julilili42/papers huggingface dataset:
SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2
2021-04-22

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination because of progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-SCA3, SCA6, and SCA17; however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7 140Q/5Q , we analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphologic alterations, pacemaker dysfunction, and motor incoordination. Strikingly, most PC genes downregulated in SCA7 have also decreased expression in SCA1 and SCA2 mice, revealing converging pathomechanisms and a common disease signature involving cGMP-PKG and phosphatidylinositol signaling pathways and LTD. Our study thus points out molecular targets for therapeutic development, which may prove beneficial for several SCAs. Furthermore, we show that SCA7 140Q/5Q males and females exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology, and photoreceptor dystrophy, which account for progressive impairment of behavior, motor, and visual functions. SCA7 140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis. SIGNIFICANCE STATEMENT Spinocerebellar ataxia 7 (SCA7) is one of the several forms of inherited SCAs characterized by cerebellar degeneration because of polyglutamine expansion in specific proteins. The ATXN7 involved in SCA7 is a subunit of SAGA transcriptional coactivator complex. To understand the pathomechanisms of SCA7, we determined the cell type-specific gene deregulation in SCA7 mouse cerebellum. We found that the Purkinje cells are the most affected cerebellar cell type and show downregulation of a large subset of neuronal identity genes, critical for their spontaneous firing and synaptic functions. Strikingly, the same Purkinje cell genes are downregulated in mouse models of two other SCAs. Thus, our work reveals a disease signature shared among several SCAs and uncovers potential molecular targets for their treatment.
Does increasing social presence enhance the effectiveness of writing explanations?
2021-04-22

Writing explanations has demonstrated to be less effective than providing oral explanations, as writing triggers less amounts of perceived social presence during explaining. In this study, we investigated whether increasing social presence during writing explanations would aid learning. University students ( N = 137) read an instructional text about immunology; their subsequent task depended on experimental condition. Students either explained the contents to a fictitious peer orally, wrote their explanations in a text editor, or wrote them in a messenger chat, which was assumed to induce higher levels of social presence. A control group retrieved the material. Surprisingly, we did not obtain any differences in learning outcomes between experimental conditions. Interestingly, explaining was more effortful, enjoyable, and interesting than retrieving. This study shows that solely inducing social presence does not improve learning from writing explanations. More importantly, the findings underscore the importance of cognitive and motivational conditions during learning activities.
Evolutionary clonal trajectories in nodular lymphocyte-predominant Hodgkin lymphoma with high risk of transformation
2021-04-22

The B-cell architecture of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is complex since it is composed of malignant lymphocyte-predominant cells along with a rich B-cell bystander environment. To gain insight into molecular determinants of disease transformation, we studied B-cell evolutionary trajectories in lymphoma tissue from diagnosis to relapse or transformation to non- Hodgkin lymphoma by next-generation sequencing of immunoglobulin heavy chains. Patients with NLPHL that later transformed were older and showed IgD negativity, absence of the characteristic IGHV3/IGHD3/IGHJ6 lymphocyte-predominant rearrangement and high repertoire clonality. We constructed phylogenetic trees within the compartment of the malignant clone to investigate clonal evolution. In all relapsing cases, the lymphocyte-predominant rearrangement was identical at diagnosis and relapse. NLPHL cases with transformation showed more complex trajectories with strong intraclonal diversification. The dominant founder clone in transformations showed clonal evolution if derived from the same cell of origin, or arose from a different cell of origin. Together, our data point to a significant role of antigenic drive in the transformation of NLHPL and identify high B-cell repertoire clonality with dominant intraclonal lymphocyte-predominant cell diversification as a hallmark of transformation. Sequencing of initial paraffin-embedded tissue may therefore be applied diagnostically to identify NLPHL cases with high risk of transformation.
The ISSPP PIPAC database: design, process, access, and first interim analysis
2021-04-22

Abstract Objectives Several trials have documented the favorable safety profile, and promising clinical results of pressurized intraperitoneal aerosol chemotherapy (PIPAC) directed treatment in different types of peritoneal malignancies. However, until the results of randomized trials are available, the quality of documentation and acceptance by the users may be improved through a worldwide registry. The International Society for the Study of Pleura and Peritoneum ( www.ISSPP.org ) facilitated this process by creating a dedicated focus group and providing the funding needed for the creation and implementation of an international database. This article describes the design and the journey of establishing this international database and the first, preliminary results from the ISSPP PIPAC online database. Methods In 2019 the ISSPP PIPAC Registry Group started to create a database with a minimal dataset relevant to many diseases and applicable in different framework conditions. The task was divided into three phases including design, testing, implementation, protocol, handbook, legal requirements, as well as registry rules and bylaws for the registry group. Results The ISSPP PIPAC online database has six key elements (patient, consent, treatment, complications, response evaluation and follow-up). Following design, testing and implementation the database was successfully launched in June 2020. Ten institutions reported on 459 PIPAC procedures in 181 patients during the first 6 months, and the recorded data were comparable to the present literature. Conclusions A new international multicenter PIPAC database has been developed, tested and implemented under the auspices of ISSPP. The database is accessible through the ISSPP website ( www.ISSPP.org ), and PIPAC institutions worldwide are highly encouraged to participate.
PET/CT in malignant melanoma: a two‐tiered healthcare system? Updated healthcare situation regarding initial staging of malignant melanoma with PET/CT
2021-04-22

Summary Background Patients with stage IIC malignant melanoma are recommended to undergo cross‐sectional imaging for initial staging. PET/CT is superior to other methods regarding its diagnostic accuracy of the tumor spread in stage III. So far there is no meaningful data on the nationwide availability, usage and cost recovery of this imaging technique. Patients and methods Questionnaires on the healthcare situation in 2018 were sent to all German dermatology clinics and PET/CT centers in March and April 2019. Results 61.2 % of the dermatology clinics (71/115) and 48.2 % of the PET/CT centers (77/160) took part in the survey. A total of 22,645 patients with malignant melanoma were seen in these clinics in 2018. 16.8 % of the patients with stage IIC melanoma received a PET/CT for primary staging. The costs of this examination were covered for all statutory and privately insured patients in 40 % and 68 % of dermatology clinics (20/50 and 34/50), respectively. 68.0 % (34/50) of all dermatology clinics reported relevant changes of treatment according to PET/CT findings. Long examination periods by the health insurance companies and the time required to submit the application were the most common reasons for dermatology clinics to reject a request for PET/CT. Relevant incidental findings were reported in 90.2 % (47/51) of all PET/CT centers. Conclusions There are clear differences in the nationwide availability and cost coverage of PET/CT in primary staging for stage IIC melanoma. For these reasons, a two‐tiered healthcare system may be assumed.
Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability
2021-04-22

Abstract Polymerase δ‐interacting protein 2 (POLDIP2, PDIP38) is a multifaceted, “moonlighting” protein, involved in binding protein partners from many different cellular processes, including mitochondrial metabolism and DNA replication and repair. How POLDIP2 interacts with many different proteins is unknown. Towards this goal, we present the crystal structure of POLDIP2 to 2.8 Å, which exhibited a compact two‐domain β‐strand‐rich globular structure, confirmed by circular dichroism and small angle X‐ray scattering approaches. POLDIP2 comprised canonical DUF525 and YccV domains, but with a conserved domain linker packed tightly, resulting in an “extended” YccV module. A central channel was observed, which we hypothesize could influence structural changes potentially mediated by redox conditions, following observation of a modified cysteine residue in the channel. Unstructured regions were rebuilt by ab initio modelling to generate a model of full‐length POLDIP2. Molecular dynamics simulations revealed a highly dynamic N‐terminal region tethered to the YccV‐domain by an extended linker, potentially facilitating interactions with distal binding partners. Models of POLDIP2 complexed with two of its partners, PrimPol and PCNA, indicated that dynamic flexibility of the POLDIP2 N‐terminus and loop regions likely mediate protein interactions.
A duplication on chromosome 16q12 affecting theIRXBgene cluster is associated with autosomal dominant cone dystrophy with early tritanopic color vision defect
2021-04-22

Abstract Cone dystrophies are a rare subgroup of inherited retinal dystrophies and hallmarked by color vision defects, low or decreasing visual acuity and central vision loss, nystagmus and photophobia. Applying genome-wide linkage analysis and array comparative genome hybridization, we identified a locus for autosomal dominant cone dystrophy on chromosome 16q12 in four independent multigeneration families. The locus is defined by duplications of variable size with a smallest region of overlap of 608 kb affecting the IRXB gene cluster and encompasses the genes IRX5 and IRX6. IRX5 and IRX6 belong to the Iroquois (Iro) protein family of homeodomain-containing transcription factors involved in patterning and regionalization of embryonic tissue in vertebrates, including the eye and the retina. All patients presented with a unique progressive cone dystrophy phenotype hallmarked by early tritanopic color vision defects. We propose that the disease underlies a misregulation of the IRXB gene cluster on chromosome 16q12 and demonstrate that overexpression of Irx5a and Irx6a, the two orthologous genes in zebrafish, results in visual impairment in 5-day-old zebrafish larvae.
The Autophagy Receptor TAX1BP1 (T6BP) is a novel player in antigen presentation by MHC-II molecules
2021-04-22

Abstract CD4 + T lymphocytes play a major role in the establishment and maintenance of immunity. They are activated by antigenic peptides derived from extracellular or newly synthesized (endogenous) proteins presented on the surface of antigen presenting cells (APCs) by the MHC-II molecules. The pathways leading to endogenous MHC-II presentation remain poorly characterized. We demonstrate here that the autophagy receptor, T6BP, influences both autophagy-dependent and -independent endogenous presentation of HIV- and HCMV-derived peptides. By studying the immunopeptidome of MHC-II molecules, we show that T6BP affects both the quantity and quality of peptides presented. T6BP silencing induces the mislocalization of the MHC-II-loading compartments and a rapid degradation of the invariant chain (CD74) without altering the expression and internalization kinetics of MHC-II molecules. We determined the interactome of T6BP, identified calnexin as a T6BP partner and show that CANX cytosolic tail is required for this interaction. Remarkably, calnexin silencing replicates the functional consequences of T6BP silencing: decreased CD4 + T cell activation and exacerbated CD74 degradation. Altogether, we unravel T6BP as a key player of the MHC-II-restricted endogenous presentation pathway and we propose one potential mechanism of action.
From Univariate to Multivariate Coupling Between Continuous Signals and Point Processes: A Mathematical Framework
2021-04-22

Abstract Time series data sets often contain heterogeneous signals, composed of both continuously changing quantities and discretely occurring events. The coupling between these measurements may provide insights into key underlying mechanisms of the systems under study. To better extract this information, we investigate the asymptotic statistical properties of coupling measures between continuous signals and point processes. We first introduce martingale stochastic integration theory as a mathematical model for a family of statistical quantities that include the phase locking value, a classical coupling measure to characterize complex dynamics. Based on the martingale central limit theorem, we can then derive the asymptotic gaussian distribution of estimates of such coupling measure that can be exploited for statistical testing. Second, based on multivariate extensions of this result and random matrix theory, we establish a principled way to analyze the low-rank coupling between a large number of point processes and continuous signals. For a null hypothesis of no coupling, we establish sufficient conditions for the empirical distribution of squared singular values of the matrix to converge, as the number of measured signals increases, to the well-known Marchenko-Pastur (MP) law, and the largest squared singular value converges to the upper end of the MP support. This justifies a simple thresholding approach to assess the significance of multivariate coupling. Finally, we illustrate with simulations the relevance of our univariate and multivariate results in the context of neural time series, addressing how to reliably quantify the interplay between multichannel local field potential signals and the spiking activity of a large population of neurons.
Endogenous but not sensory-driven activity controls migration, morphogenesis and survival of adult-born neurons in the mouse olfactory bulb
2021-04-22

Summary The development and survival of adult-born neurons is believed to be driven by sensory signaling. By genetically manipulating excitability of adult-born cells (via cell-specific overexpression of either Kv1.2 or Kir2.1 K + channels), longitudinal in vivo monitoring of their Ca 2+ signaling and transcriptome analyses, we show that endogenous but not sensory-driven activity governs migration, morphogenesis, survival, and functional integration of adult-born juxtaglomerular neurons in the mouse olfactory bulb. The proper development of these cells required fluctuations of cytosolic Ca 2+ levels, phosphorylation of CREB, and pCREB-mediated gene expression. Attenuating Ca 2+ fluctuations via K + channel overexpression strongly downregulated genes involved in neuronal migration, differentiation, and morphogenesis and upregulated apoptosis-related genes, thus locking adult-born cells in the vulnerable and immature state. Together, the data reveal signaling pathways connecting the endogenous intermittent neuronal activity/Ca 2+ fluctuations as well as proper Kv1.2/Kir2.1 K + channel function to migration, maturation, and survival of adult-born neurons.
Structure-based design of selective Salt-inducible kinase (SIK) inhibitors
2021-04-22

The Salt inducible kinases (SIKs) are key metabolic regulators and an imbalance of their function is related to many diseases, most prominently in the context of breast, gastric and ovarian cancer. The currently available chemical tools used to study the roles of SIK in different diseases are still lacking selectivity within the family of protein kinases. In this work we present the structure-based design of new SIK inhibitors that led to a new chemical tool <strong>10</strong> (MRIA9) - a highly potent dual panSIK and PAK1-3 inhibitor with excellent cellular activity. We show that MRIA9 can sensitize ovarian cancer cells to the treatment with the mitotic agent paclitaxel arguing for a beneficial combination therapy first demonstrated by genetic knock down studies. Additionally, we present MRIA9 as a chemical probe for delineating the complex biology of SIK kinases when used in combination with a selective PAK inhibitor such as the highly selective allosteric inhibitor NVS-PAK1 as a control. Here you will find enclosed the raw trajectories for MD simulations for SIK2 and MST3 with the lead compounds. (trajectory format is out.cms and the full trj files, Schrödinger, LLC, New York, NY, 2018-2019, more details on the materials and methods section of the respective publication).
DamageProfiler: fast damage pattern calculation for ancient DNA
2021-04-23

Abstract Motivation In ancient DNA research, the authentication of ancient samples based on specific features remains a crucial step in data analysis. Because of this central importance, researchers lacking deeper programming knowledge should be able to run a basic damage authentication analysis. Such software should be user-friendly and easy to integrate into an analysis pipeline. Results DamageProfiler is a Java-based, stand-alone software to determine damage patterns in ancient DNA. The results are provided in various file formats and plots for further processing. DamageProfiler has an intuitive graphical as well as command line interface that allows the tool to be easily embedded into an analysis pipeline. Availability and implementation All of the source code is freely available on GitHub (https://github.com/Integrative-Transcriptomics/DamageProfiler). Supplementary information Supplementary data are available at Bioinformatics online.
Dietary Modulation of Bacteriophages as an Additional Player in Inflammation and Cancer
2021-04-23

Natural compounds such as essential oils and tea have been used successfully in naturopathy and folk medicine for hundreds of years. Current research is unveiling the molecular role of their antibacterial, anti-inflammatory, and anticancer properties. Nevertheless, the effect of these compounds on bacteriophages is still poorly understood. The application of bacteriophages against bacteria has gained a particular interest in recent years due to, e.g., the constant rise of antimicrobial resistance to antibiotics, or an increasing awareness of different types of microbiota and their potential contribution to gastrointestinal diseases, including inflammatory and malignant conditions. Thus, a better knowledge of how dietary products can affect bacteriophages and, in turn, the whole gut microbiome can help maintain healthy homeostasis, reducing the risk of developing diseases such as diverse types of gastroenteritis, inflammatory bowel disease, or even cancer. The present review summarizes the effect of dietary compounds on the physiology of bacteriophages. In a majority of works, the substance class of polyphenols showed a particular activity against bacteriophages, and the primary mechanism of action involved structural damage of the capsid, inhibiting bacteriophage activity and infectivity. Some further dietary compounds such as caffeine, salt or oregano have been shown to induce or suppress prophages, whereas others, such as the natural sweeter stevia, promoted species-specific phage responses. A better understanding of how dietary compounds could selectively, and specifically, modulate the activity of individual phages opens the possibility to reorganize the microbial network as an additional strategy to support in the combat, or in prevention, of gastrointestinal diseases, including inflammation and cancer.
Basic reading and reading-related language skills in adults with deficient reading comprehension who read a transparent orthography
2021-04-23

Abstract This study set out to examine the basic reading skills (accuracy and fluency in decoding, word and text reading) and some of the reading-related language skills (phonological awareness and rapid-naming) of 54 adults with low reading comprehension, who read the transparent German orthography. Participants were born in Germany and showed a typical non-verbal processing speed. With the exception of reading accuracy, participants were expected to present deficits in all basic reading and reading-related skills. The average performance in measures of decoding and word reading fluency was extremely low. A notable proportion of the sample, however, did not present a deficit in these measures. As expected, the average rate of reading errors was generally low. Nevertheless, text reading accuracy was deficient for one quarter of the sample. Tests addressing the reading-related language skills also indicated an average low performance in phonological awareness, but not in rapid-naming. Here too, a notable variance was observed. These results suggest that deficits in the basic reading skills and in phonological awareness characterise, on average, adults with low reading comprehension. At the same time, significant deficits in reading comprehension in this population do not necessarily imply deficits in the more basic skills of reading as well. In addition, the results indicate that reading accuracy constitutes a source of difficulty for some of these adults, despite the reading of a transparent orthography. The sources for the variance in performance throughout the different reading and reading-related measures remain to be explored.