bluuebunny/crossref_metadata_2025 huggingface dataset:
PRL/microRNA-183/IRS1 Pathway Regulates Milk Fat Metabolism in Cow Mammary Epithelial Cells
Authors: Jiao Peixin , Yuan Yuan , Zhang Meimei , Sun Youran , Wei Chuanzi , Xie Xiaolai , Zhang Yonggen , Wang Sutian , Chen Zhi , Wang Xiaolong
Published: February 2020

The aim of the study was to understand the internal relationship between milk quality and lipid metabolism in cow mammary glands. A serial of studies was conducted to assess the molecular mechanism of PRL/microRNA-183/IRS1 (Insulin receptor substrate) pathway, which regulates milk fat metabolism in dairy cows. microRNA-183 (miR-183) was overexpressed and inhibited in cow mammary epithelial cells (CMECs), and its function was detected. The function of miR-183 in inhibiting milk fat metabolism was clarified by triglycerides (TAG), cholesterol and marker genes. There is a CpG island in the 5′-flanking promoter area of miR-183, which may inhibit the expression of miR-183 after methylation. Our results showed that prolactin (PRL) inhibited the expression of miR-183 by methylating the 5′ terminal CpG island of miR-183. The upstream regulation of PRL on miR-183 was demonstrated, and construction of the lipid metabolism regulation network of microRNA-183 and target gene IRS1 was performed. These results reveal the molecular mechanism of PRL/miR-183/IRS1 pathway regulating milk fat metabolism in dairy cows, thus providing an experimental basis for the improvement of milk quality.
Prognostic Value and Potential Regulatory Mechanism of Alternative Splicing in Geriatric Breast Cancer
Authors: Li Xin , Wang Yaxuan , Li Bingjie , Ma Wang
Published: February 2020

Breast cancer has the highest mortality and morbidity among women, especially in elderly women over 60 years old. Abnormal alternative splicing (AS) events are associated with the occurrence and development of geriatric breast cancer (GBC), yet strong evidence is lacking for the prognostic value of AS in GBC and the regulatory network of AS in GBC, which may highlight the mechanism through which AS contributes to GBC. In the present study, we obtained splicing event information (SpliceSeq) and clinical information for GBC from The Cancer Genome Atlas, and we constructed a GBC prognosis model based on AS events to predict the survival outcomes of GBC. Kaplan–Meier analysis was conducted to evaluate the predictive accuracy among different molecular subtypes of GBC. We conducted enrichment analysis and constructed a splicing network between AS and the splicing factor (SF) to examine the possible regulatory mechanisms of AS in GBC. We constructed eight prognostic signatures with very high statistical accuracy in predicting GBC survival outcomes from 45,421 AS events of 10,480 genes detected in 462 GBC patients; the prognostic model based on exon skip (ES) events had the highest accuracy, indicating its significant value in GBC prognosis. The constructed regulatory SF–AS network may explain the potential regulatory mechanism between SF and AS, which may be the mechanism through which AS events contribute to GBC survival outcomes. The findings confirm that AS events have a significant prognostic value in GBC, and we found a few effective prognostic signatures. We also hypothesized the mechanism underlying AS in GBC and discovered a potential regulatory mechanism between SF and AS.
Maintenance of Yeast Genome Integrity by RecQ Family DNA Helicases
Authors: Gupta Sonia Vidushi , Schmidt Kristina Hildegard
Published: February 2020

With roles in DNA repair, recombination, replication and transcription, members of the RecQ DNA helicase family maintain genome integrity from bacteria to mammals. Mutations in human RecQ helicases BLM, WRN and RecQL4 cause incurable disorders characterized by genome instability, increased cancer predisposition and premature adult-onset aging. Yeast cells lacking the RecQ helicase Sgs1 share many of the cellular defects of human cells lacking BLM, including hypersensitivity to DNA damaging agents and replication stress, shortened lifespan, genome instability and mitotic hyper-recombination, making them invaluable model systems for elucidating eukaryotic RecQ helicase function. Yeast and human RecQ helicases have common DNA substrates and domain structures and share similar physical interaction partners. Here, we review the major cellular functions of the yeast RecQ helicases Sgs1 of Saccharomyces cerevisiae and Rqh1 of Schizosaccharomyces pombe and provide an outlook on some of the outstanding questions in the field.
Transforming Ocean Conservation: Applying the Genetic Rescue Toolkit
Authors: Novak Ben J. , Fraser Devaughn , Maloney Thomas H.
Published: February 2020

Although oceans provide critical ecosystem services and support the most abundant populations on earth, the extent of damage impacting oceans and the diversity of strategies to protect them is disconcertingly, and disproportionately, understudied. While conventional modes of conservation have made strides in mitigating impacts of human activities on ocean ecosystems, those strategies alone cannot completely stem the tide of mounting threats. Biotechnology and genomic research should be harnessed and developed within conservation frameworks to foster the persistence of viable ocean ecosystems. This document distills the results of a targeted survey, the Ocean Genomics Horizon Scan, which assessed opportunities to bring novel genetic rescue tools to marine conservation. From this Horizon Scan, we have identified how novel approaches from synthetic biology and genomics can alleviate major marine threats. While ethical frameworks for biotechnological interventions are necessary for effective and responsible practice, here we primarily assessed technological and social factors directly affecting technical development and deployment of biotechnology interventions for marine conservation. Genetic insight can greatly enhance established conservation methods, but the severity of many threats may demand genomic intervention. While intervention is controversial, for many marine areas the cost of inaction is too high to allow controversy to be a barrier to conserving viable ecosystems. Here, we offer a set of recommendations for engagement and program development to deploy genetic rescue safely and responsibly.
Form from Function, Order from Chaos in Male Germline Chromatin
Authors: Ellis Peter J. I. , Griffin Darren K.
Published: February 2020

Spermatogenesis requires radical restructuring of germline chromatin at multiple stages, involving co-ordinated waves of DNA methylation and demethylation, histone modification, replacement and removal occurring before, during and after meiosis. This Special Issue has drawn together papers addressing many aspects of chromatin organization and dynamics in the male germ line, in humans and in model organisms. Two major themes emerge from these studies: the first is the functional significance of nuclear organisation in the developing germline; the second is the interplay between sperm chromatin structure and susceptibility to DNA damage and mutation. The consequences of these aspects for fertility, both in humans and other animals, is a major health and social welfare issue and this is reflected in these nine exciting manuscripts.
Inhibition of Angiotensin-Converting Enzyme Ameliorates Renal Fibrosis by Mitigating DPP-4 Level and Restoring Antifibrotic MicroRNAs
Authors: Srivastava Swayam Prakash , Goodwin Julie E. , Kanasaki Keizo , Koya Daisuke
Published: February 2020

Two class of drugs 1) angiotensin-converting enzyme inhibitors (ACEis) and 2) angiotensin II receptor blockers (ARBs) are well-known conventional drugs that can retard the progression of chronic nephropathies to end-stage renal disease. However, there is a lack of comparative studies on the effects of ACEi versus ARB on renal fibrosis. Here, we observed that ACEi ameliorated renal fibrosis by mitigating DPP-4 and TGFβ signaling, whereas, ARB did not show. Moreover, the combination of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), one of the substrates of ACE, with ACEi slightly enhanced the inhibitory effects of ACEi on DPP-4 and associated-TGFβ signaling. Further, the comprehensive miRome analysis in kidneys of ACEi+AcSDKP (combination) treatment revealed the emergence of miR-29s and miR-let-7s as key antifibrotic players. Treatment of cultured cells with ACEi alone or in combination with AcSDKP prevented the downregulated expression of miR-29s and miR-let-7s induced by TGFβ stimulation. Interestingly, ACEi also restored miR-29 and miR-let-7 family cross-talk in endothelial cells, an effect that is shared by AcSDKP suggesting that AcSDKP may be partially involved in the anti-mesenchymal action of ACEi. The results of the present study promise to advance our understanding of how ACEi regulates antifibrotic microRNAs crosstalk and DPP-4 associated-fibrogenic processes which is a critical event in the development of diabetic kidney disease.
Characteristics of Microsatellites Mined from Transcriptome Data and the Development of Novel Markers in Paeonia lactiflora
Authors: Wan Yingling , Zhang Min , Hong Aiying , Zhang Yixuan , Liu Yan
Published: February 2020

The insufficient number of available simple sequence repeats (SSRs) inhibits genetic research on and molecular breeding of Paeonia lactiflora, a flowering crop with great economic value. The objective of this study was to develop SSRs for P. lactiflora with Illumina RNA sequencing and assess the role of SSRs in gene regulation. The results showed that dinucleotides with AG/CT repeats were the most abundant type of repeat motif in P. lactiflora and were preferentially distributed in untranslated regions. Significant differences in SSR size were observed among motif types and locations. A large number of unigenes containing SSRs participated in catalytic activity, metabolic processes and cellular processes, and 28.16% of all transcription factors and 21.74% of hub genes for inflorescence stem straightness were found to contain SSRs. Successful amplification was achieved with 89.05% of 960 pairs of SSR primers, 55.83% of which were polymorphic, and most of the 46 tested primers had a high level of transferability to the genus Paeonia. Principal component and cluster dendrogram analyses produced results consistent with known genealogical relationships. This study provides a set of SSRs with abundant information for future accession identification, marker-trait association and molecular assisted breeding in P. lactiflora.
Effect of Phenotype Selection on Genome Size Variation in Two Species of Diptera
Authors: Hjelmen Carl E. , Parrott Jonathan J. , Srivastav Satyam P. , McGuane Alexander S. , Ellis Lisa L. , Stewart Andrew D. , Johnston J. Spencer , Tarone Aaron M.
Published: February 2020

Genome size varies widely across organisms yet has not been found to be related to organismal complexity in eukaryotes. While there is no evidence for a relationship with complexity, there is evidence to suggest that other phenotypic characteristics, such as nucleus size and cell-cycle time, are associated with genome size, body size, and development rate. However, what is unknown is how the selection for divergent phenotypic traits may indirectly affect genome size. Drosophila melanogaster were selected for small and large body size for up to 220 generations, while Cochliomyia macellaria were selected for 32 generations for fast and slow development. Size in D. melanogaster significantly changed in terms of both cell-count and genome size in isolines, but only the cell-count changed in lines which were maintained at larger effective population sizes. Larger genome sizes only occurred in a subset of D. melanogaster isolines originated from flies selected for their large body size. Selection for development time did not change average genome size yet decreased the within-population variation in genome size with increasing generations of selection. This decrease in variation and convergence on a similar mean genome size was not in correspondence with phenotypic variation and suggests stabilizing selection on genome size in laboratory conditions.
Development of Molecular Marker Linked with Bacterial Fruit Blotch Resistance in Melon (Cucumis melo L.)
Authors: Islam Md. Rafiqul , Hossain Mohammad Rashed , Jesse Denison Michael Immanuel , Jung Hee-Jeong , Kim Hoy-Taek , Park Jong-In , Nou Ill-Sup
Published: February 2020

Bacterial fruit blotch (BFB) causes losses in melon marketable yield. However, until now, there has been no information about the genetic loci responsible for resistance to the disease or their pattern of inheritance. We determined the inheritance pattern of BFB resistance from a segregating population of 491 F2 individuals raised by crossing BFB-resistant (PI 353814) and susceptible (PI 614596) parental accessions. All F1 plants were resistant to Acidovorax citrulli strain KACC18782, and F2 plants segregated with a 3:1 ratio for resistant and susceptible phenotypes, respectively, in a seedling bioassay experiment, indicating that BFB resistance is controlled by a monogenic dominant gene. In an investigation of 57 putative disease-resistance related genes across the melon genome, only the MELO3C022157 gene (encoding TIR-NBS-LRR domain), showing polymorphism between resistant and susceptible parents, revealed as a good candidate for further investigation. Cloning, sequencing and quantitative RT-PCR expression of the polymorphic gene MELO3C022157 located on chromosome 9 revealed multiple insertion/deletions (InDels) and single nucleotide polymorphisms (SNPs), of which the SNP A2035T in the second exon of the gene caused loss of the LRR domain and truncated protein in the susceptible accession. The InDel marker MB157-2, based on the large (504 bp) insertion in the first intron of the susceptible accession, was able to distinguish resistant and susceptible accessions among 491 F2 and 22 landraces/inbred accessions with 98.17% and 100% detection accuracy, respectively. This novel PCR-based, co-dominant InDel marker represents a practical tool for marker-assisted breeding aimed at developing BFB-resistant melon accessions.
AaCOI1, Encoding a CORONATINE INSENSITIVE 1-Like Protein of Artemisia annua L., Is Involved in Development, Defense, and Anthocyanin Synthesis
Authors: Liu Rong , Wang Jinbiao , Xiao Mu , Gao Xiewang , Chen Jin , Dai Yanjiao
Published: February 2020

Artemisia annua is an important medicinal plant producing the majority of the antimalarial compound artemisinin. Jasmonates are potent inducers of artemisinin accumulation in Artemisisa annua plants. As the receptor of jasmonates, the F-box protein COI1 is critical to the JA signaling required for plant development, defense, and metabolic homeostasis. AaCOI1 from Artemisia annua, homologous to Arabidopsis AtCOI1, encodes a F-box protein located in the nuclei. Expressional profiles of the AaCOI1 in the root, stem, leaves, and inflorescence was investigated. The mRNA abundance of AaCOI1 was the highest in inflorescence, followed by in the leaves. Upon mechanical wounding or MeJA treatment, expression of AaCOI1 was upregulated after 6 h. When ectopically expressed, driven by the native promoter from Arabidopsis thaliana, AaCOI1 could partially complement the JA sensitivity and defense responses, but fully complemented the fertility, and the JA-induced anthocyanin accumulation in a coi1-16 loss-of-function mutant. Our study identifies the paralog of AtCOI1 in Artemisia annua, and revealed its implications in development, hormone signaling, defense, and metabolism. The results provide insight into JA perception in Artemisia annua, and pave the way for novel molecular breeding strategies in the canonical herbs to manipulate the anabolism of pharmaceutic compounds on the phytohormonal level.
Yeast Genome Maintenance by the Multifunctional PIF1 DNA Helicase Family
Authors: Muellner Julius , Schmidt Kristina H.
Published: February 2020

The two PIF1 family helicases in Saccharomyces cerevisiae, Rrm3, and ScPif1, associate with thousands of sites throughout the genome where they perform overlapping and distinct roles in telomere length maintenance, replication through non-histone proteins and G4 structures, lagging strand replication, replication fork convergence, the repair of DNA double-strand break ends, and transposable element mobility. ScPif1 and its fission yeast homolog Pfh1 also localize to mitochondria where they protect mitochondrial genome integrity. In addition to yeast serving as a model system for the rapid functional evaluation of human Pif1 variants, yeast cells lacking Rrm3 have proven useful for elucidating the cellular response to replication fork pausing at endogenous sites. Here, we review the increasingly important cellular functions of the yeast PIF1 helicases in maintaining genome integrity, and highlight recent advances in our understanding of their roles in facilitating fork progression through replisome barriers, their functional interactions with DNA repair, and replication stress response pathways.
Comparative Transcriptome Analysis Reveals Stem Secondary Growth of Grafted Rosa rugosa ‘Rosea’ Scion and R. multiflora ‘Innermis’ Rootstock
Authors: Sun Jing-shuang , Hu Rui-yang , Lv Fu-ling , Yang Yan-fang , Tang Zhi-min , Zheng Guang-shun , Li Jian-bo , Tian Hua , Xu Yan , Li Shao-feng
Published: February 2020

Grafted plant is a chimeric organism formed by the connection of scion and rootstock through stems, so stem growth and development become one of the important factors to affect grafted plant state. However, information regarding the molecular responses of stems secondary growth after grafting is limited. A grafted Rosa plant, with R. rugosa ‘Rosea’ as the scion (Rr_scion) grafted onto R. multiflora ‘Innermis’ as the stock (Rm_stock), has been shown to significantly improve stem thickness. To elucidate the molecular mechanisms of stem secondary growth in grafted plant, a genome-wide transcription analysis was performed using an RNA sequence (RNA-seq) method between the scion and rootstock. Comparing ungrafted R. rugosa ‘Rosea’ (Rr) and R. multiflora ‘Innermis’ (Rm) plants, there were much more differentially expressed genes (DEGs) identified in Rr_scion (6887) than Rm_stock (229). Functional annotations revealed that DEGs in Rr_scion are involved in two Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways: the phenylpropanoid biosynthesis metabolism and plant hormone signal transduction, whereas DEGs in Rm_stock were associated with starch and sucrose metabolism pathway. Moreover, different kinds of signal transduction-related DEGs, e.g., receptor-like serine/threonine protein kinases (RLKs), transcription factor (TF), and transporters, were identified and could affect the stem secondary growth of both the scion and rootstock. This work provided new information regarding the underlying molecular mechanism between scion and rootstock after grafting.
Hearing Impairment Overview in Africa: the Case of Cameroon
Authors: Wonkam Tingang Edmond , Noubiap Jean Jacques , F. Fokouo Jean Valentin , Oluwole Oluwafemi Gabriel , Nguefack Séraphin , Chimusa Emile R. , Wonkam Ambroise
Published: February 2020

The incidence of hearing impairment (HI) is higher in low- and middle-income countries when compared to high-income countries. There is therefore a necessity to estimate the burden of this condition in developing world. The aim of our study was to use a systematic approach to provide summarized data on the prevalence, etiologies, clinical patterns and genetics of HI in Cameroon. We searched PubMed, Scopus, African Journals Online, AFROLIB and African Index Medicus to identify relevant studies on HI in Cameroon, published from inception to 31 October, 2019, with no language restrictions. Reference lists of included studies were also scrutinized, and data were summarized narratively. This study is registered with PROSPERO, number CRD42019142788. We screened 333 records, of which 17 studies were finally included in the review. The prevalence of HI in Cameroon ranges from 0.9% to 3.6% in population-based studies and increases with age. Environmental factors contribute to 52.6% to 62.2% of HI cases, with meningitis, impacted wax and age-related disorder being the most common ones. Hereditary HI comprises 0.8% to 14.8% of all cases. In 32.6% to 37% of HI cases, the origin remains unknown. Non-syndromic hearing impairment (NSHI) is the most frequent clinical entity and accounts for 86.1% to 92.5% of cases of HI of genetic origin. Waardenburg and Usher syndromes account for 50% to 57.14% and 8.9% to 42.9% of genetic syndromic cases, respectively. No pathogenic mutation was described in GJB6 gene, and the prevalence of pathogenic mutations in GJB2 gene ranged from 0% to 0.5%. The prevalence of pathogenic mutations in other known NSHI genes was <10% in Cameroonian probands. Environmental factors are the leading etiology of HI in Cameroon, and mutations in most important HI genes are infrequent in Cameroon. Whole genome sequencing therefore appears as the most effective way to identify variants associated with HI in Cameroon and sub-Saharan Africa in general.
Comprehensive Sequence Analysis of IQD Gene Family and their Expression Profiling in Grapevine (Vitis vinifera)
Authors: Liu Zhongjie , Haider Muhammad Salman , Khan Nadeem , Fang Jinggui
Published: February 2020

The plant-specific IQ67-domain (IQD) protein family members are downstream targets of calcium sensors, known to regulate plant growth and lateral organ polarity, and basal defense response against environmental cues. No systematic study of IQD gene family has been performed on grapevine. The public availability of grapevine genome enables us to perform identification, phylogeny, chromosomal orientation, and gene structure analysis of the IQD genes in grapevine. We identified 49 VvIQD genes (VvIQD1–VvIQD49) and further classified them into eight subgroups based on phylogenetic relationships. The 49 VvIQD genes were assigned to 19 different chromosomal positions. The collinear relationship between grapevine and Arabidopsis IQDs (VvIQD and AtIQD), and within grapevine VvIQDs, was highly conserved. In addition, most of duplicated gene pairs showed Ka/Ks ratio less than 1.00, indicating purifying selection within these gene pairs, implying functional discrepancy after duplication. Transcription profiling of VvIQD genes shed light on their specific role in grapevine tissue and organ development. The qRT-PCR validation of the 49 VvIQD genes in grape berry tissue from cultivars with distinct berry shape during developmental phases suggested candidate genes involved in the shape of grape berries. The subcellular prediction of VvIQD22, VvIQD23, VvIQD38, and VvIQD49 genes validated their localization in the nucleus and plasma membrane. The VvIQD49 protein interaction with VvCaM2 was also verified by bimolecular fluorescence complementation (BiFC) analysis in the plasma membrane. Our findings will be valuable for the functional genomic studies for desirable shape development of grape berries.
Modulation of Sex Pheromone Discrimination by a UDP-Glycosyltransferase in Drosophila melanogaster
Authors: Fraichard Stéphane , Legendre Arièle , Lucas Philippe , Chauvel Isabelle , Faure Philippe , Neiers Fabrice , Artur Yves , Briand Loïc , Ferveur Jean-François , Heydel Jean-Marie
Published: February 2020

The detection and processing of chemical stimuli involve coordinated neuronal networks that process sensory information. This allows animals, such as the model species Drosophila melanogaster, to detect food sources and to choose a potential mate. In peripheral olfactory tissues, several classes of proteins are acting to modulate the detection of chemosensory signals. This includes odorant-binding proteins together with odorant-degrading enzymes (ODEs). These enzymes, which primarily act to eliminate toxic compounds from the whole organism also modulate chemodetection. ODEs are thought to neutralize the stimulus molecule concurrently to its detection, avoiding receptor saturation thus allowing chemosensory neurons to respond to the next stimulus. Here, we show that one UDP-glycosyltransferase (UGT36E1) expressed in D. melanogaster antennal olfactory sensory neurons (OSNs) is involved in sex pheromone discrimination. UGT36E1 overexpression caused by an insertion mutation affected male behavioral ability to discriminate sex pheromones while it increased OSN electrophysiological activity to male pheromones. Reciprocally, the decreased expression of UGT36E1, controlled by an RNAi transgene, improved male ability to discriminate sex pheromones whereas it decreased electrophysiological activity in the relevant OSNs. When we combined the two genotypes (mutation and RNAi), we restored wild-type-like levels both for the behavioral discrimination and UGT36E1 expression. Taken together, our results strongly suggest that this UGT plays a pivotal role in Drosophila pheromonal detection.
Genetic Modifiers and Rare Mendelian Disease
Authors: Rahit K. M. Tahsin Hassan , Tarailo-Graovac Maja
Published: February 2020

Despite advances in high-throughput sequencing that have revolutionized the discovery of gene defects in rare Mendelian diseases, there are still gaps in translating individual genome variation to observed phenotypic outcomes. While we continue to improve genomics approaches to identify primary disease-causing variants, it is evident that no genetic variant acts alone. In other words, some other variants in the genome (genetic modifiers) may alleviate (suppress) or exacerbate (enhance) the severity of the disease, resulting in the variability of phenotypic outcomes. Thus, to truly understand the disease, we need to consider how the disease-causing variants interact with the rest of the genome in an individual. Here, we review the current state-of-the-field in the identification of genetic modifiers in rare Mendelian diseases and discuss the potential for future approaches that could bridge the existing gap.
Effectiveness of Swallowing Care on Safe Oral Intake Using Ultrasound-Based Observation of Residues in the Epiglottis Valley: A Pragmatic, Quasi-Experimental Study
Authors: Yoshida Mikako , Miura Yuka , Okada Shingo , Yamada Masako , Kagaya Hitoshi , Saitoh Eiichi , Kamakura Yayoi , Okawa Yohei , Matsuyama Yutaka , Sanada Hiromi
Published: February 2020

The demand for methods to ensure safe oral consumption of food and liquids in order to prevent aspiration pneumonia has increased over the last decade. This study investigated the safety of swallowing care selected by adding ultrasound-based observation, evaluated its efficacy, and determined effective content of selected swallowing care. The study employed a pragmatic quasi-experimental research design. Participants were 12 community-dwelling adult patients (age: 44–91 years) who had experienced choking within 1 month prior to the study. After the control phase, in which conventional swallowing care was provided, trained nurses provided ultrasound observation-based swallowing care for a minimum period of 2 weeks. Outcome measurements were compared across three points, namely T1—beginning of the control phase, T2 and T3—before and end of the intervention phase. The mean durations of intervention were 30.8 days in the control phase and 36.5 days in the intervention phase. Pneumonia and suffocation did not occur in the control phase or the intervention phase. The safe intake food level and the food intake level score significantly improved during the intervention phase (p = 0.032 and 0.017, respectively) by adding eating training based on the ultrasound observation. However, there was no significant improvement in the strength of the muscle related to swallowing by the selected basic training. Our results suggest that swallowing care selected based on the ultrasound observation, especially eating training, safely improved safe oral intake among community-dwelling adults with swallowing dysfunction.
Outbreak of Novel Coronavirus (SARS-CoV-2): First Evidences From International Scientific Literature and Pending Questions
Authors: Amodio Emanuele , Vitale Francesco , Cimino Livia , Casuccio Alessandra , Tramuto Fabio
Published: February 2020

On 31 December, 2019, a cluster of 27 pneumonia cases of unknown etiology was reported by Chinese health authorities in Wuhan City (China) [...]
Reconceptualising Rural Cancer Inequalities: Time for a New Research Agenda
Authors: Dobson Christina , Rubin Greg , Murchie Peter , Macdonald Sara , Sharp Linda
Published: February 2020

Evidence has shown for over 20 years that patients residing in rural areas face poorer outcomes for cancer. The inequalities in survival that rural cancer patients face are observed throughout the developed world, yet this issue remains under-examined and unexplained. There is evidence to suggest that rural patients are more likely to be diagnosed as a result of an emergency presentation and that rural patients may take longer to seek help for symptoms. However, research to date has been predominantly epidemiological, providing us with an understanding of what is occurring in these populations, yet failing to explain why. In this paper we outline the problems inherent in current research approaches to rural cancer inequalities, namely how ‘cancer symptoms’ are conceived of and examined, and the propensity towards a reductionist approach to rural environments and populations, which fails to account for their heterogeneity. We advocate for a revised rural cancer inequalities research agenda, built upon in-depth, community-based examinations of rural patients’ experiences across the cancer pathway, which takes into account both the micro and macro factors which exert influence on these experiences, in order to develop meaningful interventions to improve cancer outcomes for rural populations.
Land Use and Land Cover Change Modeling and Future Potential Landscape Risk Assessment Using Markov-CA Model and Analytical Hierarchy Process
Authors: Nath Biswajit , Wang Zhihua , Ge Yong , Islam Kamrul , P. Singh Ramesh , Niu Zheng
Published: February 2020

Land use and land cover change (LULCC) has directly played an important role in the observed climate change. In this paper, we considered Dujiangyan City and its environs (DCEN) to study the future scenario in the years 2025, 2030, and 2040 based on the 2018 simulation results from 2007 and 2018 LULC maps. This study evaluates the spatial and temporal variations of future LULCC, including the future potential landscape risk (FPLR) area of the 2008 great (8.0 Mw) earthquake of south-west China. The Cellular automata–Markov chain (CA-Markov) model and multicriteria based analytical hierarchy process (MC-AHP) approach have been considered using the integration of remote sensing and GIS techniques. The analysis shows future LULC scenario in the years 2025, 2030, and 2040 along with the FPLR pattern. Based on the results of the future LULCC and FPLR scenarios, we have provided suggestions for the development in the close proximity of the fault lines for the future strong magnitude earthquakes. Our results suggest a better and safe planning approach in the Belt and Road Corridor (BRC) of China to control future Silk-Road Disaster, which will also be useful to urban planners for urban development in a safe and sustainable manner.
Metabolic and Redox Signaling of the Nucleoredoxin-Like-1 Gene for the Treatment of Genetic Retinal Diseases
Authors: Clérin Emmanuelle , Marussig Myriam , Sahel José-Alain , Léveillard Thierry
Published: February 2020

The loss of cone photoreceptor function in retinitis pigmentosa (RP) severely impacts the central and daily vision and quality of life of patients affected by this disease. The loss of cones follows the degeneration of rods, in a manner independent of the causing mutations in numerous genes associated with RP. We have explored this phenomenon and proposed that the loss of rods triggers a reduction in the expression of rod-derived cone viability factor (RdCVF) encoded by the nucleoredoxin-like 1 (NXNL1) gene which interrupts the metabolic and redox signaling between rods and cones. After providing scientific evidence supporting this mechanism, we propose a way to restore this lost signaling and prevent the cone vision loss in animal models of RP. We also explain how we could restore this signaling to prevent cone vision loss in animal models of the disease and how we plan to apply this therapeutic strategy by the administration of both products of NXNL1 encoding the trophic factor RdCVF and the thioredoxin enzyme RdCVFL using an adeno-associated viral vector. We describe in detail all the steps of this translational program, from the design of the drug, its production, biological validation, and analytical and preclinical qualification required for a future clinical trial that would, if successful, provide a treatment for this incurable disease.
Impact of Hyponatremia on COPD Exacerbation Prognosis
Authors: García-Sanz María-Teresa , Martínez-Gestoso Sandra , Calvo-Álvarez Uxío , Doval-Oubiña Liliana , Camba-Matos Sandra , Rábade-Castedo Carlos , Rodríguez-García Carlota , González-Barcala Francisco-Javier
Published: February 2020

The most common electrolyte disorder among hospitalized patients, hyponatremia is a predictor of poor prognosis in various diseases. The aim of this study was to establish the prevalence of hyponatremia in patients admitted for acute exacerbation of chronic obstructive pulmonary disease (AECOPD), as well as its association with poor clinical progress. Prospective observational study carried out from 1 October 2016 to 1 October 2018 in the following hospitals: Salnés in Vilagarcía de Arousa, Arquitecto Marcide in Ferrol, and the University Hospital Complex of Santiago de Compostela, Galicia, Spain, on patients admitted for AECOPD. Patient baseline treatment was identified, including hyponatremia-inducing drugs. Poor progress was defined as follows: prolonged stay, death during hospitalization, or readmission within one month after the index episode discharge. 602 patients were enrolled, 65 cases of hyponatremia (10.8%) were recorded, all of a mild nature (mean 131.6; SD 2.67). Of all the patients, 362 (60%) showed poor progress: 18 (3%) died at admission; 327 (54.3%) had a prolonged stay; and 91 (15.1%) were readmitted within one month after discharge. Patients with hyponatremia had a more frequent history of atrial fibrillation (AF) (p 0.005), pleural effusion (p 0.01), and prolonged stay (p 0.01). The factors independently associated with poor progress were hyponatremia, pneumonia, and not receiving home O2 treatment prior to admission. Hyponatremia is relatively frequent in patients admitted for AECOPD, and it has important prognostic implications, even when mild in nature.
Time-Dependent Response of Human Deciduous Tooth-Derived Dental Pulp Cells Treated with TheraCal LC: Functional Analysis of Gene Interactions Compared to MTA
Authors: Nam Ok Hyung , Kim Jae-Hwan , Choi Sung Chul , Kim Young
Published: February 2020

Pulp capping material should facilitate hard tissue regeneration on the injured pulp tissue. TheraCal LC (TC) was recently developed. Although TC has shown reliable clinical outcomes after direct pulp capping, there are still remaining concerns regarding its detrimental effect on pulp cells. Therefore, this study aimed to identify the gene expression of human deciduous tooth-derived dental pulp cells exposed to TC compared to mineral trioxide aggregate (MTA). The cells were cultured and exposed to TC and MTA for 24 and 72 h. Next, total RNA was isolated. QuantSeq 3′ mRNA-sequencing was used to examine differentially expressed genes (DEGs) in exposed to TC and MTA. Functional analysis of DEGs was performed using bioinformatics analysis. In gene ontology (GO) functional enrichment analysis, cells in TC for 24 h presented significantly enriched immune response (p < 0.001) and inflammatory response (p < 0.01) compared to MTA. TC showed enriched positive regulation of cell migration at 72 h (p < 0.001). In Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, neuroactive ligand–receptor interaction (p = 1.19 × 10−7) and calcium signaling pathway (p = 2.96 × 10−5) were confirmed in the shared DEGs in TC. In conclusion, DEGs in TC may be involved in pathways associated with osteoclastogenesis and osteoclastic differentiation.
Degenerative Cervical Myelopathy: A Brief Review of Past Perspectives, Present Developments, and Future Directions
Authors: Nouri Aria , Cheng Joseph S. , Davies Benjamin , Kotter Mark , Schaller Karl , Tessitore Enrico
Published: February 2020

Degenerative cervical myelopathy (DCM) is the most common cause of spinal cord injury in developed countries; its prevalence is increasing due to the ageing of the population. DCM causes neurological dysfunction and is a significant cause of disability in the elderly. It has important negative impacts on the quality of life of those affected, as well as on their caregivers. DCM is triggered by a variety of degenerative changes in the neck, which affect one or more anatomical structures, including intervertebral discs, vertebrae, and spinal canal ligaments. These changes can also lead to structural abnormalities, leading to alterations in alignment, mobility, and stability. The principle unifying problem in this disease, regardless of the types of changes present, is injury to the spinal cord due to compression by static and/or dynamic forces. This review is partitioned into three segments that focus on key elements of the past, the present, and the future in the field, which serve to introduce the focus issue on “Degenerative Cervical Myelopathy and the Aging Spine”. Emerging from this review is that tremendous progress has been made in the field, particularly in recent years, and that there are exciting possibilities for further advancements of patient care.
Comparison of High-Dose Cytarabine, Mitoxantrone, and Pegaspargase (HAM-pegA) to High-Dose Cytarabine, Mitoxantrone, Cladribine, and Filgrastim (CLAG-M) as First-Line Salvage Cytotoxic Chemotherapy for Relapsed/Refractory Acute Myeloid Leukemia
Authors: Patzke Ciera L. , Duffy Alison P. , Duong Vu H. , El Chaer Firas , Trovato James A. , Baer Maria R. , Bentzen Søren M. , Emadi Ashkan
Published: February 2020

Currently, no standard of care exists for the treatment of relapsed or refractory acute myeloid leukemia (AML). We present our institutional experience with using either CLAG-M or HAM-pegA, a novel regimen that includes pegaspargase. This is a retrospective comparison of 34 patients receiving CLAG-M and 10 receiving HAM-pegA as first salvage cytotoxic chemotherapy in the relapsed or refractory setting. Composite complete response rates were 47.1% for CLAG-M and 90% for HAM-pegA (p = 0.027). Event-free survival was significantly different in favor of HAM-pegA (p = 0.045), though overall survival was similar between groups. There were no significant differences in toxicities experienced by patients treated with the two regimens, including adverse events of special interest related to pegaspargase (venous thromboembolism, hemorrhage, hepatotoxicity, pancreatitis, and hypersensitivity reactions). HAM-pegA is a novel regimen for relapsed or refractory AML that resulted in improved response rates and similar toxicities compared to CLAG-M.
Incubation Period and Other Epidemiological Characteristics of 2019 Novel Coronavirus Infections with Right Truncation: A Statistical Analysis of Publicly Available Case Data
Authors: Linton Natalie , Kobayashi Tetsuro , Yang Yichi , Hayashi Katsuma , Akhmetzhanov Andrei , Jung Sung-mok , Yuan Baoyin , Kinoshita Ryo , Nishiura Hiroshi
Published: February 2020

The geographic spread of 2019 novel coronavirus (COVID-19) infections from the epicenter of Wuhan, China, has provided an opportunity to study the natural history of the recently emerged virus. Using publicly available event-date data from the ongoing epidemic, the present study investigated the incubation period and other time intervals that govern the epidemiological dynamics of COVID-19 infections. Our results show that the incubation period falls within the range of 2–14 days with 95% confidence and has a mean of around 5 days when approximated using the best-fit lognormal distribution. The mean time from illness onset to hospital admission (for treatment and/or isolation) was estimated at 3–4 days without truncation and at 5–9 days when right truncated. Based on the 95th percentile estimate of the incubation period, we recommend that the length of quarantine should be at least 14 days. The median time delay of 13 days from illness onset to death (17 days with right truncation) should be considered when estimating the COVID-19 case fatality risk.
Diagnosis of Inherited Platelet Disorders on a Blood Smear
Authors: Zaninetti Carlo , Greinacher Andreas
Published: February 2020

Inherited platelet disorders (IPDs) are rare diseases featured by low platelet count and defective platelet function. Patients have variable bleeding diathesis and sometimes additional features that can be congenital or acquired. Identification of an IPD is desirable to avoid misdiagnosis of immune thrombocytopenia and the use of improper treatments. Diagnostic tools include platelet function studies and genetic testing. The latter can be challenging as the correlation of its outcomes with phenotype is not easy. The immune-morphological evaluation of blood smears (by light- and immunofluorescence microscopy) represents a reliable method to phenotype subjects with suspected IPD. It is relatively cheap, not excessively time-consuming and applicable to shipped samples. In some forms, it can provide a diagnosis by itself, as for MYH9-RD, or in addition to other first-line tests as aggregometry or flow cytometry. In regard to genetic testing, it can guide specific sequencing. Since only minimal amounts of blood are needed for the preparation of blood smears, it can be used to characterize thrombocytopenia in pediatric patients and even newborns further. In principle, it is based on visualizing alterations in the distribution of proteins, which result from specific genetic mutations by using monoclonal antibodies. It can be applied to identify deficiencies in membrane proteins, disturbed distribution of cytoskeletal proteins, and alpha as well as delta granules. On the other hand, mutations associated with impaired signal transduction are difficult to identify by immunofluorescence of blood smears. This review summarizes technical aspects and the main diagnostic patterns achievable by this method.
TLR2 Expression on Select Lymphocyte Subsets as a New Marker in Glomerulonephritis
Authors: Mertowski Sebastian , Grywalska Ewelina , Gosik Krzysztof , Smarz-Widelska Iwona , Hymos Anna , Dworacki Grzegorz , Niedźwiedzka-Rystwej Paulina , Drop Bartłomiej , Roliński Jacek , Załuska Wojciech
Published: February 2020

Toll-like receptor (TLR) signaling may be involved in autoimmune kidney disorders and has been implicated in proliferative and non-proliferative glomerulonephritis (PGN and NPGN). In this study, we investigated the expression of TLR2 on T and B lymphocytes in relation to selected clinical parameters in patients with PGN and NPGN. We collected peripheral blood from the ulnar vein of patients with PGN (n = 15) or NPGN (n = 22) and healthy volunteers (n = 20). The percentage of peripheral blood mononuclear cells expressing TLR2 was determined with flow cytometry. TLR2 expression on T and B lymphocytes was increased in PGN patients compared with NPGN patients and controls (p ≤ 0.001). In patients with PGN, TLR2 expression correlated negatively with the serum concentrations of IgG and albumin and positively with urine protein excretion. Receiver operating characteristic (ROC) analysis indicated that TLR2 expression is a highly specific marker to distinguish PGN patients from NPGN patients and controls, especially on CD4+ T lymphocytes. Its use as a non-invasive marker of disease should be further investigated.
Progress in Microneedle-Mediated Protein Delivery
Authors: Jamaledin Rezvan , Di Natale Concetta , Onesto Valentina , Taraghdari Zahra , Zare Ehsan , Makvandi Pooyan , Vecchione Raffaele , Netti Paolo
Published: February 2020

The growing demand for patient-compliance therapies in recent years has led to the development of transdermal drug delivery, which possesses several advantages compared with conventional methods. Delivering protein through the skin by transdermal patches is extremely difficult due to the presence of the stratum corneum which restricts the application to lipophilic drugs with relatively low molecular weight. To overcome these limitations, microneedle (MN) patches, consisting of micro/miniature-sized needles, are a promising tool to perforate the stratum corneum and to release drugs and proteins into the dermis following a non-invasive route. This review investigates the fabrication methods, protein delivery, and translational considerations for the industrial scaling-up of polymeric MNs for dermal protein delivery.
Combining Novel Biomarkers for Risk Stratification of Two-Year Cardiovascular Mortality in Patients with ST-Elevation Myocardial Infarction
Authors: Zagidullin Naufal , Motloch Lukas J. , Gareeva Diana , Hamitova Aysilu , Lakman Irina , Krioni Ilja , Popov Denis , Zulkarneev Rustem , Paar Vera , Kopp Kristen , Jirak Peter , Ishmetov Vladimir , Hoppe Uta C. , Tulbaev Eduard , Pavlov Valentin
Published: February 2020

ST-elevation myocardial infarction (STEMI) is one of the main reasons for morbidity and mortality worldwide. In addition to the classic biomarker NT-proBNP, new biomarkers like ST2 and Pentraxin-3 (Ptx-3) have emerged as potential tools in stratifying risk in cardiac patients. Indeed, multimarker approaches to estimate prognosis of STEMI patients have been proposed and their potential clinical impact requires investigation. In our study, in 147 patients with STEMI, NT-proBNP as well as serum levels of ST2 and Ptx-3 were evaluated. During two-year follow-up (FU; 734.2 ± 61.2 d) results were correlated with risk for cardiovascular mortality (CV-mortality). NT-proBNP (HR = 1.64, 95% CI = 1.21–2.21, p = 0.001) but also ST2 (HR = 1.000022, 95% CI = 1.00–1.001, p < 0.001) were shown to be reliable predictors of CV-mortality, while the highest predictive power was observed with Ptx-3 (HR = 3.1, 95% CI = 1.63–5.39, p < 0.001). When two biomarkers were combined in a multivariate Cox regression model, relevant improvement of risk assessment was only observed with NT-proBNP+Ptx-3 (AIC = 209, BIC = 214, p = 0.001, MER = 0.75, MEV = 0.64). However, the highest accuracy was seen using a three-marker approach (NT-proBNP + ST2 + Ptx-3: AIC = 208, BIC = 214, p < 0.001, MER = 0.77, MEV = 0.66). In conclusion, after STEMI, ST2 and Ptx-3 in addition to NT-proBNP were associated with the incidence of CV-mortality, with multimarker approaches enhancing the accuracy of prediction of CV-mortality.
Atrial Ectopy Increases Asynchronous Activation of the Endo- and Epicardium at the Right Atrium
Authors: van der Does Lisette J.M.E. , Kharbanda Rohit K. , Teuwen Christophe P. , Knops Paul , Kik Charles , Bogers Ad J.J.C. , de Groot Natasja M.S.
Published: February 2020

The predisposition of atrial extrasystoles (AES) to trigger cardiac tachyarrhythmia may arise from intramural conduction disorders causing endo-epicardial asynchrony (EEA). This study aimed to determine whether spontaneous AES disturb endo-epicardial conduction. Simultaneous endo-epicardial mapping of the right atrium was performed in patients during cardiac surgery with two 128-electrode arrays. Sixty spontaneous AES were observed in 23 patients and were analyzed for incidence of conduction delay, conduction block and amount of EEA compared to the previous sinus rhythm beat. Both conduction delay and block occurred more often in AES compared to sinus rhythm. The difference in lines of conduction block between the epicardium and endocardium increased in AES causing a greater imbalance of conduction disorders between the layers. The incidence of EEA with differences ≥10 ms increased significantly in AES. AES caused delays between the epicardium and endocardium up to 130 ms and EEA to increase for up to half (47%) of the mapping area. Conduction disturbances between the epicardial and endocardial layer giving rise to EEA increase during AES. Asynchronous activation of the atrial layers increases during AES which may be a mechanism for triggering cardiac tachyarrhythmia under the right conditions but EEA cannot be recognized by current mapping tools.