotactic and temperature-dependent behaviours of very closely related parasitic and non-parasitic nematodes. To this end, we examined the temperature-dependent and chemotactic responses of the Strongyloidoidea superfamily of nematodes. We found differences in temperature response between the different species and within infective larvae. Chemotactic responses were highly divergent, with different attraction profiles between all species studied. When examining direct stimulation with fur, we found that it was insufficient to cause an attractive response. Overall, our results support the notion that olfactory sensation is more closely related to lifestyle and host range than phylogeny, and that multiple cues are required to initiate host-seeking behaviour.
English varieties in Asia: Features, implications and practices - Andy Kirkpatrick & Wang Lixun (eds.), Is English an Asian Language? Queensland/ Hong Kong: Cambridge University Press, 2020. Pp. viii+238. Hardback $110.00(C), ISBN: 9781107134683
2021-10-05

English varieties in Asia: Features, implications and practices - Andy Kirkpatrick &amp; Wang Lixun (eds.), Is English an Asian Language? Queensland/ Hong Kong: Cambridge University Press, 2020. Pp. viii+238. Hardback $110.00(C), ISBN: 9781107134683
Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein
2021-10-05

Abstract Pathologic inclusions composed of α-synuclein called Lewy pathology are hallmarks of Parkinson’s Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and α-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of α- synuclein, and enhances formation of pathologic α-synuclein, particularly when synaptic activity is increased. α-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence α-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences α-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of α-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo , was used to more precisely resolve the presynaptic localization of α-synuclein. Live imaging of axonal transport of α-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on α-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases α-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of α- synuclein-GFP. In vivo , LRRK2 inhibition increases α-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of α-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of α-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.
Inherited variants in CHD3 demonstrate variable expressivity in Snijders Blok-Campeau syndrome
2021-10-05

Summary Interpretation of next-generation sequencing data of individuals with an apparent sporadic neurodevelopmental disorder (NDD) often focusses on pathogenic variants in genes associated with NDD, assuming full clinical penetrance with limited variable expressivity. Consequently, inherited variants in genes associated with dominant disorders may be overlooked when the transmitting parent is clinically unaffected. While de novo variants explain a substantial proportion of cases with NDDs, a significant number remains undiagnosed possibly explained by coding variants associated with reduced penetrance and variable expressivity. We characterized twenty families with inherited heterozygous missense or protein-truncating variants (PTVs) in CHD3 , a gene in which de novo variants cause Snijders Blok-Campeau syndrome, characterized by intellectual disability, speech delay and recognizable facial features (SNIBCPS). Notably, the majority of the inherited CHD3 variants were maternally transmitted. Computational facial and human phenotype ontology-based comparisons demonstrated that the phenotypic features of probands with inherited CHD3 variants overlap with the phenotype previously associated with de novo variants in the gene, while carrier parents are mildly or not affected, suggesting variable expressivity. Additionally, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of related healthy carriers with a CHD3 PTV, suggested that compensation of expression from the wildtype allele is unlikely to be an underlying mechanism. Our results point to a significant role of inherited variation in SNIBCPS, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation towards understanding the broader contributions of such variation to the landscape of human disease.
Report on 2104.11160v2
2021-10-05

We study the dynamics of a one-dimensional Rydberg lattice gas under facilitation (anti-blockade) conditions which implements a so-called kinetically constrained spin system.Here an atom can only be excited to a Rydberg state when one of its neighbors is already excited.Once two or more atoms are simultaneously excited mechanical forces emerge, which couple the internal electronic dynamics of this many-body system to external vibrational degrees of freedom in the lattice.This electron-phonon coupling results in a so-called phonon dressing of many-body states which in turn impacts on the facilitation dynamics.In our theoretical study we focus on a scenario in which all energy scales are sufficiently separated such that a perturbative treatment of the coupling between electronic and vibrational states is possible.This allows to analytically derive an effective Hamiltonian for the evolution of consecutive clusters of Rydberg excitations in the presence of phonon dressing.We analyze the spectrum of this Hamiltonian and show -by employing Fano resonance theory -that the interaction between Rydberg excitations and lattice vibrations leads to the emergence of slowly decaying bound states that inhibit fast relaxation of certain initial states.
A multimodal cell census and atlas of the mammalian primary motor cortex
2021-10-06

Abstract Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization 1–5 . First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
Intracellular Lipid Accumulation and Mitochondrial Dysfunction Accompanies Endoplasmic Reticulum Stress Caused by Loss of the Co-chaperone DNAJC3
2021-10-06

Recessive mutations in DNAJC3 , an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation.
Optimizing Research Output: How Can Psychological Research Methods Be Improved?
2021-10-06

Recent evidence suggests that research practices in psychology and many other disciplines are far less effective than previously assumed, which has led to what has been called a “crisis of confidence” in psychological research (e.g., Pashler &amp; Wagenmakers 2012 ). In response to the perceived crisis, standard research practices have come under intense scrutiny, and various changes have been suggested to improve them. The burgeoning field of metascience seeks to use standard quantitative data-gathering and modeling techniques to understand the reasons for inefficiency, to assess the likely effects of suggested changes, and ultimately to tell psychologists how to do better science. We review the pros and cons of suggested changes, highlighting the many complex research trade-offs that must be addressed to identify better methods.
Follicular lymphoma subgroups with and without t(14;18) differ in their N-glycosylation pattern and IGHV usage
2021-10-06

Abstract We previously reported that t(14;18)-negative follicular lymphomas (FL) show a clear reduction of newly acquired N-glycosylation sites (NANGS) in immunoglobulin genes. We therefore aimed to investigate in-depth the occurrence of NANGS in a larger cohort of t(14;18)-positive and t(14;18)-negative FL, including early (I/II) and advanced (III/IV) stage treatment-naive and relapsed tumors. The clonotype was determined by using a next-generation sequencing approach in a series of 68 FL with fresh frozen material [36 t(14;18) positive and 32 t(14;18) negative]. The frequency of NANGS differed considerably between t(14;18)-positive and t(14;18)-negative FL stage III/IV, but no difference was observed among t(14;18)-positive and t(14;18)-negative FL stage I/II. The introduction of NANGS in all t(14;18)-negative clinical subgroups occurred significantly more often in the FR3 region. Moreover, t(14;18)-negative treatment-naive FL, specifically those with NANGS, showed a strong bias for IGHV4-34 usage compared with t(14;18)-positive treatment-naive cases with NANGS; IGHV4-34 usage was never recorded in relapsed FL. In conclusion, subgroups of t(14;18)-negative FL might use different mechanisms of B-cell receptor stimulation compared with the lectin-mediated binding described in t(14;18)-positive FL, including responsiveness to autoantigens as indicated by biased IGHV4-34 usage and strong NANGS enrichment in FR3.
Contrast Sensitivity Testing in Healthy and Blurred Vision Conditions Using a Novel Optokinetic Nystagmus Live-Detection Method
2021-10-06

OKN-based CS is a novel approach to assess spatial vision, which is sensitive to subtle effects of defocus, allowing use with nonverbal patients and infants. Furthermore, the newly developed tool may improve the performance of such measurements.
No Evidence of Robust Noun-Referent Associations in German-Learning 6- to 14-Month-Olds
2021-10-06

Work with the looking-while-listening (LWL-) paradigm suggested that 6-month-old English-learning infants associated several labels for common nouns with pictures of their referents: While one distractor picture was present, infants systematically fixated the named target picture. However, recent work revealed constraints of infants' noun comprehension. The age at which these abilities can be obtained appears to relate to the infants' familiarity with the talker, the target language, and word frequency differences in target-distractor pairs. Here, we present further data to this newly established field of research. We tested 42 monolingual German-learning infants aged 6–14 months by means of the LWL-paradigm. Infants saw two pictures side-by-side on a screen, whilst an unfamiliar male talker named one of both. Overall, infants did not fixate the target picture more than the distractor picture. In line with previous results, infants' performance on the task was higher when target and distractor differed within their word frequency—as operationalized by the parental rating of word exposure. Together, our results add further evidence for constraints on early word learning. They point to cross-linguistic differences in early word learning and strengthen the view that infants might use extra-linguistic cues within the stimulus pairing, such as frequency imbalance, to disambiguate between two potential referents.