bluuebunny/crossref_metadata_2025 huggingface dataset:
Combinations of Indole based alkaloids fromMitragyna speciosa(Kratom) and cisplatin inhibit cell proliferation and migration of Nasopharyngeal carcinoma cell lines
Authors: Domnic Gregory , Chear Nelson Jeng-Yeou , Rahman Siti Fairus Abdul , Ramanathan Surash , Lo Kwok-Wai , Singh Darshan , Mohana-Kumaran Nethia
Published: December 2020

Ethnopharmacological relevance

Mitragyna speciosa(Korth.) or kratom is a medicinal plant indigenous to Southeast Asia. The leaves ofM. speciosais used as a medication in pain management including cancer related pain, in a similar way as opioids and cannabis. Despite its well-known analgesic effect, there is a scarce of information on the cancer-suppressing potential ofM. speciosaand its active constituents.

Aim of the study

To assess the potential applicability ofM. speciosaalkaloids (mitragynine, speciociliatine or paynantheine) as chemosensitizers for cisplatin in Nasopharyngeal carcinoma (NPC) cell lines.

Materials and Methods

The cytotoxic effects of the extracts, fractions and compounds were determined by conductingin vitrocytotoxicity assays. Based on the cytotoxic screening, the alkaloid extract ofM. speciosaexhibited potent inhibitory effect on the NPC cell line HK-1, and therefore, was chosen for further fractionation and purification. NPC cell lines HK-1 and C666-1 were treated with combinations of cisplatin andM. speciosaalkaloids in 2D monolayer culture. The effect of the drug combination on cell migration was tested usingin vitrowound healing and spheroid invasion assays.

Results

In our bioassay guided isolation, both methanolic and alkaloid extracts showed mild to moderate cytotoxic effect against the HK-1 cell line. Both NPC cell lines were insensitive to single agent and combination treatments of theM. speciosaalkaloids. However, mitragynine and speciociliatine sensitised the HK-1 and C666-1 to cisplatin ~4- and >5-fold, respectively in 2D monolayer culture. The combination of mitragynine and cisplatin also significantly inhibited cell migration of the NPC cell lines. Similarly, combination of mitragynine and cisplatin inhibited growth and invasion of HK-1 spheroids in a dose-dependent manner. Moreover, the spheroids did not rapidly develop resistance to the drug combinations at high concentrations over 10 days.

Conclusion

Collectively, data shows that both mitragynine and speciociliatine could be potential chemosensitizers for cisplatin. Further extensive drug mechanistic studies and investigations in animal models are necessary to delineate the applicability ofM. speciosaalkaloids for NPC therapy.
Designing an irreversible metabolic switch for scalable induction of microbial chemical production
Authors: Mannan Ahmad A. , Bates Declan G.
Published: December 2020

Bacteria can be harnessed to synthesise high-value chemicals. A promising strategy for increasing productivity uses inducible control systems to switch metabolism from growth to chemical synthesis once a large population of cell factories are generated. However, use of expensive chemical inducers limits scalability of this approach for biotechnological applications. Switching using cheap nutrients is an appealing alternative, but their tightly regulated uptake and consumption again limits scalability. Here, using mathematical models of fatty acid uptake inE. colias an exemplary case study, we unravel how the cell’s native regulation and program of induction can be engineered to minimise inducer usage. We show that integrating positive feedback loops into the circuitry creates an irreversible metabolic switch, which, requiring only temporary induction, drastically reduces inducer usage. Our proposed switch should be widely applicable, irrespective of the product of interest, and brings closer the realization of scalable and sustainable microbial chemical production.
The first insight into the genetic structure of the population of modern Serbia
Authors: Drljaca Tamara , Zukic Branka , Kovacevic Vladimir , Gemovic Branislava , Klaassen-Ljubicic Kristel , Perovic Vladimir , Lazarevic Mladen , Pavlovic Sonja , Veljkovic Nevena
Published: December 2020

The complete understanding of the genomic contribution to complex traits, diseases, and response to treatments, as well as genomic medicine application to the well-being of all humans will be achieved through the global variome that encompasses fine-scale genetic diversity. Despite significant efforts in recent years, uneven representation still characterizes genomic resources and among the underrepresented European populations are the Western Balkans including the Serbian population. Our research addresses this gap and presents the first ever dataset of variants in clinically relevant genes in the population sample of contemporary Serbia. A few variants significantly more frequent in the analyzed sample population compared to the European population as a whole are distinguished as its unique genetic determinants. We explored thoroughly their potential functional impact and its correlation with the health burden of the population of Serbia. Our variant’s catalogue improves the understanding of genetics of modern Serbia, contributes to application of precision medicine and health equity. In addition, this resource may also be applicable in neighboring regions and in worldwide functional analyses of genetic variants in individuals of European descent.
Effect of Deletion of the Ribonucleotide Reductase Gene in Wild Type and Virion Associated Host Shutoff (vhs-1) Mutant Herpes Simplex Virus-1 on Viral Proliferation and Infected-Carcinoma Cell Cultures Growth
Authors: Schlesinger Pnina , Frenkel Niza
Published: December 2020

Glioblastoma multiforme is the most prevalent and deadliest form of glioma and brain cancer, with a very poor prognosis. In an effort to develop an oncolytic viral vector for the treatment of Glioblastoma multiforme, we replaced the UL39 and UL40 genes encoding ribonucleotide reductase (RR) with green fluorescence protein and luciferase genes in wild type KOS and in the virion host shutoff mutant vhs-1, resulting in strains KOS-RR and Vhs-RR, respectively. KOS-RR and Vhs-RR caused death of infected U87 Glioblastoma multiforme cell cultures within one day after infection, whereas KOS and vhs-1-infected cells were more viable. All four viral strains caused apoptotic DNA laddering in infected H1299 lung cancer cells, while only Vhs-RR caused apoptosis in U87 cell cultures. Vhs-RR gave higher yields on U87 than on Vero cells, while it barely proliferated on non-dividing Goiter cells. These results indicate that Vhs-RR proliferates well in actively growing U87 Glioblastoma multiforme cells, causing their death in a mechanism involving apoptosis, while sparing non-dividing cells. Therefore, Vhs-RR is a promising candidate for oncolytic treatment of brain tumor malignancies.
Differential compartmentalization of BMP4/NOGGIN requires NOGGIN trans-epithelial transport
Authors: Phan-Everson Tien Minh-Thuy , Etoc Fred , Brivanlou Ali H , Siggia Eric D
Published: December 2020

Using self-organizing human models of gastrulation, we previously showed that (i) BMP4 initiates the cascade of events leading to gastrulation; (ii) BMP4 signal-reception is restricted to the basolateral domain; and (iii) in a human-specific manner, BMP4 directly induces the expression of NOGGIN. Here, we report the surprising discovery that in human epiblasts, NOGGIN and BMP4 were secreted into opposite extracellular spaces. Interestingly, apically-presented NOGGIN could inhibit basally-delivered BMP4. Apically-imposed microfluidic flow demonstrated that NOGGIN traveled in the apical extracellular space. Our co-localization analysis detailed the endocytotic route that trafficked NOGGIN from the apical space to the basolateral intercellular space where BMP4 receptors were located. This apical-to-basal transcytosis was indispensable for NOGGIN inhibition. Taken together, the segregation of activator/inhibitor into distinct extracellular spaces challenges classical views of morphogen movement. We propose that the transport of morphogen inhibitors regulates the spatial availability of morphogens during embryogenesis.
The loss of IL-31 signaling attenuates bleomycin-induced pulmonary fibrosis
Authors: Yombo Dan JK , Odayar Varshini , Gupta Nishanth , Jegga Anil G , Madala Satish K
Published: December 2020

Idiopathic Pulmonary Fibrosis (IPF) is a severe fibrotic lung disease characterized by excessive collagen deposition and progressive decline in lung function. Th2 T cell-derived cytokines including IL-4 and IL-13 have been shown to contribute to inflammation and fibrotic remodeling in multiple tissues. Interleukin-31 (IL-31) is a newly identified cytokine that is predominantly produced by CD4 Th2 T cells, but its signaling receptor IL-31RA is primarily expressed by non-hematopoietic cells. However, the potential role of the IL-31-IL31RA axis in pulmonary inflammation and fibrosis has remained largely unknown. To determine the role of IL-31 signaling in pulmonary fibrosis, wildtype, and IL-31RA knockout mice were treated with bleomycin and measured changes in collagen deposition and lung function. Notably, the loss of IL-31 signaling attenuated collagen deposition and lung function decline during bleomycin-induced pulmonary fibrosis. However, the loss of IL-31RA signaling did not affect inflammation in the lungs. The total lung transcriptome analysis showed a significant reduction in fibrosis-associated gene transcripts including extracellular matrix and epithelial cell-associated gene networks. Furthermore, the lungs of human IPF showed an elevated expression of IL-31 when compared to healthy subjects. In support, the percentage of IL-31 producing CD4+ T cells was greater in the lungs and PBMCs from IPF patients compared to healthy controls. Our findings suggest a pathogenic role for IL-31/IL-31RA signaling during bleomycin-induced pulmonary fibrosis. Thus, therapeutic targeting the IL-31-IL-31RA axis may prevent collagen deposition, improve lung function, and have therapeutic potential in pulmonary fibrosis.
Helium as anIn VitroFurin Inhibitor
Authors: Beihl David
Published: December 2020

Aims

Certain cancers, pathogenic infections, and other diseases are facilitated by the host enzyme furin, a calcium-dependent serine protease that is the most prominent member of the family of proprotein convertases. Furin and the other proprotein convertases modify certain other proteins to change them from their inactive to active forms. Previous attempts to find an effective, non-toxic furin inhibitor to treat diseases facilitated by furin have had only limited success, due to toxicity or large molecular size that impedes absorption of the molecule. This has placed increased importance on the development of small-molecule furin inhibitors. The object of this study was to consider the effect of the noble gas helium as a furin inhibitor.

Methods

This study uses a fluorometric furin inhibition assay to compare the enzymatic activity of recombinant human furin after exposure to balloon-grade helium gas, compared to the enzymatic activity of untreated recombinant human furin.

Results

Helium exposure was found to decrease thein vitroenzymatic activity of recombinant human furin by as much as 55%; this inhibition lasted for up to 16 hours. Fluorescence measurements of enzymatic activity were taken for 24 hours.

Conclusions

These findings appear to be the first to report helium as a partial furin inhibitor. The observed partial inhibition was consistent throughout the experiment. The effectiveness of helium as a partial furin inhibitor, its favorable side-effect profile, and its long history of safe use in respiratory therapy,when mixed with 20% oxygen or more and administered under direct medical supervision, make it a promising treatment for diseases facilitated by furin or its substrates. Further studies in cell culture or clinical trials may expand its clinical role for such diseases.
Long term survival ofDehalococcoides mccartyistrains in mixed cultures under electron acceptor and ammonium limitation
Authors: Morson Nadia , Molenda Olivia , Picott Katherine J. , Richardson Ruth E. , Edwards Elizabeth A.
Published: December 2020

Few strains ofDehalococcoides mccartyiharbour and express the vinyl chloride reductase (VcrA) that catalyzes the dechlorination of vinyl chloride (VC), a carcinogenic soil and groundwater contaminant. ThevcrAoperon is found on a Genomic Island (GI) and therefore believed to participate in horizontal gene transfer. To try to induce horizontal gene transfer of thevcrA-GI, we blended two enrichment cultures in medium without ammonium while providing VC. We hypothesized that these conditions would select for a mutant strain ofD. mccartyithat could both fix nitrogen and respire VC. However, after more than 4 years of incubation, we found no evidence for horizontal gene transfer of thevcrA-GI. Rather, we observed VC-dechlorinating activity attributed to the trichloroethene reductase TceA. Sequencing and protein modelling revealed a mutation in the predicted active site of TceA which may have influenced substrate specificity. We also identified two nitrogen-fixingD. mccartyistrains in the KB-1 culture. The presence of multiple strains ofD. mccartyiwith distinct phenotypes is a feature of natural environments and certain enrichment cultures (such as KB-1) and may enhance bioaugmentation success. The fact that multiple distinct strains persist in the culture for decades and that we could not induce horizontal gene transfer of thevcrA-GI suggests that it is not as mobile as predicted, or that mobility is restricted in ways yet to be discovered to specific sub-clades ofDehalococcoides.

TOC Art
The Chemical Structure of Widespread Microbial Aryl Polyene Lipids
Authors: Grammbitter Gina L. C. , Shi Yi-Ming , Shi Yan-Ni , Vemulapalli Sahithya P. B. , Richter Christian , Schwalbe Harald , Alanjary Mohammad , Schüffler Anja , Witt Matthias , Griesinger Christian , Bode Helge B.
Published: December 2020

Biosynthetic gene clusters (BGC) involved in aryl polyene (APE) biosynthesis are supposed to represent the most widespread BGC in the bacterial world.[1–3]Still, only hydrolysis products[4–8]and not the full-length product(s) have been identified, hindering studies on their biosynthesis and natural function. Here, we apply subsequent chromatographic separations to purify the aryl polyene-containing lipids (APELs) from the entomopathogenic bacteriumXenorhabdus doucetiae. Structure elucidation using a combination of isotope labeling, nuclear magnetic resonance techniques, and tandem mass spectrometry reveals an array of APELs featuring an all-transC26:5 conjugated fatty acyl and a galactosamine-phosphate-glycerol moiety. In combination with extensive genetic studies, this research broadens the bacterial natural product repertoire and paves the way for future functional characterization of this almost universal microbial compound class. Due to their protective function against reactive oxygen species,[5,9]APELs might be important for virulence or symbiosis, mediating organismic interactions in several ecological niches.
Soil microbial communities are not altered by garlic mustard in recently invaded central Illinois forests
Authors: Edwards Joseph D. , Yang Wendy H. , Yannarell Anthony C.
Published: December 2020

The invasive forest plant garlic mustard (Alliaria petiolata) has been shown to alter soil microbial communities in the northeastern part of its invaded range in the United States, and this disruption of soil communities may contribute to its invasion success. However, garlic mustard allelochemistry can vary with invasion age, and it is not clear whether garlic mustard’s impacts on soil microbes are consistent over its invaded range. Here, we compare the composition and diversity of soil fungal, bacterial, and archaeal communities among garlic mustard present, absent, and removed treatments in replicated blocks across five forests in the midwestern United States with relatively young garlic mustard invasions (approximately 17-26 years old, with consistent management). We collected samples in May and August, corresponding to garlic mustard active and senescent life history stages. While soil fungal and bacterial/ archaeal communities (based on ITS2 region and 16S rRNA gene DNA sequencing, respectively) differed significantly between different blocks/ forests and over time, we found no significant effect of garlic mustard treatment on soil microbial community composition or the relative abundance of mycorrhizal, saprotrophic, or pathogenic fungal guilds. The lack of garlic mustard impacts on the soil microbial community in recently invaded central Illinois forests suggests that these well-documented impacts in the northeastern United States and in older invasions cannot necessarily be generalized across all environmental contexts.
TheSINGLE FLOWER (SFL)gene encodes a MYB transcription factor that regulates the number of flowers produced by the inflorescence of chickpea
Authors: Caballo Cristina , Berbel Ana , Ortega Raul , Gil Juan , Millán Teresa , Rubio Josefa , Madueño Francisco
Published: December 2020

research conducted & rationale

Legume species usually have compound inflorescences, where flowers appear in secondary inflorescences (I2), at lateral positions of the primary inflorescence (I1), in contrast to simple inflorescences, as inArabidopsis, where flowers are formed in the primary inflorescence stem. The number of flowers per I2, characteristic of each legume species, determines inflorescence diversity, and the number of pods produced, which can affect yield. Gene Regulatory Network that controls the activity of I2 meristems, and therefore the number of flowers per secondary inflorescence is mostly unknown, as well as how specific are factors controlling this trait and whether they share this function in other meristems.

methods

Chickpea produces one flower per I2 butsingle flower(sfl) mutants produce two (double-pod phenotype). By mapping thesfl-dmutation and identification and analysis of a second mutant allele we have isolatedSFL. We used scanning electron microscopy to study the effect ofsflmutations on inflorescence ontogeny andin situhybridization to study the expression ofSFLand of meristem identity genes in the developing chickpea inflorescence.

key result

We show that theSFLgene corresponds toCaRAX1/2a, encoding a MYB transcription factor. Our results show thatCaRAX1/2a / SFLis specifically expressed in the I2 meristem, possibly activated byCaVEGETATIVE1.

main conclusion & key points for discussion

Our findings reveal thatSFLplays a central role in the control of chickpea inflorescence architecture, specifically acting in the I2 meristem to control the time length for which it is active, and therefore determining the number of floral meristems that it can produce.
A comprehensive transcriptome analysis reveals broader but weaker host response of SARS-CoV-2 than SARS-CoV
Authors: Leung Chi Sum , Xie Songhong , Feng Jiali , Chen Dongjing , Dai Aimei
Published: December 2020

COVID-19, which has resulted a worldwide health crisis with more than 74.9 million confirmed cases worldwide by December 2020, is caused by a newly emerging coronavirus identified and named SARS-CoV-2 in February in Wuhan, China. Experiences in defeating SARS, which infested during 2002-2003, can be used in treating the new disease. However, comparative genomics and epidemiology studies have shown much difference between SARS-CoV and SARS-CoV-2, which underlies the different clinical features and therapies in between those two diseases. Further studies comparing transcriptomes infected by these two viruses to uncover the differences in host responses would be necessary. Here we conducted a comprehensive transcriptome analysis of SARS-CoV and SARS-CoV-2-infected human cell lines, including Caco-2, Calu-3, H1299. Clustering analysis and expression of ACE2 show that SARS-CoV-2 has broader but weaker infection, where the largest discrepancy occurs in the epithelial lung cancer cell, Calu-3. SARS-CoV-2 genes also show less tissue specificity than SARS-CoV genes. Furthermore, we detected more general but moderate immune responses in SARS-CoV-2 infected transcriptomes by comparing weighted gene co-expression networks and modules. Our results suggest a different immune therapy and treatment scheme for COVID-19 patients than the ones used on SARS patients. The wider but weaker permissiveness and host responses of virus infection may also imply a long-term existence of SARS-CoV-2 among human populations.
End-to-end optimization of prosthetic vision
Authors: de Ruyter van Steveninck Jaap , Güçlü Umut , van Wezel Richard , van Gerven Marcel
Published: December 2020

Neural prosthetics may provide a promising solution to restore visual perception in some forms of blindness. The restored prosthetic percept is rudimentary compared to normal vision and can be optimized with a variety of image preprocessing techniques to maximize relevant information transfer. Extracting the most useful features from a visual scene is a non-trivial task and optimal preprocessing choices strongly depend on the context. Despite rapid advancements in deep learning, research currently faces a difficult challenge in finding a general and automated preprocessing strategy that can be tailored to specific tasks or user requirements. In this paper we present a novel deep learning approach that explicitly addresses this issue by optimizing the entire process of phosphene generation in an end-to-end fashion. The proposed model is based on a deep auto-encoder architecture and includes a highly adjustable simulation module of prosthetic vision. In computational validation experiments we show that such an approach is able to automatically find a task-specific stimulation protocol. The presented approach is highly modular and could be extended to dynamically optimize prosthetic vision for everyday tasks and requirements of the end-user.
Transcriptional analysis of immune modulatory genes in melanoma treated with PD-1 blockade
Authors: Song Hyojin , Lee Sungyoung , Lee Se-Hoon , Kim Miso , Lee Sang Yup , Yoon Sung-Soo , Yun Hongseok , Koh Youngil
Published: December 2020

Abstract/Summary

We aimed to characterize immunological features of melanoma patients treated with PD-1 blockade using tumor transcriptomic datasets. Response-dependent and response-independent predictors based on biological knowledge were investigated. Domain knowledge-driven regression-based analysis identifiedCEACAM1, CD40, B7-H3, andCD112as key genes that determine the melanoma immune status. We devised the transcriptional deviance score (TDS) representing the individual sample-wise contribution to the immune network. TheTDSnot only showed good predictive power for immune checkpoint inhibitor (ICI) responses but also suggested specific gene interactions that determine ICI responses. DynamicTDSchanges following ICI treatment were related to long survival, indicating immune network modulation by ICIs occurred in responders. A predictive model incorporatingB7-H3andCEACAM1expression, mutational status, clinical features, and theTDSshowed excellent performance for ICI response. Thus, our approaches suggest a novel measure for the tumor immune temperature and provide insight into melanoma immunobiology.

Highlights

We applied outcome-independent and outcome-dependent methods to investigate melanoma immunobiology.

CEACAM1, CD40, B7-H3, andCD112expression levels are key determinants of immune status.

We devised aTDSthat could measure tumor immune network status at the individual level.

Incorporating regression and correlation approaches greatly improves predictive power.
Growth stage-dependent changes of the levels of keratin 1 and keratin 10 as well as skin’s green autofluorescence of the back and the ears of C57BL/6 mice under basal conditions and after UVC irradiation
Authors: Yang Zhaoxia , Zhang Mingchao , Ying Weihai
Published: December 2020

Our previous studies have indicated that oxidative stress and inflammation can dose-dependently induce increased skin’s green autofluorescence (AF) of mice, which results at least partially from keratin 1 (K1) cleavage. Increased green AF was also found in patients’ skin of several major diseases, which may become a novel biomarker for non-invasive diagnosis. We also found age-dependent changes of the skin’s green AF of natural populations. In this study we tested our hypothesis that there are growth stage-dependent changes of K1 and keratin 10 (K10) levels in the skin of mice, which may underlie the age-dependent changes of the skin’s green AF. We found that in the skin of both mice’s back and ears, there were growth stage-dependent changes of the levels of K1 and K10 as well as the basal green AF. The K1 and K10 levels in the back’s skin were significantly different from those in the ear’s skin. There were also growth stage-dependent changes of the UVC-induced changes of K1 and K10 levels of both the ears and the back. Collectively, our study has provided first evidence showing growth stage-dependent and differential changes of the levels of K1 and K10 as well as skin’s green AF in the back and the ears of mice under basal conditions and after UVC irradiation. These findings are valuable for understanding the age-dependent changes of the skin’s green AF of natural populations, which are also important for establishing the keratins’ AF-based method for non-invasive diagnosis of diseases.
Comprehensive analysis of hsa-miR-654-5p’s tumor-suppressing functions
Authors: Liu Chuanyang , Min Lu , Kuang Jingyu , Zhu Chu-shu , Qiu Xinyuan , Wu Xiaomin , Zhang Tianyi , Xie Sisi , Zhu Lingyun
Published: December 2020

The pivotal roles of miRNAs in carcinogenesis, metastasis, and prognosis have been demonstrated recently in various cancers. This study intended to investigate the specific roles of hsa-miR-654-5p in lung cancer, which was poorly discussed. A series of closed-loop bioinformatic functional analyses were integrated within vitroexperimental validation to explore the overall biological functions and pan-cancer regulation pattern of miR-654-5p. We found that miR-654-5p abundance was significantly elevated in LUAD tissues and correlated with patients’ survival. 275 potential targets of miR-654-5p were then identified and the miR-654-5p-RNF8 regulation axis was validatedin vitroas a proof of concept. Furthermore, we revealed the tumor-suppressing roles of miR-654-5p and demonstrated that miR-654-5p inhibited lung cancer cell epithelial-mesenchymal transition (EMT) process, cell proliferation, and migration using target-based, abundance-based and ssGSEA-based bioinformatic methods andin vitrovalidation. Following the construction of a protein-protein interaction network, 11 highly interconnected hub genes were identified and a five genes risk scoring model was developed to assess their potential prognostic ability. Our study will not only provide a basic miRNA-mRNA-phenotypes reference map for understanding the function of miR-654-5p in different cancers but also reveal the tumor-suppressing roles and prognostic values of miR-654-5p in lung cancer.

Graphical abstract
A Community Challenge for Pancancer Drug Mechanism of Action Inference from Perturbational Profile Data
Authors: Douglass Eugene F , Allaway Robert J , Szalai Bence , Wang Wenyu , Tian Tingzhong , Fernández-Torras Adrià , Realubit Ron , Karan Charles , Zheng Shuyu , Pessia Alberto , Tanoli Ziaurrehman , Jafari Mohieddin , Wan Fangping , Li Shuya , Xiong Yuanpeng , Duran-Frigola Miquel , Bertoni Martino , Badia-i-Mompel Pau , Mateo Lídia , Guitart-Pla Oriol , Chung Verena ,   DREAM CTD-squared Pancancer Drug Activity Challenge Consortium, Tang Jing , Zeng Jianyang , Aloy Patrick , Saez-Rodriguez Julio , Guinney Justin , Gerhard Daniela S. , Califano Andrea
Published: December 2020

The Columbia Cancer Target Discovery and Development (CTD2) Center has developed PANACEA (PANcancer Analysis of Chemical Entity Activity), a collection of dose-response curves and perturbational profiles for 400 clinical oncology drugs in cell lines selected to optimally represent 19 cancer subtypes. This resource, developed to study tumor-specific drug mechanism of action, was instrumental in hosting a DREAM Challenge to assess computational models forde novodrug polypharmacology prediction. Dose-response and perturbational profiles for 32 kinase inhibitors were provided to 21 participating teams who were asked to predict high-affinity binding target among 255 possible protein kinases. Best performing methods leveraged both gene expression profile similarity analysis, and deep-learning methodologies trained on individual datasets. This study lays the foundation for future integrative analyses of pharmacogenomic data, reconciliation of polypharmacology effects in different tumor contexts, and insights into network-based assessment of context-specific drug mechanism of action.
Disinfection of Methicillin-ResistantStaphylococcus aureus, Vancomycin-resistantEnterococcus faeciumandAcinetobacter baumanniiusing Klaran WD array system
Authors: Mariita Richard M. , Randive Rajul V.
Published: December 2020

Healthcare-associated infections (HAIs) are a major burden in healthcare systems. In this study, UVC LEDs emitting radiation from 260-270 nm were evaluated for effectiveness in reducing methicillin-resistantStaphylococcus aureus(MRSA), vancomycin-resistant enterococci (VRE), andAcinetobacter baumannii. The array has four WD LEDs, each with 70mW placed at 7cm from test organism. With 11.76 mJ/cm2, the study obtained 99.99% reduction (log10 reduction factor of 4) against MRSA and VRE. ForA. baumannii, 9 mJ/cm2obtained 99.999% reduction (log10 reduction factor of 5). These results present scientific evidence on how effective UVC LEDs can be used in the fight against HAIs.
Evidence of a dysregulated Vitamin D pathway in SARS-CoV-2 infected patient’s lung cells
Authors: George Bijesh , Amjesh Ravikumar , Paul Aswathy Mary , Kumar T. R. Santhosh , Pillai Madhavan Radhakrishna , Kumar Rakesh
Published: December 2020

Although a defective vitamin D pathway has been widely suspected to be associated in SARS-CoV-2 pathobiology, the status of the vitamin D pathway and vitamin D-modulated genes in lung cells of patients infected with SARS-CoV-2 remains unknown. To understand the significance of the vitamin D pathway in SARS-CoV-2 pathobiology, computational approaches were applied to transcriptomic datasets from bronchoalveolar lavage fluid (BALF) cells of such patients or healthy individuals. Levels of vitamin D receptor, retinoid X receptor, and CYP27A1 in BALF cells of patients infected with SARS-CoV-2 were found to be reduced. Additionally, 107 differentially expressed, predominantly downregulated genes modulated by vitamin D were identified in transcriptomic datasets from patient’s cells. Further analysis of differentially expressed genes provided eight novel genes with a conserved motif with vitamin D-responsive elements, implying the role of both direct and indirect mechanisms of gene expression by the dysregulated vitamin D pathway in SARS-CoV-2-infected cells. Network analysis of differentially expressed vitamin D-modulated genes identified pathways in the immune system, NF-KB/cytokine signaling, and cell cycle regulation as top predicted pathways that might be affected in the cells of such patients. In brief, the results provided computational evidence to implicate a dysregulated vitamin D pathway in the pathobiology of SARS-CoV-2 infection.
Coordinated Changes in Gene Expression Kinetics Underlie both Mouse and Human Erythroid Maturation
Authors: Barile Melania , Imaz-Rosshandler Ivan , Inzani Isabella , Ghazanfar Shila , Nichols Jennifer , Marioni John C. , Guibentif Carolina , Göttgens Berthold
Published: December 2020

Background

Single cell technologies are transforming biomedical research, including the recent demonstration that unspliced pre-mRNA present in single cell RNA-Seq permits prediction of future expression states. Here we applied this ‘RNA velocity concept’ to an extended timecourse dataset covering mouse gastrulation and early organogenesis.

Results

Intriguingly, RNA velocity correctly identified epiblast cells as the starting point, but several trajectory predictions at later stages were inconsistent with both real time ordering and existing knowledge. The most striking discrepancy concerned red blood cell maturation, with velocity-inferred trajectories opposing the true differentiation path. Investigating the underlying causes revealed a group of genes with a coordinated step-change in transcription, thus violating the assumptions behind current velocity analysis suites, which do not accommodate time-dependent changes in expression dynamics. Using scRNA-Seq analysis of chimeric mouse embryos lacking the major erythroid regulatorGata1, we show that genes with the step-changes in expression dynamics during erythroid differentiation fail to be up-regulated in the mutant cells, thus underscoring the coordination of modulating transcription rate along a differentiation trajectory. In addition to the expected block in erythroid maturation, theGata1-chimera dataset revealed induction of PU.1 and expansion of megakaryocyte progenitors. Finally, we show that erythropoiesis in human fetal liver is similarly characterized by a coordinated step-change in gene expression.

Conclusions

By identifying a limitation of the current velocity framework coupled within vivoanalysis of mutant cells, we reveal a coordinated step-change in gene expression kinetics during erythropoiesis, with likely implications for many other differentiation processes.
A derived ZW chromosome system inAmborella trichopoda, the sister species to all other extant flowering plants
Authors: Käfer Jos , Bewick Adam , Andres-Robin Amélie , Lapetoule Garance , Harkess Alex , Caïus José , Fogliani Bruno , Gâteblé Gildas , Ralph Paula , dePamphilis Claude W. , Picard Franck , Scutt Charlie P. , Leebens-Mack James , Marais Gabriel AB
Published: December 2020

Sex determination is poorly understood in plants.Amborella trichopodais a well-known plant model for evo-devo studies, which is also dioecious (has male and female individuals), with an unknown sex determination mechanism.A. trichopodais a “sex switcher”, which points to possible environmental factors that act on sex, but populations grown from seed under greenhouse conditions exhibit a 50:50 sex ratio, which indicates the operation of genetic factors. Here, we use a new method (SDpop) to identify sex-linked genes from genotyping data of male and female individuals sampled in the field, and find thatA. trichopodahas a ZW sex-chromosome system. The sex-linked genes map to a 4 Mb sex-determining region on chromosome 9. The low extent of ZW divergence suggests these sex chromosomes are of recent origin, which is consistent with dioecy being derived character in theA. trichopodalineage. Our work has uncovered clearly formed sex chromosomes in a species in which both genetic and environmental factors can influence sex.

One Sentence Summary

Amborella trichopoda, a dioecious species in which both genetics and the environment influence sex, possesses a pair of quite recently evolved ZW chromosomes.
Liver Electrical Impedance Tomography for Early Identification of Fatty Infiltrate in Obesity
Authors: Chang Chih-Chiang , Huang Zi-Yu , Shih Shu-Fu , Luo Yuan , Ko Arthur , Cui Qingyu , Cavallero Susana , Das Swarna , Thames Gail , Bui Alex , Jacobs Jonathan P. , Pajukanta Päivi , Wu Holden , Tai Yu-Chong , Li Zhaoping , Hsiai Tzung K.
Published: December 2020

Non-alcoholic fatty liver disease (NAFLD) is endemic in developed countries and is one of the most common causes of cardiometabolic diseases in overweight/obese individuals. While liver biopsy or magnetic resonance imaging (MRI) is the current gold standard to diagnose NAFLD, the former is prone to bleeding and the latter is costly. We hereby demonstrated liver electrical impedance tomography (EIT) as a non-invasive and portable detection method for fatty infiltrate. We enrolled 19 subjects (15 females and 4 males; 27 to 74 years old) to undergo liver MRI scans, followed by EIT measurements via a multi-electrode array. The liver MRI scans provided subject-specifica prioriknowledge of the liver boundary conditions for segmentation and EIT reconstruction, and the 3-D multi-echo MRI data quantified liver proton-density fat fraction (PDFF%) as a recognized reference standard for validating liver fat infiltrate. Using acquired voltage data and the reconstruction algorithm for the EIT imaging, we computed the absolute conductivity distribution of abdomen in 2-D. Correlation analyses were performed to compare the individual EIT conductivity vs. MRI PDFF with their demographics in terms of gender, BMI (kg·m−2), age (years), waist circumference (cm), height (cm), and weight (kg). Our results indicate that EIT conductivity (S·m−1) and liver MRI for PDFF were not correlated with the demographics, whereas the decrease in EIT conductivity was correlated with the increase in MRI PDFF (R= − 0.69,p= 0.003). Thus, EIT conductivity holds promise for developing a non-invasive, portable, and quantitative method to detect fatty liver disease.
The Urinary Microbiome in Postmenopausal Women with Recurrent Urinary Tract Infections
Authors: Vaughan Monique H. , Mao Jialiang , Karstens Lisa A. , Ma Li , Amundsen Cindy L. , Schmader Kenneth E. , Siddiqui Nazema Y.
Published: December 2020

Recurrent urinary tract infections (UTI) are highly prevalent in postmenopausal women, where vaginal estrogen and prophylactic antibiotics are used for treatment. The etiology of recurrent UTIs is not completely known, but the urinary microbiome is thought to be implicated. Thus, we aimed to compare the “steady state” urinary microbiome in three groups of menopausal women who were all using topically-applied vaginal estrogen: 1) women with recurrent UTIsondaily antibiotic prophylaxis; 2) women with recurrent UTIsnot onantibiotic prophylaxis; and 3) age-matched controls without recurrent UTIs. Here we present a cross-sectional analysis of baseline data from 64 women enrolled in a longitudinal cohort study. Catheterized urine samples were collected > 4 weeks after last treatment for UTI. Samples were evaluated using expanded quantitative urine culture (EQUC) and 16S rRNA gene sequencing. With EQUC techniques, there were no significant differences in the median numbers of microbial species isolated among groups (p=0.96), even when consideringLactobacilli(p=0.72). However, there were trends towards differentLactobacillusspecies between groups. With sequencing the overwhelming majority of urinary samples containedLactobacilli, with non-significant trends in relative abundance ofLactobacilliamong groups. Using a Bayesian regression analysis for compositional data, we identified significant differences in anaerobic taxa that were associated with phenotypic groups. Most of these differences centered on Bacteroidales and the familyPrevotellaceae, though differences were also noted in Actinobacteria and certain genera of Clostridiales. Associations between anaerobes within the urinary microbiome and recurrent UTI warrants further investigation.

IMPORTANCE

In menopausal women with recurrent urinary tract infections (UTIs) compared to those without, the abundance ofLactobacilluswithin the urinary microbiome is not significantly different when vaginal estrogen is regularly used. In this population,Lactobacillaceaewere identified in 97% of urine samples using culture-independent techniques. However, with expanded urine cultures, women with recurrent UTIs taking daily antibiotics had a disproportionately low amount ofL. gasseri/L. acidophiluscompared to the other phenotypic groups. These findings support the theory that certainLactobacillusspecies may be more important than others in the pathophysiology of postmenopausal recurrent UTIs. Furthermore, when using culture-independent techniques to explore urinary microbiota across phenotypic groups, we identified differences in multiple anaerobic taxa. Taken together, these results suggest that altered ratios of anaerobes and certainLactobacillusspecies within the urinary microbiome may be implicated in postmenopausal recurrent UTI.
Surface white spot and pitting corrosion of 316 L stainless steel
Authors: Yi Guanghui , Zheng Dajiang , Song Guang-Ling
Published: December 2020

Purpose

The purpose of this paper is to address the concern of some stainless steel users. To understand the effect of surface white spots on corrosion performance of stainless steel.

Design/methodology/approach

White spots appeared on some component surfaces made of 316 L stainless steel in some industrial applications. To address the concern about the pitting performance in the spot areas, the pitting corrosion potential and corrosion resistance were measured in the spot and non-spot areas by means of potentiodynamic polarization and electrochemical impedance spectroscopy and the two different surface characteristics were analytically compared by using optical microscopy, laser confocal microscopy, scanning electron microscopy, x-ray diffraction, energy dispersive spectroscopy and auger energy spectroscopy. The results indicated that the pitting performance of the 316 L stainless steel was not negatively influenced by the spots and the white spots simply resulted from the slightly different surface morphology in the spot areas.

Findings

The white spots are actually the slightly rougher surface areas with some carbon-containing species. They do not reduce the pitting resistance. Interestingly, the white spot areas even have slightly improved general corrosion resistance.

Research limitations/implications

Not all surface contamination or roughening can adversely affect the corrosion resistance of stainless steel.

Practical implications

Stainless steel components with such surface white spots are still qualified products in terms of corrosion performance.

Originality/value

The surface spot of stainless steel was systematically investigated for the first time for its effect on corrosion resistance and the conclusion was new to the common knowledge.
Modeling and prediction of the average roughness of UNS S31600 in superfinishing turning
Authors: Ech-charqy Younes , Radouani Rachid , Essahli Mohamed
Published: December 2020

Purpose

The purpose of this paper is to realize an effective hybrid modeling (empirical-geometric) in order to describe the real behavior of the average roughness variation of the workpiece surface in turning with an elementary operation of superfinishing, using different analytic methodologies. The previous works are limited to describe the roughness for the usual elementary operations, citing the roughing and the semi-finishing, while this analysis builds technical rails for the industrialists in order to well conduct the operation of superfinishing in turning, by choosing the cutting parameters from the proposed model.

Design/methodology/approach

A statistical analysis of the average roughness measurements capability study, by the statistical process control method SPC and the ANN artificial neuron network, Levenberg–Marquardt's methods modified Monte Carlo SRM response surface.

Findings

The objective of this work was to describe the average roughness generated by the penetration of the cutting tool into a part in superfinishing turning. First, the authors used artificial colony analysis to determine optimal cutting conditions in order to have an average roughness lower than 0.8 µm. The cutting conditions selected: (1) the feed rate f ϵ [0.05; 0.2] mm/rev; (2) the pass depth ap ϵ [0.25; 1] mm; (3) the corner radius re = 0.2 mm and (4) cutting speed Vc ϵ [75; 100] m/min.

Originality/value

This work consists to realize an effective hybrid modeling (empirical-geometric) in order to describe the real behavior of the average roughness variation of the workpiece surface in turning with an elementary operation of superfinishing, using different analytic methodologies. The previous works are limited to describe the roughness for the usual elementary operations, citing the roughing and the semi-finishing, while this analysis builds technical rails for the industrialists in order to well conduct the operation of superfinishing in turning, by choosing the cutting parameters from the proposed model.
Combined robot‐assisted mitral valve plasty and Nuss procedure via small ports
Authors: Ishikawa Norihiko , Watanabe Go , Horikawa Takafumi , Tarui Tatsuya , Seguchi Ryuta , Kiuchi Ryuta , Tomita Shigeyuki , Ohtsuka Toshiya , Kasagi Yasushi
Published: December 2020

Pectus excavatum (PE) can be associated with cardiac disorders that also require surgical repair. Totally endoscopic robot‐assisted mitral valve plasty for mitral valve regurgitation was performed while elevating the sternum with the aid of our original electrical sternum lifting system. Then, the Nuss procedure was performed successfully via small incision. Simultaneous robot‐assisted cardiac surgery and the Nuss procedure is effective. Sternal elevation during cardiac surgery is very important for a safe procedure. The Nuss technique prevents perioperative cardiac compression and allows for correction of the pectus deformity with good cosmetic and functional results.
Phytocannabinoid‐dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity
Authors: Damstra‐Oddy Joseph L. , Warren Eleanor C. , Perry Christopher J. , Desfougères Yann , Fitzpatrick John‐Mark K. , Schaf Judith , Costelloe Lisa , Hind William , Downer Eric J. , Saiardi Adolfo , Williams Robin S.B.
Published: December 2020

Background and Purpose

Cannabidiol (CBD) has been shown to differentially regulate the mechanistic target of rapamycin complex 1 (mTORC1) in preclinical models of disease, where it reduces activity in models of epilepsies and cancer and increases it in models of multiple sclerosis (MS) and psychosis. Here, we investigate the effects of phytocannabinoids on mTORC1 and define a molecular mechanism.

Experimental Approach

A novel mechanism for phytocannabinoids was identified using the tractable model system, Dictyostelium discoideum. Using mouse embryonic fibroblasts, we further validate this new mechanism of action. We demonstrate clinical relevance using cells derived from healthy individuals and from people with MS (pwMS).

Key Results

Both CBD and the more abundant cannabigerol (CBG) enhance mTORC1 activity in D. discoideum. We identify a mechanism for this effect involving inositol polyphosphate multikinase (IPMK), where elevated IPMK expression reverses the response to phytocannabinoids, decreasing mTORC1 activity upon treatment, providing new insight on phytocannabinoids' actions. We further validated this mechanism using mouse embryonic fibroblasts. Clinical relevance of this effect was shown in primary human peripheral blood mononuclear cells, where CBD and CBG treatment increased mTORC1 activity in cells derived from healthy individuals and decreased mTORC1 activity in cells derived from pwMS.

Conclusion and Implications

Our findings suggest that both CBD and the abundant CBG differentially regulate mTORC1 signalling through a mechanism dependent on the activity of the upstream IPMK signalling pathway, with potential relevance to the treatment of mTOR‐related disorders, including MS.
Modeling the Influence of Language Input Statistics on Children's Speech Production
Authors: Roete Ingeborg , Frank Stefan L. , Fikkert Paula , Casillas Marisa
Published: December 2020

We trained a computational model (the Chunk‐Based Learner; CBL) on a longitudinal corpus of child–caregiver interactions in English to test whether one proposed statistical learning mechanism—backward transitional probability—is able to predict children's speech productions with stable accuracy throughout the first few years of development. We predicted that the model less accurately reconstructs children's speech productions as they grow older because children gradually begin to generate speech using abstracted forms rather than specific “chunks” from their speech environment. To test this idea, we trained the model on both recently encountered and cumulative speech input from a longitudinal child language corpus. We then assessed whether the model could accurately reconstruct children's speech. Controlling for utterance length and the presence of duplicate chunks, we found no evidence that the CBL becomes less accurate in its ability to reconstruct children's speech with age.