bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decreased intrinsic excitability of cerebellar Purkinje cells following optokinetic learning in mice
Authors: Kim Yong Gyu , Kim Sang Jeong 
Published: October 2020

AbstractThe optokinetic response (OKR), a reflexive eye movement evoked by a motion of the visual field, is known to adapt its strength to cope with an environmental change throughout life, which is a type of cerebellum-dependent learning. Previous studies suggested that OKR learning induces changes in in-vivo spiking activity and synaptic transmission of the cerebellar Purkinje cell (PC). Despite the recent emphasis on the importance of the intrinsic excitability related to learning and memory, the direct correlation between the intrinsic excitability of PCs and OKR learning has not been tested. In the present study, by utilizing the whole-cell patch-clamp recording, we compared the responses of cerebellar PCs to somatic current injection between the control and learned groups. We found that the neurons from the learned group showed a significant reduction in mean firing rate compared with neurons in the control group. In the analysis of single action potential (AP), we revealed that the rheobase current for the generation of single AP was increased by OKR learning, while AP threshold, AP amplitude, and afterhyperpolarization amplitude were not altered. Taken together, our result suggests that the decrease in the intrinsic excitability was induced in the cerebellar PC of learned group by an increase in the current threshold for generating AP.
Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress
Authors: Sheng Weiwei , Wang Guosen , Tang Jingtong , Shi Xiaoyang , Cao Rongxian , Sun Jian , Lin Yi Heng , Jia Chao , Chen Chuanping , Zhou Jianping , Dong Ming 
Published: October 2020

Abstract
Background
Our previous study showed that calreticulin (CRT) promoted EGF-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer (PC) via Integrin/EGFR-ERK/MAPK signaling. We next investigated the novel signal pathway and molecular mechanism involving the oncogenic role of CRT in PC.

Methods
We investigated the potential role and mechanism of CRT in regulating intracellular free Ca2+ dependent acute and chronic endoplasmic reticulum stress (ERS)-induced EMT in PC in vitro and vivo.

Results
Thapsigargin (TG) induced acute ERS via increasing intracellular free Ca2+ in PC cells, which was reversed by CRT silencing. Additionally, CRT silencing inhibited TG-induced EMT in vitro by reversing TG-induced changes of the key proteins in EMT signaling (ZO-1, E-cadherin and Slug) and ERK/MAPK signaling (pERK). TG-promoted cell invasion and migration was also rescued by CRT silencing but enhanced by IRE1α silencing (one of the key stressors in unfolded protein response). Meanwhile, CRT was co-immunoprecipitated and co-localized with IRE1α in vitro and its silencing led to the chronic ERS via upregulating IRE1α independent of IRE1-XBP1 axis. Moreover, CRT silencing inhibited IRE1α silencing-promoted EMT, including inhibiting the activation of EMT and ERK/MAPK signaling and the promotion of cell mobility. In vivo, CRT silencing decreased subcutaneous tumor size and distant liver metastasis following with the increase of IRE1α expression. A negative relationship between CRT and IRE1α was also observed in clinical PC samples, which coordinately promoted the advanced clinical stages and poor prognosis of PC patients.

Conclusions
CRT promotes EMT in PC via mediating intracellular free Ca2+ dependent TG-induced acute ERS and IRE1α-mediated chronic ERS via Slug and ERK/MAPK signaling.
Nicotinamide inhibits melanoma in vitro and in vivo
Authors: Scatozza Francesca , Moschella Federica , D’Arcangelo Daniela , Rossi Stefania , Tabolacci Claudio , Giampietri Claudia , Proietti Enrico , Facchiano Francesco , Facchiano Antonio 
Published: October 2020

Abstract
Background
Even though new therapies are available against melanoma, novel approaches are needed to overcome resistance and high-toxicity issues. In the present study the anti-melanoma activity of Nicotinamide (NAM), the amide form of Niacin, was assessed in vitro and in vivo.

Methods
Human (A375, SK-MEL-28) and mouse (B16-F10) melanoma cell lines were used for in vitro investigations. Viability, cell-death, cell-cycle distribution, apoptosis, Nicotinamide Adenine Dinucleotide+ (NAD+), Adenosine Triphosphate (ATP), and Reactive Oxygen Species (ROS) levels were measured after NAM treatment. NAM anti-SIRT2 activity was tested in vitro; SIRT2 expression level was investigated by in silico transcriptomic analyses. Melanoma growth in vivo was measured in thirty-five C57BL/6 mice injected subcutaneously with B16-F10 melanoma cells and treated intraperitoneally with NAM. Interferon (IFN)-γ-secreting murine cells were counted with ELISPOT assay. Cytokine/chemokine plasmatic levels were measured by xMAP technology. Niacin receptors expression in human melanoma samples was also investigated by in silico transcriptomic analyses.

Results
NAM reduced up to 90% melanoma cell number and induced: i) accumulation in G1-phase (40% increase), ii) reduction in S- and G2-phase (about 50% decrease), iii) a 10-fold increase of cell-death and 2.5-fold increase of apoptosis in sub-G1 phase, iv) a significant increase of NAD+, ATP, and ROS levels, v) a strong inhibition of SIRT2 activity in vitro. NAM significantly delayed tumor growth in vivo (p ≤ 0.0005) and improved survival of melanoma-bearing mice (p ≤ 0.0001). About 3-fold increase (p ≤ 0.05) of Interferon-gamma (IFN-γ) producing cells was observed in NAM treated mice. The plasmatic expression levels of 6 cytokines (namely: Interleukin 5 (IL-5), Eotaxin, Interleukin 12 (p40) (IL12(p40)), Interleukin 3 (IL-3), Interleukin 10 (IL-10) and Regulated on Activation Normal T Expressed and Secreted (RANTES) were significantly changed in the blood of NAM treated mice, suggesting a key role of the immune response. The observed inhibitory effect of NAM on SIRT2 enzymatic activity confirmed previous evidence; we show here that SIRT2 expression is significantly increased in melanoma and inversely related to melanoma-patients survival. Finally, we show for the first time that the expression levels of Niacin receptors HCAR2 and HCAR3 is almost abolished in human melanoma samples.

Conclusion
NAM shows a relevant anti-melanoma activity in vitro and in vivo and is a suitable candidate for further clinical investigations.
The Mayaro virus and its potential epidemiological consequences in Colombia: an exploratory biomathematics analysis
Authors: Valencia-Marín Bryan Steven , Gandica Irene Duarte , Aguirre-Obando Oscar Alexander 
Published: October 2020

AbstractBackgroundMayaro virus (Togaviridae) is an endemic arbovirus of the Americas with epidemiological similarities with the agents of other more prominent diseases such as dengue (Flaviviridae), Zika (Flaviviridae), and chikungunya (Togaviridae). It is naturally transmitted in a sylvatic/rural cycle byHaemagogusspp., but, potentially, it could be incorporated and transmitted in an urban cycle byAedes aegypti, a vector widely disseminated in the Americas.MethodsThe Mayaro arbovirus dynamics was simulated mathematically in the colombian population in the eight biogeographical provinces, bearing in mind the vector’s population movement between provinces through passive transportviatruck cargo. The parameters involved in the virus epidemiological dynamics, as well as the vital rates ofAe. aegyptiin each of the biogeographical provinces were obtained from the literature. These data were included in a meta-population model in differential equations, represented by a model structured by age for the dynamic population ofAe. aegypticombined with an epidemiological SEI/SEIR-type model. In addition, the model was incorporated with a term of migration to represent the connectivity between the biogeographical provinces.ResultsThe vital rates and the development cycle ofAe. aegyptivaried between provinces, having greater biological potential between 23 °C and 28 °C in provinces of Imerí, biogeographical Chocó, and Magdalena, with respect to the North-Andean Moorland (9.33–21.38 °C). Magdalena and Maracaibo had the highest flow of land cargo. The results of the simulations indicate that Magdalena, Imerí, and biogeographical Chocó would be the most affected regarding the number of cases of people infected by Mayaro virus over time.ConclusionsThe temperature in each of the provinces influences the local population dynamics ofAe. aegyptiand passive migrationviatransport of land cargo plays an important role on how the Mayaro virus would be disseminated in the human population. Once this arbovirus begins an urban cycle, the most-affected departments would be Antioquia, Santander, Norte de Santander, Cesar (Provinces of Magdalena), and Valle del Cauca, and Chocó (biogeographical province of Chocó), which is why vector control programmes must aim their efforts at these departments and include some type of vector control to the transport of land cargo to avoid a future Mayaro epidemic.
Interplay of pericentromeric genome organization and chromatin landscape regulates the expression of Drosophila melanogaster heterochromatic genes
Authors: Saha Parna , Sowpati Divya Tej , Soujanya Mamilla , Srivastava Ishanee , Mishra Rakesh Kumar 
Published: October 2020

Abstract
Background
Transcription of genes residing within constitutive heterochromatin is paradoxical to the tenets of epigenetic code. The regulatory mechanisms of Drosophila melanogaster heterochromatic gene transcription remain largely unknown. Emerging evidence suggests that genome organization and transcriptional regulation are inter-linked. However, the pericentromeric genome organization is relatively less studied. Therefore, we sought to characterize the pericentromeric genome organization and understand how this organization along with the pericentromeric factors influences heterochromatic gene expression.

Results
Here, we characterized the pericentromeric genome organization in Drosophila melanogaster using 5C sequencing. Heterochromatic topologically associating domains (Het TADs) correlate with distinct epigenomic domains of active and repressed heterochromatic genes at the pericentromeres. These genes are known to depend on the heterochromatic landscape for their expression. However, HP1a or Su(var)3-9 RNAi has minimal effects on heterochromatic gene expression, despite causing significant changes in the global Het TAD organization. Probing further into this observation, we report the role of two other chromatin proteins enriched at the pericentromeres-dMES-4 and dADD1 in regulating the expression of a subset of heterochromatic genes.

Conclusions
Distinct pericentromeric genome organization and chromatin landscapes maintained by the interplay of heterochromatic factors (HP1a, H3K9me3, dMES-4 and dADD1) are sufficient to support heterochromatic gene expression despite the loss of global Het TAD structure. These findings open new avenues for future investigations into the mechanisms of heterochromatic gene expression.
Efficient and accurate determination of genome-wide DNA methylation patterns in Arabidopsis thaliana with enzymatic methyl sequencing
Authors: Feng Suhua , Zhong Zhenhui , Wang Ming , Jacobsen Steven E. 
Published: October 2020

Abstract
Background
5′ methylation of cytosines in DNA molecules is an important epigenetic mark in eukaryotes. Bisulfite sequencing is the gold standard of DNA methylation detection, and whole-genome bisulfite sequencing (WGBS) has been widely used to detect methylation at single-nucleotide resolution on a genome-wide scale. However, sodium bisulfite is known to severely degrade DNA, which, in combination with biases introduced during PCR amplification, leads to unbalanced base representation in the final sequencing libraries. Enzymatic conversion of unmethylated cytosines to uracils can achieve the same end product for sequencing as does bisulfite treatment and does not affect the integrity of the DNA; enzymatic methylation sequencing may, thus, provide advantages over bisulfite sequencing.

Results
Using an enzymatic methyl-seq (EM-seq) technique to selectively deaminate unmethylated cytosines to uracils, we generated and sequenced libraries based on different amounts of Arabidopsis input DNA and different numbers of PCR cycles, and compared these data to results from traditional whole-genome bisulfite sequencing. We found that EM-seq libraries were more consistent between replicates and had higher mapping and lower duplication rates, lower background noise, higher average coverage, and higher coverage of total cytosines. Differential methylation region (DMR) analysis showed that WGBS tended to over-estimate methylation levels especially in CHG and CHH contexts, whereas EM-seq detected higher CG methylation levels in certain highly methylated areas. These phenomena can be mostly explained by a correlation of WGBS methylation estimation with GC content and methylated cytosine density. We used EM-seq to compare methylation between leaves and flowers, and found that CHG methylation level is greatly elevated in flowers, especially in pericentromeric regions.

Conclusion
We suggest that EM-seq is a more accurate and reliable approach than WGBS to detect methylation. Compared to WGBS, the results of EM-seq are less affected by differences in library preparation conditions or by the skewed base composition in the converted DNA. It may therefore be more desirable to use EM-seq in methylation studies.
Prevalence of people at risk of developing type 2 diabetes mellitus and the involvement of community pharmacies in a national screening campaign: a pioneer action in Brazil
Authors: Correr Cassyano J. , Coura-Vital Wendel , Frade Josélia C. Q. P. , Nascimento Renata C. R. M. , Nascimento Lúbia G. , Pinheiro Eliete B. , Ferreira Wesley M. , Reis Janice S. , Melo Karla F. S. , Pontarolo Roberto , Lenzi Mônica S. A. , Almeida José V. , Pedrosa Hermelinda C. , João Walter S. J. 
Published: October 2020

Abstract
Background
Brazil is one of top 10 countries with the highest number of people with diabetes mellitus (DM), affecting 16.8 million peoples. It is estimated that 7.7 million people (20–79 years) in the country have not yet been diagnosed, representing an under-diagnosis rate of 46.0%. Herein we aimed to screen people for high blood glucose or risk for developing type 2 DM (T2DM) through community pharmacies in Brazil.

Methods
A cross-sectional study was carried out in November 2018, involving 977 pharmacists from 345 municipalities in Brazil. The study evaluated people between 20 and 79 years old without a previous diagnosis of DM. Glycemia was considered high when its value was ≥ 100 mg/dL fasting and ≥ 140 mg/dL in a casual feeding state. The FINDRISC (Finnish Diabetes Risk Score) was used to estimate the risk for developing T2DM. The prevalence of high blood glucose was estimated and the associated factors were obtained using Poisson's multivariate analysis with robust variance.

Results
During the national screening campaign, 17,580 people were tested with the majority of the consultations (78.2%) being carried out in private pharmacies. The population was composed mainly of women (59.5%) and people aged between 20 and 45 years (47.9%). The frequency of participants with high blood glucose was 18.4% (95% CI 17.9–19.0). Considering the FINDRISC, 22.7% of people had a high or very high risk for T2DM. The risk factors associated with high blood glucose were: Body Mass Index > 25 kg/m2, abdominal circumference > 94 cm for men and > 80 cm for women; education level below 15 years of study, no daily intake of vegetables and fruits; previous diagnosis of arterial hypertension; history of high blood glucose and family history of DM.

Conclusions
This is the largest screening study that evaluated the frequency of high blood glucose and its associated factors in a population without a previous diagnosis ever performed in community pharmacies in Brazil. These results may help to improve public health policies and reinforce the role of pharmacists in screening and education actions aimed at this undiagnosed population in a continent-size country such as Brazil.
Increased levels of circulating IL-10 in persons recovered from hepatitis C virus (HCV) infection compared with persons with active HCV infection
Authors: Owusu Dorcas Ohui , Phillips Richard , Owusu Michael , Sarfo Fred Stephen , Frempong Margaret 
Published: October 2020

Abstract
Objective
Approximately 70% of all hepatitis C (HCV) infections develop chronic disease. Active or exacerbated chronic hepatitis C infection subsequently progress to liver disease. The role of T-cells secretions in achieving viral clearance is still not well understood. Thus, the current study was set to determine the relationship between the T cell cytokine profiles, biochemical parameters and persistent HCV infection or spontaneous recovery.

Results
Twenty-five percent (41/163) of the anti-HCV positive participants had recovered from HCV and had significantly higher concentration of IL-10 compared to those with active HCV infection (P < 0.012). Other circulating cytokines measured; IL-2, IFN gamma, TNF alpha, IL-5 and IL-17 were similar in both groups. Participants with active HCV infection had significantly higher aspartate transaminase (AST) (35 units) and alanine transaminase (46 units) compared to those in the recovered state (P < 0.001). Thus, serum levels of IL10 could be explored in larger prospective cohort study as a predictive marker of recovering from an active HCV infection.
White matter hyperintensities across the adult lifespan: relation to age, Aβ load, and cognition
Authors: Garnier-Crussard Antoine , Bougacha Salma , Wirth Miranka , André Claire , Delarue Marion , Landeau Brigitte , Mézenge Florence , Kuhn Elizabeth , Gonneaud Julie , Chocat Anne , Quillard Anne , Ferrand-Devouge Eglantine , de La Sayette Vincent , Vivien Denis , Krolak-Salmon Pierre , Chételat Gaël 
Published: October 2020

Abstract
Background
White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical β-amyloid (Aβ) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults.

Methods
One hundred and thirty-seven cognitively unimpaired adults from the community were enrolled (IMAP cohort). Participants underwent (i) a comprehensive neuropsychological assessment of episodic memory, processing speed, working memory, and executive functions; (ii) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of total and regional (frontal, parietal, temporal, occipital, and corpus callosum) WMH; and (iii) a Florbetapir-PET scan to measure cortical Aβ. The relationships of total and regional WMH to age, vascular risk factors, cortical Aβ, and cognition were assessed within the whole sample, but also splitting the sample in two age groups (≤ or > 60 years old).

Results
WMH increased with age across the adult lifespan, i.e., even in young and middle-aged adults. Systolic blood pressure, diastolic blood pressure, and glycated hemoglobin were all associated with higher WMH before, but not after, adjusting for age and the other vascular risk factors. Higher frontal, temporal, and occipital WMH were associated with greater Aβ, but this association was no longer significant when adjusting for age and vascular risk factors. Higher total and frontal WMH were associated with worse performance in executive functions, with no interactive effect of the age group. In contrast, there was a significant interaction of the age group on the link between WMH and working memory, which was significant within the subgroup of young/middle-aged adults only. Adding cortical Aβ load in the models did not alter the results, and there was no interaction between WMH and Aβ on cognition.

Conclusion
WMH increased with age and were associated with worse executive functions across the adult lifespan and with worse working memory in young/middle-aged adults. Aβ load was weakly associated with WMH and did not change the relationship found between WMH and executive functions. This study argues for the clinical relevance of WMH across the adult lifespan, even in young and middle-aged adults with low WMH.
De novo missense variants disrupting protein–protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types
Authors: Chen Siwei , Wang Jiebiao , Cicek Ercument , Roeder Kathryn , Yu Haiyuan , Devlin Bernie 
Published: October 2020

Abstract
Background
Whole-exome sequencing studies have been useful for identifying genes that, when mutated, affect risk for autism spectrum disorder (ASD). Nonetheless, the association signal primarily arises from de novo protein-truncating variants, as opposed to the more common missense variants. Despite their commonness in humans, determining which missense variants affect phenotypes and how remains a challenge. We investigate the functional relevance of de novo missense variants, specifically whether they are likely to disrupt protein interactions, and nominate novel genes in risk for ASD through integrated genomic, transcriptomic, and proteomic analyses.

Methods
Utilizing our previous interactome perturbation predictor, we identify a set of missense variants that are likely disruptive to protein–protein interactions. For genes encoding the disrupted interactions, we evaluate their expression patterns across developing brains and within specific cell types, using both bulk and inferred cell-type-specific brain transcriptomes. Connecting all disrupted pairs of proteins, we construct an “ASD disrupted network.” Finally, we integrate protein interactions and cell-type-specific co-expression networks together with published association data to implicate novel genes in ASD risk in a cell-type-specific manner.

Results
Extending earlier work, we show that de novo missense variants that disrupt protein interactions are enriched in individuals with ASD, often affecting hub proteins and disrupting hub interactions. Genes encoding disrupted complementary interactors tend to be risk genes, and an interaction network built from these proteins is enriched for ASD proteins. Consistent with other studies, genes identified by disrupted protein interactions are expressed early in development and in excitatory and inhibitory neuronal lineages. Using inferred gene co-expression for three neuronal cell types—excitatory, inhibitory, and neural progenitor—we implicate several hundred genes in risk (FDR $$\le \hspace{0.17em}$$

≤

0.05), ~ 60% novel, with characteristics of genuine ASD genes. Across cell types, these genes affect neuronal morphogenesis and neuronal communication, while neural progenitor cells show strong enrichment for development of the limbic system.

Limitations
Some analyses use the imperfect guilt-by-association principle; results are statistical, not functional.

Conclusions
Disrupted protein interactions identify gene sets involved in risk for ASD. Their gene expression during brain development and within cell types highlights how they relate to ASD.