Miracle-dz/UniFAR-FTUs huggingface dataset:
CRISPR/Cas9-generated mouse model with humanizing single-base substitution in the Gnao1 for safety studies of RNA therapeutics

The development of personalized medicine for genetic diseases requires preclinical testing in the appropriate animal models. GNAO1 encephalopathy is a severe neurodevelopmental disorder caused by heterozygous de novo mutations in the GNAO1 gene. GNAO1 c.607 G>A is one of the most common pathogenic variants, and the mutant protein Gαo-G203R likely adversely affects neuronal signaling. As an innovative approach, sequence-specific RNA-based therapeutics such as antisense oligonucleotides or effectors of RNA interference are potentially applicable for selective suppression of the mutant GNAO1 transcript. While in vitro validation can be performed in patient-derived cells, a humanized mouse model to rule out the safety of RNA therapeutics is currently lacking. In the present work, we employed CRISPR/Cas9 technology to introduce a single-base substitution into exon 6 of the Gnao1 to replace the murine Gly203-coding triplet (GGG) with the codon used in the human gene (GGA). We verified that genome-editing did not interfere with the Gnao1 mRNA or Gαo protein synthesis and did not alter localization of the protein in the brain structures. The analysis of blastocysts revealed the off-target activity of the CRISPR/Cas9 complexes; however, no modifications of the predicted off-target sites were detected in the founder mouse. Histological staining confirmed the absence of abnormal changes in the brain of genome-edited mice. The created mouse model with the “humanized” fragment of the endogenous Gnao1 is suitable to rule out unintended targeting of the wild-type allele by RNA therapeutics directed at lowering GNAO1 c.607 G>A transcripts.
Improving in-season wheat yield prediction using remote sensing and additional agronomic traits as predictors

The development of accurate grain yield (GY) multivariate models using normalized difference vegetation index (NDVI) assessments obtained from aerial vehicles and additional agronomic traits is a promising option to assist, or even substitute, laborious agronomic in-field evaluations for wheat variety trials. This study proposed improved GY prediction models for wheat experimental trials. Calibration models were developed using all possible combinations of aerial NDVI, plant height, phenology, and ear density from experimental trials of three crop seasons. First, models were developed using 20, 50 and 100 plots in training sets and GY predictions were only moderately improved by increasing the size of the training set. Then, the best models predicting GY were defined in terms of the lowest Bayesian information criterion (BIC) and the inclusion of days to heading, ear density or plant height together with NDVI in most cases were better (lower BIC) than NDVI alone. This was particularly evident when NDVI saturates (with yields above 8 t ha-1) with models including NDVI and days to heading providing a 50% increase in the prediction accuracy and a 10% decrease in the root mean square error. These results showed an improvement of NDVI prediction models by the addition of other agronomic traits. Moreover, NDVI and additional agronomic traits were unreliable predictors of grain yield in wheat landraces and conventional yield quantification methods must be used in this case. Saturation and underestimation of productivity may be explained by differences in other yield components that NDVI alone cannot detect (e.g. differences in grain size and number).
On the fluid dynamics of the aortic valve

An aortic-valve model is developed, having a quadratic cross-section, two rigid cusps and two wedge-shaped aortic sinuses. The flow through this valve is assumed to be one-dimensional, just as the flow behind the cusps should be one-dimensional. The resulting model equations are two nonlinear ordinary differential equations of second order for the valve opening area as a function of time in two different ranges. This model allows the size of the aortic sinus to be varied; it also permits a computation of the pressure at both sides of the cusps (unlike previous models of this kind, which consider the flow behind the cusps as stagnant). The computed valve motion due to this pressure difference is in good agreement with experimental results, although no vortex with circular streamlines is postulated in the aortic sinuses. Obviously such vortices trapped in the sinuses are not important for the valve closure, which is controlled solely by the flow deceleration.
Comparative analysis of newly identified rodent arteriviruses and porcine reproductive and respiratory syndrome virus to characterize their evolutionary relationships

Porcine reproductive and respiratory syndrome virus (PRRSV) has caused huge economic losses for the global pig industry, but its origins and evolution remain a mystery. In 2018, the genome sequences of seven arteriviruses isolated from rodents were determined, and here we publish new analysis showing that they may be ancestors of PRRSV. The sequence similarity of these viruses to PRRSV was ~60%, with shared genome organization and other characteristics, such as slippery sequences and C-rich motifs in nsp2, and a transactivated protein sequence in nsp1β. Codon usage basis analysis showed that PRRSV was closer to these rodent arteriviruses than lactate dehydrogenase-elevating virus (LDV) and they were both under pressure of natural selection. Evolutionary analysis revealed that four of the rodent arteriviruses shared the same genus with PRRSV, and were more closely related to PRRSV-2 than PRRSV-1. In addition to this, they all appeared earlier than PRRSV according to evolutionary modeling, and we speculate that they represent an intermediate step in the origin of PRRSV by arterivirus transmission from rodents to swine. Our in-depth analysis furthers our understanding of arteriviruses, and will serve as the basis for subsequent exploration of the evolution of PRRSV and other arteriviruses.
A simple modification of deadlock prevention policy of S3PR based on elementary siphons

We propose to extend our proprietary approach of siphon synthesis to a new simple deadlock control policy. To prevent each strict minimal siphon (SMS) S from becoming empty of tokens, we often add a control place VS and associated arcs to form an invariant to control the number of tokens leaking from S. In a disturbanceless approach, the control (called Type-1) arcs are chosen to disturb the original uncontrolled model as little as possible, to reach as many states as possible. However, this policy may generate new SMSs and hence require adding too many control places and arcs to the original Petri net model. Thus, Ezpeleta et al. moved all output (called Type-2) arcs of each VS to the output transition of the entry (called idle place) of input raw materials to limit their rate into the system, called all-sided, or SMSless approach. This may overly constrain the system so that many reachable states are no longer attainable. We hence propose an intermediate, called the one-sided, approach, which does not g.
Toward carbon neutrality: The impact of manufacturing agglomeration on total factor energy efficiency

Improving energy efficiency is an effective way to achieve carbon neutrality in the context of growing advocacy for a green economy in both academia and government. In this study, we analyzed the impact mechanism of the manufacturing agglomeration on total factor energy efficiency. Based on this work, we identified 30 provinces (autonomous regions and municipalities) in China using 2002 to 2017 panel data. We used the data envelopment analysis game cross-efficiency model to calculate the interprovincial current state of energy efficiency. We constructed a spatial Durbin model and used an adjacent space weight matrix, geographic distance weight matrix, and economic distance weight matrix to study the impact of manufacturing agglomeration on total factor energy efficiency. The results showed that under different spatial weights, the interprovincial total factor energy efficiency had a significant spatial dependence; under the three spatial weights, we identified a U-shaped relationship between manufacturing agglomeration and total factor energy efficiency. Industrial agglomeration had obvious spatial spillover effects on total factor energy efficiency, and the spillover effects under the weight of geographic distance were higher than other spatial weights. During the sample period, the direct, indirect, and total effects of the manufacturing industry had an impact on energy efficiency. It all had a negative number indicating that there was a crowding effect in manufacturing agglomeration, and it had an inhibitory effect on energy efficiency.
The singing activity of the Yellowhammer (Emberiza citrinella) under traffic noise around highways

Steadily increasing human population is changing the environment in many ways. One of the most disturbing impacts is the development of anthropogenic noise pollution connected to ever-growing traffic intensity. The road network can have both positive and negative effects on biodiversity and populations. Many bird species use acoustic communication to establish and maintain their territories and for intra-pair and adult–young communication. Noise pollution can impact negatively on breeding success and biorhythm if this communication is masked by noise and the individuals must adjust their singing activity. Yellowhammer (Emberiza citrinella) is a common bird species of agricultural landscapes whose population is declining due to agricultural intensification. It is found also in habitats near highways with forest steppe-like characteristics, where it is affected by the high levels of anthropogenic noise pollution. This study aimed to determine how this species adapts to noise from highway traffic by adjusting its singing activity. The influence of locality type, immediate and long-term impact of traffic noise on the average and total length of song sequences in the birdsong, and influence on the total number of recorded song sequences during the second hour after sunrise were evaluated in this study. Our results showed that Yellowhammer’s singing activity changed in localities close to highways compared to agricultural landscape. With increasing long-term traffic intensity on highways, song duration of the Yellowhammer song was decreasing. The present traffic intensity led to later onset of dawn chorus and decreasing strophe length with increasing number of passing vehicles. Furthermore, in the agricultural landscape, Yellowhammer’s song duration increased with increasing distance from the nearest road.
Geniposide plus chlorogenic acid reverses non-alcoholic steatohepatitis via regulation of gut microbiota and bile acid signaling in a mouse model in vivo

Background: Geniposide and chlorogenic acid are the major active ingredients in Yinchenhao Decoction and are widely used as herbal medicines in Asia. This study further assessed their effects on improvement of non-alcoholic steatohepatitis (NASH) in a mouse model and explored the underlying molecular events in vivo. Methods: Male C57BL/6 and farnesoid X receptor knockout (FXR−/−) mice were used to establish the NASH model and were treated with or without geniposide, chlorogenic acid, obeticholic acid (OCA), and antibiotics for assessment of the serum and tissue levels of various biochemical parameters, bile acid, DNA sequencing of bacterial 16S amplicon, protein expression, and histology. Results: The data showed that the combination of geniposide and chlorogenic acid (GC) reduced the levels of blood and liver lipids, serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and the liver tissue index in NASH mice. In addition, GC treatment improved the intestinal microbial disorders in the NASH mice as well as the intestinal and serum bile acid metabolism. At the gene level, GC induced FXR signaling, i.e., increased the expression of FXR, small heterodimer partner (SHP), and bile salt export pump (BSEP) in liver tissues and fibroblast growth factor 15 (FGF15) expression in the ileal tissues of NASH mice. However, antibiotics (ampicillin, neomycin, vancomycin, and tinidazole) in drinking water (ADW) reversed the effect of GC on NASH and altered the gut microbiota in NASH mice in vivo. Furthermore, GC treatment failed to improve NASH in the FXR−/− mouse NASH model in vivo, indicating that the effectiveness of GC treatment might be through FXR signaling activation. Conclusion: GC was able to alleviate NASH by improving the gut microbiome and activating FXR signaling; its effect was better than each individual agent alone.
Prediction of CTCF loop anchor based on machine learning

Introduction: Various activities in biological cells are affected by three-dimensional genome structure. The insulators play an important role in the organization of higher-order structure. CTCF is a representative of mammalian insulators, which can produce barriers to prevent the continuous extrusion of chromatin loop. As a multifunctional protein, CTCF has tens of thousands of binding sites in the genome, but only a portion of them can be used as anchors of chromatin loops. It is still unclear how cells select the anchor in the process of chromatin looping. Methods: In this paper, a comparative analysis is performed to investigate the sequence preference and binding strength of anchor and non-anchor CTCF binding sites. Furthermore, a machine learning model based on the CTCF binding intensity and DNA sequence is proposed to predict which CTCF sites can form chromatin loop anchors. Results: The accuracy of the machine learning model that we constructed for predicting the anchor of the chromatin loop mediated by CTCF reached 0.8646. And we find that the formation of loop anchor is mainly influenced by the CTCF binding strength and binding pattern (which can be interpreted as the binding of different zinc fingers). Discussion: In conclusion, our results suggest that The CTCF core motif and it’s flanking sequence may be responsible for the binding specificity. This work contributes to understanding the mechanism of loop anchor selection and provides a reference for the prediction of CTCF-mediated chromatin loops.
Influence management and disturbances on the regeneration of forest stands

The renewal and sustainability of the forest stands are attained through regeneration. There are three basic methods to regenerate high forest stands: natural regeneration, direct seeding, and planting. This study reviews the factors affecting regeneration, the three methods of regeneration and the effect of stand structure on regeneration. Overall, regeneration success can be quite variable due to edaphic and climatic conditions, seed losses and/or seedling mortality. The silvicultural system is relevant to the choice of the regeneration method. Natural regeneration is used in selection and irregular shelterwood systems whereas direct seeding and planting are used in uniform shelterwood and clear-cut systems. In the former, stand stocking management is primordial to regeneration success while for the latter are species selection, seed predators and spontaneous vegetation control.
Star formation in the bright-rimmed molecular cloud IC 1848 A

A bright IR source has been detected within a bright-rimmed dust cloud at the edge of the IC 1848 H II region. The source appears to be an early-type star with a circumstellar dust shell typical of protostars. This star is associated with the position of greatest CO excitation in a dense molecular cloud. The contours of CO emission correspond to those of the bright-rimmed dust cloud, showing that the star formed within the bright rim. Formaldehyde observations at 6 cm, 2 cm, and 2 mm are used to determine the density of the layer between the star and the ionized gas of the bright H.cap alpha. rim. The location of this star, with respect to the dense molecular cloud which is subject to the external pressure of HII region, indicates the possible role of the expansion of IC 1848 in triggering star formation in dense regions at the perimeter of the H II region. The observed CO emission is used to determine the required luminosity of the embedded star. An early-type star of this luminosity should be detectable as a compact continuum source.
The association of maternal smoking and other sociobehavioral factors with dental caries in toddlers: A cross-sectional study

Background Severe early childhood caries (S-ECC) is a form of dental caries in toddlers, which can strongly affect general health and quality of life. Studies on factors that can contribute to the development of caries immediately after tooth eruption are sparse. The aim of this study was to assess the role of sociobehavioural factors and pre- and postnatal exposure to tobacco smoke in the aetiology of dental caries in children up to 3 years old. Methods A cross-sectional study was conducted between 2011 and 2017 to assess oral health and teething in urban children 0–4 years of age. The number of teeth and surfaces with white spot lesions (d1,2), as well as decayed (d), missing (m), and filled (f) teeth classified according to ICDAS II was evaluated in a dental office setting. d1,2dmft and d1,2dmfs were calculated. Severe early childhood caries was diagnosed for d1,2dmfs > 0. Parents completed a self-administered questionnaire on socioeconomic factors, maternal health, course of pregnancy, child's perinatal parameters, hygiene and dietary practices, as well as maternal smoking during and after pregnancy. Data on children aged 12–36 months were collected and analysed statistically using the t-test, Spearman rank correlations and Poisson regression. Significance level was set at 0.05. Results Dental caries was found in 46% of 496 children aged 12–36 months. Mean d1,2dmft and d1,2dmfs were 2.62 ± 3.88 and 4.46 ± 8.42, respectively. Tobacco smoking during and after pregnancy was reported by 8.9% and 24.8% of women, respectively. Spearman's rank correlation analysis confirmed a relationship between S-ECC and parental education, maternal smoking, bottle feeding, avoiding springy foods, number of meals, and the age of tooth brushing initiation. Pre- and postnatal exposure to tobacco smoke increased the risk of S-ECC especially in children in age 19–24 months. Maternal smoking was correlated with the level of education and dietary practices. Conclusion Our study confirmed that prenatal smoking is associated with increased risk of severe-early childhood caries (S-ECC) while the association with post-natal smoking is also evident, the increase in risk is not statistically clear. Both maternal smoking and the child's tooth decay are associated with poor parental education and other improper oral health behaviours. The positive impact of quitting smoking on the oral health in children should be part of anti-smoking advice.
Kif21B mediates the effect of estradiol on the morphological plasticity of mouse hippocampal neurons

Introduction Neurons are polarized cells, and their ability to change their morphology has a functional implication in the development and plasticity of the nervous system in order to establish new connections. Extracellular factors strongly influence neuronal shape and connectivity. For instance, the developmental actions of estradiol on hippocampal neurons are well characterized, and we have demonstrated in previous studies that Ngn3 mediates these actions. On the other hand, Kif21B regulates microtubule dynamics and carries out retrograde transport of the TrkB/brain-derived neurotrophic factor (BDNF) complex, essential for neuronal development. Methods In the present study, we assessed the involvement of kinesin Kif21B in the estradiol-dependent signaling mechanisms to regulate neuritogenesis through cultured mouse hippocampal neurons. Results We show that estradiol treatment increases BDNF expression, and estradiol and BDNF modify neuron morphology through TrkB signaling. Treatment with K252a, a TrkB inhibitor, decreases dendrite branching without affecting axonal length, whereas. Combined with estradiol or BDNF, it blocks their effects on axons but not dendrites. Notably, the downregulation of Kif21B abolishes the actions of estradiol and BDNF in both the axon and dendrites. In addition, Kif21B silencing also decreases Ngn3 expression, and downregulation of Ngn3 blocks the effect of BDNF on neuron morphology. Discussion These results suggest that Kif21B is required for the effects of estradiol and BDNF on neuronal morphology, but phosphorylation-mediated activation of TrkB is essential only for axonal growth. Our results show that the Estradiol/BDNF/TrkB/Kif21B/Ngn3 is a new and essential pathway mediating hippocampal neuron development.
Learning from real world data about combinatorial treatment selection for COVID-19

COVID-19 is an unprecedented global pandemic with a serious negative impact on virtually every part of the world. Although much progress has been made in preventing and treating the disease, much remains to be learned about how best to treat the disease while considering patient and disease characteristics. This paper reports a case study of combinatorial treatment selection for COVID-19 based on real-world data from a large hospital in Southern China. In this observational study, 417 confirmed COVID-19 patients were treated with various combinations of drugs and followed for four weeks after discharge (or until death). Treatment failure is defined as death during hospitalization or recurrence of COVID-19 within four weeks of discharge. Using a virtual multiple matching method to adjust for confounding, we estimate and compare the failure rates of different combinatorial treatments, both in the whole study population and in subpopulations defined by baseline characteristics. Our analysis reveals that treatment effects are substantial and heterogeneous, and that the optimal combinatorial treatment may depend on baseline age, systolic blood pressure, and c-reactive protein level. Using these three variables to stratify the study population leads to a stratified treatment strategy that involves several different combinations of drugs (for patients in different strata). Our findings are exploratory and require further validation.