bluuebunny/crossref_metadata_2025 huggingface dataset:
Reward learning and working memory: effects of massed versus spaced training and post-learning delay period
Authors: Wimmer G. Elliott , Poldrack Russell A.
Published: March 2020

Neuroscience research has illuminated the mechanisms supporting learning from reward feedback, demonstrating a critical role for the striatum and midbrain dopamine system. However, in humans, short-term working memory that is dependent on frontal and parietal cortices can also play an important role, particularly in commonly-used paradigms in which learning is relatively condensed in time. Given the growing use of reward-based learning tasks in translational studies in computational psychiatry, it is important to understand the degree of working memory contributions and whether gradual learning mechanisms can be better isolated. In our experiments, we manipulated the spacing between repetitions along with a post-learning delay preceding a test phase. We found that learning was slower for stimuli repeated after a long delay (spaced-trained) compared to those repeated immediately (massed-trained), likely reflecting the remaining contribution of feedback learning mechanisms when working memory is not available. Brief interruptions of massed learning led to drops in subsequent performance. Further, individual differences in working memory capacity positively correlated with massed learning performance. Critically, after a delay period but not immediately, relative preferences decayed in the massed condition and increased in the spaced condition. Overall, our results provide additional support for a large role of working memory in reward-based learning in temporally condensed designs. We suggest that spacing training within or between sessions is a promising approach to better isolate and understand mechanisms supporting gradual reward-based learning, with particular importance for understanding potential learning dysfunctions in addiction and psychiatric disorders.
Fine-mapping and QTL tissue-sharing information improve causal gene identification and transcriptome prediction performance
Authors: Barbeira Alvaro N. , Liang Yanyu , Bonazzola Rodrigo , Wang Gao , Wheeler Heather E. , Melia Owen J. , Aguet François ,   GTEx Consortiumt, Ardlie Kristin G , Wen Xiaoquan , Im Hae K.
Published: March 2020

The integration of transcriptomic studies and GWAS (genome-wide association studies) via imputed expression has seen extensive application in recent years, enabling the functional characterization and causal gene prioritization of GWAS loci. However, the techniques for imputing transcriptomic traits from DNA variation remain underdeveloped. Furthermore, associations found when linking eQTL studies to complex traits through methods like PrediXcan can lead to false positives due to linkage disequilibrium between distinct causal variants. Therefore, the best prediction performance models may not necessarily lead to more reliable causal gene discovery. With the goal of improving discoveries without increasing false positives, we develop and compare multiple transcriptomic imputation approaches using the most recent GTEx release of expression and splicing data on 17,382 RNA-sequencing samples from 948 post-mortem donors in 54 tissues. We find that informing prediction models with posterior causal probability from fine-mapping (dap-g) and borrowing information across tissues (mashr) lead to better performance in terms of number and proportion of significant associations that are colocalized and the proportion of silver standard genes identified as indicated by precision-recall and ROC (Receiver Operating Characteristic) curves. All prediction models are made publicly available atpredictdb.org.

Author summary

Integrating molecular biology information with genome-wide association studies (GWAS) sheds light on the mechanisms tying genetic variation to complex traits. However, associations found when linking eQTL studies to complex traits through methods like PrediXcan can lead to false positives due to linkage disequilibrium of distinct causal variants. By integrating fine-mapping information into the models, and leveraging the widespread tissue-sharing of eQTLs, we improve the proportion of likely causal genes among significant gene-trait associations, as well as the prediction of “ground truth” genes.
Transcriptome-wide profiles of circular RNA and RNA binding protein interactions reveal effects on circular RNA biogenesis and cancer pathway expression
Authors: Okholm Trine Line Hauge , Sathe Shashank , Park Samuel S. , Kamstrup Andreas Bjerregaard , Rasmussen Asta Mannstaedt , Shankar Archana , Fristrup Niels , Nielsen Morten Muhlig , Vang Søren , Dyrskjøt Lars , Aigner Stefan , Damgaard Christian Kroun , Yeo Gene , Pedersen Jakob Skou
Published: March 2020

Circular RNAs (circRNAs) are stable, often highly expressed RNA transcripts with potential to modulate other regulatory RNAs. A few circRNAs have been shown to bind RNA binding proteins (RBPs), however, little is known about the prevalence and strength of these interactions in different biological contexts. Here, we comprehensively evaluate the interplay between circRNAs and RBPs in the ENCODE cell lines, HepG2 and K562, by profiling the expression of circRNAs in fractionated total RNA-sequencing samples and analyzing binding sites of 150 RBPs in large eCLIP data sets. We show that KHSRP binding sites are enriched in flanking introns of circRNAs in both HepG2 and K562 cells, and that KHSRP depletion affects circRNA biogenesis. Additionally, we show that exons forming circRNAs are generally enriched with RBP binding sites compared to non-circularizing exons. To detect individual circRNAs with regulatory potency, we computationally identify circRNAs that are highly covered by RBP binding sites and experimentally validate circRNA-RBP interactions by RNA immunoprecipitations. We characterize circCDYL, a highly expressed circRNA with clinical and functional implications in bladder cancer, which is covered with GRWD1 binding sites. We confirm that circCDYL binds GRWD1in vivoand functionally characterizes the effect of circCDYL-GRWD1 interactions on target genes in HepG2. Furthermore, we confirm interactions between circCDYL and RBPs in bladder cancer cells and demonstrate that circCDYL depletion affects hallmarks of cancer and perturbs the expression of key cancer genes, e.g.TP53andMYC. Finally, we show that elevated levels of highly RBP-covered circRNAs, including circCDYL, are associated with overall survival of bladder cancer patients. Our study demonstrates transcriptome-wide and cell-type-specific circRNA-RBP interactions that could play important regulatory roles in tumorigenesis.
In SilicoInvestigations on Curcuminoids fromCurcuma longaas Positive Regulators of Wnt/β-catenin Signaling Pathway in Wound Healing
Authors: Islam Reshad Riyan Al , Alam Sayka , Raihan Humaira Binte , Meem Kamrun Nahar , Rahman Fatima , Zahid Fardin , Rafid Md. Ikram , Rahman S. M. Obaydur , Omit Sadman , Ali Md. Hazrat
Published: March 2020

Curcuma longa(Turmeric) is a traditionally used herb in wound healing. The efficacy of fresh Turmeric paste to heal wound has already been investigated in multiple ethnobotanical studies. Wnt/β-catenin signaling pathway plays a significant role in wound healing and injury repair processes which has been evident in differentin vitrostudies. This study aims to analyze the potentiality of Curcuminoids (Curcumin I, Curcumin II and Curcumin III) fromCurcuma longato bind and enhance the activity of two intracellular signaling proteins-Casein Kinase-1 (CK1) and Glycogen Synthase Kinase-3β (GSK3B) involved in Wnt/β-catenin signaling pathway. Present study is largely based on computer-based molecular docking program which mimics thein vivocondition and works on specific algorithm to interpret the binding affinity and poses of a ligand molecule to a receptor. Curcumin I showed better affinity of binding with CK1 (−10.31 Kcal/mol binding energy) and Curcumin II showed better binding affinity (−7.55 Kcal/mol binding energy) for GSK3B. Subsequently, Drug likeness property, ADME/Toxicity profile, Pharmacological activity and Site of metabolism of the Curcuminoids were also analyzed. All of the ligand molecules showed quite similar pharmacological properties.
Angiotensin II induces apoptosis in human induced pluripotent stem cell-derived cardiomyocytes
Authors: Gao Qiang , Wang Ping , Wu Zhiming , Qiu Hailong , Lin Bin , Chen Jimei , Cen Jianzheng , Zhuang Jian
Published: March 2020

Background

The renin-angiotensin system (RAS) functions fundamentally to regulate the pathological process of cardiovascular diseases, such as heart failure and hypertension. As the major effector in RAS, angiotensin II activates angiotensin II receptors to initiate the downstream pathways, which lead to the phenotypes including apoptosis, hypertrophy, and cardiac remodeling. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) are being applied as a promising platform for personalized medicine to heart diseases. However, whether angiotensin II induces apoptosis in iPSC-CM is still obscure, which raises an uncertainty about the clinical applications of iPSC-CM.

Methods

We treated iPSC-CM with angiotensin II at eight concentrations (0 nM, 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 100 μM and 1 mM) and four incubation durations (24 hours, 48 hours, 6 days and 10 days), then PrestoBlue reagent and a apoptosis marker were used to examine the viability and apoptosis status of cardiomyocytes from each group. The expression levels of some apoptosis and proliferation related genes were also analyzed.

Results

High concentration angiotensin II with a long-term treatment caused apoptosis and cell viability drop-off in iPSC-CM. Specifically, under a 10-day treatment with 1 mM angiotensin II, the viability of iPSC-CM was reduced by an average of 41% (p=2.073E-08), and the percentage of apoptotic cells was 2.74 times higher than the controls averagely (p=6.248E-12). The data mining of previous RNA-seq data revealed that angiotensin II receptor type I was the major receptor in iPSC-CM. Conclusions: For the first time, our data confirmed the apoptotic effect of angiotensin II to iPSC-CM. The angiotensin II concentrations and exposure time for apoptosis induction were depicted in our study, which provided supports to iPSC-CM as anin vitromodel for cardiovascular disease study.
Population sequencing enhances understanding of tea plant evolution
Authors: Wang Xinchao , Feng Hu , Chang Yuxiao , Ma Chunlei , Wang Liyuan , Hao Xinyuan , Li A’lun , Cheng Hao , Wang Lu , Cui Peng , Jin Jiqiang , Wang Xiaobo , Wei Kang , Ai Cheng , Zhao Sheng , Wu Zhichao , Li Youyong , Liu Benying , Wang Guo-Dong , Chen Liang , Ruan Jue , Yang Yajun
Published: March 2020

Tea is an economically important plant characterized by a large genome size and high heterozygosity and species diversity. In this study, we assembled a 3.26 Gb high-quality chromosome-scale genome for tea using the ‘Longjing 43’ cultivar ofCamellia sinensisvar.sinensis. Population resequencing of 139 tea accessions from around the world was used to investigate the evolution of tea and to reveal the phylogenetic relationships among tea accessions. With the spread of tea cultivation, hybridization has increased the heterozygosity and wide-ranging gene flow among tea populations. Population genetics and transcriptomics analyses revealed that during domestication, the selection for disease resistance and flavor inC. sinensisvar.sinensispopulations has been stronger than that inC. sinensisvar.assamicapopulations. The data compiled in this study provide new resources for the marker assisted breeding of tea and are a basis for further research on the genetics and evolution of tea.
A displacement and velocity based dual model of saccadic eye movements best explains kinematic variability
Authors: Varsha V , Padhi Radhakant , Murthy Aditya
Published: March 2020

Noise is a ubiquitous component of motor systems which leads to behavioral variability of all types of movements, including saccadic eye movements. Nonetheless, systems-based models of saccadic eye movements are deterministic and do not explain the observed saccade variability, only their central tendencies. Using stochastic models, we studied the variability in saccade behavior to test and distinguish between previously proposed deterministic saccade models. For this, the inter-trial variability in saccade displacement trajectories of human subjects was quantified while they performed repeated saccadic eye movements to a peripheral target. Based on fits to the data, we showed that existing models based on either displacement or velocity failed to capture the observed patterns in the variability of saccade trajectories. However, the observed behavior was captured by a dual control system, using a combination of displacement and velocity signal. The proposed model fits the mean displacement trajectory as well as the existing deterministic models. Taken together, our results suggest that the saccade system uses both desired displacement and velocity information.

New and Noteworthy

We studied saccade behavior with a focus on the variability of the saccade trajectory. A stochastic model of the saccade system suggests that a dual control involving the control of displacement and velocity explains saccade behavior better than previously proposed models that utilize only displacement or velocity information. Our study resolves previous ambiguity regarding the use of displacement or velocity signals to guide saccades and provides a natural explanation for neural recordings that indicate multiplexing of displacement and velocity related information in the firing activity of neurons in the superior colliculus, a critical node in the oculomotor network that codes for saccadic eye movements.
Gonadulins, the fourth type of Insulin-related peptides in Decapods
Authors: Veenstra Jan A.
Published: March 2020

Insulin and related peptides play important roles in the regulation of growth and reproduction. Until recently three different types of insulin-related peptides had been identified from decapod crustaceans. The identification of two novel insulin-related peptides fromSagmariasus verreauxiandCherax quadricarinatussuggested that there might a fourth type. Publicly available short read archives show that orthologs of these peptides are commonly present in these animals. Most decapods have two genes coding such peptides, butPenaeusspecies have likely only one and some palaemonids have three. Interestingly, expression levels can vary more than thousand-fold in the gonads ofPortunus trituberculatus, where gonadulin 1 is expressed by the testis and gonadulin 2 by the ovary. Although these peptides are also expressed in other tissues, the occasionally very high expression in the gonads led to them being called gonadulins.
Widespread transfer of mobile antibiotic resistance genes within individual gut microbiomes revealed through bacterial Hi-C
Authors: Kent Alyssa , Vill Albert , Shi Qiaojuan , Satlin Michael J. , Brito Ilana Lauren
Published: March 2020

The gut microbiome harbors a ‘silent reservoir’ of antibiotic resistance (AR) genes that is thought to contribute to the emergence of multidrug-resistant pathogens through the process of horizontal gene transfer (HGT). To counteract the spread of AR genes, it is paramount to know which organisms harbor mobile AR genes and with which organisms they engage in HGT. Despite methods to characterize the bulk presence1, abundance2and function3of AR genes in the gut, technological limitations of short-read sequencing have precluded linking bacterial taxa to specific mobile genetic elements (MGEs) and their concomitant AR genes. Here, we apply and evaluate a high-throughput, culture-independent method for surveilling the bacterial carriage of MGEs, based on bacterial Hi-C protocols. We compare two healthy individuals with a cohort of seven neutropenic patients undergoing hematopoietic stem cell transplantation, who receive multiple courses of antibiotics throughout their prolonged hospitalizations, and are thus acutely vulnerable to the threat of multidrug-resistant infections4. We find that the networks of HGT are surprisingly distinct between individuals, yet AR and mobile genes are more dispersed across taxa within the neutropenic patients than the healthy subjects. Our data further suggest that HGT is occurring throughout the course of treatment in the microbiomes of neutropenic patients and within the guts of healthy individuals over a similar timeframe. Whereas most efforts to understand the spread of AR genes have focused on pathogenic species, our findings shed light on the role of the human gut microbiome in this process.
Acarbose Protects From Central and Peripheral Metabolic Imbalance Induced by Benzene Exposure
Authors: Debarba LK. , Mulka A. , Lima J.B.M. , Didyuk O. , Fakhoury P. , Koshko L. , Awada AA. , Zhang K. , Klueh U. , Sadagurski M.
Published: March 2020

Benzene is a well-known human carcinogen that is one of the major components of air pollution. Sources of benzene in ambient air include cigarette smoke, e-cigarettes vaping and evaporation of benzene containing petrol processes. While carcinogenic effects of benzene exposure have been well studied, less is known about metabolic effects of benzene exposure. We show that chronic exposure to benzene at low levels induces severe metabolic imbalance in a sex-specific manner, which is associated with hypothalamic inflammation and endoplasmic reticulum (ER) stress. Benzene exposure rapidly activates hypothalamic ER stress and neuroinflammatory responses in male mice, while pharmacological inhibition of ER stress response by inhibiting IRE1α-XBP1 pathway significantly alleviates benzene-induced glial inflammatory responses. Additionally, feeding mice with Acarbose, a clinically available anti-diabetes drug, protected against benzene induced central and peripheral metabolic imbalance. Acarbose imitates the slowing of dietary carbohydrate digestion, suggesting that choosing a diet with a low glycemic index might be a potential strategy for reducing the negative metabolic effect of chronic exposure to benzene for smokers or for people living/working in urban environments with high concentrations of exposure to automobile exhausts.
Excessive E2F transcription in single cancer cells precludes transient cell cycle exit after DNA damage
Authors: Segeren Hendrika A. , van Rijnberk Lotte M. , Moreno Eva , Riemers Frank M. , Yuan Ruixue , Wubbolts Richard , de Bruin Alain , Westendorp Bart
Published: March 2020

E2F transcription factors control the expression of cell cycle genes. Cancers often demonstrate enhanced E2F target gene expression, which can be explained by increased percentages of replicating cells. However, we now demonstrate in human cancer biopsies that individual neoplastic cells display abnormally high levels of E2F-dependent transcription. To mimic this situation, we deleted the atypical E2F repressors (E2F7/8) in untransformed cells. Individual cells with elevated E2F-activity during S/G2-phase failed to exit the cell cycle after DNA damage and underwent mitosis. In contrast, wild type cells completed S-phase and then exit the cell cycle by activating the APC/CCdh1via repression of the E2F-target Emi1. Strikingly, many arrested wildtype cells could eventually inactivate APC/CCdh1to execute a second round of DNA replication and mitosis, thereby becoming tetraploid. Cells with elevated E2F-transcription fail to exit the cell cycle after DNA damage which potentially causes genomic instability, promotes malignant progression and reduces drug sensitivity.
Lamin A redistribution mediated by nuclear deformation determines dynamic localization of YAP
Authors: Koushki Newsha , Ghagre Ajinkya , Srivastava Luv Kishore , Sitaras Chris , Yoshie Haruka , Molter Clayton , Ehrlicher Allen J.
Published: March 2020

YAP is a key mechanotransduction protein with essential roles in diverse physiological processes. Dysregulation in YAP activity is associated with multiple diseases such as atherosclerosis, fibrosis, and cancer progression. Here we examine the physical stimuli that regulate dynamic YAP translocation to the nucleus. Through a combination of biophysical studies, we demonstrate that YAP localization is insensitive to cell substrate stiffness, but strongly determined by cellular contractile work, which in turn deforms the nucleus. We show that nuclear deformation from LINC-mediated cytoskeletal contractility or extracellular osmotic forces triggers YAP nuclear localization. By modulating the expression of lamin A and nuclear stiffness, we illustrate that nuclear rigidity modulates deformation-mediated YAP nuclear localization. Finally, we show that nuclear deformation causes relocalization of lamin A from the nuclear membrane to the nucleoplasm, and this is essential in allowing YAP to enter the nucleus. These results reveal key physical nuclear deformation mechanics that drive YAP nuclear import.
Blunted Diurnal Firing in Lateral Habenula Projections to Dorsal Raphe Nucleus and Delayed Photoentrainment in Stress-Susceptible Mice
Authors: Liu He , Rastogi Ashutosh , Sabanovic Merima , Alhammadi Aisha Darwish , Xu Qing , Guo Lihua , Cao Jun-Li , Zhang Hongxing , Narain Priyam , Aqel Hala , Mlambo Vongai , Rezgui Rachid , Radwan Basma , Chaudhury Dipesh
Published: March 2020

Daily rhythms are disrupted in patients suffering from mood disorders. The lateral habenula (LHb) and dorsal raphe nucleus (DRN) contribute to circadian timekeeping and regulate mood. Thus, pathophysiology in these nuclei may be responsible for aberrations in daily rhythms during mood disorders. Using the chronic social defeat stress (CSDS) paradigm andin-vitroslice electrophysiology we measured the effects of stress on diurnal rhythms in firing of LHb cells projecting to the DRN (cellsLHb→DRN) and DRN cells alone. We also performed optogenetic experiments to investigate if increased firing in cellsLHb→DRNduring exposure to subthreshold social defeat stress (SSDS), induces stress-susceptibility. Last we investigated whether exposure to CSDS affected the ability of mice to phototentrain to a new LD cycle. The cellsLHb→DRNand DRN cells alone of stress-susceptible mice express greater blunted diurnal firing compared to stress-naive (control) and stress-resilient mice. Day-time optogenetic activation of cellsLHb→DRNduring SSDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stress-susceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that CSDS induces blunted daily rhythms in firing in cellsLHb→DRNand slow rate of photoentrainment in susceptible-mice. In contrast, resilientmice may undergo homeostatic adaptations that maintain daily rhythms in firing in cellsLHb→DRNand also show rapid photoentrainment to a new LD-cycle.
An Experimental Validation of the Computer Fluid Dynamics of Normal Human Nasal Airflow Using a Precise 3-D Printing Model
Authors: Fu Xiaoli , Cheng Yin , Liu Huanhai , Liao Jianchun , Kou Mingqing , Shen Chao , Ge Qinghua , Yan Shenglin , Peng Hu
Published: March 2020

Computer Fluid Dynamics(CFD) is a popular method for studying airflow of nasal cavities. However, the data of CFD studies has rarely been validated through experiments. To test the accuracy of CFD computation, we studied the consistency of the air pressure of nasal cavities in the CFD and the experiment. A proportional resin model of a normal human subject’s nasal cavities was created by a 3-d printer with a precision value of 0.1mm. The pressure of 63 check points in the nasal cavities in different breathing states was measured. The experimental data was compared with the data obtained by CFD simulation. At the flow rates of 180 ml s-1and 560 ml s-1, the pressure in all check points remained highly consistent with the CFD data. At 1100 ml s-1flow rate, there was a significant deviation in the posterior segment of the nasal cavity during exhalation. The method used in this study to measure the pressure in the nasal cavities can be used in experimental validation of CFD data. The computational methods and the boundary conditions used in this study resulted in a high agreement between the results of the CFD simulation and the experiment.

Author Summary

In the contemporary era, Computer fluid dynamics (CFD) is the mainstream method for studying air flow. Due to the complex anatomical structure of the nasal cavity, the CFD results of the nasal flow have rarely been experimentally verified. This study provides a method to verify the methods and results of nasal CFD. We printed an accurate model of a normal person’s nasal cavity with a high-precision 3D printer. In this nasal cavity model, we set 63 small holes to detect the air pressure of the places we concerned. Three different nasal flow quantity are used to represent different breathing conditions: high (1100 ml s-1), medium (560 ml s-1), and low (180 ml s-1). In medium and low nasal flow quantities, our CFD results are in good agreement with the experimental pressure values. On this basis, we analyzed the characteristics of nasal airflow in normal people. The method used in this study to measure the pressure in the nasal cavities can be used in experimental measurements of the partial resistance of the nasal cavity. With proper modification, it can be applied to the clinical practice for nasal resistance, giving more help for the design of the operation plan.
Assessing the statistical reporting quality in high-impact factor urology journals
Authors: Dai Shuangyang , Xu Hong , Li Beibei , Zhang Jingao , Zhou Xiaobin
Published: March 2020

Backgrounds

Observational studies plays an important role in urology studies, But few studies have paid attention to the statistical reporting quality of observational studies. The purpose of this study was to investigate the frequency and evaluate the reporting quality of statistical methods of the published observational studies in urology.

Methods

The five urology journals were selected according to the 5-year impact factor. A systematic literature search was performed in PubMed for relevant articles. The quality of statistical reporting was assessed according to assessment criteria.

Results

A total of 193 articles were included in this study. The mean statistical reporting score of included articles was 0.42 (SD=0.15), accounting for 42% of total score. The items that must be reported with a reporting rate more than 50% were: alpha level (n=122, 65.2%), confidence intervals (n=134, 69.4%), name of statistical package (n=158, 84.5%) and exactP-values (n=161, 86.1%). The items with a reporting rate less than 50% were: outliers (n=2, 1.0%) and sample size (n=13, 6.7%). For multivariable regression models (liner, logistic and Cox), variables coding (n=27, 40.7%), validation analysis of assumptions (n=58, 40.3%), interaction test (n=43, 30.0%), collinearity diagnostics (n=5, 3.5%) and goodness of fit test (n=6, 5.9%) were reported. Number of authors more than 7(OR=2.06, 95%CI=1.04-4.08) and participation of statistician or epidemiologist (OR=1.73, 95%CI=1.18-3.39) were associated with the superior reporting quality.

Conclusion

The statistical reporting quality of published observational studies in 5 high-impact factor urological journals was alarming. We encourage researchers to collaborate with statistician or epidemiologist. The authors, reviewers and editors should increase their knowledge of statistical methods, especially new and complex methods.
The dominance hierarchy of the female Yunnan snub-nosed monkeys (Rhinopithecus bieti)
Authors: Huang Kai , Xia Wancai , Fu Yi , Wan Yaqiong , Feng Hao , Krzton Ali , Li Jiaqi , Li Dayong
Published: March 2020

Dominance hierarchies are common in social mammals, especially primates. The formation of social hierarchies is conducive to solving the problem of the allocation of scarce resources among individuals. From August 2015 to July 2016, we observed a wild, provisioned Yunnan snub-nosed monkey (Rhinopithecus bieti) group at Xiangguqing in Baimaxueshan National Nature Reserve, Yunnan Province, China. Aggressive and submissive behaviors were used to investigate dominance hierarchies between female individuals in the same one-male unit (OMU), and the grooming reciprocity index was used to detect reciprocal relationships between these females within the OMU. The results showed that loose social hierarchies exist among the females in each OMU, and more dominant individuals have higher grooming incomes. These results are consistent with the aggressive-submissive hypothesis and the resource control hypothesis.
The effects of Hurricane Otto on the soil ecosystems of three forest types in the Northern Zone of Costa Rica
Authors: Eaton William D. , McGee Katie M. , Alderfer Kiley , Jimenez Angie Ramirez , Hajibabaei Mehrdad
Published: March 2020

Hurricanes rapidly deposit large amounts of canopy material onto tropical forest floors, stimulating metabolic processes involved in the decomposition of these materials and production of N and C resources into the food web. However, little is known about the effects that hurricanes have on specific soil microbial taxa or functional groups involved in these processes. The objectives of this study were to determine how Hurricane Otto influenced three different tropical forest soil ecosystems within the first 8 months after causing damage to a tropical forest by assessing the soil C and N factors and how the soil bacterial and fungal community compositions differed before and after the hurricane. Soil samples were collected from five 2000 m2permanent plots in Lowland, Upland and Riparian forest systems within the same area in the Northern Zone of Costa Rica. Standard methods were used to measure the amounts Total N, NO3-, NH4+, Total organic C, and Biomass C, while Illumina MiSeq methods were used to generate bacterial and fungal sequences. All data were analyzed using univariate and multivariate statistical methods. Using this “before and after” study design, it was found that the levels of the inorganic N and Biomass C were greater in the Post-Hurricane soil samples. The mean proportion of DNA sequences of complex C degrading/lignin degrading, NH4+-producing, and ammonium oxidizing bacteria, and the complex C degrading/wood rot/lignin degrading and ectomycorrhizal fungi also were greater in the Post-Hurricane soils. We also provide evidence that the excessive amounts of canopy leaf litter and woody debris deposited on the forest floor during Hurricane Otto appears to be selecting for genera that become more dominant Post-Hurricane, perhaps because they may be better able to rapidly process the newly deposited C and N-rich canopy material. This is a rare “before and after” a natural hurricane design that warrants further monitoring.
Single cell derived mRNA signals across human kidney tumors
Authors: Young Matthew D , Mitchell Thomas J , Custers Lars , Margaritis Thanasis , Morales Francisco , Kwakwa Kwasi , Khabirova Eleonora , Kildisiute Gerda , Oliver Thomas RW , de Krijger Ronald R. , van den Heuvel-Eibrink Marry M. , Comitani Federico , Piapi Alice , Bugallo-Blanco Eva , Thevanesan Christine , Burke Christina , Prigmore Elena , Ambridge Kirsty , Roberts Kenny , Vieira Braga Felipe A , Coorens Tim HH , Del Valle Ignacio , Wilbrey-Clark Anna , Mamanova Lira , Stewart Grant D , Gnanapragasam Vincent J , Rampling Dyanne , Sebire Neil , Coleman Nicholas , Hook Liz , Warren Anne , Haniffa Muzlifah , Kool Marcel , Pfister Stefan M , Achermann John C , He Xiaoling , Barker Roger A , Shlien Adam , Bayraktar Omer A , Teichmann Sarah , Holstege Frank C. , Meyer Kerstin B , Drost Jarno , Straathof Karin , Behjati Sam
Published: March 2020

The cellular transcriptome may provide clues into the differentiation state and origin of human cancer, as tumor cells may retain patterns of gene expression similar to the cell they derive from. Here, we studied the differentiation state and cellular origin of human kidney tumors, by assessing mRNA signals in 1,300 childhood and adult renal tumors, spanning seven different tumor types. Using single cell mRNA reference maps of normal tissues generated by theHuman Cell Atlasproject, we measured the abundance of reference “cellular signals” in each tumor. Quantifying global differentiation states, we found that, irrespective of tumor type, childhood tumors exhibited fetal cellular signals, thus replacing the long-held presumption of “fetalness” with a precise, quantitative readout of immaturity. By contrast, in adult cancers our assessment refuted the suggestion of dedifferentiation towards a fetal state in the overwhelming majority of cases, with the exception of lethal variants of clear cell renal cell carcinoma. Examining the specific cellular phenotype of each tumor type revealed an intimate connection between the different mesenchymal populations of the developing kidney and childhood renal tumors, whereas adult tumors mostly represented specific mature tubular cell types. RNA signals of each tumor type were remarkably uniform and specific, indicating a possible therapeutic and diagnostic utility. We demonstrated this utility with a case study of a cryptic renal tumor. Whilst not classifiable by clinical pathological work-up, mRNA signals revealed the diagnosis. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.
Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer
Authors: Eichelberger Laura , Saini Massimo , Moreno Helena Domínguez , Klein Corinna , Bartsch Johanna M. , Falcone Mattia , Reitberger Manuel , Espinet Elisa , Vogel Vanessa , Graf Elisabeth , Schwarzmayr Thomas , Strom Tim-Matthias , Lehmann Mareike , Königshoff Melanie , Pfarr Nicole , Würth Roberto , Donato Elisa , Haas Simon , Spaich Saskia , Sütterlin Marc , Schneeweiss Andreas , Weichert Wilko , Schotta Gunnar , Trumpp Andreas , Sprick Martin R. , Scheel Christina H.
Published: March 2020

Despite important advances in the treatment of breast cancer, the 5-year survival rate for patients with distant metastasis remains less than 30%. Metastasis is a complex, multi-step process beginning with local invasion and ending with the outgrowth of systemically disseminated cells into actively proliferating metastases that ultimately cause the destruction of vital organs. It is this last step that limits patient survival and, at the same time, remains the least understood mechanistically. Here, we focus on understanding determinants of metastatic outgrowth using metastatic effusion biopsies from stage IV breast cancer patients. By modelling metastatic outgrowth through xenograft transplantation, we show that tumour initiation potential of patient-derived metastatic breast cancer cells across breast cancer subtypes is strongly linked to high levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels are caused by the irreversible reprogramming to a mesenchymal state with concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to retain epithelial traits is tied to a global epigenetic program that limits the actions of EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide direct evidence that maintenance of epithelial identity is required for metastatic outgrowth while concomitant expression of mesenchymal markers enables plasticity. In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our data provide a framework for the intricate intercalation of mesenchymal and epithelial traits in metastatic growth.
Clinal and seasonal change are correlated inDrosophila melanogasternatural populations
Authors: Rodrigues Murillo F. , Vibranovski Maria D. , Cogni Rodrigo
Published: March 2020

Spatial and seasonal variation in the environment are ubiquitous. Environmental heterogeneity can affect natural populations and lead to covariation between environment and allele frequencies.Drosophila melanogasteris known to harbor polymorphisms that change both with latitude and seasons. Identifying the role of selection in driving these changes is not trivial, because non-adaptive processes can cause similar patterns. Given the environment changes in similar ways across seasons and along the latitudinal gradient, one promising approach may be to look for parallelism between clinal and seasonal change. Here, we test whether there is a genome-wide correlation between clinal and seasonal change, and whether the pattern is consistent with selection. Allele frequency estimates were obtained from pooled samples from seven different locations along the east coast of the US, and across seasons within Pennsylvania. We show that there is a genome-wide correlation between clinal and seasonal variation, which cannot be explained by linked selection alone. This pattern is stronger in genomic regions with higher functional content, consistent with natural selection. We derive a way to biologically interpret these correlations and show that around 3.7% of the common, autosomal variants could be under parallel seasonal and spatial selection. Our results highlight the contribution of natural selection in driving fluctuations in allele frequencies in natural fly populations and point to a shared genomic basis to climate adaptation which happens over space and time inD. melanogaster.
Recollection-related hippocampal fMRI effects predict longitudinal memory change in healthy older adults
Authors: Hou Mingzhu , de Chastelaine Marianne , Jayakumar Manasi , Donley Brian E. , Rugg Michael D.
Published: March 2020

Prior fMRI studies have reported relationships between memory-related activity in the hippocampus and in-scanner memory performance, but whether such activity is predictive of longitudinal memory change remains unclear. Here, we administered a neuropsychological test battery to a sample of cognitively healthy older adults on three occasions, the second and third sessions occurring one month and three years after the first session. Structural and functional MRI data were acquired between the first two sessions. The fMRI data were derived from an associative recognition procedure and allowed estimation of hippocampal effects associated with both successful associative encoding and successful associative recognition (recollection). Baseline memory performance and memory change were evaluated using memory component scores derived from a principal components analysis of the neuropsychological test scores. Across participants, right hippocampal encoding effects correlated significantly with baseline memory performance after controlling for chronological age. Additionally, both left and right hippocampal associative recognition effects correlated significantly with longitudinal memory change after controlling for age, and the relationship with the left hippocampal effect remained after also controlling for left hippocampal volume. Thus, in cognitively healthy older adults, the magnitude of hippocampal recollection effects appears to be a robust predictor of future memory change.
α-Synuclein strains that cause distinct pathologies differentially inhibit proteasome
Authors: Suzuki Genjiro , Imura Sei , Hosokawa Masato , Katsumata Ryu , Nonaka Takashi , Hisanaga Shin-Ichi , Saeki Yasushi , Hasegawa Masato
Published: March 2020

Abnormal α-synuclein aggregation has been implicated in several diseases and is known to spread in a prion-like manner. There is a relationship between protein aggregate structure (strain) and clinical phenotype in prion diseases, however, whether differences in the strains of α-synuclein aggregates account for the different pathologies remained unclear. Here, we generated two types of α-synuclein fibrils from identical monomer and investigated their seeding and propagation ability in mice and primary-cultured neurons. One α-synuclein fibril induced marked accumulation of phosphorylated α-synuclein and ubiquitinated protein aggregates, while the other did not, indicating the formation of α-synuclein two strains. Notably, the former α-synuclein strain inhibited proteasome activity and co-precipitated with 26S proteasome complex. Further examination indicated that structural differences in the C-terminal region of α-synuclein strains lead to different effects on proteasome activity. These results provide a possible molecular mechanism to account for the different pathologies induced by different α-synuclein strains.
Generation and biobanking of patient-derived glioblastoma organoids and their application in CAR-T cell testing
Authors: Jacob Fadi , Ming Guo-li , Song Hongjun
Published: March 2020

Glioblastoma tumors exhibit extensive inter- and intra-tumoral heterogeneity, which has contributed to poor outcomes of numerous clinical trials and continues to complicate the development of effective therapeutic strategies. Currentin vitromodels do not preserve the cellular and mutational diversity of parent tumors and often require a lengthy generation time with variable efficiency. Here, we describe detailed procedures for generating glioblastoma organoids (GBOs) from surgically resected patient tumor tissue using a chemically defined medium without cell dissociation. By preserving cell-cell interactions and minimizing clonal selection, GBOs maintain the cellular heterogeneity of parent tumors. We include methods for passaging and cryopreserving GBOs for continued use, biobanking, and long-term recovery. We further describe procedures for investigating patient-specific responses to immunotherapies by co-culturing GBOs with chimeric antigen receptor (CAR) T cells. This protocol takes approximately 2-4 weeks to generate GBOs and 5-7 days to perform CAR-T cell co-culture. Competence with human cell culture, tissue processing, immunohistology, and microscopy is required for optimal results.

Short Summary

Detailed procedures for generating and biobanking glioblastoma organoids from resected patient tumor tissue and testing CAR-T cell efficacy by co-culture. Additional procedures for tissue processing, immunohistology, and detecting hypoxia gradients and actively proliferating cells.

Associated Link Box for Key Reference

Jacob, F. et al. A Patient-derived glioblastoma organoid model and biobank recapitulates inter- and intra-tumoral heterogeneity. Cell 180, 188-204 e122, doi:10.1016/j.cell.2019.11.036 (2020).
Unclusterable, underdispersed arrangement of insect-pollinated plants in pollinator niche space
Authors: Herrera Carlos M.
Published: March 2020

Pollinators can mediate facilitative or competitive relationships between plant species, but the comparative importance of these two conflicting phenomena in shaping community-wide pollinator resource use remains unexplored. This paper examines the idea that the arrangement in pollinator niche space of plant species samples comprising complete or nearly complete regional or local plant communities can help to evaluate the relative importance of facilitation and competition as drivers of community-wide pollinator resource use. Pollinator composition data for insect-pollinated plants from the Sierra de Cazorla mountains (southeastern Spain), comprising 85% of families and ~95% of widely distributed insect-pollinated species, were used to address the following questions at regional (45 sites, 221 plant species) and local (one site, 73 plant species) spatial scales: (1) Do objectively identifiable plant species clusters occur in pollinator niche space ? Four different pollinator niche spaces were considered whose axes were defined by insect orders, families, genera and species; and (2) If all plant species form a single, indivisible cluster in pollinator niche space, Are they overdispersed or underdispersed relative to a random arrangement ? “Clusterability” tests failed to reject the null hypothesis that there was only one pollinator-defined plant species cluster in pollinator niche space, irrespective of spatial scale, pollinator niche space or pollinator importance measurement (proportions of pollinator individuals or flowers visited by each pollinator type). Observed means of pairwise interspecific dissimilarity in pollinator composition were smaller than randomly simulated values in the order-, family- and genus-defined pollinator niche spaces at both spatial scales, thus revealing significantly non-random, underdispersed arrangement of plant species within the single cluster existing in each of these pollinator niche spaces. In the undisturbed montane habitats studied, arrangement of insect-pollinated plant species in pollinator niche space did not support a major role for interspecific competition as a force shaping community-wide pollinator resource use by plants, but rather suggested a situation closer to the facilitation-dominated extreme in a hypothetical competition-facilitation gradient. Results also highlight the importance of investigations on complete or nearly complete insect-pollinated plant communities for addressing novel hypotheses on the ecology and evolution of plant-pollinator systems.
A Novel Small Animal Model of Norovirus Diarrhea
Authors: Roth Alexa N. , Helm Emily W. , Mirabelli Carmen , Kirsche Erin , Smith Jonathan C. , Eurell Laura B. , Ghosh Sourish , Altan-Bonnet Nihal , Wobus Christiane E. , Karst Stephanie M.
Published: March 2020

Human noroviruses are the leading cause of severe childhood diarrhea worldwide yet we know very little about their pathogenic mechanisms. Murine noroviruses cause diarrhea in interferon-deficient adult mice but these hosts also develop systemic pathology and lethality, reducing confidence in the translatability of findings to human norovirus disease. Herein we report that a murine norovirus causes self-resolving diarrhea in the absence of systemic disease in wild-type neonatal mice, thus mirroring the key features of human norovirus disease and representing a robust norovirus small animal disease model. Intriguingly, lymphocytes are critical for controlling acute norovirus replication while simultaneously contributing to disease severity, likely reflecting their dual role as targets of viral infection and key components of the host response.
Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix substrate-level phosphorylation arrest
Authors: Saragovi Amijai , Abramovitch Ifat , Omar Ibrahim , Arbib Eliran , Toker Ori , Gottlieb Eyal , Berger Michael
Published: March 2020

Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions including chronic obstructive pulmonary disease (COPD). However, the influence of SOR on T cell protective immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells. We find that low oxygen diminishes CD8+ T cell viral responsein vivo. Using genetic and pharmacological models, we demonstrate that respiratory restriction inhibits ATP dependent matrix processes, all critical for mitochondrial biogenesis. The effect mediated by respiratory restriction could be rescued by TCA cycle re-stimulation, which led to increased mitochondrial matrix localized ATP via substrate-level phosphorylation. Finally, we demonstrate that short exposure to atmospheric oxygen pressure rescues the CD8+ viral response under systemic oxygen restrictionin vivo. Our findings reveal the detrimental effect of hypoxia on mitochondrial biogenesis in activated CD8+ T cells and provide a new approach for reducing viral infections in COPD.

Highlights

Systemic chronic hypoxia compromises CD8+ T cell activation

Shortly upon activation, T cells’ cytoplasmic activity becomes independent of mitochondrial ATP outflux

Respiratory-blockade arrests mitochondrial remodeling due to energy depletion

Uncoupler-based TCA stimulation rescues respiratory-restricted activated CD8+ T cells by stimulating matrix localized substrate-level phosphorylation

CD8+ T cell arrest due to hypoxiain vivocan be rescued by short exposure to atmospheric oxygen pressure.