bluuebunny/crossref_metadata_2025 huggingface dataset:
Which Gridded Population Data Product Is Better? Evidences from Mainland Southeast Asia (MSEA)
Authors: Yin Xu , Li Peng , Feng Zhiming , Yang Yanzhao , You Zhen , Xiao Chiwei
Published: October 2021

The release of global gridded population datasets, including the Gridded Population of the World (GPW), Global Human Settlement Population Grid (GHS-POP), WorldPop, and LandScan, have greatly facilitated cross-comparison for ongoing research related to anthropogenic impacts. However, little attention is paid to the consistency and discrepancy of these gridded products in the regions with rapid changes in local population, e.g., Mainland Southeast Asia (MSEA), where the countries have experienced fast population growth since the 1950s. This awkward situation is unsurprisingly aggravated because of national scarce demographics and incomplete census counts, which further limits their appropriate usage. Thus, comparative analyses of them become the priority of their better application. Here, the consistency and discrepancy of the four common global gridded population datasets were cross-compared by combing the 2015 provincial population statistics (census and yearbooks) via error-comparison based statistical methods. The results showed that: (1) the LandScan performs the best both in spatial accuracy and estimated errors, then followed by the WorldPop, GHS-POP, and GPW in MSEA. (2) Provincial differences in estimated errors indicated that the LandScan better reveals the spatial pattern of population density in Thailand and Vietnam, while the WorldPop performs slightly better in Myanmar and Laos, and both fit well in Cambodia. (3) Substantial errors among the four gridded datasets normally occur in the provincial units with larger population density (over 610 persons/km2) and a rapid population growth rate (greater than 1.54%), respectively. The new findings in MSEA indicated that future usage of these datasets should pay attention to the estimated population in the areas characterized by high population density and rapid population growth.
Geospatial Semantics Analysis of the Qinghai–Tibetan Plateau Based on Microblog Short Texts
Authors: Xu Jun , Hu Lei
Published: October 2021

Place descriptions record qualitative information related to places and their spatial relationships; thus, the geospatial semantics of a place can be extracted from place descriptions. In this study, geotagged microblog short texts recorded in 2017 from the Tibetan Autonomous Region and Qinghai Province were used to extract the place semantics of the Qinghai–Tibetan Plateau (QTP). ERNIE, a language representation model enhanced by knowledge, was employed to extract thematic topics from the microblog short texts, which were then geolocated and used to analyze the place semantics of the QTP. Considering the large number of microblogs published by tourists in both Qinghai and Tibet, we separated the texts into four datasets according to the user, i.e., local users in Tibet, tourists in Tibet, local users in Qinghai, and tourists in Qinghai, to explore the place semantics of the QTP from different perspectives. The results revealed clear spatial variability in the thematic topics. Tibet is characterized by travel- and scenery-related language, whereas Qinghai is characterized by emotion, work, and beauty salon-related language. The human cognition of place semantics differs between local residents and tourists, and with a greater difference between the two in Tibet than in Qinghai. Weibo texts also indicate that local residents and tourists are concerned with different aspects of the same thematic topics. The cities on the QTP can be classified into three groups according to their geospatial semantic components, i.e., tourism-focused, life-focused, and religion-focused cities.
Distinct Mechanisms Account for In Vitro Activation and Sensitization of TRPV1 by the Porphyrin Hemin
Authors: Palmaers Natalie E. , Wiegand Steffen B. , Herzog Christine , Echtermeyer Frank G. , Eberhardt Mirjam J. , Leffler Andreas
Published: October 2021

TRPV1 mediates pain occurring during sickling episodes in sickle cell disease (SCD). We examined if hemin, a porphyrin released during intravascular hemolysis modulates TRPV1. Calcium imaging and patch clamp were employed to examine effects of hemin on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1 and TRPA1. Hemin induced a concentration-dependent calcium influx in DRG neurons which was abolished by the unspecific TRP-channel inhibitor ruthenium red. The selective TRPV1-inhibitor BCTC or genetic deletion of TRPV1 only marginally impaired hemin-induced calcium influx in DRG neurons. While hTRPV1 expressed in HEK293 cells mediated a hemin-induced calcium influx which was blocked by BCTC, patch clamp recordings only showed potentiated proton- and heat-evoked currents. This effect was abolished by the PKC-inhibitor chelerythrine chloride and in protein kinase C (PKC)-insensitive TRPV1-mutants. Hemin-induced calcium influx through TRPV1 was only partly PKC-sensitive, but it was abolished by the reducing agent dithiothreitol (DTT). In contrast, hemin-induced potentiation of inward currents was not reduced by DTT. Hemin also induced a redox-dependent calcium influx, but not inward currents on hTRPA1. Our data suggest that hemin induces a PKC-mediated sensitization of TRPV1. However, it also acts as a photosensitizer when exposed to UVA-light used for calcium imaging. The resulting activation of redox-sensitive ion channels such as TRPV1 and TRPA1 may be an in vitro artifact with limited physiological relevance.
Research Progress of Mitochondrial Mechanism in NLRP3 Inflammasome Activation and Exercise Regulation of NLRP3 Inflammasome
Authors: Zhang Tan , Ding Shuzhe , Wang Ru
Published: October 2021

NLRP3 is an important pattern recognition receptor in the innate immune system, and its activation induces a large number of pro-inflammatory cytokines, IL-1β and IL-18 which are involved in the development of various diseases. In recent years, it has been suggested that mitochondria are the platform for NLRP3 inflammasome activation. Additionally, exercise is considered as an important intervention strategy to mediate the innate immune responses. Generally, chronic moderate-intensity endurance training, resistance training and high-intensity interval training inhibit NLRP3 inflammasome activation in response to various pathological factors. In contrast, acute exercise activates NLRP3 inflammasome. However, the mechanisms by which exercise regulates NLRP3 inflammasome activation are largely unclear. Therefore, the mechanism of NLRP3 inflammasome activation is discussed mainly from the perspective of mitochondria in this review. Moreover, the effect and potential mechanism of exercise on NLRP3 inflammasome are explored, hoping to provide new target for relevant research.
Stem Cell and Macrophage Roles in Skeletal Muscle Regenerative Medicine
Authors: Scala Pasqualina , Rehak Laura , Giudice Valentina , Ciaglia Elena , Puca Annibale Alessandro , Selleri Carmine , Della Porta Giovanna , Maffulli Nicola
Published: October 2021

In severe muscle injury, skeletal muscle tissue structure and functionality can be repaired through the involvement of several cell types, such as muscle stem cells, and innate immune responses. However, the exact mechanisms behind muscle tissue regeneration, homeostasis, and plasticity are still under investigation, and the discovery of pathways and cell types involved in muscle repair can open the way for novel therapeutic approaches, such as cell-based therapies involving stem cells and peripheral blood mononucleate cells. Indeed, peripheral cell infusions are a new therapy for muscle healing, likely because autologous peripheral blood infusion at the site of injury might enhance innate immune responses, especially those driven by macrophages. In this review, we summarize current knowledge on functions of stem cells and macrophages in skeletal muscle repairs and their roles as components of a promising cell-based therapies for muscle repair and regeneration.
Comprehensive Analysis of Five Phyllostachys edulis SQUA-like Genes and Their Potential Functions in Flower Development
Authors: Zhang Yuting , Zhang Junhong , Song Minyan , Lin Xinchun , Tong Zaikang , Ding Mingquan
Published: October 2021

Bamboo is one of the most important non-timber forest resources worldwide. It has considerable economic value and unique flowering characteristics. The long juvenile phase in bamboo and unpredictable flowering time limit breeding and genetic improvement and seriously affect the productivity and application of bamboo forests. Members of SQUA-like subfamily genes play an essential role in controlling flowering time and floral organ identity. A comprehensive study was conducted to explain the functions of five SQUA-like subfamily genes in Phyllostachys edulis. Expression analysis revealed that all PeSQUAs have higher transcript levels in the reproductive period than in the juvenile phase. However, PeSQUAs showed divergent expression patterns during inflorescence development. The protein–protein interaction (PPI) patterns among PeSQUAs and other MADS-box members were analyzed by yeast two-hybrid (Y2H) experiments. Consistent with amino acid sequence similarity and phylogenetic analysis, the PPI patterns clustered into two groups. PeMADS2, 13, and 41 interacted with multiple PeMADS proteins, whereas PeMADS3 and 28 hardly interacted with other proteins. Based on our results, PeSQUA might possess different functions by forming protein complexes with other MADS-box proteins at different flowering stages. Furthermore, we chose PeMADS2 for functional analysis. Ectopic expression of PeMADS2 in Arabidopsis and rice caused early flowering, and abnormal phenotype was observed in transgenic Arabidopsis lines. RNA-seq analysis indicated that PeMADS2 integrated multiple pathways regulating floral transition to trigger early flowering time in rice. This function might be due to the interaction between PeMADS2 and homologous in rice. Therefore, we concluded that the five SQUA-like genes showed functional conservation and divergence based on sequence differences and were involved in floral transitions by forming protein complexes in P. edulis. The MADS-box protein complex model obtained in the current study will provide crucial insights into the molecular mechanisms of bamboo’s unique flowering characteristics.
Calmodulin as Ca2+-Dependent Interactor of FTO Dioxygenase
Authors: Marcinkowski Michał , Pilžys Tomaš , Garbicz Damian , Piwowarski Jan , Przygońska Kaja , Winiewska-Szajewska Maria , Ferenc Karolina , Skorobogatov Oleksandr , Poznański Jarosław , Grzesiuk Elżbieta
Published: October 2021

FTO is an N6-methyladenosine demethylase removing methyl groups from nucleic acids. Several studies indicate the creation of FTO complexes with other proteins. Here, we looked for regulatory proteins recognizing parts of the FTO dioxygenase region. In the Calmodulin (CaM) Target Database, we found the FTO C-domain potentially binding CaM, and we proved this finding experimentally. The interaction was Ca2+-dependent but independent on FTO phosphorylation. We found that FTO–CaM interaction essentially influences calcium-binding loops in CaM, indicating the presence of two peptide populations—exchanging as CaM alone and differently, suggesting that only one part of CaM interacts with FTO, and the other one reminds free. The modeling of FTO–CaM interaction showed its stable structure when the half of the CaM molecule saturated with Ca2+ interacts with the FTO C-domain, whereas the other part is disconnected. The presented data indicate calmodulin as a new FTO interactor and support engagement of the FTO protein in calcium signaling pathways.
Characterization of the Human Eccrine Sweat Proteome—A Focus on the Biological Variability of Individual Sweat Protein Profiles
Authors: Burat Bastien , Reynaerts Audrey , Baiwir Dominique , Fléron Maximilien , Eppe Gauthier , Leal Teresinha , Mazzucchelli Gabriel
Published: October 2021

The potential of eccrine sweat as a bio-fluid of interest for diagnosis and personalized therapy has not yet been fully evaluated, due to the lack of in-depth sweat characterization studies. Thanks to recent developments in omics, together with the availability of accredited sweat collection methods, the analysis of human sweat may now be envisioned as a standardized, non-invasive test for individualized monitoring and personalized medicine. Here, we characterized individual sweat samples, collected from 28 healthy adult volunteers under the most standardized sampling methodology, by applying optimized shotgun proteomics. The thorough characterization of the sweat proteome allowed the identification of 983 unique proteins from which 344 were identified across all samples. Annotation-wise, the study of the sweat proteome unveiled the over-representation of newly addressed actin dynamics, oxidative stress and proteasome-related functions, in addition to well-described proteolysis and anti-microbial immunity. The sweat proteome composition correlated with the inter-individual variability of sweat secretion parameters. In addition, both gender-exclusive proteins and gender-specific protein abundances were highlighted, despite the high similarity between human female and male sweat proteomes. In conclusion, standardized sample collection coupled with optimized shotgun proteomics significantly improved the depth of sweat proteome coverage, far beyond previous similar studies. The identified proteins were involved in many diverse biological processes and molecular functions, indicating the potential of this bio-fluid as a valuable biological matrix for further studies. Addressing sweat variability, our results prove the proteomic profiling of sweat to be a promising bio-fluid analysis for individualized, non-invasive monitoring and personalized medicine.
Utilization of Pharmacological Ascorbate to Enhance Hydrogen Peroxide-Mediated Radiosensitivity in Cancer Therapy
Authors: Mehdi Zain , Petronek Michael S. , Stolwijk Jeffrey M. , Mapuskar Kranti A. , Kalen Amanda L. , Buettner Garry R. , Cullen Joseph J. , Spitz Douglas R. , Buatti John M. , Allen Bryan G.
Published: October 2021

Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer in cancer. The results of these studies are promising. This review summarizes data on pharmacological ascorbate (1) as a safe and efficacious adjuvant to cancer therapy; (2) as a selective radiosensitizer of cancer via a mechanism involving hydrogen peroxide; and (3) as a radioprotector in normal tissues. Additionally, we present new data demonstrating the ability of pharmacological ascorbate to enhance radiation-induced DNA damage in glioblastoma cells, facilitating cancer cell death. We propose that pharmacological ascorbate may be a general radiosensitizer in cancer therapy and simultaneously a radioprotector of normal tissue.
Agroinfiltration Mediated Scalable Transient Gene Expression in Genome Edited Crop Plants
Authors: Kaur Maninder , Manchanda Pooja , Kalia Anu , Ahmed Farah K. , Nepovimova Eugenie , Kuca Kamil , Abd-Elsalam Kamel A.
Published: October 2021

Agrobacterium-mediated transformation is one of the most commonly used genetic transformation method that involves transfer of foreign genes into target plants. Agroinfiltration, an Agrobacterium-based transient approach and the breakthrough discovery of CRISPR/Cas9 holds trending stature to perform targeted and efficient genome editing (GE). The predominant feature of agroinfiltration is the abolishment of Transfer-DNA (T-DNA) integration event to ensure fewer biosafety and regulatory issues besides showcasing the capability to perform transcription and translation efficiently, hence providing a large picture through pilot-scale experiment via transient approach. The direct delivery of recombinant agrobacteria through this approach carrying CRISPR/Cas cassette to knockout the expression of the target gene in the intercellular tissue spaces by physical or vacuum infiltration can simplify the targeted site modification. This review aims to provide information on Agrobacterium-mediated transformation and implementation of agroinfiltration with GE to widen the horizon of targeted genome editing before a stable genome editing approach. This will ease the screening of numerous functions of genes in different plant species with wider applicability in future.
At a Crossroads to Cancer: How p53-Induced Cell Fate Decisions Secure Genome Integrity
Authors: Rizzotto Dario , Englmaier Lukas , Villunger Andreas
Published: October 2021

P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may be cell-type- and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview of multiple ways that p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems, is critical to understand the cell-type-specific cell fate induced by p53 upon its activation in order to resolve the remaining mystery of its tumor-suppressive function.
A Survey of Autoencoder Algorithms to Pave the Diagnosis of Rare Diseases
Authors: Pratella David , Ait-El-Mkadem Saadi Samira , Bannwarth Sylvie , Paquis-Fluckinger Véronique , Bottini Silvia
Published: October 2021

Rare diseases (RDs) concern a broad range of disorders and can result from various origins. For a long time, the scientific community was unaware of RDs. Impressive progress has already been made for certain RDs; however, due to the lack of sufficient knowledge, many patients are not diagnosed. Nowadays, the advances in high-throughput sequencing technologies such as whole genome sequencing, single-cell and others, have boosted the understanding of RDs. To extract biological meaning using the data generated by these methods, different analysis techniques have been proposed, including machine learning algorithms. These methods have recently proven to be valuable in the medical field. Among such approaches, unsupervised learning methods via neural networks including autoencoders (AEs) or variational autoencoders (VAEs) have shown promising performances with applications on various type of data and in different contexts, from cancer to healthy patient tissues. In this review, we discuss how AEs and VAEs have been used in biomedical settings. Specifically, we discuss their current applications and the improvements achieved in diagnostic and survival of patients. We focus on the applications in the field of RDs, and we discuss how the employment of AEs and VAEs would enhance RD understanding and diagnosis.
Diets with Higher ω-6/ω-3 Ratios Show Differences in Ceramides and Fatty Acid Levels Accompanied by Increased Amyloid-Beta in the Brains of Male APP/PS1 Transgenic Mice
Authors: Ordóñez-Gutiérrez Lara , Fábrias Gemma , Casas Josefina , Wandosell Francisco
Published: October 2021

Senile plaque formation as a consequence of amyloid-β peptide (Aβ) aggregation constitutes one of the main hallmarks of Alzheimer’s disease (AD). This pathology is characterized by synaptic alterations and cognitive impairment. In order to either prevent or revert it, different therapeutic approaches have been proposed, and some of them are focused on diet modification. Modification of the ω-6/ω-3 fatty acids (FA) ratio in diets has been proven to affect Aβ production and senile plaque formation in the hippocampus and cortex of female transgenic (TG) mice. In these diets, linoleic acid is the main contribution of ω-6 FA, whereas alpha-linoleic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA) are the contributors of ω-3 FA. In the present work, we have explored the effect of ω-6/ω-3 ratio modifications in the diets of male double-transgenic APPswe/PS1ΔE9 (AD model) and wild-type mice (WT). Amyloid burden in the hippocampus increased in parallel with the increase in dietary ω-6/ω-3 ratio in TG male mice. In addition, there was a modification in the brain lipid profile proportional to the ω-6/ω-3 ratio of the diet. In particular, the higher the ω-6/ω-3 ratio, the lower the ceramides and higher the FAs, particularly docosatetraenoic acid. Modifications to the cortex lipid profile was mostly similar between TG and WT mice, except for gangliosides (higher levels in TG mice) and some ceramide species (lower levels in TG mice).
Identification of Binding Proteins for TSC22D1 Family Proteins Using Mass Spectrometry
Authors: Kamimura Ryouta , Uchida Daisuke , Kanno Shin-ichiro , Shiraishi Ryo , Hyodo Toshiki , Sawatani Yuta , Shimura Michiko , Hasegawa Tomonori , Tsubura-Okubo Maki , Yaguchi Erika , Komiyama Yuske , Fukumoto Chonji , Izumi Sayaka , Fujita Atsushi , Wakui Takahiro , Kawamata Hitoshi
Published: October 2021

TSC-22 (TGF-β stimulated clone-22) has been reported to induce differentiation, growth inhibition, and apoptosis in various cells. TSC-22 is a member of a family in which many proteins are produced from four different family genes. TSC-22 (corresponding to TSC22D1-2) is composed of 144 amino acids translated from a short variant mRNA of the TSC22D1 gene. In this study, we attempted to determine the intracellular localizations of the TSC22D1 family proteins (TSC22D1-1, TSC-22 (TSC22D1-2), and TSC22(86) (TSC22D1-3)) and identify the binding proteins for TSC22D1 family proteins by mass spectrometry. We determined that TSC22D1-1 was mostly localized in the nucleus, TSC-22 (TSC22D1-2) was localized in the cytoplasm, mainly in the mitochondria and translocated from the cytoplasm to the nucleus after DNA damage, and TSC22(86) (TSC22D1-3) was localized in both the cytoplasm and nucleus. We identified multiple candidates of binding proteins for TSC22D1 family proteins in in vitro pull-down assays and in vivo binding assays. Histone H1 bound to TSC-22 (TSC22D1-2) or TSC22(86) (TSC22D1-3) in the nucleus. Guanine nucleotide-binding protein-like 3 (GNL3), which is also known as nucleostemin, bound to TSC-22 (TSC22D1-2) in the nucleus. Further investigation of the interaction of the candidate binding proteins with TSC22D1 family proteins would clarify the biological roles of TSC22D1 family proteins in several cell systems.
Immunohistochemical Evaluation of Periodontal Regeneration Using a Porous Collagen Scaffold
Authors: Imber Jean-Claude , Roccuzzo Andrea , Stähli Alexandra , Saulacic Nikola , Deschner James , Sculean Anton , Bosshardt Dieter Daniel
Published: October 2021

(1) Aim: To immunohistochemically evaluate the effect of a volume-stable collagen scaffold (VCMX) on periodontal regeneration. (2) Methods: In eight beagle dogs, acute two-wall intrabony defects were treated with open flap debridement either with VCMX (test) or without (control). After 12 weeks, eight defects out of four animals were processed for paraffin histology and immunohistochemistry. (3) Results: All defects (four test + four control) revealed periodontal regeneration with cementum and bone formation. VCMX remnants were integrated in bone, periodontal ligament (PDL), and cementum. No differences in immunohistochemical labeling patterns were observed between test and control sites. New bone and cementum were labeled for bone sialoprotein, while the regenerated PDL was labeled for periostin and collagen type 1. Cytokeratin-positive epithelial cell rests of Malassez were detected in 50% of the defects. The regenerated PDL demonstrated a larger blood vessel area at the test (14.48% ± 3.52%) than at control sites (8.04% ± 1.85%, p = 0.0007). The number of blood vessels was higher in the regenerated PDL (test + control) compared to the pristine one (p = 0.012). The cell proliferative index was not statistically significantly different in pristine and regenerated PDL. (4) Conclusions: The data suggest a positive effect of VCMX on angiogenesis and an equally high cell turnover in the regenerated and pristine PDL. This VCMX supported periodontal regeneration in intrabony defects.
Primary Immune Thrombocytopenia and Essential Thrombocythemia: So Different and yet Somehow Similar—Cases Series and a Review of the Literature
Authors: Sobas Marta , Podolak-Dawidziak Maria , Lewandowski Krzysztof , Bator Michał , Wróbel Tomasz
Published: October 2021

This article collects several published cases in which immune thrombocytopenic purpura (ITP) is followed by essential thrombocythemia (ET) and vice versa. This surprising clinical condition is possible, but very rare and difficult to diagnose and manage. We have made an attempt to analyse the possible causes of the sequential appearance of ITP and ET taking into consideration the following: alteration of the thrombopoietin (TPO) receptor, the role of autoimmunity and inflammation, and cytokine modulation. A better understanding of these interactions may provide opportunities to determine predisposing factors and aid in finding new treatment modalities both for ITP and ET patients.
Quantitative Estimate Index for Early-Stage Screening of Compounds Targeting Protein-Protein Interactions
Authors: Kosugi Takatsugu , Ohue Masahito
Published: October 2021

Drug-likeness quantification is useful for screening drug candidates. Quantitative estimates of drug-likeness (QED) are commonly used to assess quantitative drug efficacy but are not suitable for screening compounds targeting protein-protein interactions (PPIs), which have recently gained attention. Therefore, we developed a quantitative estimate index for compounds targeting PPIs (QEPPI), specifically for early-stage screening of PPI-targeting compounds. QEPPI is an extension of the QED method for PPI-targeting drugs that models physicochemical properties based on the information available for drugs/compounds, specifically those reported to act on PPIs. FDA-approved drugs and compounds in iPPI-DB, which comprise PPI inhibitors and stabilizers, were evaluated using QEPPI. The results showed that QEPPI is more suitable than QED for early screening of PPI-targeting compounds. QEPPI was also considered an extended concept of the “Rule-of-Four” (RO4), a PPI inhibitor index. We evaluated the discriminatory performance of QEPPI and RO4 for datasets of PPI-target compounds and FDA-approved drugs using F-score and other indices. The F-scores of RO4 and QEPPI were 0.451 and 0.501, respectively. QEPPI showed better performance and enabled quantification of drug-likeness for early-stage PPI drug discovery. Hence, it can be used as an initial filter to efficiently screen PPI-targeting compounds.
Insight into the Binding and Hydrolytic Preferences of hNudt16 Based on Nucleotide Diphosphate Substrates
Authors: Chrabąszczewska Magdalena , Winiewska-Szajewska Maria , Ostrowska Natalia , Bojarska Elżbieta , Stępiński Janusz , Mancewicz Łukasz , Łukaszewicz Maciej , Trylska Joanna , Taube Michał , Kozak Maciej , Darżynkiewicz Edward , Grzela Renata
Published: October 2021

Nudt16 is a member of the NUDIX family of hydrolases that show specificity towards substrates consisting of a nucleoside diphosphate linked to another moiety X. Several substrates for hNudt16 and various possible biological functions have been reported. However, some of these reports contradict each other and studies comparing the substrate specificity of the hNudt16 protein are limited. Therefore, we quantitatively compared the affinity of hNudt16 towards a set of previously published substrates, as well as identified novel potential substrates. Here, we show that hNudt16 has the highest affinity towards IDP and GppG, with Kd below 100 nM. Other tested ligands exhibited a weaker affinity of several orders of magnitude. Among the investigated compounds, only IDP, GppG, m7GppG, AppA, dpCoA, and NADH were hydrolyzed by hNudt16 with a strong substrate preference for inosine or guanosine containing compounds. A new identified substrate for hNudt16, GppG, which binds the enzyme with an affinity comparable to that of IDP, suggests another potential regulatory role of this protein. Molecular docking of hNudt16-ligand binding inside the hNudt16 pocket revealed two binding modes for representative substrates. Nucleobase stabilization by Π stacking interactions with His24 has been associated with strong binding of hNudt16 substrates.
Ferroptosis: At the Crossroad of Gemcitabine Resistance and Tumorigenesis in Pancreatic Cancer
Authors: Yang Jianhui , Xu Jin , Zhang Bo , Tan Zhen , Meng Qingcai , Hua Jie , Liu Jiang , Wang Wei , Shi Si , Yu Xianjun , Liang Chen
Published: October 2021

The overall five-year survival rate of pancreatic cancer has hardly changed in the past few decades (less than 10%) because of resistance to all known therapies, including chemotherapeutic drugs. In the past few decades, gemcitabine has been at the forefront of treatment for pancreatic ductal adenocarcinoma, but more strategies to combat drug resistance need to be explored. One promising possibility is ferroptosis, a form of a nonapoptotic cell death that depends on intracellular iron and occurs through the accumulation of lipid reactive oxygen species, which are significant in drug resistance. In this article, we reviewed gemcitabine-resistance mechanisms; assessed the relationship among ferroptosis, tumorigenesis and gemcitabine resistance, and explored a new treatment method for pancreatic cancer.
Bisphenol a Induces Autophagy Defects and AIF-Dependent Apoptosis via HO-1 and AMPK to Degenerate N2a Neurons
Authors: Lee Ching-Tien , Hsieh Cheng-Fang , Wang Jiz-Yuh
Published: October 2021

Bisphenol A (BPA) is an environmental contaminant widely suspected to be a neurological toxicant. Epidemiological studies have demonstrated close links between BPA exposure, pathogenetic brain degeneration, and altered neurobehaviors, considering BPA a risk factor for cognitive dysfunction. However, the mechanisms of BPA resulting in neurodegeneration remain unclear. Herein, cultured N2a neurons were subjected to BPA treatment, and neurotoxicity was assessed using neuronal viability and differentiation assays. Signaling cascades related to cellular self-degradation were also evaluated. BPA decreased cell viability and axon outgrowth (e.g., by down-regulating MAP2 and GAP43), thus confirming its role as a neurotoxicant. BPA induced neurotoxicity by down-regulating Bcl-2 and initiating apoptosis and autophagy flux inhibition (featured by nuclear translocation of apoptosis-inducing factor (AIF), light chain 3B (LC3B) aggregation, and p62 accumulation). Both heme oxygenase (HO)-1 and AMP-activated protein kinase (AMPK) up-regulated/activated by BPA mediated the molecular signalings involved in apoptosis and autophagy. HO-1 inhibition or AIF silencing effectively reduced BPA-induced neuronal death. Although BPA elicited intracellular oxygen free radical production, ROS scavenger NAC exerted no effect against BPA insults. These results suggest that BPA induces N2a neurotoxicity characterized by AIF-dependent apoptosis and p62-related autophagy defects via HO-1 up-regulation and AMPK activation, thereby resulting in neuronal degeneration.
Identification, Molecular Characteristic, and Expression Analysis of PIFs Related to Chlorophyll Metabolism in Tea Plant (Camellia sinensis)
Authors: Zhang Xiangna , Xiong Ligui , Luo Yong , Wen Beibei , Wang Kunbo , Liu Zhonghua , Huang Jian-an , Li Juan
Published: October 2021

The phytochrome-interacting factors (PIFs) proteins belong to the subfamily of basic helix–loop–helix (bHLH) transcription factors and play important roles in chloroplast development and chlorophyll biosynthesis. Currently, knowledge about the PIF gene family in Camellia sinensis remains very limited. In this study, seven PIF members were identified in the C. sinensis genome and named based on homology with AtPIF genes in Arabidopsis thaliana. All C. sinensis PIF (CsPIF) proteins have both the conserved active PHYB binding (APB) and bHLH domains. Phylogenetic analysis revealed that CsPIFs were clustered into four groups—PIF1, PIF3, PIF7, and PIF8—and most CsPIFs were clustered in pairs with their corresponding orthologs in Populus tremula. CsPIF members in the same group tended to display uniform or similar exon–intron distribution patterns and motif compositions. CsPIF genes were differentially expressed in C. sinensis with various leaf colors and strongly correlated with the expression of genes involved in the chlorophyll metabolism pathway. Promoter analysis of structural genes related to chlorophyll metabolism found DNA-binding sites of PIFs were abundant in the promoter regions. Protein–protein interaction networks of CsPIFs demonstrated a close association with phytochrome, PIF4, HY5, TOC1, COP1, and PTAC12 proteins. Additionally, subcellular localization and transcriptional activity analysis suggested that CsPIF3b was nuclear localized protein and possessed transcriptional activity. We also found that CsPIF3b could activate the transcription of CsHEMA and CsPOR in Nicotiana benthamiana leaves. This work provides comprehensive research of CsPIFs and would be helpful to further promote the regulation mechanism of PIF on chlorophyll metabolism in C. sinensis.
Selective Activation of Endoplasmic Reticulum Stress by Reactive-Oxygen-Species-Mediated Ochratoxin A-Induced Apoptosis in Tubular Epithelial Cells
Authors: Khoi Chong-Sun , Lin Yu-Wen , Chen Jia-Huang , Liu Biing-Hui , Lin Tzu-Yu , Hung Kuan-Yu , Chiang Chih-Kang
Published: October 2021

Ochratoxin A (OTA), one of the major food-borne mycotoxins, impacts the health of humans and livestock by contaminating food and feed. However, the underlying mechanism of OTA nephrotoxicity remains unknown. This study demonstrated that OTA induced apoptosis through selective endoplasmic reticulum (ER) stress activation in human renal proximal tubular cells (HK-2). OTA increased ER-stress-related JNK and precursor caspase-4 cleavage apoptotic pathways. Further study revealed that OTA increased reactive oxygen species (ROS) levels, and N-acetyl cysteine (NAC) could reduce OTA-induced JNK-related apoptosis and ROS levels in HK-2 cells. Our results demonstrate that OTA induced ER stress-related apoptosis through an ROS-mediated pathway. This study provides new evidence to clarify the mechanism of OTA-induced nephrotoxicity.
Biocompatibility and Cytotoxicity of Gold Nanoparticles: Recent Advances in Methodologies and Regulations
Authors: Kus-Liśkiewicz Małgorzata , Fickers Patrick , Ben Tahar Imen
Published: October 2021

Recent advances in the synthesis of metal nanoparticles (MeNPs), and more specifically gold nanoparticles (AuNPs), have led to tremendous expansion of their potential applications in different fields, ranging from healthcare research to microelectronics and food packaging. The properties of functionalised MeNPs can be fine-tuned depending on their final application, and subsequently, these properties can strongly modulate their biological effects. In this review, we will firstly focus on the impact of MeNP characteristics (particularly of gold nanoparticles, AuNPs) such as shape, size, and aggregation on their biological activities. Moreover, we will detail different in vitro and in vivo assays to be performed when cytotoxicity and biocompatibility must be assessed. Due to the complex nature of nanomaterials, conflicting studies have led to different views on their safety, and it is clear that the definition of a standard biosafety label for AuNPs is difficult. In fact, AuNPs’ biocompatibility is strongly affected by the nanoparticles’ intrinsic characteristics, biological target, and methodology employed to evaluate their toxicity. In the last part of this review, the current legislation and requirements established by regulatory authorities, defining the main guidelines and standards to characterise new nanomaterials, will also be discussed, as this aspect has not been reviewed recently. It is clear that the lack of well-established safety regulations based on reliable, robust, and universal methodologies has hampered the development of MeNP applications in the healthcare field. Henceforth, the international community must make an effort to adopt specific and standard protocols for characterisation of these products.
A Retrospective Cohort Study of Clinical Factors Associated with Transitions of Care among COVID-19 Patients
Authors: Swearingen Dennis , Boverman Gregory , Tgavalekos Kristen , Noren David P. , Ravindranath Shreyas , Ghosh Erina , Xu Minnan , Wondrely Lisa , Thompson Pam , Cowden J. David , Antonescu Corneliu
Published: October 2021

Coronavirus Disease 2019 (COVID-19) is an international health crisis. In this article, we report on patient characteristics associated with care transitions of: 1) hospital admission from the emergency department (ED) and 2) escalation to the intensive care unit (ICU). Analysis of data from the electronic medical record (EMR) was performed for patients with COVID-19 seen in the ED of a large Western U.S. Health System from April to August of 2020, totaling 10,079 encounters. Of these, 5172 resulted in admission as an inpatient within 72 h. Inpatient encounters (n = 6079) were also considered for patients with positive COVID-19 test results, of which 970 resulted in a transfer to the ICU or in-hospital mortality. Laboratory results, vital signs, symptoms, and comorbidities were investigated for each of these care transitions. Different top risk factors were found, but two factors common to hospital admission and ICU transfer were respiratory rate and the need for oxygen support. Comorbidities common to both settings were cerebrovascular disease and congestive heart failure. Regarding laboratory results, the neutrophil-to-lymphocyte ratio was associated with transitions to higher levels of care, along with the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT).
Why Did All Patients with Atrial Fibrillation and High Risk of Stroke Not Receive Oral Anticoagulants? Results of the Polish Atrial Fibrillation (POL-AF) Registry
Authors: Szpotowicz Anna , Gorczyca Iwona , Jelonek Olga , Uziębło-Życzkowska Beata , Maciorowska Małgorzata , Wójcik Maciej , Błaszczyk Robert , Kapłon-Cieślicka Agnieszka , Gawałko Monika , Budnik Monika , Tokarek Tomasz , Rajtar-Salwa Renata , Bil Jacek , Wojewódzki Michał , Bednarski Janusz , Bakuła-Ostalska Elwira , Tomaszuk-Kazberuk Anna , Szyszkowska Anna , Wełnicki Marcin , Mamcarz Artur , Krzciuk Małgorzata , Wożakowska-Kapłon Beata
Published: October 2021

Background: Most atrial fibrillation (AF) patients are at high risk of thromboembolic, and the use of oral anticoagulants (OACs) is advised in such cases. The aim of the study was to evaluate the frequency at which OACs were used in patients with AF and high risk thromboembolic complications, and identify factors that result in OACs not being used in the researched group of patients. Methods: The prospective, multicenter and non-interventional POL-AF registry is a study that includes AF patients from ten Polish cardiology centers. They were consecutively hospitalized between January and December of 2019. All the patients in the study were of high stroke risk. Results: A total of 3614 patients with AF and high stroke risk were included. Among the total study population, 91.5% received OAC therapy; antiplatelet therapy was prescribed for 3.7% of patients, heparin for 2.7%, and 2.1% of patients did not receive any stroke prevention therapy. Independent predictors of no OAC prescription were intracranial bleeding (OR 0.15, 95%CI 0.07–0.35, p < 0.001), gastrointestinal bleeding (OR 0.25, 95%CI 0.17–0.37, p < 0.001), cancer (OR 0.37, 95%CI 0.25–0.55, p < 0.001), hospitalization due to acute coronary syndrome (OR 0.48, 95%CI 0.33–0.69, p < 0.001), and anemia (OR 0.62, 95%CI 0.48–0.81, p < 0.001). Conclusions: Most AF patients with a high thromboembolic risk received OACs. The factors predisposing a lack of OAC use in these patients were conditions that significantly increased the risk of bleeding complications.
Current Status of Endoscopic Biliary Drainage in Patients with Distal Malignant Biliary Obstruction
Authors: Tanisaka Yuki , Mizuide Masafumi , Fujita Akashi , Ogawa Tomoya , Katsuda Hiromune , Saito Youichi , Miyaguchi Kazuya , Jinushi Ryuhei , Terada Rie , Nakano Yuya , Tashima Tomoaki , Mashimo Yumi , Ryozawa Shomei
Published: October 2021

Distal malignant biliary obstruction is caused by various malignant diseases that require biliary drainage. In patients with operable situations, preoperative biliary drainage is required to control jaundice and cholangitis until surgery. In view of tract seeding, endoscopic biliary drainage is the first choice. Since neoadjuvant therapies are being developed, the time to surgery is increasing, especially in pancreatic cancer cases. Therefore, it requires long stent patency. Recently, preoperative biliary drainage using self-expandable metal stents has been reported as a useful modality to secure long stent patency. In patients with unresectable distal malignant biliary obstruction, self-expandable metal stent is the first choice for maintaining long stent patency. Although there are many comparison studies between a covered and an uncovered self-expandable metal stent, their use is still controversial. Recently, endoscopic ultrasound-guided biliary drainage has been performed as an alternative treatment. The clinical success and stent patency are favorable. We should take into consideration that both endoscopic retrograde cholangiopancreatography-guided biliary drainage and endoscopic ultrasound-guided biliary drainage have advantages and disadvantages and chose the drainage method depending on the patient’s situation or the expertise of the endoscopist. Here, we discuss the current status of endoscopic biliary drainage in patients with distal malignant biliary obstruction.
NOTCH3 rs1043996 Polymorphism Is Associated with the Occurrence of Alcoholic Liver Cirrhosis Independently of PNPLA3 and TM6SF2 Polymorphisms
Authors: Bainrauch Ana , Šisl Dino , Markotić Antonio , Ostojić Ana , Gašparov Slavko , Bralić Lang Valerija , Kovačić Nataša , Grčević Danka , Mrzljak Anna , Kelava Tomislav
Published: October 2021

Alcoholic liver cirrhosis (ALC) is the most common indication for liver transplantation (LT) in Croatia and presents a risk factor for the development of hepatocellular carcinoma (HCC). However, genetic susceptibility has not yet been systematically studied. We aimed to investigate the contribution of the risk polymorphisms PNPLA3 rs738409, EGF rs4444903, TM6SF2 rs58542926, MTHFR rs1801133, previously identified in other populations and, additionally, the contribution of Notch-related polymorphisms (NOTCH1 rs3124591, NOTCH3 rs1043996 and rs1044116, NOTCH4 rs422951). The study included 401 patients. The ALC group consisted of 260 LT candidates, 128 of whom had histopathologically confirmed HCC, and 132 of whom were without HCC. The control group included 141 patients without liver disease. Genotyping was performed by PCR using Taqman assays. The patients’ susceptibility to ALC was significantly associated with PNPLA3 rs738409, TM6SF2 rs58542926, and NOTCH3 rs1043996 polymorphisms. These polymorphisms remained significantly associated with ALC occurrence in a logistic regression model, even after additional model adjustment for sex and age. Cirrhotic patients with the PNPLA3 GG genotype demonstrated higher activity of ALT aminotransferases than patients with CC or CG genotypes. The susceptibility to the development of HCC in ALC was significantly associated with PNPLA3 rs738409 and EGF rs4444903 polymorphisms, and logistic regression confirmed these polymorphisms as independent predictors.
Infantile Hemangiomas: An Update on Pathogenesis and Treatment
Authors: Kowalska Małgorzata , Dębek Wojciech , Matuszczak Ewa
Published: October 2021

Infantile hemangiomas are the most common benign vascular tumors in infancy. This review includes an update on the current knowledge on pathogenesis, a discussion on indications for treatment, and a review of the mechanisms underlying the different treatment methods. Although most infantile hemangiomas require only active observation because of their natural course, which results in involution, about 10% present with complications that require immediate treatment. The basic treatment includes systemic and topical options. In cases of insufficient response or rebound growth, other forms of treatment should be considered. In some cases, combined therapy might be initiated.
Esthetic Assessment Succeeding Anterior Atrophic Maxilla Augmentation with Cancellous Bone-Block Allograft and Late Restoration Loading
Authors: Naishlos Sarit , Zenziper Eran , Zelikman Helena , Nissan Joseph , Mizrahi Shaked , Chaushu Gavriel , Matalon Shlomo , Chaushu Liat
Published: October 2021

Background: Various conditions may lead to bony deficiency in the anterior maxilla. The present study evaluated esthetic (PES—pink esthetic score and WES—white esthetic score) results after augmentation of the anterior atrophic maxilla using cancellous bone-block allograft followed by implant placement and late (conventional) loading. Methods: Cohort study that included 33 patients with missing teeth in the upper anterior region characterized by extensive bone loss. Allogeneic cancellous bone-blocks were used for augmentation. Six months later, a dental implant was inserted. After a waiting time of an additional six-months, implant exposure and reconstruction were performed. The mean follow-up period was 62.93 ± 17.37 months (range 19–82 months). Results: The mean value of PES/WES was 17.8 ± 2.78. All patients had a PES/WES value above 12 (threshold value defined as clinically acceptable esthetics). The mean value of PES was 9.0 ± 1.79 and the mean value of WES was 8.8 ±1.84. Conclusions: Bone augmentation of the anterior atrophic maxilla using cancellous block-allograft and late loading supports achievement of a predictable esthetic result with long-term stability of soft and hard tissues around implant-supported reconstructions.