bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of serotonin on small intestinal contractility in healthy volunteers
Authors: Hansen MB , Arif F , Gregersen H , Bruusgaard H , Wallin L
Published: April 2021

The physiological significance of serotonin released into the
intestinal lumen for the regulation of motility is unknown in
humans. The aim of this study was to evaluate the effect of
serotonin infused into the lumen of the gastric antrum,
duodenum or the jejunum, on antro-duodeno-jejunal contractility
in healthy human volunteers. Manometric recordings were
obtained and the effects of either a standard meal, continuous
intravenous infusion of serotonin (20 nmol/kg/min) or
intraluminal bolus infusions of graded doses of serotonin (2.5, 25
or 250 nmol) were compared. In addition, platelet-depleted
plasma levels of serotonin, blood pressure, heart rate and
electrocardiogram were evaluated. All subjects showed similar
results. Intravenous serotonin increased migrating motor
complex phase III frequency 3-fold and migrating velocity 2-fold.
Intraluminal infusion of serotonin did not change contractile
activity. Platelet-depleted-plasma levels of serotonin increased 2-
fold following both intravenous and high doses of intraluminal
infusions of serotonin. All subjects reported minor short-lived
adverse effects following intravenous serotonin stimulation, while
only half of the subjects reported minor short-lived adverse
effects following intraluminal serotonin stimulations. We conclude
that exogenous serotonin in the lumen of the upper part of the
small intestine does not seem to change antro-duodeno-jejunal
contractility significantly in healthy adult volunteers.
Case study concerning successful Romanian SMEs development by students education and entrepreneurial training
Authors: Radulescu Irina , Radulescu Alexandru
Published: April 2021

The European Commission has published in 2020 the SMEs Strategy for a Sustainable
and Digital Europe that aims to increase the number of SMEs engaged in sustainable business
practices, as well as the SMEs number that use digital technologies. Important opportunities for
SMEs can be provided by digitization, to improve the production processes efficiency and the
ability to innovate products and business models, by using advanced disruptive technologies.
Good management is needed for a successful SME, education and entrepreneurship training
have the role of consolidating business knowledge and skills. Educational activities and skills
upgrading are essential for all SMEs managers and employees. Romania is on the last place in
EU, regarding SMEs number and it ranks 11th place out of 28, in terms of connectivity.
Regarding the digital maturity of Romanian SMEs, the White Papers on Romanian SMEs
presents their main working elements: computer, e-mail applications, internet, intranet, social
networks, the company's own website, online sales / purchases transactions. The objectives of
the Bachelor's degree specialization of Economic Engineering in Mechanical field and Industrial
Entrepreneurship Master are students training and education, in order to be able to sustain
digitization and sustainable technologies. The university curriculum and the educational
disciplines offered by the Economic Engineering in Mechanical field specialization and
Industrial Entrepreneurship Master is connected to the society requirements and must follow the
economic trend, by educating, training and getting good specialists.
Keywords: SMEs development, education, entrepreneurship
Histone Modifications and Chondrocyte Fate: Regulation and Therapeutic Implications
Authors: Wan Chao , Zhang Fengjie , Yao Hanyu , Li Haitao , Tuan Rocky S.
Published: April 2021

The involvement of histone modifications in cartilage development, pathology and regeneration is becoming increasingly evident. Understanding the molecular mechanisms and consequences of histone modification enzymes in cartilage development, homeostasis and pathology provides fundamental and precise perspectives to interpret the biological behavior of chondrocytes during skeletal development and the pathogenesis of various cartilage related diseases. Candidate molecules or drugs that target histone modifying proteins have shown promising therapeutic potential in the treatment of cartilage lesions associated with joint degeneration and other chondropathies. In this review, we summarized the advances in the understanding of histone modifications in the regulation of chondrocyte fate, cartilage development and pathology, particularly the molecular writers, erasers and readers involved. In addition, we have highlighted recent studies on the use of small molecules and drugs to manipulate histone signals to regulate chondrocyte functions or treat cartilage lesions, in particular osteoarthritis (OA), and discussed their potential therapeutic benefits and limitations in preventing articular cartilage degeneration or promoting its repair or regeneration.
Identification and Distinction of Tenocytes and Tendon-Derived Stem Cells
Authors: Li Yuange , Wu Tianyi , Liu Shen
Published: April 2021

Restoring the normal structure and function of injured tendons is one of the biggest challenges in orthopedics and sports medicine department. The discovery of tendon-derived stem cells (TDSCs) provides a novel perspective to treat tendon injuries, which is expected to be an ideal seed cell to promote tendon repair and regeneration. Because of the lack of specific markers, the identification of tenocytes and TDSCs has not been conclusive in thein vitrostudy of tendons. In addition, the morphology of tendon derived cells is similar, and the comparison and identification of tenocytes and TDSCs are insufficient, which causes some obstacles to thein vitrostudy of tendon. In this review, the characteristics of tenocytes and TDSCs are summarized and compared based on some existing research results (mainly in terms of biomarkers), and a potential marker selection for identification is suggested. It is of profound significance to further explore the mechanism of biomarkersin vivoand to find more specific markers.
Proteostasis in the Male and Female Germline: A New Outlook on the Maintenance of Reproductive Health
Authors: Cafe Shenae L. , Nixon Brett , Ecroyd Heath , Martin Jacinta H. , Skerrett-Byrne David A. , Bromfield Elizabeth G.
Published: April 2021

For fully differentiated, long lived cells the maintenance of protein homeostasis (proteostasis) becomes a crucial determinant of cellular function and viability. Neurons are the most well-known example of this phenomenon where the majority of these cells must survive the entire course of life. However, male and female germ cells are also uniquely dependent on the maintenance of proteostasis to achieve successful fertilization. Oocytes, also long-lived cells, are subjected to prolonged periods of arrest and are largely reliant on the translation of stored mRNAs, accumulated during the growth period, to support meiotic maturation and subsequent embryogenesis. Conversely, sperm cells, while relatively ephemeral, are completely reliant on proteostasis due to the absence of both transcription and translation. Despite these remarkable, cell-specific features there has been little focus on understanding protein homeostasis in reproductive cells and how/whether proteostasis is “reset” during embryogenesis. Here, we seek to capture the momentum of this growing field by highlighting novel findings regarding germline proteostasis and how this knowledge can be used to promote reproductive health. In this review we capture proteostasis in the context of both somatic cell and germline aging and discuss the influence of oxidative stress on protein function. In particular, we highlight the contributions of proteostasis changes to oocyte aging and encourage a focus in this area that may complement the extensive analyses of DNA damage and aneuploidy that have long occupied the oocyte aging field. Moreover, we discuss the influence of common non-enzymatic protein modifications on the stability of proteins in the male germline, how these changes affect sperm function, and how they may be prevented to preserve fertility. Through this review we aim to bring to light a new trajectory for our field and highlight the potential to harness the germ cell’s natural proteostasis mechanisms to improve reproductive health. This manuscript will be of interest to those in the fields of proteostasis, aging, male and female gamete reproductive biology, embryogenesis, and life course health.
Fluorescence-Based Sensing of Pesticides Using Supramolecular Chemistry
Authors: Levine Mindy
Published: April 2021

The detection of pesticides in real-world environments is a high priority for a broad range of applications, including in areas of public health, environmental remediation, and agricultural sustainability. While many methods for pesticide detection currently exist, the use of supramolecular fluorescence-based methods has significant practical advantages. Herein, we will review the use of fluorescence-based pesticide detection methods, with a particular focus on supramolecular chemistry-based methods. Illustrative examples that show how such methods have achieved success in real-world environments are also included, as are areas highlighted for future research and development.
Perovskite Oxide–Based Materials for Photocatalytic and Photoelectrocatalytic Treatment of Water
Authors: Nkwachukwu Oluchi V. , Arotiba Omotayo A.
Published: April 2021

Meeting the global challenge of water availability necessitates diversification from traditional water treatment methods to other complementary methods, such as photocatalysis and photoelectrocatalysis (PEC), for a more robust solution. Materials play very important roles in the development of these newer methods. Thus, the quest and applications of a myriad of materials are ongoing areas of water research. Perovskite and perovskite-related materials, which have been largely explored in the energy sectors, are potential materials in water treatment technologies. In this review, attention is paid to the recent progress in the application of perovskite materials in photocatalytic and photoelectrocatalytic degradation of organic pollutants in water. Water treatment applications of lanthanum, ferrite, titanate, and tantalum (and others)-based perovskites are discussed. The chemical nature and different synthetic routes of perovskites or perovskite composites are presented as fundamental to applications.
Linguistic Complexity: Relationships Between Phoneme Inventory Size, Syllable Complexity, Word and Clause Length, and Population Size
Authors: Fenk-Oczlon Gertraud , Pilz Jürgen
Published: April 2021

Starting from a view on language as a complex, hierarchically organized system composed of many parts that have many interactions, this paper investigates statistical relationships between the linguistic variables “phoneme inventory size,” “syllable size,” “length of words,” “length of clauses,” and the nonlinguistic variable “population size.” By analyzing parallel textual material of 61 languages (18 language families) we found strong positive correlations between phoneme inventory size, mean number of phonemes per syllable, and mean number of monosyllables. We observed significant negative correlations between phoneme inventory size and the mean length of words and the mean length of clauses, measured as number of syllables. We then correlated the linguistic complexity data with estimated speaker population sizes and could reveal that languages with more speakers tend to have more phonemes per syllable, shorter words in number of syllables, a higher number of monosyllabic words, and a higher number of words per clause. Moreover, we reproduce the results of former studies that found a positive correlation between population size and phoneme inventory size for our language sample. The findings are discussed in light of previous research and within the framework of Systemic Typology. We propose that syllable complexity is a key factor in the correlations identified in this study, and that Zipf's law of Abbreviation explains the associations between “word length,” “syllable complexity,” “phoneme inventory size,” and the extralinguistic variable “population size.”
How the Visual Design of Video Game Antagonists Affects Perception of Morality
Authors: Pradantyo Reyhan , Birk Max V. , Bateman Scott
Published: April 2021

The visual design of antagonists—typically thought of as “bad guys”—is crucial for game design. Antagonists are key to providing the backdrop to a game's setting and motivating a player's actions. The visual representation of antagonists is important because it affects player expectations about the character's personality and potential actions. Particularly important is how players perceive an antagonist's morality. For example, an antagonist appearing disloyal might foreshadow betrayal; a character who looks cruel suggests that tough fights are ahead; or, a player might be surprised when a friendly looking character attacks them. Today, the art of designing character morality is informed by archetypal elements, existing characters, and the artist's own background. However, little work has provided insight into how an antagonist's appearance can lead players to make moral judgments. Using Mechanical Turk, we collected participant ratings on a stimulus image set of 105 antagonists from popular video games. The results of our work provide insights into how the visual attributes of antagonists can influence judgments of character morality. Our findings provide a valuable new lens for understanding and deepening an important aspect of game design. Our results can be used to help ensure that a particular character design has the best chance to be universally seen as “evil,” or to help create more complex and conflicted emotional experiences through carefully designed characters that do not appear to be bad. Our research extends current research practices that seek to build an understanding of game design and provides exciting new directions for exploring how design and aesthetic practices can be better studied and supported.
Chronic Thromboembolic Pulmonary Hypertension – What Have We Learned From Large Animal Models
Authors: Stam Kelly , Clauss Sebastian , Taverne Yannick J. H. J. , Merkus Daphne
Published: April 2021

Chronic thrombo-embolic pulmonary hypertension (CTEPH) develops in a subset of patients after acute pulmonary embolism. In CTEPH, pulmonary vascular resistance, which is initially elevated due to the obstructions in the larger pulmonary arteries, is further increased by pulmonary microvascular remodeling. The increased afterload of the right ventricle (RV) leads to RV dilation and hypertrophy. This RV remodeling predisposes to arrhythmogenesis and RV failure. Yet, mechanisms involved in pulmonary microvascular remodeling, processes underlying the RV structural and functional adaptability in CTEPH as well as determinants of the susceptibility to arrhythmias such as atrial fibrillation in the context of CTEPH remain incompletely understood. Several large animal models with critical clinical features of human CTEPH and subsequent RV remodeling have relatively recently been developed in swine, sheep, and dogs. In this review we will discuss the current knowledge on the processes underlying development and progression of CTEPH, and on how animal models can help enlarge understanding of these processes.
Attenuation of Seismic Waves in Partially Saturated Berea Sandstone as a Function of Frequency and Confining Pressure
Authors: Tisato Nicola , Madonna Claudio , Saenger Erik H.
Published: April 2021

Frequency-dependent attenuation (1/Q) should be used as a seismic attribute to improve the accuracy of seismic methods and imaging of the subsurface. In rocks, 1/Q is highly sensitive to the presence of saturating fluids. Thus, 1/Q could be crucial to monitor volcanic and hydrothermal domains and to explore hydrocarbon and water reservoirs. The experimental determination of seismic and teleseismic attenuation (i.e., for frequencies < 100 Hz) is challenging, and as a consequence, 1/Q is still uncertain for a broad range of lithologies and experimental conditions. Moreover, the physics of elastic energy absorption (i.e., 1/Q) is often poorly constrained and understood. Here, we provide a series of measurements of seismic wave attenuation and dynamic Young’s modulus for dry and partially saturated Berea sandstone in the 1–100 Hz bandwidth and for confining pressure ranging between 0 and 20 MPa. We present systematic relationships between the frequency-dependent 1/Q and the liquid saturation, and the confining pressure. Data in the seismic bandwidth are compared to phenomenological models, ultrasonic elastic properties and theoretical models for wave-induced-fluid-flow (i.e., squirt-flow and patchy-saturation). The analysis suggests that the observed frequency-dependent attenuation is caused by wave-induced-fluid-flow but also that the physics behind this attenuation mechanism is not yet fully determined. We also show, that as predicted by wave-induced-fluid-flow theories, attenuation is strongly dependent on confining pressure. Our results can help to interpret data for near-surface geophysics to improve the imaging of the subsurface.
Triglyceride Induced Metabolic Inflammation: Potential Connection of Insulin Resistance and Recurrent Pregnancy Loss
Authors: Liu Yongjie , Du Mengyang , Gan Yuexin , Bao Shihua , Feng Liping , Zhang Jun
Published: April 2021

The underlying correlative mechanisms between Insulin resistance (IR) and recurrent pregnancy loss (RPL) in patients without polycystic ovarian syndrome (PCOS) remain inconclusive. To investigate the association between triglyceride (TG) levels, lymphocyte subsets, and IR in RPL patients without PCOS and obesity. Eighty-nine subjects with an unexplained RPL, independent of PCOS/obesity were enrolled in this study. A 75-g oral glucose tolerance test was performed on each subject with plasma tested for glucose and insulin. The fasting venous blood of all subjects was collected for routine clinical chemistry analysis. Lymphocyte subsets were analyzed by four-color flow cytometry. As a result, TG levels were significantly elevated in RPL patients with IR compared to those without IR. Pearson linear correlation model and receiver operating characteristic (ROC) curve analyses revealed a significant positive association between TG and HOMA-IR index value. In multiple logistic regression analysis, TG was significantly associated with the risk of hyperinsulinemia and increased CD3+CD4+/CD3+CD8+ ratio which was significantly negatively correlated with disposition index (DI30) and DI120, indicators for insulin sensitivity. In addition, DI30 and DI120 were significantly decreased in the higher CD3+CD4+/CD3+CD8+ group. Our findings showed that the elevated TG and altered immune responses in RPL patients with IR are independent of PCOS and obesity, and could be used as an indicator of IR in RPL patients. These results contribute to the understanding of the pathophysiology of IR in RPL for potential prevention and therapeutic targets.
Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy
Authors: Fallahi Poupak , Ferrari Silvia Martina , Elia Giusy , Ragusa Francesca , Paparo Sabrina Rosaria , Patrizio Armando , Camastra Stefania , Miccoli Mario , Cavallini Gabriella , Benvenga Salvatore , Antonelli Alessandro
Published: April 2021

Graves’ disease (GD) is an organ-specific autoimmune disorder of the thyroid, which is characterized by circulating TSH-receptor (TSH-R) stimulating antibodies (TSAb), leading to hyperthyroidism. Graves’ ophthalmopathy (GO) is one of GD extra-thyroidal manifestations associated with the presence of TSAb, and insulin-like growth factor-1 receptor (IGF-1R) autoantibodies, that interact with orbital fibroblasts. Cytokines are elevated in autoimmune (i.e., IL-18, IL-6) and non-autoimmune hyperthyroidism (i.e., TNF-α, IL-8, IL-6), and this could be associated with the chronic effects of thyroid hormone increase. A prevalent Th1-immune response (not related to the hyperthyroidism per se, but to the autoimmune process) is reported in the immune-pathogenesis of GD and GO; Th1-chemokines (CXCL9, CXCL10, CXCL11) and the (C-X-C)R3 receptor are crucial in this process. In patients with active GO, corticosteroids, or intravenous immunoglobulins, decrease inflammation and orbital congestion, and are considered first-line therapies. The more deepened understanding of GO pathophysiology has led to different immune-modulant treatments. Cytokines, TSH-R, and IGF-1R (on the surface of B and T lymphocytes, and fibroblasts), and chemokines implicated in the autoimmune process, are possible targets of novel therapies. Drugs that target cytokines (etanercept, tocilizumab, infliximab, adalimumab) have been tested in GO, with encouraging results. The chimeric monoclonal antibody directed against CD20, RTX, reduces B lymphocytes, cytokines and the released autoantibodies. A multicenter, randomized, placebo-controlled, double-masked trial has investigated the human monoclonal blocking antibody directed against IGF-1R, teprotumumab, reporting its effectiveness in GO. In conclusion, large, controlled and randomized studies are needed to evaluate new possible targeted therapies for GO.
Comparison of Pregnancy and Neonatal Outcomes of Single Frozen Blastocyst Transfer Between Letrozole-Induction and HRT Cycles in Patients With Abnormal Ovulation
Authors: Zhang Junwei , Li Zhen , Sun Lijun , Guan Yichun , Du Mingze
Published: April 2021

Background

The use of frozen embryo transfer (FET) cycles has dramatically risen. The optimal endometrial preparation method for women undergoing FET is of utmost importance to provide the optimal chances of pregnancy. For patients with abnormal ovulation in particular, there have been few studies on FET protocols; notably, most of these studies focus only on the clinical pregnancy rate or live birth rate (LBR) and pay little attention to the regimen’s safety for offspring.

Methods

It was a retrospective cohort study. First FET cycle with a single blastocyst from whole embryo frozen IVF/ICSI at the Reproductive Center of Third Affiliated Hospital of Zhengzhou University between January 2016 and January 2020. The LBR was the primary outcome of interest. The secondary outcome measures were miscarriage rate and offspring safety, including preterm birth, low birthweight (LBW), small-for-gestational age (SGA), macrosomia and large-for-gestational age (LGA).

Results

In total, 2782 FET cycles met the eligibility criteria for analysis. Additionally, there were 1178 singleton births from FET cycles. The clinical pregnancy rate was 58.4% in the L-FET group and 54.5% in the HRT group, with no statistical significance (P=.116). The miscarriage rate was higher in the HRT group than in the L-FET group (21.7% vs. 14.3%, P=.005). The LBR was significantly higher in the L-FET group than in the HRT group (49.6% vs. 41.7%, P=.001). Neonatal outcomes were similar between the two groups. After adjustments for confounding factors, the LBR was higher in the L-FET group (aOR 1.30, 95% CI 1.06-1.58). The rate of miscarriage was lower in the L-FET group (aOR 0.63, 95% CI 0.44-0.90).

Conclusion

For patients with abnormal ovulation, the L-FET regimen has a higher LBR and lower miscarriage rate than HRT. The neonatal outcomes were similar between the two groups.
Case Report: Extended Clinical Spectrum of the Neonatal Diabetes With Congenital Hypothyroidism Syndrome
Authors: Splittstoesser Vera , Vollbach Heike , Plamper Michaela , Garbe Werner , De Franco Elisa , Houghton Jayne A. L. , Dueker Gesche , Ganschow Rainer , Gohlke Bettina , Schreiner Felix
Published: April 2021

Background

Neonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLI-similar 3 coding gene GLIS3. Almost 20 patients have been reported to date, with significant phenotypic variability.

Case presentation

We describe a boy with a homozygous deletion (exons 5-9) in the GLIS3 gene, who presents novel clinical aspects not reported previously. In addition to neonatal diabetes, congenital hypothyroidism and other known multi-organ manifestations such as cholestasis and renal cysts, he suffered from hyporegenerative anemia during the first four months of life and presents megalocornea in the absence of elevated intraocular pressure. Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove. Considering reports on persistent fetal hemoglobin detected in a few children with GLIS3 mutations, the transient anemia seen in our patient may represent a further symptom associated with either the GLIS3 defect itself or, secondarily, micronutrient deficiency related to exocrine pancreatic deficiency or cholestasis.

Conclusions

Our report expands the phenotypic spectrum of patients with GLIS3 mutations and adds important information on the clinical course, highlighting the possible beneficial effects of pancreatic enzyme and antioxidative vitamin substitutions on characteristic NDH syndrome manifestations such as TSH resistance and cholestasis. We recommend to carefully screen infants with GLIS3 mutations for subtle biochemical signs of partial exocrine pancreatic deficiency or to discuss exploratory administration of pancreatic enzymes and antioxidative vitamins, even in case of good weight gain and fecal elastase concentrations in the low-to-normal range.
Optimisation of Mass Transport Parameters in a Polymer Electrolyte Membrane Electrolyser Using Factorial Design-of-Experiment
Authors: Majasan Jude O. , Cho Jason I. S. , Maier Maximilian , Shearing Paul R. , Brett Dan J. L.
Published: April 2021

Optimised mass transport is crucial for high current density operations in Polymer Electrolyte Membrane Water Electrolysers (PEMWEs). This study investigates the effect and interactions of mass transport parameters on the performance of a PEMWE using a 23 full-factorial Design-of-Experiments (DoE) approach with replication. The effects of anode flow-field design, anode porous transport layer (PTL) and water flow rate on the cell performance were studied. At 95% confidence level, the result shows that all three factors and their two-way interactions significantly affect the cell performance. Among them, the water flow rate showed the most significant contribution, followed by the interaction between the flow-field and the PTL. A regression model was developed to relate the cell performance and the mass transfer parameters. Results of analysis of variance (ANOVA), regression analysis and R2 test indicated good accuracy of the model. The best PEMWE cell performance was obtained with a parallel flow-field configuration, a small average pore diameter of PTL and high anode water flow rate. The DoE is shown to be a suitable method for investigating interactions and optimising the operating conditions to maximise PEMWE performance.
Time-Varying Impacts of Carbon Price Drivers in the EU ETS: A TVP-VAR Analysis
Authors: Li Peng , Zhang Hao , Yuan Yongna , Hao Aimin
Published: April 2021

This study analyzes the impacts of different drivers on the pricing of EU carbon futures in various periods by using the time-varying parameter vector autoregressive (TVP-VAR) model. The results indicate that: (1) The relationships between oil, gas, electricity, stock prices and carbon price have significant time-varying characteristics and those relationships have experienced an inversion in 2016. This might be due to the pressure of achieving the “EU 20-20-20” targets and the signing of the Paris Agreement as well as the fine-tuning of the European Union Emissions Trading Scheme (EU ETS). (2) The impacts of different drivers on carbon price are various. The carbon price is more sensitive to oil, gas, electricity prices as well as the stock price before the inversion in the short-term, while its response to changes in the stock price after the inversion is more obvious in the mid-long term. (3) After the signing of the Paris Agreement in the second quarter of 2016, the carbon price has a greater response to changes in its drivers. The oil price’s impact on carbon price became the most significant one among them.
Where Might We Find Ecologically Intact Communities?
Authors: Plumptre Andrew J. , Baisero Daniele , Belote R. Travis , Vázquez-Domínguez Ella , Faurby Soren , Jȩdrzejewski Włodzimierz , Kiara Henry , Kühl Hjalmar , Benítez-López Ana , Luna-Aranguré Carlos , Voigt Maria , Wich Serge , Wint William , Gallego-Zamorano Juan , Boyd Charlotte
Published: April 2021

Conservation efforts should target the few remaining areas of the world that represent outstanding examples of ecological integrity and aim to restore ecological integrity to a much broader area of the world with intact habitat and minimal species loss while this is still possible. There have been many assessments of “intactness” in recent years but most of these use measures of anthropogenic impact at a site, rather than faunal intactness or ecological integrity. This paper makes the first assessment of faunal intactness for the global terrestrial land surface and assesses how many ecoregions have sites that could qualify as Key Biodiversity Areas (KBAs – sites contributing significantly to the global persistence of biodiversity) based on their outstanding ecological integrity (under KBA Criterion C). Three datasets are combined on species loss at sites to create a new spatially explicit map of numbers of species extirpated. Based on this map it is estimated that no more than 2.9% of the land surface can be considered to be faunally intact. Additionally, using habitat/density distribution data for 15 large mammals we also make an initial assessment of areas where mammal densities are reduced, showing a further decrease in surface area to 2.8% of the land surface that could be considered functionally intact. Only 11% of the functionally intact areas that were identified are included within existing protected areas, and only 4% within existing KBAs triggered by other criteria. Our findings show that the number of ecoregions that could qualify as Criterion C KBAs could potentially increase land area up to 20% if their faunal composition was restored with the reintroduction of 1–5 species. Hence, if all necessary requirements are met in order to reintroduce species and regain faunal integrity, this will increase ecological integrity across much of the area where human impacts are low (human footprint ≤4). Focusing restoration efforts in these areas could significantly increase the area of the planet with full ecological integrity.
The GUL-1 Protein Binds Multiple RNAs Involved in Cell Wall Remodeling and Affects the MAK-1 Pathway in Neurospora crassa
Authors: Herold Inbal , Zolti Avihai , Garduño-Rosales Marisela , Wang Zheng , López-Giráldez Francesc , Mouriño-Pérez Rosa R. , Townsend Jeffrey P. , Ulitsky Igor , Yarden Oded
Published: April 2021

TheNeurospora crassaGUL-1 is part of the COT-1 pathway, which plays key roles in regulating polar hyphal growth and cell wall remodeling. We show that GUL-1 is a bona fide RNA-binding protein (RBP) that can associate with 828 “core” mRNA species. When cell wall integrity (CWI) is challenged, expression of over 25% of genomic RNA species are modulated (2,628 mRNAs, including the GUL-1 mRNA). GUL-1 binds mRNAs of genes related to translation, cell wall remodeling, circadian clock, endoplasmic reticulum (ER), as well as CWI and MAPK pathway components. GUL-1 interacts with over 100 different proteins, including stress-granule and P-body proteins, ER components and components of the MAPK, COT-1, and STRIPAK complexes. Several additional RBPs were also shown to physically interact with GUL-1. Under stress conditions, GUL-1 can localize to the ER and affect the CWI pathway—evident via altered phosphorylation levels of MAK-1, interaction withmak-1transcript, and involvement in the expression level of the transcription factoradv-1. We conclude that GUL-1 functions in multiple cellular processes, including the regulation of cell wall remodeling, via a mechanism associated with the MAK-1 pathway and stress-response.
KLF4, a Key Regulator of a Transitive Triplet, Acts on the TGF-β Signaling Pathway and Contributes to High-Altitude Adaptation of Tibetan Pigs
Authors: Wang Tao , Guo Yuanyuan , Liu Shengwei , Zhang Chaoxin , Cui Tongyan , Ding Kun , Wang Peng , Wang Xibiao , Wang Zhipeng
Published: April 2021

Tibetan pigs are native mammalian species on the Tibetan Plateau that have evolved distinct physiological traits that allow them to tolerate high-altitude hypoxic environments. However, the genetic mechanism underlying this adaptation remains elusive. Here, based on multitissue transcriptional data from high-altitude Tibetan pigs and low-altitude Rongchang pigs, we performed a weighted correlation network analysis (WGCNA) and identified key modules related to these tissues. Complex network analysis and bioinformatics analysis were integrated to identify key genes and three-node network motifs. We found that among the six tissues (muscle, liver, heart, spleen, kidneys, and lungs), lung tissue may be the key organs for Tibetan pigs to adapt to hypoxic environment. In the lung tissue of Tibetan pigs, we identified KLF4, BCL6B, EGR1, EPAS1, SMAD6, SMAD7, KDR, ATOH8, and CCN1 genes as potential regulators of hypoxia adaption. We found that KLF4 and EGR1 genes might simultaneously regulate the BCL6B gene, forming a KLF4–EGR1–BCL6B complex. This complex, dominated by KLF4, may enhance the hypoxia tolerance of Tibetan pigs by mediating the TGF-β signaling pathway. The complex may also affect the PI3K-Akt signaling pathway, which plays an important role in angiogenesis caused by hypoxia. Therefore, we postulate that the KLF4–EGR1–BCL6B complex may be beneficial for Tibetan pigs to survive better in the hypoxia environments. Although further molecular experiments and independent large-scale studies are needed to verify our findings, these findings may provide new details of the regulatory architecture of hypoxia-adaptive genes and are valuable for understanding the genetic mechanism of hypoxic adaptation in mammals.
Comparative Small RNA Profiling and Functional Exploration on Wheat With High- and Low-Cadmium Accumulation
Authors: Liu Yuqing , Wang Xudong , Yuan Leyi , Liu Yuxiang , Shen Tong , Zhang Yunhua
Published: April 2021

Cadmium is a toxic metal widely found in workplaces and plant soil because of extensive industrialization. Wheat is an important source of food generated from plant soil. The different responses of wheat against different omic levels of cadmium have been observed and widely studied worldwide. With the development of high-throughput sequencing, micro-level biological research has extended to the microRNA level. In this study, high-cadmium-accumulating wheat cultivars (Annong9267) and low-cadmium-accumulating wheat cultivars (Qian 102032) were used as experimental models. The two cultivars were treated by Cd for 2 h to explore the microRNA profiles in root and leaf tissues through small RNA sequencing. Important small RNAs, such as tae-miR9663-5p and tae-miR6201, and potential small RNA-mediated mechanisms associated with cadmium accumulation were identified by summarizing specific microRNA profiling patterns and their respective target genes. At the wheat roots and leaves, differentially expressed small RNAs related to cadmium accumulation in different plant tissues (roots or leaves) were identified, and functional enrichment analyses on target genes of differentially expressed miRNAs in low- and high-cadmium-accumulating wheat cultivars in different plant tissues (roots or leaves) obtained some known mature miRNAs and new miRNAs. The identified miRNA will be regarded as a potential screening biomarker for low-cadmium-accumulating wheat.
Three-in-One Simultaneous Extraction of Proteins, Metabolites and Lipids for Multi-Omics
Authors: Kang Jianing , David Lisa , Li Yangyang , Cang Jing , Chen Sixue
Published: April 2021

Elucidation of complex molecular networks requires integrative analysis of molecular features and changes at different levels of information flow and regulation. Accordingly, high throughput functional genomics tools such as transcriptomics, proteomics, metabolomics, and lipidomics have emerged to provide system-wide investigations. Unfortunately, analysis of different types of biomolecules requires specific sample extraction procedures in combination with specific analytical instrumentation. The most efficient extraction protocols often only cover a restricted type of biomolecules due to their different physicochemical properties. Therefore, several sets/aliquots of samples are needed for extracting different molecules. Here we adapted a biphasic fractionation method to extract proteins, metabolites, and lipids from the same sample (3-in-1) for liquid chromatography-tandem mass spectrometry (LC-MS/MS) multi-omics. To demonstrate utility of the improved method, we used bacteria-primed Arabidopsis leaves to generate multi-omics datasets from the same sample. In total, we were able to analyze 1849 proteins, 1967 metabolites, and 424 lipid species in single samples. The molecules cover a wide range of biological and molecular processes, and allow quantitative analyses of different molecules and pathways. Our results have shown the clear advantages of the multi-omics method, including sample conservation, high reproducibility, and tight correlation between different types of biomolecules.
Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions
Authors: Li Yueran , Deshpande Pooja , Hertzman Rebecca J. , Palubinsky Amy M. , Gibson Andrew , Phillips Elizabeth J.
Published: April 2021

Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.
Immunohistochemical Expression of Five Protein Combinations Revealed as Prognostic Markers in Asian Oral Cancer
Authors: Wang Hui-Ching , Chiang Chien-Jung , Liu Ta-Chih , Wu Chun-Chieh , Chen Yi-Ting , Chang Jan-Gowth , Shieh Grace S.
Published: April 2021

Oral squamous cell carcinoma (OSCC) has a high mortality rate (∼50%), and the 5-year overall survival rate is not optimal. Cyto- and histopathological examination of cancer tissues is the main strategy for diagnosis and treatment. In the present study, we aimed to uncover immunohistochemical (IHC) markers for prognosis in Asian OSCC. From the collected 742 synthetic lethal gene pairs (of various cancer types), we first filtered genes relevant to OSCC, performed 29 IHC stains at different cellular portions and combined these IHC stains into 398 distinct pairs. Next, we identified novel IHC prognostic markers in OSCC among Taiwanese population, from the single and paired IHC staining by univariate Cox regression analysis. Increased nuclear expression of RB1 [RB1(N)↑], CDH3(C)↑-STK17A(N)↑ and FLNA(C)↑-KRAS(C)↑were associated with survival, but not independent of tumor stage, where C and N denote cytoplasm and nucleus, respectively. Furthermore, multivariate Cox regression analyses revealed that CSNK1E(C)↓-SHC1(N)↓ (P = 5.9 × 10–5; recommended for clinical use), BRCA1(N)↓-SHC1(N)↓ (P = 0.030), CSNK1E(C)↓-RB1(N)↑ (P = 0.045), [CSNK1E(C)-SHC1(N), FLNA(C)-KRAS(C)] (P = 0.000, rounded to three decimal places) and [BRCA1(N)-SHC1(N), FLNA(C)-KRAS(C)] (P = 0.020) were significant factors of poor prognosis, independent of lymph node metastasis, stage and alcohol consumption. An external dataset from The Cancer Genome Atlas HNSCC cohort confirmed that CDH3↑-STK17A↑ was a significant predictor of poor survival. Our approach identified prognostic markers with components involved in different pathways and revealed IHC marker pairs while neither single IHC was a marker, thus it improved the current state-of-the-art for identification of IHC markers.
Identification of a MicroRNA Signature Associated With Lymph Node Metastasis in Endometrial Endometrioid Cancer
Authors: Fu Kaiyou , Li Yanrui , Song Jianyuan , Cai Wangyu , Wu Wei , Ye Xiaohang , Xu Jian
Published: April 2021

Background

Lymph node metastasis (LNM) is an important prognostic factor in endometrial cancer. Anomalous microRNAs (miRNAs) are associated with cell functions and are becoming a powerful tool to characterize malignant transformation and metastasis. The aim of this study was to construct a miRNA signature to predict LNM in endometrial endometrioid carcinoma (EEC).

Method

Candidate target miRNAs related to LNM in EEC were screened by three methods including differentially expressed miRNAs (DEmiRs), weighted gene co-expression network analysis (WGCNA), and decision tree algorithms. Samples were randomly divided into the training and validation cohorts. A miRNA signature was built using a logistic regression model and was evaluated by the area under the curve (AUC) of receiver operating characteristic curve (ROC) and decision curve analysis (DCA). We also conducted pathway enrichment analysis and miRNA–gene regulatory network to look for potential genes and pathways engaged in LNM progression. Survival analysis was performed, and the miRNAs were tested whether they expressed differently in another independent GEO database.

Result

Thirty-one candidate miRNAs were screened and a final 15-miRNA signature was constructed by logistic regression. The model showed good calibration in the training and validation cohorts, with AUC of 0.824 (95% CI, 0.739–0.912) and 0.821 (95% CI, 0.691–0.925), respectively. The DCA demonstrated the miRNA signature was clinically useful. Hub miRNAs in signature seemed to contribute to EEC progression via mitotic cell cycle, cellular protein modification process, and molecular function. MiR-34c was statistically significant in survival that a higher expression of miR-34c indicated a higher survival time. MiR-34c-3p, miR-34c-5p, and miR-34b-5p were expressed differentially in GSE75968.

Conclusion

The miRNA signature could work as a noninvasive method to detect LNM in EEC with a high prediction accuracy. In addition, miR-34c cluster may be a key biomarker referring LNM in endometrial cancer.
Novel Intronic Mutations Introduce Pseudoexons in DMD That Cause Muscular Dystrophy in Patients
Authors: Lu Xinguo , Han Chunxi , Mai Jiahui , Jiang Xianping , Liao Jianxiang , Hou Yanqi , Cui Di
Published: April 2021

Background: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are two subtypes of muscular dystrophy diseases caused by pathogenic mutations in the DMD gene. Until now, more than 4,600 disease-causing mutations in DMD have been reported. However, only 33 mutations were deep intronic, cases with this type of mutations were limited.

Methods: In this study, we used a combination of complementary DNA (cDNA) and target DNA sequencing analysis in addition to conventional whole-exome sequencing (WES).

Results: Three novel hemizygous mutations IVS11 + 17811C > G (c.1331 + 17811C > G), IVS21 + 3252A > G (c.2803 + 3252A > G) and IVS40 + 362A > G (c.5739 + 362A > G) were identified in DMD patients, while a reported hemizygous mutation IVS62-285A > G (c.9225-285A > G) was found in the BMD patient. These DMD mutations lead to pseudoexon insertions, causing the generation of truncated and dysfunctional dystrophin.

Conclusion: This study defines three novel and one reported intronic mutations, which can result in DMD/BMD. We also emphasize the need to combine WES and cDNA-based methods to detect the variant in the very large DMD gene in which the mutational spectrum is complex.
Pedigree Analysis of Warmblood Horses Participating in Competitions for Young Horses
Authors: Próchniak Tomasz , Kasperek Kornel , Knaga Sebastian , Rozempolska-Rucińska Iwona , Batkowska Justyna , Drabik Kamil , Ziȩba Grzegorz
Published: April 2021

The aim of the study was to characterize the population structure and assess the genetic diversity of warmblood horses used in the show jumping discipline. Pedigree data of 1,048 horses participating in the Polish Championships for Young Horses were analyzed. The pedigree of these animals included 12 863 individuals. The study consisted in analysis of the pedigree structure of the horses and characterization of the homozygosity and genetic diversity in the population. It was found that pedigree completeness and depth were sufficient for reliable assessment of the genetic diversity in the analyzed population. Although the average inbreeding coefficient exhibited at an acceptable level (approx. 1.01%), the increasing percentage of inbred animals seems disturbing. The results have shown that modern sport horses are derived from a small number of high-quality sires whose offspring were intensively used for breeding—bottleneck effect. In consequence, a greater part of the genetic variation reduction was observed in the non-founder generations. Given the changes in the studied population, the level of inbreeding in modern sport horses should be monitored, and pedigree data should be effectively used in selection for mating.