bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison of ImageJ and machine learning based image analysis methods to measure cassava bacterial blight disease severity
Authors: Elliott Kiona , Berry Jeffrey C. , Kim Hobin , Bart Rebecca S.
Published: May 2022

Background

Methods to accurately quantify disease severity are fundamental to plant pathogen interaction studies. Commonly used methods include visual scoring of disease symptoms, tracking pathogen growth in planta over time, and various assays that detect plant defense responses. Several image-based methods for phenotyping of plant disease symptoms have also been developed. Each of these methods has different advantages and limitations which should be carefully considered when choosing an approach and interpreting the results.

Results

In this paper, we developed two image analysis methods and tested their ability to quantify different aspects of disease lesions in the cassava-Xanthomonas pathosystem. The first method uses ImageJ, an open-source platform widely used in the biological sciences. The second method is a few-shot support vector machine learning tool that uses a classifier file trained with five representative infected leaf images for lesion recognition. Cassava leaves were syringe infiltrated with wildtype Xanthomonas, a Xanthomonas mutant with decreased virulence, and mock treatments. Digital images of infected leaves were captured overtime using a Raspberry Pi camera. The image analysis methods were analyzed and compared for the ability to segment the lesion from the background and accurately capture and measure differences between the treatment types.

Conclusions

Both image analysis methods presented in this paper allow for accurate segmentation of disease lesions from the non-infected plant. Specifically, at 4-, 6-, and 9-days post inoculation (DPI), both methods provided quantitative differences in disease symptoms between different treatment types. Thus, either method could be applied to extract information about disease severity. Strengths and weaknesses of each approach are discussed.
FebRNA: an automated fragment-ensemble-based model for building RNA 3D structures
Authors: Zhou Li , Wang Xunxun , Yu Shixiong , Tan Ya-Lan , Tan Zhi-Jie
Published: May 2022

Knowledge of RNA 3-dimensional (3D) structures is critical to understanding the important biological functions of RNAs. Although various structure prediction models have been developed, high accuracy of predicted RNA 3D structures is still limited to the RNAs with short length or with simple topology. In this work, we proposed a new model, namely FebRNA, for building RNA 3D structures through fragment assembly based on coarse-grained (CG) fragment ensembles. Specifically, FebRNA is composed of four processes: establishing the library of different types of CG fragment ensembles, building CG 3D structure ensemble through fragment assembly, identifying top-1 CG structure through a CG scoring function, and rebuilding the all-atom structure from the top-1 CG one. Extensive examination on different types of RNA structures indicates that FebRNA gives consistently reliable predictions on RNA 3D structures including pseudoknots, 3-way junction, 4-way and 5-way junctions, and RNAs in the RNA-Puzzles. FebRNA is available at website: https://github.com/Tan-group/FebRNA.
Transcranial Direct Current Stimulation Alters the Waveform Shape of Cortical Gamma Oscillations
Authors: Marshall Tom R. , Quinn Andrew J. , Jensen Ole , Bergmann Til Ole
Published: May 2022

Neuronal oscillations in different frequency bands have been linked to a wide variety of cognitive functions, and may even be a fundamental mechanism of inter-regional communication. For this reason, manipulation of oscillatory activity via brain stimulation is a central goal in neuroscience research. However, the vast majority of studies characterise oscillatory activity solely in terms of amplitude and frequency. Oscillations can also be characterised by their waveform shape; the degree to which they resemble or deviate from sinusoids. Here we exploit Empirical Mode Decomposition (EMD), a novel method that allows quantification of oscillatory waveform shape. We show for the first time that transcranial direct current stimulation (tDCS) alters the waveform shape of gamma oscillatory activity in the visual cortex. Notably, changes in waveform shape were limited to one half of the phase cycle; anodal stimulation led to a relatively slower, and cathodal to a relatively faster, descending half-wave. tDCS is generally believed to affect cortical excitability via alteration of resting membrane potential. Interestingly, simulations of altered cortical excitability in a gamma-generating neuronal population indicated the waveform shape changes observed experimentally likely stem from stimulation of pyramidal neurons. These findings have implications for understanding the neural consequences of tDCS at the level of neuronal population phenomena such as cortical oscillations and underscore the importance of waveform shape as an important feature of neuronal oscillations.
Human Cytomegalovirus induces neuronal enolase to support virally-mediated metabolic remodeling
Authors: Moreno Isreal , Rodríguez-Sánchez Irene , Schafer Xenia , Munger Joshua
Published: May 2022

Viruses depend on cellular metabolic resources to supply the energy and biomolecular building blocks necessary for their replication. Human Cytomegalovirus (HCMV), a leading cause of birth defects and morbidity in immunosuppressed individuals, induces numerous metabolic activities that are important for productive infection. However, many of the mechanisms through which these metabolic activities are induced and how they contribute to infection are unclear. We find that HCMV infection of fibroblasts induces a neuronal gene signature, as well as the expression of several metabolic enzyme isoforms that are typically expressed in other tissue types. Of these, the most substantially induced gene was the neuron-specific isoform of enolase (ENO2). Induction of ENO2 expression is important for HCMV-mediated glycolytic activation, as well as for the virally-induced remodeling of pyrimidine-sugar metabolism, which provides the glycosyl subunits necessary for protein glycosylation. Inhibition of ENO2 expression or activity reduced UDP-sugar pools, attenuated the accumulation of viral glycoproteins, and induced the accumulation of non-infectious viral particles. In addition, our data indicate that the induction of ENO2 expression depends on the HCMV UL38 protein. Collectively, our data indicate that HCMV infection induces a tissue atypical neuronal glycolytic enzyme to activate glycolysis and UDP-sugar metabolism to provide the glycosyl building blocks necessary for viral protein glycosylation and the production of infectious virions.

Significance Statement

Viruses are obligate parasites that obtain energy and mass from their host cell. Control over the metabolic resources of the cell has emerged as an important host-pathogen interaction that can determine infectious outcomes. We find that the Human Cytomegalovirus (HCMV), a major cause of birth defects and morbidity in immunosuppressed patient populations, induces a neuronal gene signature in fibroblasts including the expression of neuronal-specific enolase (ENO2). Our data indicate that ENO2 is important for HCMV-mediated metabolic remodeling including glycolytic activation and the production of pyrimidine sugars, as well as for viral infectivity. These findings indicate that viruses are capable of tapping into alternative tissue-specific metabolic programs to support infection, highlighting an important viral mechanism of metabolic modulation.
Analysis of Aedes aegypti microRNAs in response to Wolbachia wAlbB infection and their potential role in mosquito longevity
Authors: Bishop Cameron , Hussain Mazhar , Hugo Leon E. , Asgari Sassan
Published: May 2022

The mosquito Aedes aegypti is the primary vector of a range of medically important viruses including dengue, Zika, West Nile, yellow fever, and chikungunya viruses. The endosymbiotic bacterium Wolbachia pipientis wAlbB strain is a promising biocontrol agent for blocking viral transmission by Ae. aegypti. To predict the long-term efficacy of field applications, a thorough understanding of the interactions between symbiont, host, and pathogen is required. Wolbachia influence host physiology in a variety of ways including reproduction, immunity, metabolism, and longevity. MicroRNAs (miRNAs) are highly conserved small non-coding RNAs that regulate gene expression in eukaryotes and viruses. A number of miRNAs are known to regulate biological processes in Drosophila and mosquitoes, including facilitating Wolbachia maintenance. We generated the first chromosomal map of Ae. aegypti miRNAs, and compared miRNA expression profiles between a wAlbB-transinfected Ae. aegypti mosquito line and a tetracycline cleared derivative, using deep small RNA-sequencing. We found limited modulation of miRNAs in response to wAlbB infection. Several miRNAs were modulated in response to age, some of which showed greater upregulation in wAlbB-infected mosquitos than in tetracycline cleared ones. By selectively inhibiting some differentially expressed miRNAs, we identified miR-2946-3p and miR-317-3p as effecting mosquito longevity.

Importance

Wolbachia is an endosymbiotic bacterium found in about 65% of insect species. It is mostly known for reproductive manipulations of the host, and also blocking replication of positive sense RNA viruses. Transinfection of Wolbachia into Aedes aegypti mosquitoes, which transmit a variety of arboviruses, including dengue virus, has provided a novel biological approach in reducing transmission of arboviruses. To gain a better understanding of Wolbachia-mosquito interactions, we investigated the impact of Wolbachia on the microRNA profile of Ae. aegypti mosquitoes. We produced the first chromosome-level map of Ae. Aegypti miRNAs. We found modulation of microRNAs in mosquitoes due to age, with two miRNAs, 317-3p and 2946-3p, showing significant increase with age. Inhibition of 317-3p and 2946-3p led to reduced mosquito life span in wAlbB-infected mosquitoes. The outcomes provide insights into underlying molecular mechanisms involved in Wolbachia-host interactions.
Astrocyte calcium dysfunction causes early network hyperactivity in Alzheimer’s Disease
Authors: Shah Disha , Gsell Willy , Wahis Jérôme , Luckett Emma S. , Jamoulle Tarik , Vermaercke Ben , Preman Pranav , Moechars Daan , Hendrickx Véronique , Jaspers Tom , Craessaerts Katleen , Horré Katrien , Wolfs Leen , Fiers Mark , Holt Matthew , Thal Dietmar Rudolf , Callaerts-Vegh Zsuzsanna , D’Hooge Rudi , Vandenberghe Rik , Himmelreich Uwe , Bonin Vincent , De Strooper Bart
Published: May 2022

Dysfunctions of network activity and functional connectivity (FC) represent early events in Alzheimer’s disease (AD), but the underlying mechanisms remain unclear. Astrocytes regulate neuronal activity in the healthy brain, but their involvement in early network hyperactivity in AD is unknown. We show increased FC in the human cingulate cortex, several years before amyloid deposition. We found the same early cingulate FC disruption and neuronal hyperactivity inAppNL-Fmice. Crucially, these network disruptions are accompanied by decreased astrocyte calcium signaling. Recovery of astroglial calcium activity normalizes neuronal hyperactivity and FC, as well as seizure susceptibility and day/night behavioral hyperactivity. In conclusion, we show for the first time that astrocytes mediate initial features of AD and drive clinically relevant phenotypes.
Regulation of human trophoblast gene expression by endogenous retroviruses
Authors: Frost Jennifer M. , Amante Samuele M. , Okae Hiroaki , Jones Eleri M. , Ashley Brogan , Lewis Rohan M. , Cleal Jane K. , Caley Matthew P. , Arima Takahiro , Maffucci Tania , Branco Miguel R.
Published: May 2022

The placenta is a fast-evolving organ with large morphological and histological differences across eutherians, but the genetic changes driving placental evolution have not been fully elucidated. Transposable elements, through their capacity to quickly generate genetic variation and affect host gene regulation, may have helped to define species-specific trophoblast gene expression programmes. Here, we assessed the contribution of transposable elements to human trophoblast gene expression as enhancers or promoters. Using epigenomic data from primary human trophoblast and trophoblast stem cell lines, we identified multiple endogenous retrovirus families with regulatory potential that lie close to genes with preferential expression in trophoblast. These largely primate-specific elements are associated with inter-species gene expression differences, and are bound by transcription factors with key roles in placental development. Using genetic editing we demonstrated that several elements act as transcriptional enhancers of important placental genes, such asCSF1RandPSG5. We also identified an LTR10A element that regulatesENGexpression, affecting secretion of soluble ENG, with potential implications for preeclampsia. Our data show that transposons have made important contributions to human trophoblast gene regulation, and suggest that their activity may affect pregnancy outcomes.
Fixational eye movements as active sensation for high visual acuity
Authors: Nghiem Trang-Anh E. , Dufour Oscar , Reiniger Jenny L. , Harmening Wolf M. , da Silveira Rava Azeredo
Published: May 2022

Perception and action are inherently entangled: our world view is shaped by how we explore and navigate our environment through complex and variable self-motion. Even when fixating on a stable stimulus, our eyes undergo small, involuntary movements. Fixational eye movements (FEM) render a stable world jittery on our retinae, which contributes noise to neural coding. Yet, empirical evidence suggests that FEM help rather than harm human perception of fine detail. Here, we elucidate this paradox by uncovering under which conditions FEM improve or impair retinal coding and human acuity. We combine theory and experiment: model accuracy is directly compared to that of healthy human subjects in a visual acuity task. Acuity is modeled by applying an ideal Bayesian classifier to simulations of retinal spiking activity in the presence of FEM. In addition, empirical FEM are monitored using high-resolution eye-tracking by an adaptive optics scanning laser ophthalmoscope. While FEM introduce noise, they also effectively pre-process visual inputs to facilitate retinal information encoding. Based on an interplay of these mechanisms, our model predicts a relation between visual acuity, FEM amplitude, and single-trial stimulus size that quantitatively accounts for experimental observations and captures the beneficial effect of FEM. Moreover, we observe that human subjects’ FEM statistics vary with stimulus size, and our model suggests that changing eye motion amplitude, as the subjects indeed do, enhances acuity as compared to maintaining eye motion size constant. Overall, our findings indicate that perception benefits from action even at the fine and noise-dominated spatio-temporal scale of FEM.

Significance Statement

Perception is inherently active: we need to move our eyes to see the world around us. Yet our eyes also undergo tiny, unconscious movements that can blur out fine visual details. Paradoxically, previous work suggested that these small movements aid fine detail perception. Here, we investigate this paradox to uncover in which contexts small eye movements help or harm visual acuity. Comparing a model of retinal responses with recordings of human visual acuity, we elucidate the mechanisms by which and conditions in which small eye movements support fine detail discrimination. Our results also suggest that varying eye movement amplitude according to stimulus size enhances retinal coding, highlighting that perception is active even at the level of very fine eye movements.
Extensive diversity of RNA viruses in ticks revealed by metagenomics in northeastern China
Authors: Liu Ziyan , Li Liang , Xu Wenbo , Yuan Yongxu , Liang Xiaojie , Zhang Li , Wei Zhengkai , Sui Liyan , Zhao Yinghua , Cui Yanyan , Yin Qing , Li Dajun , Li Qianxue , Wei Feng , Hou Zhijun , Liu Quan , Wang Zedong
Published: May 2022

Recently, several emerging tick-borne viruses have been identified to be associated with human diseases in northeastern China. Here, we used metagenomics to investigate the virome diversity in Haemaphysalis japonica, H. conicinna, Dermacentor silvarum, and Ixodes persulcatus ticks in northeastern China. A total of 22 RNA viruses were identified and belonged to more eight viral families, including four each in Nairoviridae and Phenuiviridae, three each in Flaviviridae, Rhabdoviridae, and Solemoviridae, two in Chuviridae, and one each in Partitiviridae, Tombusviridae, and unclassified. Of them, eight viruses were novel species, belonging to Nairoviridae (Ji’an nairovirus and Yichun nairovirus), Phenuiviridae (Mudanjiang phlebovirus), Rhabdoviridae (Tahe rhabdovirus 1-3), Chuviridae (Yichun mivirus), and Tombusviridae (Yichun tombus-like virus), and five members were established human pathogens, including Alongshan virus, tick-borne encephalitis virus, Songling virus, Beiji nairovirus, and Nuomin virus. I. persulcatus ticks had significant higher viral species than those in H. japonica, H. concinna, and D. silvarum ticks. Significant differences in tick viromes were observed among Daxingan, Xiaoxingan and Changbai mountains. These findings showed an extensive diversity of RNA viruses in ticks in northeastern China, revealed potential public health threats from the emerging tick-borne viruses. Further studies are needed to explain the natural circulation and pathogenicity of these viruses.
Seroprevalence of SARS-CoV-2 Antibodies among vaccinated and non-vaccinated adults in the West Bank: Results of a repeated cross-sectional study
Authors: Awartani Faisal , Qutob Nouar , Asia Mohammad
Published: May 2022

Background

Seroprevalence studies provide an accurate measure of SARS-CoV-2 spread at a population level and the number of undiagnosed individuals. Repeated cross-sectional sero-studies are encouraged to monitor the spread of the virus. The aim of this study is to assess the seroprevalence rate among a random sample of Palestinians residing in the West Bank region of Palestine.

Methods

This second round cross-sectional study involved 1451 participants, who agreed to be interviewed and answer the questionnaire, where 910 of them agreed to participate in the sero- study and donate a blood sample to be tested for antibodies. The sample was randomly selected from the adult population, 18 years or older, living the West Bank region of Palestine.

Serological tests for 910 adequate serum samples were done using immunoassays for detection of antibodies against SARS-CoV-2. Sociodemographic information and medical history data was collected.

Results

Study findings indicate that as of October 2021, a seroprevalence rate of 75.9% (30% due to infection with Covid-19 virus and 45.9% due to vaccination), 95% CI (73.1-78.7). The results indicate that the prevalence of antibodies among those who are unvaccinated and undiagnosed was 45.2% with 95% CI (39.9-50.5%).

The average age of participants was 37.6 years old. 49.2% were females and 50.8% were males. In relation to COVID-19, 13.6% of respondents reported getting infected by Covid-19 with statistically significant difference (P_value=0.001) between males (10.7%) and females (16.5%).

. In terms of vaccination, 52.8% of respondents reported getting vaccinated with an important difference between males (64.3%) and females (40.9%), (P-value=0.000).

Conclusion

Our findings reveal a drastic rise in seroprevalence of SARS-CoV-2 antibodies due to infection and vaccination. This information is useful for assessing the degree of herd immunity among the adult population and provides better understanding of the pandemic. Population-based seroprevalence studies should be conducted periodically to monitor the SARS-CoV-2 seroprevalence in Palestine and inform policymakers about the efficacy of the surveillance system and the public compliance with vaccination policies especially among females
Associations between vitamin D and disease risk may be attributed to the confounding influence of adiposity during childhood and adulthood: a lifecourse Mendelian randomization study
Authors: Richardson Tom G , Power Grace M , Smith George Davey
Published: May 2022

Background

Vitamin D supplements are widely prescribed to help reduce disease risk. However, this strategy is based on findings using conventional epidemiological methods which are prone to confounding and reverse causation.

Methods

In this short report, we leveraged genetic variants which differentially influence body size during childhood and adulthood within a multivariable Mendelian randomization (MR) framework, allowing us to separate the genetically predicted effects of adiposity at these two timepoints in the lifecourse.

Results

Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), there was strong evidence that higher childhood body size has a direct effect on lower vitamin D levels in early life (mean age: 9.9 years, range=8.9 to 11.5 years) after accounting for the effect of the adult body size genetic score (Beta=-0.32, 95% CI=-0.54 to -0.10, P=0.004). Conversely, we found evidence that the effect of childhood body size on vitamin D levels in midlife (mean age: 56.5 years, range=40 to 69 years) is putatively mediated along the causal pathway involving adulthood adiposity (Beta=-0.17, 95% CI=-0.21 to -0.13, P=4.6×10−17).

Conclusions

Our findings have important clinical implications in terms of the causal influence of vitamin D deficiency on disease risk. Furthermore, they serve as a compelling proof of concept that the timepoints across the lifecourse at which exposures and outcomes are measured can meaningfully impact overall conclusions drawn by MR studies.
Evidence for a common mechanism supporting invigoration of action selection and action execution
Authors: Kita Kahori , Du Yue , Haith Adrian M.
Published: May 2022

The speed, or vigor, of our movements can vary depending on circumstances. For instance, the promise of a reward leads to faster movements. Reward also leads us to move with a lower reaction time, suggesting that the process of action selection can also be invigorated by reward. It has been proposed that invigoration of action selection and of action execution might occur through a common mechanism, and thus these aspects of behavior might be coupled. To test this hypothesis, we asked participants to make reaching movements to “shoot” through a target at varying speeds to assess whether moving more quickly was also associated with more rapid action selection. We found that, when participants were required to move with a lower velocity, the speed of their action selection was also significantly slowed. This finding was recapitulated in a further dataset in which participants determined their own movement speed, but had to move slowly in order to stop their movement inside the target. By re-analyzing a previous dataset, we also found evidence for the converse relationship between action execution and action selection: when pressured to select actions more rapidly, people also executed movements with higher velocity. Our results establish that invigoration of action selection and action execution vary in tandem with one another, supporting the hypothesis of a common underlying mechanism.

Significance statement

We show that voluntary increases in the vigor of action execution lead action selection to also occur more rapidly. Conversely, hastening action selection by imposing a deadline to act also leads to increases in movement speed. These findings provide evidence that these two distinct aspects of behavior are modulated by a common underlying mechanism.
Demonstrating multi-country calibration of a tuberculosis model using new history matching and emulation package - hmer
Authors: Scarponi Danny , Iskauskas Andrew , Clark Rebecca A , Vernon Ian , McKinley Trevelyan J. , Goldstein Michael , Mukandavire Christinah , Deol Arminder , Weerasuriya Chathika , Bakker Roel , White Richard G , McCreesh Nicky
Published: May 2022

Infectious disease models are widely used by epidemiologists to improve the understanding of transmission dynamics and disease natural history, and to predict the possible effects of interventions. As the complexity of such models increases, however, it becomes increasingly challenging to robustly calibrate them to empirical data. History matching with emulation is a calibration method that has been successfully applied to such models, but has not been widely used in epidemiology partly due to the lack of available software. To address this issue, we developed a new, user-friendly R package hmer to simply and efficiently perform history matching with emulation. In this paper, we demonstrate the first use of hmer for calibrating a complex deterministic model for the country-level implementation of tuberculosis vaccines to 115 low-and middle-income countries. The model was fit to 9–13 target measures, by varying 19–22 input parameters. Overall, 105 countries were successfully calibrated. Among the remaining countries, hmer visualisation tools, combined with derivative emulation methods, provided strong evidence that the models were misspecified and could not be calibrated to the target ranges. This work shows that hmer can be used to simply and rapidly calibrate a complex model to data from over 100 countries, making it a useful addition to the epidemiologist’s calibration tool-kit.
Developing a predictive model for an emerging epidemic on cassava in sub-Saharan Africa
Authors: Godding David , Stutt Richard O. J. H. , Alicai Titus , Abidrabo Phillip , Okao-Okuja Geoffrey , Gilligan Christopher A.
Published: May 2022

The agricultural productivity of smallholder farmers in sub-Saharan Africa (SSA) is severely constrained by pests and pathogens, impacting economic stability and food security. Since 2004, an epidemic of cassava brown streak disease (CBSD) has been spreading rapidly from Uganda, with the disease causing necrosis of the edible root tissue. Based on sparse surveillance data, the epidemic front is currently believed to be at least as far west as central DRC and as far south as Zambia. The DRC is the world’s highest per capita consumer of cassava and future spread threatens production in West Africa which includes Nigeria, the world’s largest producer of cassava. Here, we take a unique Ugandan CBSD surveillance dataset spanning 2004 to 2017 and develop, parameterise, and validate a landscape-scale, spatiotemporal epidemic model of CBSD at a 1 km2 resolution. While this paper focuses on Uganda, the model is designed to be readily extended to make predictions beyond Uganda for all 32 major cassava producing countries of SSA, laying the foundations for a tool capable of informing strategic policy decisions at a national and regional scale.
Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14thcentury
Authors: Waldman Shamam , Backenroth Daniel , Harney Éadaoin , Flohr Stefan , Neff Nadia C. , Buckley Gina M. , Fridman Hila , Akbari Ali , Rohland Nadin , Mallick Swapan , Nistal Jorge Cano , Yu Jin , Barzilai Nir , Peter Inga , Atzmon Gil , Ostrer Harry , Lencz Todd , Maruvka Yosef E. , Lämmerhirt Maike , Rutgers Leonard V. , Renson Virginie , Prufer Keith M. , Schiffels Stephan , Ringbauer Harald , Sczech Karin , Carmi Shai , Reich David
Published: May 2022

We report genome-wide data for 33 Ashkenazi Jews (AJ), dated to the 14thcentury, following a salvage excavation at the medieval Jewish cemetery of Erfurt, Germany. The Erfurt individuals are genetically similar to modern AJ and have substantial Southern European ancestry, but they show more variability in Eastern European-related ancestry than modern AJ. A third of the Erfurt individuals carried the same nearly-AJ-specific mitochondrial haplogroup and eight carried pathogenic variants known to affect AJ today. These observations, together with high levels of runs of homozygosity, suggest that the Erfurt community had already experienced the major reduction in size that affected modern AJ. However, the Erfurt bottleneck was more severe, implying substructure in medieval AJ. Together, our results suggest that the AJ founder event and the acquisition of the main sources of ancestry pre-dated the 14thcentury and highlight late medieval genetic heterogeneity no longer present in modern AJ.
In vitrogeneration of human embryonic stem cell-derived heart organoids possessing physiological ion currents
Authors: Lee Jiyoung , Matsukawa Hiroshi , Sawada Kohei , Kaneko Rin , Ishino Fumitoshi
Published: May 2022

Recently, methods forin vitroorganogenesis have been broadly developed due to their strong potential for human applications in medicine. In the present study, we optimized the culturing method of human heart organoids (hHOs) from embryonic stem cells (ESCs) in the presence of the highly concentrated laminin-entactin and fibroblast growth factor 4. The resulting hHOs showed distinctive cardiac morphology with atrium- and ventricle-like chambers composed of cardiac cells as well as expressed the integral proteins of gap junctions and ion channels. In fact, isolated cardiomyocytes from these hHOs exhibited Na and Ca currents by patch clamp analysis. These results indicated that the present method will provide a powerful tool for cardiac safety assessment of newly developed drugs as anin vitrohuman ESC-derived test system.

One-Sentence Summary

FGF4 and ECM contribute to the generation of human HOs with heart compartments and electrophysiological properties.
Trimethylamine N-oxide reduces neurite density and plaque intensity in a murine model of Alzheimer’s disease
Authors: Zarbock Katie R. , Han Jessica H. , Singh Ajay P. , Thomas Sydney P. , Bendlin Barbara B. , Denu John M. , Yu John-Paul J. , Rey Federico E. , Ulland Tyler K.
Published: May 2022

Background

Alzheimer’s disease (AD) is the most common aging-associated neurodegenerative disease; nevertheless, the etiology and progression of the disease is still incompletely understood. We have previously shown that the microbially-derived metabolite trimethylamine N-oxide (TMAO) is elevated in the cerebrospinal fluid (CSF) of individuals with cognitive impairment due to AD and positively correlates with increases in CSF biomarkers for tangle, plaque, and neuronal pathology.

Objective

We assessed the direct impact of TMAO on AD progression.

Methods

To do so, transgenic 5XFAD mice were supplemented with TMAO for 12 weeks.

Results

Oral TMAO administration resulted in significantly reduced neurite density in several regions of the brain, as assessed through quantitative brain microstructure imaging with neurite orientation dispersion and density imaging (NODDI) magnetic resonance imaging (MRI). Amyloid-β plaque mean intensity was reduced, while plaque count and size remained unaltered. Proteomics analysis of the cortex revealed that TMAO treatment impacted the expression of 31 proteins (1.5-fold cut-off) in 5XFAD mice, including proteins known to influence neuronal health and amyloid-β precursor protein processing. TMAO treatment did not alter astrocyte and microglial response (as determined by histological analysis) nor cortical synaptic protein expression.

Conclusion

These data suggest that elevated plasma TMAO impacts AD pathology via reductions in neurite density.
Genomic insights into the adaptive and convergent evolution of Leuciscus waleckii inhabiting extremely alkaline environments
Authors: Zhou Zhixiong , Yang Junyi , Lv Hongzao , Zhou Tao , Zhao Ji , Bai Huaqiang , Pu Fei , Xu Peng
Published: May 2022

Leuciscus waleckii is widely distributed in Northeast Asia and has high economic value. Different from its freshwater counterparts, the population in Lake Dali Nur has a strong alkalinity tolerance and can adapt to extremely alkaline–saline water with bicarbonate over 50 mmol/L (pH 9.6), thus providing an exceptional model with which to explore the mechanisms of adaptive evolution under extreme alkaline environments. Here, we assembled a high quilty chromosome-level reference genome for L. waleckii from Lake Dali Nur, which provides an important genomic resource for the exploitation of alkaline water fishery resources and adaptive evolution research across teleost fish. Notably, we identified significantly expanded long terminal repeats (LTRs) and long interspersed nuclear elements (LINEs) in L. waleckii compared to other Cypriniformes fish, suggesting their more recent insertion into the L. waleckii genome. We also identified expansions in genes encoding gamma-glutamyltransferase, which possibly underlie the adaptation to extreme environmental stress. Based on the resequencing of 85 L.waleckii individuals from divergent populations, the historical population size of L.waleckii in Lake Dali Nur dramatically expanded in a thousand years approximately 13,000 years ago, and experienced a cliff recession in the process of adapting to the alkaline environment of Lake Dali Nur approximately 6,000 years ago. Genome scans further revealed the significant selective sweep regions from Lake Dali Nur, which harbour a set of candidate genes involved in hypoxia tolerance, ion transport, acid-base regulation and nitrogen metabolism. In particular, 5 alkali population specific nonsynonymous mutations were identified in CA15 gene copies. In addition, two sites with convergent amino acid mutation were detected in the RHCG-a gene among several alkali environment adapted Cypriniformes fish, this mutation may increase the NH3 excretion rate of the RHCG channel. Our findings provide comprehensive insight into the genomic mechanisms of L. waleckii and reveal their adaptative evolution under extreme alkaline environments.
Interneurons of fan-shaped body promote arousal in Drosophila
Authors: Kato Yoshiaki S. , Tomita Jun , Kume Kazuhiko
Published: May 2022

Sleep is required to maintain physiological functions and is widely conserved across species. To understand the sleep-regulatory mechanisms, sleep-regulating genes and neuronal circuits are studied in various animal species. In the sleep-regulatory neuronal circuits in Drosophila melanogaster, the dorsal fan-shaped body (dFB) is a major sleep-promoting region. However, other sleep-regulating neuronal circuits were not well identified. We recently found a novel sleep-regulatory circuit consisting of arousal-promoting T1 dopamine neurons and protocerebral bridge (PB) neurons innervating the ventral part of the FB, which we named “the PB-FB pathway”. However, the post-synaptic target of the PB-FB pathway was still unknown. To identify it, we performed anterograde tracing, immunohistochemistry, and Ca2+ imaging analysis and found that the PB-FB pathway projects to FB interneurons, also known as pontine neurons. Besides, we found that cholinergic pontine neurons promote arousal. Moreover, we indicated that pontine neurons form an anatomical connection with sleep-promoting dFB neurons. Together, we showed that pontine neurons receive excitatory signals from the PB-FB pathway and cholinergic pontine neurons promote arousal. These results completed one of the output pathways from the PB-FB pathway.
Deep phenotyping of women with endometriosis-associated pain and bladder pain syndrome: the TRiPP (Translational Research in Pelvic Pain) study protocol
Authors: Demetriou Lysia , Coxon Lydia , Krassowski Michal , Rahmioglu Nilufer , Arendt-Nielsen Lars , Aziz Qasim , Becker Christian M. , Birch Judy , Cruz Franscisco , Hoffman Anja , Horne Andrew W. , Hummelshoj Lone , McMahon Stephen , Meijlink Jane , Pogatzki-Zahn Esther , Sieberg Christine B. , Tracey Irene , Treede Rolf-Detlef , Missmer Stacey A. , Zondervan Krina T. , Nagel Jens , Vincent Katy
Published: May 2022

Objectives

Chronic pelvic pain is common, poorly understood, and many women suffer for years without proper diagnosis and effective treatment. The Translational Research in Pelvic Pain (TRiPP) project takes a phenotyping approach, with a particular focus on endometriosis-associated pain (EAP) and bladder pain syndrome (IC/BPS), to improve our fundamental understanding of chronic pelvic pain. We believe that reconceptualising these conditions in the context of the multisystem dysfunction known for other chronic pain conditions rather than as end-organ pathologies has the potential to improve our understanding of the conditions. Our approach combines clinical, biological, physiological and psychological data to establish perturbations in the functions of pain-relevant systems that are specific to EAP and IC/BPS, and those that overlap both conditions and chronic pelvic pain more generally and associated quantitative biomarker profiles.

Discussion

We believe that TRiPP’s novel methodological approach will produce clinical data to aid our understanding of pelvic pain and identify underlying pathways for the development of refined animal models and targeted therapeutic treatments.
Rare Gli1+ perivascular fibroblasts promote skin wound repair
Authors: Sun Xiaoyan , Annusver Karl , Dalessandri Tim , Kasper Maria
Published: May 2022

Growing evidence suggests that perivascular cells play important roles in tissue repair of various organs. In the skin, the contribution and importance of these cells for wound repair is not resolved. Here we demonstrate that a specific Gli1+ subpopulation residing in the perivascular niche serves as an important cellular source for wound healing fibroblast. First, we show that Gli1 expression marks small subsets of both pericytes and perivascular adventitial cells. Upon injury both cell types rapidly responded already within their original niche, however only the progeny of Gli1+ adventitial cells expanded and differentiated into wound-contracting myofibroblasts. Genetic ablation of these cells significantly impaired wound healing, which was associated with the reduction of aSMA+ myofibroblast-mediated wound contraction. After wound closure these cells reverted to an aSMA-negative fibroblast state, and intriguingly, they persisted in wounds over long term and adopted a non-fibrotic fibroblast signature. In sum, our data sheds new light on the functional diversity of perivascular-cell subtypes in the skin, and proposes a new mesenchymal cell source that promotes wound healing.
Terminal differentiation and persistence of effector regulatory T cells essential for the prevention of intestinal inflammation
Authors: Dikiy Stanislav , Levine Andrew G. , Giovanelli Paolo , Wang Zhong-Min , Beroshvili Giorgi , Pritykin Yuri , Krishna Chirag , Glasner Ariella , Leslie Christina S. , Rudensky Alexander Y.
Published: May 2022

Regulatory T (Treg) cells represent a specialized CD4+T cell lineage with essential anti-inflammatory functions. Recent studies of the adaptations of Treg cells to non-lymphoid tissues which enable their specialized immunosuppressive and tissue supportive functions raise questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Using novel genetic tools, we characterized the transcriptional programs of distinct colonic effector Treg cell types. We found that attenuated T cell receptor (TCR) signaling and acquisition of substantial TCR independent functionality appears to facilitate the terminal differentiation of a population of colonic effector Treg cells distinguished by stable expression of immunomodulatory cytokine interleukin-10 (IL-10). Functional studies revealed that this subset of effector Treg cells, but not their expression of IL-10, was indispensable for colonic health. These findings suggest core features of terminal differentiation of effector Treg cells in non-lymphoid tissues and their function therein.
Cheaters among pollinators: Floral traits drive spatiotemporal variation in nectar robbing and thieving in Afrotropical rainforests
Authors: Sakhalkar Sailee P. , Janeček Štěpán , Klomberg Yannick , Mertens Jan E.J. , Hodeček Jiří , Tropek Robert
Published: May 2022

Nectar robbing and thieving can substantially affect the reproduction of animal-pollinated plants. Although the intensity of nectar exploitation remains unexplored at the community level, it probably varies along environmental gradients.

We video-recorded flower visits to animal-pollinated plants in Afrotropical rainforests along a complete elevational gradient in the wet and dry seasons on Mount Cameroon. We analysed how the proportion of nectar robbing and thieving in the communities changes spatiotemporally, especially in association with the floral traits of the flowering plants.

We recorded 14,391 flower visits, of which ~4.3% were from robbers (mostly bees and birds), and ~2.1% were from thieves (mostly flies, bees, and moths). Of the 194 studied plants, only 29 and 39 were nectar robbed and thieved, respectively. Robbers and thieves were most frequent at mid-elevations, with more frequent robbing in the wet season and thieving in the dry season. These trends were linked to the local composition of floral traits, and cheating groups’ associations to particular traits. Floral traits that prevented thieving made flowers susceptible to robbing, and vice versa.

Spatiotemporal variation in floral traits across drives the cheating behaviour of flower visitors across communities, while indicating a trade-off between preventing nectar robbing and thieving.
A comprehensive investigation of statistical and machine learning approaches for predicting complex human diseases on genomic variants
Authors: Wang Chonghao , Zhang Jing , Zhou Xin , Zhang Lu
Published: May 2022

Background

Quantifying an individual’s risk for common diseases is an important goal of precision health. The polygenic risk score (PRS), which aggregates multiple risk alleles of candidate diseases, has emerged as a standard approach for identifying high-risk individuals. A variety of tools have been developed to implement PRS. However, benchmarks for comparatively evaluating the performance of these different methods and for assessing their potential to guide future clinical applications are lacking.

Results

We systematically validated and compared thirteen statistical methods, five machine learning models and two ensemble models using simulated data, twenty-two common diseases with internal training sets and four diseases with external summary statistics from the UK Biobank resource. The effects of disease heritability, single nucleotide polymorphism (SNP) effect size and sample size are evaluated using simulated data. We also investigated the correlations between methods and their standard deviations of different diseases.

Conclusions

In general, statistical methods outperform machine learning models, and ensemble models, such as Super Learner, generally perform the best for most situations. We observed the correlations were relatively high if the methods were from the same category and the external summary statistics from large cohort GWAS could decrease the standard deviation of method correlations. By varying three factors in the simulated data, we also identified that disease heritability had a strong effect on the predictive performance of individual methods. Both the number and effect sizes of risk SNPs are important; and while sample size strongly influences the performance of machine learning models, but not statistical methods.
A key role of the WEE1-CDK1 axis in mediating TKI-therapy resistance in FLT3-ITD positive acute myeloid leukemia patients
Authors: Massacci Giorgia , Venafra Veronica , Latini Sara , Bica Valeria , Pugliese Giusj Monia , Klingelhuber Felix , Krahmer Natalie , Fischer Thomas , Mougiakakos Dimitrios , Boettcher Martin , Perfetto Livia , Sacco Francesca
Published: May 2022

Internal tandem duplications (ITDs) in the FLT3 gene are frequently identified and confer a poor prognosis in patient affected by acute myeloid leukemia (AML). The insertion site of the ITDs in FLT3 significantly impacts the sensitivity to tyrosine kinase inhibitors (TKIs) therapy, affecting patient’s clinical outcome. To decipher the molecular mechanisms driving the different sensitivity to TKIs therapy of FLT3-ITD mutation, we used high-sensitive mass spectrometry-based (phospho)proteomics and deep sequencing. Here, we present a novel generally-applicable strategy that supports the integration of unbiased large-scale datasets with literature-derived signaling networks. The approach produced FLT3-ITDs specific predictive models and revealed a crucial and conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, we found that pharmacological inhibition of the WEE1 kinase synergizes and strengthens the pro-apoptotic effect of TKIs therapy in cell lines and patient-derived primary blasts. In conclusion, this work proposes a new molecular mechanism of TKIs resistance in AML and suggests a combination therapy as option to improve therapeutic efficacy.
The time course of categorical and perceptual similarity effects in visual search
Authors: Yeh Lu-Chun , Peelen Marius V.
Published: May 2022

During visual search for objects (e.g., an apple), the surrounding distractor objects may share perceptual (tennis ball), categorical (banana), or both (peach) properties with the target. Previous studies showed that the perceptual similarity between target and distractor objects influences visual search. Here, we tested whether categorical target-distractor similarity also influences visual search, and how this influence depends on perceptual similarity. By orthogonally manipulating categorical and perceptual target-distractor similarity, we could investigate how and when the two similarities interactively affect search performance and neural correlates of spatial attention (N2pc) using electroencephalography (EEG). Behavioral results showed that categorical target-distractor similarity interacted with perceptual target-distractor similarity, such that the effect of categorical similarity was strongest when target and distractor objects were perceptually similar. EEG results showed that perceptual similarity influenced the early part of the N2pc (200-250 ms after stimulus onset), while categorical similarity influenced the later part (250-300 ms). Mirroring the behavioral results, categorical similarity interacted with perceptual similarity during this later time window, with categorical effects only observed for perceptually similar target-distractor pairs. Together, these results provide evidence for hierarchical processing in visual search: categorical properties influence spatial attention only when perceptual properties are insufficient to guide attention to the target.

Public significance statement

Searching for a target object among perceptually similar distractor objects (e.g., looking for an apple among peaches) is relatively difficult. In daily life, target and distractor objects may not only share perceptual but also non-perceptual properties, such as category membership (e.g., fruit). Here, we show that categorical similarity between target and distractor objects influences search performance, particularly when target and distractor objects are perceptually similar. Using electrophysiological recordings, we demonstrate that attentional selection is first influenced by perceptual and then by categorical information. This later categorical influence depended on perceptual similarity, being strongest for perceptually similar objects. These findings provide evidence for hierarchical processing in visual search, with categorical properties extracted after perceptual properties.