Short-term inhibition of autophagy benefits pancreatic β-cells by augmenting ether lipids and peroxisomal function, and by countering depletion of n-3 polyunsaturated fatty acids after fat-feeding.

Mol Metab. 2020 Jun 03;:101028

Authors: Hingst JR, Kjøbsted R, Birk JB, Jørgensen NO, Larsen MR, Kido K, Larsen JK, Kjeldsen SAS, Fentz J, Frøsig C, Holm S, Fritzen AM, Dohlmann TL, Larsen S, Foretz M, Viollet B, Schjerling P, Overby P, Halling JF, Pilegaard H, Helsten Y, Wojtaszewski JFP

Abstract
OBJECTIVE: Current evidence for AMPK-mediated regulation of skeletal muscle metabolism during exercise is mainly based on transgenic mouse models with chronic (lifelong) disruption of AMPK function. Findings based on such models are potentially biased by secondary effects related to chronic lack of AMPK function. In an attempt to study the direct effect(s) of AMPK on muscle metabolism during exercise, we generated a new mouse model with inducible muscle-specific deletion of AMPKα catalytic subunits in adult mice.
METHODS: Tamoxifen-inducible and muscle-specific AMPKα1/α2 double KO mice (AMPKα imdKO) were generated using the Cre/loxP system with the Cre driven by the human skeletal muscle actin (HSA) promotor.
RESULTS: During treadmill running at the same relative exercise intensity, AMPKα imdKO mice showed greater depletion of muscle ATP, which was associated with accumulation of the deamination product IMP. Muscle-specific deletion of AMPKα in adult mice promptly reduced maximal running speed, muscle glycogen content and was associated with reduced expression of UGP2, a key component of the glycogen synthesis pathway. Muscle mitochondrial respiration, whole body substrate utilization as well as muscle glucose uptake and fatty acid (FA) oxidation during muscle contractile activity remained unaffected by muscle-specific deletion AMPKα subunits in adult mice.
CONCLUSIONS: Inducible deletion of AMPKα subunits in adult mice reveals that AMPK is required for maintaining muscle ATP levels and nucleotide balance during exercise, but is dispensable for regulating muscle glucose uptake, FA oxidation and substrate utilization during exercise.

PMID: 32504885 [PubMed - as supplied by publisher]

Single-Cell RNA Sequencing of Human, Macaque, and Mouse Testes Uncovers Conserved and Divergent Features of Mammalian Spermatogenesis.

Dev Cell. 2020 Jun 02;:

Authors: Shami AN, Zheng X, Munyoki SK, Ma Q, Manske GL, Green CD, Sukhwani M, Orwig KE, Li JZ, Hammoud SS

Abstract
Spermatogenesis is a highly regulated process that produces sperm to transmit genetic information to the next generation. Although extensively studied in mice, our current understanding of primate spermatogenesis is limited to populations defined by state-specific markers from rodent data. As between-species differences have been reported in the duration and differentiation hierarchy of this process, it remains unclear how molecular markers and cell states are conserved or have diverged from mice to man. To address this challenge, we employ single-cell RNA sequencing to identify transcriptional signatures of major germ and somatic cell types of the testes in human, macaque, and mice. This approach reveals similarities and differences in expression throughout spermatogenesis, including the stem/progenitor pool of spermatogonia, markers of differentiation, potential regulators of meiosis, RNA turnover during spermatid differentiation, and germ cell-soma communication. These datasets provide a rich foundation for future targeted mechanistic studies of primate germ cell development and in vitro gametogenesis.

PMID: 32504559 [PubMed - as supplied by publisher]

Genome-wide association reveals a complex architecture for rust resistance in 2300 worldwide bread wheat accessions screened under various Australian conditions.

Theor Appl Genet. 2020 Jun 05;:

Authors: Joukhadar R, Hollaway G, Shi F, Kant S, Forrest K, Wong D, Petkowski J, Pasam R, Tibbits J, Bariana H, Bansal U, Spangenberg G, Daetwyler H, Gendall T, Hayden M

Abstract
We utilized 2300 wheat accessions including worldwide landraces, cultivars and primary synthetic-derived germplasm with three Australian cultivars: Annuello, Yitpi and Correll, to investigate field-based resistance to leaf (Lr) rust, stem (Sr) rust and stripe (Yr) rust diseases across a range of Australian wheat agri-production zones. Generally, the resistance in the modern Australian cultivars, synthetic derivatives, South and North American materials outperformed other geographical subpopulations. Different environments for each trait showed significant correlations, with average r values of 0.53, 0.23 and 0.66 for Lr, Sr and Yr, respectively. Single-trait genome-wide association studies (GWAS) revealed several environment-specific and multi-environment quantitative trait loci (QTL). Multi-trait GWAS confirmed a cluster of Yr QTL on chromosome 3B within a 4.4-cM region. Linkage disequilibrium and comparative mapping showed that at least three Yr QTL exist within the 3B cluster including the durable rust resistance gene Yr30. An Sr/Lr QTL on chromosome 3D was found mainly in the synthetic-derived germplasm from Annuello background which is known to carry the Agropyron elongatum 3D translocation involving the Sr24/Lr24 resistance locus. Interestingly, estimating the SNP effects using a BayesR method showed that the correlation among the highest 1% of QTL effects across environments (excluding GWAS QTL) had significant correlations, with average r values of 0.26, 0.16 and 0.55 for Lr, Sr and Yr, respectively. These results indicate the importance of small effect QTL in achieving durable rust resistance which can be captured using genomic selection.

PMID: 32504212 [PubMed - as supplied by publisher]

A synthesis of bacterial and archaeal phenotypic trait data.

Sci Data. 2020 Jun 05;7(1):170

Authors: Madin JS, Nielsen DA, Brbic M, Corkrey R, Danko D, Edwards K, Engqvist MKM, Fierer N, Geoghegan JL, Gillings M, Kyrpides NC, Litchman E, Mason CE, Moore L, Nielsen SL, Paulsen IT, Price ND, Reddy TBK, Richards MA, Rocha EPC, Schmidt TM, Shaaban H, Shukla M, Supek F, Tetu SG, Vieira-Silva S, Wattam AR, Westfall DA, Westoby M

Abstract
A synthesis of phenotypic and quantitative genomic traits is provided for bacteria and archaea, in the form of a scripted, reproducible workflow that standardizes and merges 26 sources. The resulting unified dataset covers 14 phenotypic traits, 5 quantitative genomic traits, and 4 environmental characteristics for approximately 170,000 strain-level and 15,000 species-aggregated records. It spans all habitats including soils, marine and fresh waters and sediments, host-associated and thermal. Trait data can find use in clarifying major dimensions of ecological strategy variation across species. They can also be used in conjunction with species and abundance sampling to characterize trait mixtures in communities and responses of traits along environmental gradients.

PMID: 32503990 [PubMed - as supplied by publisher]

MYC functions as a switch for natural killer cell-mediated immune surveillance of lymphoid malignancies.

Nat Commun. 2020 Jun 05;11(1):2860

Authors: Swaminathan S, Hansen AS, Heftdal LD, Dhanasekaran R, Deutzmann A, Fernandez WDM, Liefwalker DF, Horton C, Mosley A, Liebersbach M, Maecker HT, Felsher DW

Abstract
The MYC oncogene drives T- and B- lymphoid malignancies, including Burkitt's lymphoma (BL) and Acute Lymphoblastic Leukemia (ALL). Here, we demonstrate a systemic reduction in natural killer (NK) cell numbers in SRα-tTA/Tet-O-MYCON mice bearing MYC-driven T-lymphomas. Residual mNK cells in spleens of MYCON T-lymphoma-bearing mice exhibit perturbations in the terminal NK effector differentiation pathway. Lymphoma-intrinsic MYC arrests NK maturation by transcriptionally repressing STAT1/2 and secretion of Type I Interferons (IFNs). Treating T-lymphoma-bearing mice with Type I IFN improves survival by rescuing NK cell maturation. Adoptive transfer of mature NK cells is sufficient to delay both T-lymphoma growth and recurrence post MYC inactivation. In MYC-driven BL patients, low expression of both STAT1 and STAT2 correlates significantly with the absence of activated NK cells and predicts unfavorable clinical outcomes. Our studies thus provide a rationale for developing NK cell-based therapies to effectively treat MYC-driven lymphomas in the future.

PMID: 32503978 [PubMed - as supplied by publisher]

Modular gateway-ness connectivity and structural core organization in maritime network science.

Nat Commun. 2020 Jun 05;11(1):2849

Authors: Xu M, Pan Q, Muscoloni A, Xia H, Cannistraci CV

Abstract
Around 80% of global trade by volume is transported by sea, and thus the maritime transportation system is fundamental to the world economy. To better exploit new international shipping routes, we need to understand the current ones and their complex systems association with international trade. We investigate the structure of the global liner shipping network (GLSN), finding it is an economic small-world network with a trade-off between high transportation efficiency and low wiring cost. To enhance understanding of this trade-off, we examine the modular segregation of the GLSN; we study provincial-, connector-hub ports and propose the definition of gateway-hub ports, using three respective structural measures. The gateway-hub structural-core organization seems a salient property of the GLSN, which proves importantly associated to network integration and function in realizing the cargo transportation of international trade. This finding offers new insights into the GLSN's structural organization complexity and its relevance to international trade.

PMID: 32503974 [PubMed - as supplied by publisher]

A Systems Biology Approach for miRNA-mRNA Expression Patterns Analysis in Rheumatoid Arthritis.

Comb Chem High Throughput Screen. 2020 Jun 05;:

Authors: Tavasolian F, Hosseini AZ, Soudi S, Naderi M, Sahebkar A

Abstract
OBJECTIVE: Considering the molecular complexity and heterogeneity of rheumatoid arthritis (RA), the identification of novel molecular contributors involved in RA initiation and progression using systems biology approaches will open up potential therapeutic strategies. The bioinformatics method allows the detection of associated miRNA-mRNA as both therapeutic and prognostic targets for RA.
METHOD: This research used a system biology approach based on a systematic re-analysis of the RA-related microarray datasets in the NCBI Gene Expression Omnibus (GEO) database to find out deregulated miRNAs. We then studied the deregulated miRNA-mRNA using Enrichr and MolecularSignatures Database (MSigDB) to identify novel RA-related markers followed by an overview of miRNA-mRNA interaction networks and RA-related pathways.
RESULTS: This research mainly focused on mRNA and miRNA interactions in all tissues and blood/serum associated with RA to obtain a comprehensive knowledge on RA. Recent systems biology approach analyzed seven independent studies and presented important RA-related deregulated miRNAs (miR-145-5p, miR-146a-5p, miR-155-5p, miR-15a-5p, miR-29c-3p, miR103a-3p, miR-125a-5p, miR-125b-5p, miR-218); upregulation of miR-125b is shown in the study (GSE71600). While the findings of the Enrichr showed cytokine and vitamin D receptor pathways and inflammatory pathways. Further analysis revealed a negative correlation between the vitamin D receptor (VDR) and miR-125b in RA-associated gene expression.
CONCLUSION: Since vitamin D is capable of regulating the immune homeostasis and decreasing the autoimmune process through its receptor (VDR), it is regarded as a potential target for RA. According to the results obtained, a comparative correlation between negative expression of the vitamin D receptor (VDR) and miR-125b was suggested in RA. The increasing miR-125b expression would reduce the VitD uptake through its receptor.

PMID: 32503403 [PubMed - as supplied by publisher]

Can We Assume the Gene Expression Profile as a Proxy for Signaling Network Activity?

Biomolecules. 2020 Jun 03;10(6):

Authors: Piran M, Karbalaei R, Piran M, Aldahdooh J, Mirzaie M, Ansari-Pour N, Tang J, Jafari M

Abstract
Studying relationships among gene products by expression profile analysis is a common approach in systems biology. Many studies have generalized the outcomes to the different levels of central dogma information flow and assumed a correlation of transcript and protein expression levels. However, the relation between the various types of interaction (i.e., activation and inhibition) of gene products to their expression profiles has not been widely studied. In fact, looking for any perturbation according to differentially expressed genes is the common approach, while analyzing the effects of altered expression on the activity of signaling pathways is often ignored. In this study, we examine whether significant changes in gene expression necessarily lead to dysregulated signaling pathways. Using four commonly used and comprehensive databases, we extracted all relevant gene expression data and all relationships among directly linked gene pairs. We aimed to evaluate the ratio of coherency or sign consistency between the expression level as well as the causal relationships among the gene pairs. Through a comparison with random unconnected gene pairs, we illustrate that the signaling network is incoherent, and inconsistent with the recorded expression profile. Finally, we demonstrate that, to infer perturbed signaling pathways, we need to consider the type of relationships in addition to gene-product expression data, especially at the transcript level. We assert that identifying enriched biological processes via differentially expressed genes is limited when attempting to infer dysregulated pathways.

PMID: 32503292 [PubMed - as supplied by publisher]

DSCAM-AS1-Driven Proliferation of Breast Cancer Cells Involves Regulation of Alternative Exon Splicing and 3'-End Usage.

Cancers (Basel). 2020 Jun 03;12(6):

Authors: Elhasnaoui J, Miano V, Ferrero G, Doria E, Leon AE, Fabricio ASC, Annaratone L, Castellano I, Sapino A, De Bortoli M

Abstract
DSCAM-AS1 is a cancer-related long noncoding RNA with higher expression levels in Luminal A, B, and HER2-positive Breast Carcinoma (BC), where its expression is strongly dependent on Estrogen Receptor Alpha (ERα). DSCAM-AS1 expression is analyzed in 30 public datasets and, additionally, by qRT-PCR in tumors from 93 BC patients, to uncover correlations with clinical data. Moreover, the effect of DSCAM-AS1 knockdown on gene expression and alternative splicing is studied by RNA-Seq in MCF-7 cells. We confirm DSCAM-AS1 overexpression in high grade Luminal A, B, and HER2+ BCs and find a significant correlation with disease relapse. In total, 908 genes are regulated by DSCAM-AS1-silencing, primarily involved in the cell cycle and inflammatory response. Noteworthily, the analysis of alternative splicing and isoform regulation reveals 2085 splicing events regulated by DSCAM-AS1, enriched in alternative polyadenylation sites, 3'UTR (untranslated region) shortening and exon skipping events. Finally, the DSCAM-AS1-interacting splicing factor heterogeneous nuclear ribonucleoprotein L (hnRNPL) is predicted as the most enriched RBP for exon skipping and 3'UTR events. The relevance of DSCAM-AS1 overexpression in BC is confirmed by clinical data and further enhanced by its possible involvement in the regulation of RNA processing, which is emerging as one of the most important dysfunctions in cancer.

PMID: 32503257 [PubMed - as supplied by publisher]

Exploration of User's Mental State Changes during Performing Brain-Computer Interface.

Sensors (Basel). 2020 Jun 03;20(11):

Authors: Ko LW, Chikara RK, Lee YC, Lin WC

Abstract
Substantial developments have been established in the past few years for enhancing the performance of brain-computer interface (BCI) based on steady-state visual evoked potential (SSVEP). The past SSVEP-BCI studies utilized different target frequencies with flashing stimuli in many different applications. However, it is not easy to recognize user's mental state changes when performing the SSVEP-BCI task. What we could observe was the increasing EEG power of the target frequency from the user's visual area. BCI user's cognitive state changes, especially in mental focus state or lost-in-thought state, will affect the BCI performance in sustained usage of SSVEP. Therefore, how to differentiate BCI users' physiological state through exploring their neural activities changes while performing SSVEP is a key technology for enhancing the BCI performance. In this study, we designed a new BCI experiment which combined working memory task into the flashing targets of SSVEP task using 12 Hz or 30 Hz frequencies. Through exploring the EEG activity changes corresponding to the working memory and SSVEP task performance, we can recognize if the user's cognitive state is in mental focus or lost-in-thought. Experiment results show that the delta (1-4 Hz), theta (4-7 Hz), and beta (13-30 Hz) EEG activities increased more in mental focus than in lost-in-thought state at the frontal lobe. In addition, the powers of the delta (1-4 Hz), alpha (8-12 Hz), and beta (13-30 Hz) bands increased more in mental focus in comparison with the lost-in-thought state at the occipital lobe. In addition, the average classification performance across subjects for the KNN and the Bayesian network classifiers were observed as 77% to 80%. These results show how mental state changes affect the performance of BCI users. In this work, we developed a new scenario to recognize the user's cognitive state during performing BCI tasks. These findings can be used as the novel neural markers in future BCI developments.

PMID: 32503162 [PubMed - as supplied by publisher]

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Injectable slurry for selective destruction of neck adipose tissue in New Zealand obese mouse model.

Sleep Breath. 2020 May 30;:

Authors: Moradi Tuchayi S, Tam J, Wojtkiewicz GR, Kawa NI, Javorsky E, Anderson RR, Garibyan L

Abstract
PURPOSE: Increased neck circumference is a major risk factor for obstructive sleep apnea (OSA). New data suggest that increased adipose tissue in the neck may be a contributory cause of OSA. The aim of this study was to investigate safety and efficacy of a recently developed injectable ice slurry in selective reduction of neck adipose tissue in a mouse model.
METHODS: We used the New Zealand obese mice that have increased volume of anterior neck fat, and are commonly used in OSA studies. MRI imaging was used to measure changes in fat tissue volume.
RESULTS: Thirty animals were used in this study. Volumetric measurements in MRI images showed thatchanges in anterior neck adipose tissue volume from baseline in treated mice was significantly different in comparison with the control group (-1.09/kg ± 0.33/kg vs 0.68/kg ± 0.37/kg; p < 0.01 by two-tailed Student's t test). Histological analysis of samples from the treated area of the neck did not show scarring or damage to the surrounding tissues.
CONCLUSIONS: Injection of ice slurry safely, effectively, and selectively reduces upper airway fat in New Zealand obese mice without scarring or damage to surrounding tissue. Our results suggest that slurry injection may be a novel and minimally invasive method of removing neck adipose tissue. This intervention should be further investigated to determine its suitability for treatment of OSA.

PMID: 32474829 [PubMed - as supplied by publisher]

SARS-CoV-2 and COVID-19: A genetic, epidemiological, and evolutionary perspective.

Infect Genet Evol. 2020 May 28;:104384

Authors: Sironi M, Hasnain SE, Phan T, Luciani F, Shaw MA, Sallum MA, Mirhashemi ME, Morand S, González-Candelas F, Editors of Infection, Genetics and Evolution

Abstract
In less than five months, COVID-19 has spread from a small focus in Wuhan, China, to more than 5 million people in almost every country in the world, dominating the concern of most governments and public health systems. The social and political distresses caused by this epidemic will certainly impact our world for a long time to come. Here, we synthesize lessons from a range of scientific perspectives rooted in epidemiology, virology, genetics, ecology and evolutionary biology so as to provide perspective on how this pandemic started, how it is developing, and how best we can stop it.

PMID: 32473976 [PubMed - as supplied by publisher]