bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reference genome for the highly transformableSetaria viridiscultivar ME034V
Authors: Thielen Peter M. , Pendleton Amanda L. , Player Robert A. , Bowden Kenneth V. , Lawton Thomas J. , Wisecaver Jennifer H. 
Published: May 2020

ABSTRACTSetaria viridis(green foxtail) is an important model system for improving cereal crops due to its diploid genome, ease of cultivation, and use of C4photosynthesis. TheS. viridiscultivar ME034V is exceptionally transformable, but the lack of a sequenced genome for this cultivar has limited its utility. We present a 397 Mb highly contiguousde novoassembly of ME034V using ultra-long nanopore sequencing technology (read N50=41kb). We estimate that this genome is largely complete based on our updated k-mer based genome size estimate of 401 Mb forS. viridis. Genome annotation identified 37,908 protein-coding genes and >300k repetitive elements comprising 46% of the genome. We compared the ME034V assembly with two other previously sequencedSetariagenomes as well as to a diversity panel of 235S. viridiscultivars. We found the genome assemblies to be largely syntenic, but numerous unique polymorphic structural variants were discovered. Several ME034V deletions may be associated with recent retrotransposition ofcopiaandgypsyLTR repeat families, as evidenced by their low genotype frequencies in the sampled population. Lastly, we performed a phylogenomic analysis to identify gene families that have expanded inSetaria, including those involved in specialized metabolism and plant defense response. The high continuity of the ME034V genome assembly validates the utility of ultra-long DNA sequencing to improve genetic resources for emerging model organisms. Structural variation present inSetariaillustrates the importance of obtaining the proper genome reference for genetic experiments. Thus, we anticipate that the ME034V genome will be of significant utility for theSetariaresearch community.
Structural and functional alterations associated with the LRRK2 G2019S mutation revealed in structured human neural networks
Authors: Valderhaug Vibeke Devold , Ramstad Ola Huse , van de Wijdeven Rosanne , Heiney Kristine , Nichele Stefano , Sandvig Axel , Sandvig Ioanna 
Published: May 2020

AbstractMutations in the LRRK2 gene have been widely linked to Parkinson’s disease. The G2019S variant has been shown to contribute uniquely to both familial and sporadic forms of the disease. LRRK2-related mutations have been extensively studied, yet the wide variety of cellular and network events directly or indirectly related to these mutations remain poorly understood. In this study, we structured multi-nodal human neural networks carrying the G2019S mutation using custom-designed microfluidic chips coupled to microelectrode-arrays. By applying live imaging approaches, immunocytochemistry and computational modelling, we have revealed alterations in both the structure and function of the resulting neural networks when compared to controls. We provide first evidence of increased neuritic density associated with the G2019S LRRK2 mutation, while previous studies have found either a strong decrease, or no change, compared to controls. Additionally, we corroborate previous findings regarding increased baseline network activity compared to control neural networks. Furthermore, we can reveal additional network alterations attributable to the specific mutation by selectively inducing transient overexcitation to confined parts of the structured multi-nodal networks. These alterations, which we were able to capture both at the micro- and mesoscale manifested as differences in relative network activity and correlation, as well as in mitochondria activation, neuritic remodelling, and synaptic alterations. Our study thus provides important new insights into early signs of neural network pathology significantly expanding upon the current knowledge relating to the G2019S Parkinson’s disease mutation.
Low protein intake compromises the recovery of lactation-induced bone loss in female mouse dams without affecting skeletal muscles
Authors: Kanakis Ioannis , Alameddine Moussira , Scalabrin Mattia , van ‘t Hof Rob J. , Liloglou Triantafillos , Ozanne Susan E. , Goljanek-Whysall Katarzyna , Vasilaki Aphrodite 
Published: May 2020

ABSTRACTLactation-induced bone loss occurs due to high calcium requirements for fetal growth but skeletal recovery is normally achieved promptly post-weaning. Dietary protein is vital for fetus and mother but the effects of protein undernutrition on the maternal skeleton and skeletal muscles is largely unknown. We used mouse dams fed with normal (N, 20%) or low (L, 8%) protein diet during gestation and lactation and maintained on the same diets (NN, LL) or switched from low to normal (LN) during a 28d skeletal restoration period post lactation. Skeletal muscle morphology and neuromuscular junction integrity was not different between any of the groups. However, dams fed the low protein diet showed extensive bone loss by the end of lactation, followed by full skeletal recovery in NN dams, partial recovery in LN and poor bone recovery in LL dams. Primary osteoblasts from low protein diet fed mice showed decreasedin vitrobone formation and decreased osteogenic marker gene expression; promoter methylation analysis by pyrosequencing showed no differences inBmpr1a, Ptch1, Sirt1, OsxandIgf1rosteoregulators, while miR-26a, -34a and -125b expression was found altered in low protein fed mice. Therefore, normal protein diet is indispensable for maternal musculoskeletal health during the reproductive period.
Rab18 Binds PLIN2 and ACSL3 to Mediate Lipid Droplet Dynamics
Authors: Deng Yaqin , Zhou Chang , Hammad Mirza Ahmed , Bamigbade Adekunle T. , Xu Shimeng , Zhang Shuyan , Liu Pingsheng 
Published: May 2020

AbstractRab18 has been linked to lipid metabolism and metabolic diseases in different model systems, but the mechanism of Rab18-mediated lipid droplet (LD) dynamics in muscle cells remains elusive. Here, we report that Rab18 plays an essential role in oleic acid (OA)-induced LD growth and formation in mouse myoblast cell line C2C12. Rab18 was translocated from endoplasmic reticulum (ER) to LDs during the LD growth induced by OA in C2C12 cells, which was directly regulated by perilipin 2 (PLIN2), a LD resident protein. LD-associated Rab18 bound with the C terminus of PLIN2, and the LD localization of Rab18 was diminished after PLIN2 deletion. Moreover, loss of function of Rab18 led to less triacylglycerol (TAG) accumulation and fewer but larger LD formation. In contrast, expression of wild type Rab18 and a constitutively active Rab18 (Q67L) mutant resulted in elevated TAG content and LD number. Furthermore, LD-associated Rab18 interacted with acyl-CoA synthetase long-chain family member 3 (ACSL3) and in turn, promoted the LD localization of ACSL3, which may play an important role in the accumulation of TAG induced by OA. These data showed that Rab18 was recruited to LD after OA treatment, and formed a complex with PLIN2 and ACSL3, which contributes to TAG accumulating and LD growth.
An artificial intelligence system reveals liquiritin inhibits SARS-CoV-2 by mimicking type I interferon
Authors: Zhu Jie , Deng Yong-Qiang , Wang Xin , Li Xiao-Feng , Zhang Na-Na , Liu Zurui , Zhang Bowen , Qin Cheng-Feng , Xie Zhengwei 
Published: May 2020

AbstractThe pandemic COVID-19 has spread to all over the world and greatly threatens safety and health of people. COVID-19 is highly infectious and with high mortality rate. As no effective antiviral treatment is currently available, new drugs are urgently needed. We employed transcriptional analysis to uncover potential antiviral drugs from natural products or FDA approved drugs. We found liquiritin significantly inhibit replication of SARS-CoV-2 in Vero E6 cells with EC50= 2.39 μM. Mechanistically, we found liquiritin exerts anti-viral function by mimicking type I interferon. Upregulated genes induced by liquiritin are enriched in GO categories including type I interferon signaling pathway, negative regulation of viral genome replication and etc. In toxicity experiment, no death was observed when treated at dose of 300 mg/kg for a week in ICR mice. All the organ indexes but liver and serum biochemical indexes were normal after treatment. Liquiritin is abundant in licorice tablet (~0.2% by mass), a traditional Chinese medicine. Together, we recommend liquiritin as a competitive candidate for treating COVID-19. We also expect liquiritin to have a broad and potent antiviral function to other viral pathogens, like HBV, HIV and etc.
Mutually opposing activity of PIN7 splicing isoforms is required for auxin-mediated tropic responses inArabidopsis thaliana
Authors: Kashkan Ivan , Hrtyan Mónika , Retzer Katarzyna , Humpolíčková Jana , Jayasree Aswathy , Filepová Roberta , Vondráková Zuzana , Simon Sibu , Rombaut Debbie , Jacobs Thomas B. , Frilander Mikko J. , Hejátko Jan , Friml Jiří , Petrášek Jan , Růžička Kamil 
Published: May 2020

SUMMARYAdvanced transcriptome sequencing has uncovered that the majority of eukaryotic genes undergo alternative splicing (AS). Nonetheless, little effort has been dedicated to investigating the functional relevance of particular splicing events, even those in the key developmental and hormonal regulators. Here we reveal, in the plant modelArabidopsis thaliana, that thePIN7gene, which encodes a polarly localized transporter for the phytohormone auxin, produces two evolutionary-conserved transcripts. These isoforms PIN7a and PIN7b, differing in a 4 amino acid motif, are present at nearly equal levels in most cells. Although both variants do not differ in the subcellular localization and transport auxin with similar capacity, they closely associate and mutually influence their stability within the plasma membrane. Phenotypic complementation tests reveal that the functional contribution of PIN7bper seis minor but it markedly attenuates the prominent PIN7a activity, which is required for correct seedling apical hook formation and auxin-mediated tropic responses. These results establish alternative splicing of the PIN family as a conserved, functionally-relevant mechanism, unveiling an additional regulatory level of auxin-mediated plant development.
Identification of synaptic PPT1 substrates highlight roles of depalmitoylation in disulfide bond formation and synaptic function
Authors: Gorenberg Erica L. , Tieze Sofia Massaro , Yücel Betül , Zhao Helen R. , Chou Vicky , Wirak Gregory S. , Tomita Susumu , Lam TuKiet T. , Chandra Sreeganga S. 
Published: May 2020

SUMMARYLoss-of-function mutations in the depalmitoylating enzyme palmitoyl protein thioesterase 1 (PPT1) cause Neuronal Ceroid Lipofuscinosis type 1 (CLN1), a devastating neurodegenerative disease. Here, we provide a resource identifying PPT1 substrates. We utilized Acyl Resin-Assisted Capture and mass spectrometry to identify proteins with increasedin vivopalmitoylation in PPT1 knockout mouse brains. We then validated putative substrates through direct depalmitoylation with recombinant PPT1. This stringent screen elucidated >100 novel PPT1 substrates at the synapse, including channels and transporters, G-protein-associated molecules, endo/exocytic components, synaptic adhesion molecules, and mitochondrial proteins. Cysteine depalmitoylation sites in transmembrane PPT1 substrates frequently participate in disulfide bonds in the mature protein. We confirmed that depalmitoylation regulates disulfide bond formation in a tertiary screen analyzing post-translational modifications. Collectively, the diverse PPT1 substrates highlight the role of PPT1 in mediating synapse functions, implicate molecular pathways in the etiology ofCLN1, and advance our basic understanding of the purpose of depalmitoylation.Highlights∼10% of palmitoylated proteins are palmitoyl protein thioesterase 1 (PPT1) substratesUnbiased proteomic approaches identify 9 distinct classes of PPT1 substrates, including synaptic adhesion molecules and endocytic proteinsProtein degradation does not require depalmitoylation by PPT1Depalmitoylation mediates disulfide bond formation in transmembrane PPT1 substrates
Revealing the high propensity of RNAs to non-specifically bind drug-like small molecules
Authors: Kelly Megan L. , Chu Chia-Chieh , Shi Honglue , Ganser Laura R. , Bogerd Hal P. , Huynh Kelly , Hou Yuze , Cullen Bryan R. , Al-Hashimi Hashim M. 
Published: May 2020

ABSTRACTIdentifying small molecules that selectively bind a single RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that minimize electrostatic and stacking interactions that lead to non-specific binding of aminoglycosides and intercalators to a variety of RNAs. Many such compounds have been reported to bind RNAs and inhibit their cellular activities, however the ability of such compounds to discriminate against RNA stem-loops commonly found in the transcriptome has not been thoroughly assessed in all cases. Here, we examined the propensities of three drug-like compounds, previously shown to bind and inhibit the cellular activity of three distinct RNAs, to non-specifically bind two HIV-1 stem-loop RNAs: the transactivation response element (TAR) and stem IIB in the rev response element (RREIIB). All three compounds bound to TAR and RREIIBin vitro, and two inhibited TAR-dependent transactivation and RRE-dependent viral export in cell-based assays while also exhibiting substantial off-target interactions consistent with non-specific cellular activity. A survey of X-ray and NMR structures of RNA-small molecule complexes revealed that drug-like molecules form hydrogen bonds with functional groups commonly accessible in canonical stem-loop RNA motifs, much like aminoglycosides, and in contrast to ligands that specifically bind riboswitches. Our results support extending the group of non-selective RNA-binders beyond aminoglycosides and intercalators to encompass drug-like compounds with capacity for non-specific hydrogen-bonding and reinforce the importance of assaying for off-target interactions and RNA selectivityin vitroand in cells when assessing novel RNA-binders.
Spatio-temporal analyses ofOCT4expression and fate transitions in human embryonic stem cells
Authors: Orozco-Fuentes Sirio , Wadkin Laura E. , Neganova Irina , Lako Majlinda , Barrio Rafael A. , Baggaley Andrew W. , Shukurov Anvar , Parker Nicholas G. 
Published: May 2020

AbstractOCT4is one of the transcription factors required to maintain an undifferentiated state in human embryonic stem cells (hESCs). Thus, it is crucial to understand howOCT4transcription is regulated both at the single-cell and colony level. Here we analyse the changes ofOCT4-mCherry intensity expression in hESCs in the presence and absence of theBMP4morphogenetic protein.We show thatOCT4expression is dynamic, reaching a maximum response 10 h afterBMP4treatment. We obtain the stationary probability distributions that govern the hESCs transitions amongst the different cell states in the presence/absence ofBMP4and establish the times at which the hESCs, that lead to differentiated and pluripotent cells, cluster in the colony. Furthermore, by quantifying the similarities between theOCT4expression amongst neighbouring hESCs, we show that hESCs express, on average, similar values in their local neighbourhood within the first two days of the experiment and beforeBMP4treatment. These results are relevant for the development of mathematical and computational models of adherent hESC colonies.
Tcf21+mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration
Authors: Shen Yu-chi , Larose Hailey , Shami Adrienne Niederriter , Moritz Lindsay , Manske Gabriel L. , Ma Qianyi , Zheng Xianing , Sukhwani Meena , Czerwinski Michael , Sultan Caleb , Clements Jourdan , Chen Haolin , Spence Jason R. , Orwig Kyle E. , Tallquist Michelle , Li Jun Z. , Hammoud Saher Sue 
Published: May 2020

SummaryTesticular development and function relies on interactions between somatic cells and the germline, but similar to other organs, regenerative capacity decline in aging and disease. Whether the adult testis maintains a reserve progenitor population with repair or regenerative capacity remains uncertain. Here, we characterized a recently identified mouse testis interstitial population expressing the transcription factor Tcf21. We found that Tcf21+cells are bipotential somatic progenitors present in fetal testis and ovary, maintain adult testis homeostasis during aging, and act as reserve somatic progenitors following injury.In vitro, Tcf21+cells are multipotent mesenchymal progenitors which form multiple somatic lineages including Leydig and myoid cells. Additionally, Tcf21+cells resemble resident fibroblast populations reported in other organs having roles in tissue homeostasis, fibrosis, and regeneration. Our findings reveal that the testis, like other organs, maintains multipotent mesenchymal progenitors that can be leveraged in development of future therapies for hypoandrogenism and/or infertility.HighlightsMultipotent Tcf21+MPs can differentiate into somatic testis cell typesTcf21+cells contribute to testis and ovary somatic cells during gonadal developmentTcf21+cells replenish somatic cells of the aging testis and in response to tissue injuryTestis Tcf21 cells resemble resident fibroblast populations in multiple organs
In silicosimulations of erythrocyte aquaporins with quantitativein vitrovalidation
Authors: Chan Ruth , Falato Michael , Liang Huiyun , Chen Liao Y. 
Published: May 2020

ABSTRACTModelling water and membrane lipids is an essential element in the computational research of biophysical/biochemical processes such as water transport across the cell membrane. In this study, we examined the accuracies of two popular water models, TIP3P and TIP4P, in the molecular dynamics simulations of erythrocyte aquaporins (AQP1 and AQP3). We modelled the erythrocyte membrane as an asymmetric lipid bilayer with appropriate lipid compositions of its inner and outer leaflet, in comparison with a symmetric lipid bilayer of a single lipid type. We computed the AQP1/3 permeabilities with the transition state theory with full correction for recrossing events. We also conducted cell swelling assays for water transport across the erythrocyte membrane. The experimental results agree with the TIP3P water-erythrocyte membrane model, in confirmation of the expected accuracy of the erythrocyte membrane model, the TIP3P water model, and the CHARMM parameters for water-protein interactions.
PIWIL1 Promotes Gastric Cancer via a piRNA-Independent Mechanism
Authors: Shi Shuo , Yang Zhen-Zhen , Liu Sanhong , Yang Fan , Lin Haifan 
Published: May 2020

ABSTRACTTargeted cancer therapy aims to achieve specific elimination of cancerous but not normal cells. Recently, PIWI proteins, a subfamily of the PAZ-PIWI Domain (PPD) protein family, have emerged as promising candidates for targeted cancer therapy. PPD proteins are essential for small non-coding RNA pathways. The Argonaute subfamily partners with microRNA and small interfering RNA, whereas the PIWI subfamily partners with PIWI-interacting RNA (piRNA). Both PIWI proteins and piRNA are mostly expressed in the germline and best known for their function in transposon silencing, with no detectable function in mammalian somatic tissues. However, PIWI proteins become aberrantly expressed in multiple types of somatic cancers, thus gaining interest in targeted therapy. Despite this, little is known about the regulatory mechanism of PIWI proteins in cancer. Here we report that one of the four PIWI proteins in humans, PIWIL1, is highly expressed in gastric cancer tissues and cell lines. Knocking out PIWIL1 expression (PIWIL1-KO) drastically reduces gastric cancer cell proliferation, migration, metastasis, and tumorigenesis. RNA deep sequencing of gastric cancer cell line SNU-1 reveals that PIWIL1-KO significantly changes the transcriptome, causing the up-regulation of most of its associated transcripts. Surprisingly, fewbona fidepiRNAs exist in gastric cancer cells. Furthermore, abolishing the piRNA-binding activity of PIWIL1 does not affect its oncogenic function. Thus, PIWIL1 function in gastric cancer cells is independent of piRNA. This piRNA-independent regulation involves interaction with the UPF1-mediated nonsense-mediated mRNA decay (NMD) mechanism. Altogether, our findings reveal a novel and piRNA-independent function of PIWIL1 in promoting gastric cancer.SIGNIFICANCEPrecision medicine aims to cure cancer without affecting normal tissues. PIWI proteins provide a promising opportunity for precision medicine because they are normally expressed only in the testis for male fertility but gain expression in diverse types of cancers. Thus, inhibitingPIWIexpression may stop cancer development (and spermatogenesis) without affecting normal body function. To establish causality between PIWI and cancer, we show here that the expression of PIWIL1, a human PIWI protein, promotes gastric cancer. Surprisingly, this oncogenic function does not require piRNA, the expected partner of PIWI proteins, but involves the nonsense-mediated mRNA decay mechanism. These findings reveal a new function and action mechanism of PIWI proteins in oncogenesis, guiding the identification of PIWI inhibitors to cure cancer.
High-throughput 3D tracking reveals the importance of near wall swimming and initial attachment behaviors of P. aeruginosa for biofilm formation on a vertical wall
Authors: Khong Nicole Zi-Jia , Zeng Yukai , Lai Soak-Kuan , Koh Cheng-Gee , Liang Zhao-Xun , Chiam Keng-Hwee , Li Hoi-Yeung 
Published: May 2020

AbstractStudying the swimming behaviour of bacteria in 3 dimensions (3D) allows us to understand critical biological processes, such as biofilm formation. It is still unclear how near wall swimming behaviour may regulate the initial attachment and biofilm formation. It is challenging to address this as visualizing the movement of bacteria with reasonable spatial and temporal resolution in a high-throughput manner is technically difficult. Here, we compared the near wall (vertical) swimming behaviour ofP. aeruginosa(PAO1) and its mutants ΔdipA(reduced in swarming motility and increased in biofilm formation) and ΔfimX(deficient in twitching motility and reduced in biofilm formation) using our new imaging technique based on light sheet microscopy. We found thatP. aeruginosa(PAO1) increases its speed and changes its swimming angle drastically when it gets closer to a wall. In contrast, ΔdipAmutant moves toward the wall with steady speed without changing of swimming angle. The near wall behavior of ΔdipAallows it to be more effective to interact with the wall or wall-attached cells, thus leading to more capture events and a larger biofilm volume during initial attachment when compared with PAO1. Furthermore, we found that ΔfimXhas a similar near wall swimming behavior as PAO1, however, it has a higher dispersal frequency and smaller biofilm formation when compared with PAO1 which can be explained by its poor twitching motility. Together, we propose that near wall swimming behavior ofP. aeruginosaplays an important role in the regulation of initial attachment and biofilm formation.ImportanceBacterial biofilm is a community of bacteria on surfaces which leads to serious problems in medical devices, food industry, and aquaculture. The initial attachment and subsequent microcolony formation play critical roles in bacterial biofilm formation. However, it is unclear how the initial attachment is regulated, in particular, on a vertical surface. To study this, we have developed a novel imaging technique based on light sheet microscopy, which overcame the limitations of other imaging techniques, to understand how 3D bacterial motility near a wall may regulate initial attachment during biofilm formation. Using our technique, we discovered that near wall swimming behavior of the bacteria,P. aeruginosa, plays an important role in the regulation of biofilm formation during initial attachment.