bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the Buffering Effects of Greenery on the Adverse Emotional, Mental and Behavioral Health during the Pandemic Period
Authors: Contini Paolo , Di Nuovo Santo , Sinatra Maria , Osmanaj Elisabeta , Monacis Lucia
Published: July 2022

In light of the adverse emotional, mental and behavioral outcomes caused by the pandemic period, this research analyzed the associations between emotional distress and poor health outcomes and the buffering effects of greenery on these outcomes. An online cross-sectional survey between June–November 2021 was distributed among 1314 young Italian adults. Bivariate associations and multivariate regression analyses were applied to the data. Findings showed that emotional distress was positively related to poor mental health outcomes and to some of the unhealthy behaviors. In addition, green pathways differently impacted on health: the indoor features confirmed buffering effects on adverse emotional and mental health responses, whereas the outdoor features played no salutogenic role. In conclusion, whereas the outbreak period of the pandemic has led to the rediscovering/reinforcement of the attachment to nature to cope with negative affective states, the successive waves characterized by selected limitations and new living rules of social adaptation may have brought about a reduced affinity toward nature. Target interventions in terms of biophilic design for indoor environmental sustainability are needed in order to increase the innate human–nature connection and thus to promote public health.
Earthquake Response for Students with Different Severe Degrees of Disabilities: An Investigation of the Special Education Classes in Primary Schools in Taipei
Authors: Chen Yung-Fang , Ma Kuo-Chen , Lee Mei-Hsiang , Chuang Mo-Hsiung
Published: July 2022

Taipei has been ranked as the most vulnerable city to a wider combination of risks. Although the Special Education Law addresses the consideration of disaster preparedness for students with disabilities enrolling in Special Education Schools, more attention needs to be given to the far larger number of students with disabilities enrolling in normal schools. These schools need to consider the care for students with different types and severe degrees of disabilities. The aim of the research is to investigate challenges of earthquake preparation and response for students with different severe degrees of disabilities who enrol in the special education classes in general primary schools. The objectives of the research include the following: (1) investigating the challenges and requirements for support of students with different severe degrees of disabilities; (2) examining the need and support for students with different degrees of disabilities during the earthquake response process; and (3) exploring the best practice in the curriculum building for students with different severity of disabilities. The purposive sampling was used to select four primary schools in Taipei as participant groups in the research. The research team used semi-structured interviews to interview eight participants: one special education class teacher and one administrator of each school were invited. Findings include the following: (1) ensuring the appropriate design of physical environment for earthquake response in schools, including rapid response, evacuation, and assembly points for students with different severe degrees of disabilities; (2) proposing suitable staff to student ratio to be planned for the response phase; (3) identifying the appropriate individualised curriculum and learning objectives to suit students with different severe degrees of disabilities.
Achieving Differential Privacy Publishing of Location-Based Statistical Data Using Grid Clustering
Authors: Yan Yan , Sun Zichao , Mahmood Adnan , Xu Fei , Dong Zhuoyue , Sheng Quan Z.
Published: July 2022

Statistical partitioning and publishing is commonly used in location-based big data services to address queries such as the number of points of interest, available vehicles, traffic flows, infected patients, etc., within a certain range. Adding noise perturbation to the location-based statistical data according to the differential privacy model can reduce various risks caused by location privacy leakage while keeping the statistical characteristics of the published data. The traditional statistical partitioning and publishing methods realize the decomposition and indexing of 2D space from top to bottom. However, they can easily cause the over-partitioning or under-partitioning phenomenon, and therefore need multiple times of data scan. This paper proposes a grid clustering and differential privacy protection method for location-based statistical big data publishing scenarios. We implement location-based big data statistics in units of equal-sized grids and perform density classification on uniformly distributed grids by discrete wavelet transform. A bottom-up grid clustering algorithm is designed to perform on the blank and the uniform grids of the same density level based on neighborhood similarity. The Laplacian noise is incorporated into the clustering results according to the differential privacy model to form the published statistics. Experimental comparison of the real-world datasets manifests that the grid clustering and differential privacy publishing method proposed in this paper is superior to other existing partition publishing methods in terms of range querying accuracy and algorithm operating efficiency.
Collagen-Based Osteogenic Nanocoating of Microrough Titanium Surfaces
Authors: Behrens Christina , Kauffmann Philipp , von Hahn Nikolaus , Schirmer Uwe , Liefeith Klaus , Schliephake Henning
Published: July 2022

The aim of the present study was to develop a collagen/heparin-based multilayer coating on titanium surfaces for retarded release of recombinant human bone morphogenic protein 2 (rhBMP2) to enhance the osteogenic activity of implant surfaces. Polyelectrolyte multilayer (PEM) coatings were constructed on sandblasted/acid-etched surfaces of titanium discs using heparin and collagen. PEM films of ten double layers were produced and overlayed with 200 µL of a rhBMP2 solution containing 15 µg rhBMP2. Subsequently, cross-linking of heparin molecules was performed using EDC/NHS chemistry to immobilize the incorporated rhBMP2. Release characteristics for 3 weeks, induction of Alkaline Phosphatase (ALP) in C2C12 cells and proliferation of human mesenchymal stem cells (hMSCs) were evaluated to analyze the osteogenic capacity of the surface. The coating incorporated 10.5 µg rhBMP2 on average per disc and did not change the surface morphology. The release profile showed a delivery of 14.5% of the incorporated growth factor during the first 24 h with a decline towards the end of the observation period with a total release of 31.3%. Cross-linking reduced the release with an almost complete suppression at 100% cross-linking. Alkaline Phosphatase was significantly increased on day 1 and day 21, indicating that the growth factor bound in the coating remains active and available after 3 weeks. Proliferation of hMSCs was significantly enhanced by the non-cross-linked PEM coating. Nanocoating using collagen/heparin-based PEMs can incorporate clinically relevant amounts of rhBMP2 on titanium surfaces with a retarded release and a sustained enhancement of osteogenic activity without changing the surface morphology.
MicroRNAs as Potential Biomarkers in the Differential Diagnosis of Lipomatous Tumors and Their Mimics
Authors: Tan Hui Min , Cheng He , Tang Yew Chung , Leong Sai Mun , Teo Poh Yin , Lee Chi Kuen , Lee Victor Kwan Min , Hue Susan Swee-Shan
Published: July 2022

Adipocytic tumors are the most common subtype of soft tissue tumors. In current clinical practice, distinguishing benign lipomas from well-differentiated liposarcomas (WDLPS), as well as dedifferentiated liposarcomas (DDLPS) from their morphologic mimics, remains a significant diagnostic challenge. This is especially so when examining small biopsy samples and without the aid of additional ancillary tests. Recognizing the important role that microRNAs (miRNAs) play in tumorigenesis and their potential utility in tumor classification, we analyzed routine clinical tissue samples of benign and malignant lipomatous tumors, as well as other sarcoma mimics, to identify distinguishing miRNA-based signatures that can aid in the differential diagnosis of these entities. We discovered a 6-miRNA signature that separated lipomas from WDLPS with high confidence (AUC of 0.963), as well as a separate 6-miRNA signature that distinguished DDLPS from their more aggressive histologic mimics (AUC of 0.740). Functional enrichment analysis unveiled possible mechanistic involvement of these predictive miRNAs in adipocytic cancer-related biological processes and pathways such as PI3K/AKT/mTOR and MAPK signaling, further supporting the relevance of these miRNAs as biomarkers for adipocytic tumors. Our results demonstrate that miRNA expression profiling may potentially be used as an adjunctive tool for the diagnosis of benign and malignant adipocytic tumors. Further validation studies are warranted.
Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy
Authors: Tringali Cristina , Giussani Paola
Published: July 2022

Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.
Characterization of MicroRNAs Associated with Reproduction in the Brown Planthopper, Nilaparvata lugens
Authors: Wang Ni , Zhang Chao , Chen Min , Shi Zheyi , Zhou Ying , Shi Xiaoxiao , Zhou Wenwu , Zhu Zengrong
Published: July 2022

Insects have a robust capacity to produce offspring for propagation, and the reproductive events of female insects have been achieved at the molecular and physiological levels via regulatory gene pathways. However, the roles of MicroRNAs (miRNAs) in the reproductive development of the brown planthopper (BPH), Nilaparvata lugens, remain largely unexplored. To understand the roles of miRNAs in reproductive development, miRNAs were identified by Solexa sequencing in short-winged (SW) female adults of BPH. Small RNA libraries derived from three developmental phases (1 day, 3 days, and 5 days after emergence) were constructed and sequenced. We identified 905 miRNAs, including 263 known and 642 novel miRNAs. Among them, a total of 43 miRNAs were differentially expressed in the three developmental phases, and 14,568 putative targets for 43 differentially expressed miRNAs (DEMs) were predicted by TargetScan and miRanda. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the predicted miRNA targets illustrated the putative roles for these DEMs in reproduction. The progress events were annotated, including oogenesis, lipid biosynthetic process, and related pathways such as apoptosis, ABC transporters, and amino acid metabolism. Four highly abundant DEMs (miR-9a-5p, miR-34-5p, miR-275-3p, and miR-317-3p) were further screened, and miR-34-5p was confirmed to be involved in the regulation of reproduction. Overexpression of miR-34-5p via injecting its mimics reduced fecundity and decreased Vg expression. Moreover, target genes prediction for miR-34-5p showed they might be involved in 20E signaling cascades, apoptosis, and gonadal development, including hormone receptor 4 (HR4), caspase-1 (Cp-1), and spermatogenesis-associated protein 20 (SPATA20). These findings provide a valuable resource for future studies on the role of miRNAs in BPH reproductive development.
Extracellular Vesicles Inhibit the Response of Pancreatic Ductal Adenocarcinoma Cells to Gemcitabine and TRAIL Treatment
Authors: Rimmer Ella , Rashid Sadaf , Kraev Igor , Miralles Francesc , Elia Androulla
Published: July 2022

Pancreatic ductal adenocarcinoma remains an aggressive cancer with a low 5-year survival rate. Although gemcitabine has been a standard treatment for advanced pancreatic cancer, patients often develop resistance to this therapeutic. We have previously shown that treating pancreatic cancer cells in vitro with a combination of gemcitabine and the cytokine TRAIL significantly reduced both cell viability and survival. The data presented here demonstrate that this response to treatment is inhibited when cells are incubated with a conditioned medium derived from untreated cells. We show that this inhibition is specifically mediated by extracellular vesicles present in the conditioned medium, as seen by a significant decrease in apoptosis. Additionally, we further demonstrate that this effect can be reversed in the presence of GW4869, an inhibitor of exosome biogenesis and release. These results show that pancreatic cancer cell-derived extracellular vesicles can confer resistance to treatment with gemcitabine and TRAIL. The implications of these findings suggest that removal of EVs during treatment can improve the response of cells to gemcitabine and TRAIL treatment in vitro.
Antibacterial Peptide NP-6 Affects Staphylococcus aureus by Multiple Modes of Action
Authors: Hou Xiaoyan , Li Jianlong , Tang Huaqiao , Li Qingye , Shen Guanghui , Li Shanshan , Chen Anjun , Peng Zixin , Zhang Yu , Li Chaowei , Zhang Zhiqing
Published: July 2022

Our previous study extracted and identified an antibacterial peptide that was named NP-6. Herein, we investigated the physicochemical properties of NP-6, and elucidated the mechanisms underlying its antimicrobial activity against Staphylococcus aureus. The results showed that the hemolysis activity of NP-6 was 2.39 ± 0.13%, lower than Nisin A (3.91 ± 0.43%) at the same concentration (512 µg/mL). Negligible cytotoxicity towards RAW264.7 cells was found when the concentration of NP-6 was lower than 512 µg/mL. In addition, it could keep most of its activity in fetal bovine serum. Moreover, transmission electron microscopy, confocal laser scanning microscopy, and flow cytometry results showed that NP-6 can destroy the integrity of the bacterial cell membrane and increase the membrane permeability. Meanwhile, NP-6 had binding activity with bacterial DNA and RNA in vitro and strongly inhibited the intracellular β-galactosidase activity of S. aureus. Our findings suggest that NP-6 could be a promising candidate against S. aureus.
Modelling the Human Blood–Brain Barrier in Huntington Disease
Authors: Vignone Domenico , Gonzalez Paz Odalys , Fini Ivan , Cellucci Antonella , Auciello Giulio , Battista Maria Rosaria , Gloaguen Isabelle , Fortuni Silvia , Cariulo Cristina , Khetarpal Vinod , Dominguez Celia , Muñoz-Sanjuán Ignacio , Di Marco Annalise
Published: July 2022

While blood–brain barrier (BBB) dysfunction has been described in neurological disorders, including Huntington’s disease (HD), it is not known if endothelial cells themselves are functionally compromised when promoting BBB dysfunction. Furthermore, the underlying mechanisms of BBB dysfunction remain elusive given the limitations with mouse models and post mortem tissue to identify primary deficits. We established models of BBB and undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived brain-like microvascular endothelial cells (iBMEC) from HD patients or unaffected controls. We demonstrated that HD-iBMECs have abnormalities in barrier properties, as well as in specific BBB functions such as receptor-mediated transcytosis.
Unkeito Suppresses RANKL-Mediated Osteoclastogenesis via the Blimp1–Bcl6 and NF-κB Signaling Pathways and Enhancing Osteoclast Apoptosis
Authors: Fang Ke , Murakami Yuki , Kanda Seiji , Shimono Takaki , Dang Anh Tuan , Ono Mitsuaki , Nishiyama Toshimasa
Published: July 2022

Osteoporosis is a common bone disease, particularly in menopausal women. Herein, we screened four Kampo medicines (Unkeito (UKT), Kamishoyosan (KSS), Kamikihito (KKT), and Ninjinyoeito (NYT)), frequently used to treat menopausal syndromes, for their effects on receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation in RAW 264 cells. Considering that UKT exhibited the most potent effect, we examined its effect on RANKL-induced osteoclastogenesis, the induction of osteoclast apoptosis, and the mechanisms underlying its effects. UKT inhibits RANKL-induced osteoclast differentiation in the early stage and decreases osteoclast-related genes, including tartrate-resistant acid phosphatase (Trap), dendritic cell-specific transmembrane protein (Dcstamp), matrix metalloproteinase-9 (Mmp9), and cathepsin K (Ctsk). Specifically, UKT inhibits the nuclear factor of activated T cells 1 (NFATc1), which is essential for osteoclastogenesis. UKT increases Bcl6, which antagonizes NFATc1 and Dc-stamp, thereby blocking the progression of osteoclasts to maturation. UKT also decreased nuclear translocation by downregulating the activity of p65/NF-κB. In addition, UKT enhances mononuclear osteoclast apoptosis via activation of caspase-3. Herein, we demonstrate that UKT suppresses RANKL-mediated osteoclastogenesis via the Blimp1–Bcl6 and NF-κB signaling pathways and enhances mononuclear osteoclast apoptosis. Furthermore, UKT prevents bone loss in OVX mice. Thus, UKT might be a potential therapeutic agent for postmenopausal osteoporosis.
The Regenerative Effects of c-Met Agonistic Antibodies in Vocal Fold Atrophy
Authors: Choi Hyunsu , Yu Seung-Shin , Choi Jiwon , Kim Choung-Soo
Published: July 2022

Background: Atrophy of the vocal folds and the accompanying glottic insufficiency affect the quality of life. Although growth factors have been used to treat muscle atrophy, their effectiveness is limited by their short half-life. Methods: In total, 15 rabbits and 24 rats were used for the study. The right recurrent laryngeal nerves of all animals were transected. One month following nerve transection, PBS (PBS group), rHGF (HGF group), or a c-Met agonistic antibody (c-Met group) was injected into the paralyzed vocal folds. The larynges of the rabbits were harvested from each group for histologic examination and subjected to PCR analysis. Results: Cross-sectional areas (CSAs) of thyroarytenoid muscles were evaluated. The c-Met group had increased CSAs compared to the PBS and HGF groups, but there were no significant differences compared to normal controls. The expression levels of myogenesis-related genes were evaluated three weeks after the injection. The expression levels of myosin heavy chain IIa were significantly increased in the PBS group, while the expression levels of MyoD were increased in the c-Met group. Conclusions: The c-Met agonistic antibody showed promise for promoting muscle regeneration in a vocal fold palsy model.
Expanding the Spectrum of Oculocutaneous Albinism: Does Isolated Foveal Hypoplasia Really Exist?
Authors: Rocca Camilla , Tiberi Lucia , Bargiacchi Sara , Palazzo Viviana , Landini Samuela , Marziali Elisa , Caputo Roberto , Tinelli Francesca , Marchi Viviana , Benedetto Alessandro , Pagliazzi Angelica , Bacci Giacomo Maria
Published: July 2022

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.
Poly(ADP-ribose) Polymerase 1 Mediates Rab5 Inactivation after DNA Damage
Authors: Mashimo Masato , Morozumi Akane , Nobeyama Akari , Kanzaki Misato , Negi Shigeru , Kato Jiro , Moss Joel , Nomura Atsuo , Fujii Takeshi
Published: July 2022

Parthanatos is programmed cell death mediated by poly(ADP-ribose) polymerase 1 (PARP1) after DNA damage. PARP1 acts by catalyzing the transfer of poly(ADP-ribose) (PAR) polymers to various nuclear proteins. PAR is subsequently cleaved, generating protein-free PAR polymers, which are translocated to the cytoplasm where they associate with cytoplasmic and mitochondrial proteins, altering their functions and leading to cell death. Proteomic studies revealed that several proteins involved in endocytosis bind PAR after PARP1 activation, suggesting endocytosis may be affected by the parthanatos process. Endocytosis is a mechanism for cellular uptake of membrane-impermeant nutrients. Rab5, a small G-protein, is associated with the plasma membrane and early endosomes. Once activated by binding GTP, Rab5 recruits its effectors to early endosomes and regulates their fusion. Here, we report that after DNA damage, PARP1-generated PAR binds to Rab5, suppressing its activity. As a result, Rab5 is dissociated from endosomal vesicles, inhibiting the uptake of membrane-impermeant nutrients. This PARP1-dependent inhibition of nutrient uptake leads to cell starvation and death. It thus appears that this mechanism may represent a novel parthanatos pathway.
Role of Histone Deacetylases in T-Cell Development and Function
Authors: Pieniawska Monika , Iżykowska Katarzyna
Published: July 2022

Histone deacetylases (HDACs) are a group of enzymes called “epigenetic erasers”. They remove the acetyl group from histones changing the condensation state of chromatin, leading to epigenetic modification of gene expression and various downstream effects. Eighteen HDACs have been identified and grouped into four classes. The role of HDACs in T-cells has been extensively studied, and it has been proven that many of them are important players in T-cell development and function. In this review, we present the current state of knowledge on the role of HDACs in the early stages of T-cell development but also in the functioning of mature lymphocytes on the periphery, including activation, cytokine production, and metabolism regulation.
Laparoscopic Sleeve Gastrectomy in Patients with Severe Obesity Restores Adaptive Responses Leading to Nonalcoholic Steatohepatitis
Authors: Cabré Noemí , Luciano-Mateo Fedra , Chapski Douglas J. , Baiges-Gaya Gerard , Fernández-Arroyo Salvador , Hernández-Aguilera Anna , Castañé Helena , Rodríguez-Tomàs Elisabet , París Marta , Sabench Fàtima , Castillo Daniel Del , del Bas Josep M. , Tomé Mercedes , Bodineau Clément , Sola-García Alejandro , López-Miranda José , Martín-Montalvo Alejandro , Durán Raúl V. , Vondriska Thomas M. , Rosa-Garrido Manuel , Camps Jordi , Menéndez Javier A. , Joven Jorge
Published: July 2022

The surgically induced remission of liver disease represents a model to investigate the signalling processes that trigger the development of nonalcoholic steatohepatitis with the aim of identifying novel therapeutic targets. We recruited patients with severe obesity with or without nonalcoholic steatohepatitis and obtained liver and plasma samples before and after laparoscopic sleeve gastrectomy for immunoblotting, immunocytochemical, metabolomic, transcriptomic and epigenetic analyses. Functional studies were performed in HepG2 cells and primary hepatocytes. Surgery was associated with a decrease in the inflammatory response and revealed the role of mitogen-activated protein kinases. Nonalcoholic steatohepatitis was associated with an increased glutaminolysis-induced production of α-ketoglutarate and the hyperactivation of mammalian target of rapamycin complex 1. These changes were crucial for adenosine monophosphate-activated protein kinase/mammalian target of rapamycin-driven pathways that modulated hepatocyte survival by coordinating apoptosis and autophagy and affected methylation-related epigenomic remodelling enzymes. Hepatic transcriptome signatures and differentially methylated genomic regions distinguished patients with and without steatohepatitis. Our results suggest that the increased glutaminolysis-induced α-ketoglutarate production and the mammalian target of rapamycin complex 1 dysregulation play a crucial role in the inefficient adaptive responses leading to steatohepatitis in obesity.
Upregulation of Mineralocorticoid Receptor Contributes to Development of Salt-Sensitive Hypertension after Ischemia–Reperfusion Injury in Rats
Authors: Matsumoto Takumi , Doi Shigehiro , Nakashima Ayumu , Ike Takeshi , Sasaki Kensuke , Masaki Takao
Published: July 2022

The ischemia–reperfusion injury (IRI) of rat kidneys is used as a model of acute kidney injury. Salt-sensitive hypertension occurs in rats after IRI, and the distal nephrons play important roles in the development of this condition. We investigated the role of the mineralocorticoid receptor (MR) in the progression of IRI-induced salt-sensitive hypertension in rats. Fourteen days after right-side nephrectomy, IRI was induced by clamping the left renal artery, with sham surgery performed as a control. IRI rats were provided with normal water or water with 1.0% NaCl (IRI/NaCl), or they were implanted with an osmotic mini-pump to infuse vehicle or aldosterone (IRI/Aldo). Esaxerenone, a non-steroidal MR blocker (MRB), was administered to IRI/NaCl and IRI/Aldo rats for 6 weeks. MR expression increased by day 7 post-IRI. Blood pressure and urinary protein excretion increased in IRI/NaCl and IRI/Aldo rats over the 6-week period, but these effects were negated by MRB administration. The MRB attenuated the expression of the gamma-epithelial sodium channel (ENaC) and renal damage. The ENaC inhibitor, amiloride, ameliorated hypertension and renal damage in IRI/NaCl and IRI/Aldo rats. Our findings thus showed that MR upregulation may play a pivotal role in ENaC-mediated sodium uptake in rats after IRI, resulting in the development of salt-sensitive hypertension in response to salt overload or the activation of the renin–angiotensin–aldosterone system.
Quantification of Caffeine Interactions in Choline Chloride Natural Deep Eutectic Solvents: Solubility Measurements and COSMO-RS-DARE Interpretation
Authors: Jeliński Tomasz , Cysewski Piotr
Published: July 2022

Solubility of active pharmaceutical ingredients is an important aspect of drug processing and formulation. Although caffeine was a subject of many studies aiming to quantify saturated solutions, many applied solvents suffer from not being environmentally friendly. This work fills this gap by presenting the results of solubility measurements in choline chloride natural deep eutectic solvents, ccNADES, comprising one of seven of the following polyalcohols: glycerol, sorbitol, xylitol, glucose, sucrose, maltose and fructose. The ratio of ccNADES components was optimized for maximizing caffeine solubility at room temperature. Additionally, temperature dependent solubility was measured for the first four systems exhibiting the highest solubility potential, both in their neat forms and in mixtures with water. Results were used for intermolecular interactions assessments using the COSMO-RS-DARE approach, which led to a perfect match between experimental and computed solubility values. An important methodological discussion was provided for an appropriate definition of the systems. Surprising linear trends were observed between the values of fitting parameters and water-ccNADES composition. In addition, comments on selection of the values of the fusion thermodynamic parameters were provided, which led to the conclusion that COSMO-RS-DARE solubility computations can effectively compensate for the inaccuracies of these important physicochemical properties.
T-Cell Intracellular Antigen 1-Like Protein in Physiology and Pathology
Authors: Velasco Beatriz Ramos , Izquierdo José M.
Published: July 2022

T-cell intracellular antigen 1 (TIA1)-related/like (TIAR/TIAL1) protein is a multifunctional RNA-binding protein (RBP) involved in regulating many aspects of gene expression, independently or in combination with its paralog TIA1. TIAR was first described in 1992 by Paul Anderson’s lab in relation to the development of a cell death phenotype in immune system cells, as it possesses nucleolytic activity against cytotoxic lymphocyte target cells. Similar to TIA1, it is characterized by a subcellular nucleo-cytoplasmic localization and ubiquitous expression in the cells of different tissues of higher organisms. In this paper, we review the relevant structural and functional information available about TIAR from a triple perspective (molecular, cellular and pathophysiological), paying special attention to its expression and regulation in cellular events and processes linked to human pathophysiology.
The Role of Platelet-Derived Extracellular Vesicles in Immune-Mediated Thrombosis
Authors: Eustes Alicia S. , Dayal Sanjana
Published: July 2022

Platelet-derived extracellular vesicles (PEVs) play important roles in hemostasis and thrombosis. There are three major types of PEVs described based on their size and characteristics, but newer types may continue to emerge owing to the ongoing improvement in the methodologies and terms used to define various types of EVs. As the literature on EVs is growing, there are continuing attempts to standardize protocols for EV isolation and reach consensus in the field. This review provides information on mechanisms of PEV production, characteristics, cellular interaction, and their pathological role, especially in autoimmune and infectious diseases. We also highlight the mechanisms through which PEVs can activate parent cells in a feedback loop.
Biliary Atresia Animal Models: Is the Needle in a Haystack?
Authors: Pal Nutan , Joy Parijat S. , Sergi Consolato M.
Published: July 2022

Biliary atresia (BA) is a progressive fibro-obliterative process with a variable degree of inflammation involving the hepatobiliary system. Its consequences are incalculable for the patients, the affected families, relatives, and the healthcare system. Scientific communities have identified a rate of about 1 case per 10,000–20,000 live births, but the percentage may be higher, considering the late diagnoses. The etiology is heterogeneous. BA, which is considered in half of the causes leading to orthotopic liver transplantation, occurs in primates and non-primates. To consolidate any model, (1) more transport and cell membrane studies are needed to identify the exact mechanism of noxa-related hepatotoxicity; (2) an online platform may be key to share data from pilot projects and new techniques; and (3) the introduction of differentially expressed genes may be useful in investigating the liver metabolism to target the most intricate bilio-toxic effects of pharmaceutical drugs and toxins. As a challenge, such methodologies are still limited to very few centers, making the identification of highly functional animal models like finding a “needle in a haystack”. This review compiles models from the haystack and hopes that a combinatorial search will eventually be the root for a successful pathway.
The Multi-Dimensional Biomarker Landscape in Cancer Immunotherapy
Authors: Lee Jing Yi , Kannan Bavani , Lim Boon Yee , Li Zhimei , Lim Abner Herbert , Loh Jui Wan , Ko Tun Kiat , Ng Cedric Chuan-Young , Chan Jason Yongsheng
Published: July 2022

The field of immuno-oncology is now at the forefront of cancer care and is rapidly evolving. The immune checkpoint blockade has been demonstrated to restore antitumor responses in several cancer types. However, durable responses can be observed only in a subset of patients, highlighting the importance of investigating the tumor microenvironment (TME) and cellular heterogeneity to define the phenotypes that contribute to resistance as opposed to those that confer susceptibility to immune surveillance and immunotherapy. In this review, we summarize how some of the most widely used conventional technologies and biomarkers may be useful for the purpose of predicting immunotherapy outcomes in patients, and discuss their shortcomings. We also provide an overview of how emerging single-cell spatial omics may be applied to further advance our understanding of the interactions within the TME, and how these technologies help to deliver important new insights into biomarker discovery to improve the prediction of patient response.
Neutrophil Activation by Mineral Microparticles Coated with Methylglyoxal-Glycated Albumin
Authors: Mikhalchik Elena V. , Ivanov Victor A. , Borodina Irina V. , Pobeguts Olga V. , Smirnov Igor P. , Gorudko Irina V. , Grigorieva Daria V. , Boychenko Olga P. , Moskalets Alexander P. , Klinov Dmitry V. , Panasenko Oleg M. , Filatova Luboff Y. , Kirzhanova Ekaterina A. , Balabushevich Nadezhda G.
Published: July 2022

Hyperglycemia-induced protein glycation and formation of advanced glycation end-products (AGEs) plays an important role in the pathogenesis of diabetic complications and pathological biomineralization. Receptors for AGEs (RAGEs) mediate the generation of reactive oxygen species (ROS) via activation of NADPH-oxidase. It is conceivable that binding of glycated proteins with biomineral particles composed mainly of calcium carbonate and/or phosphate enhances their neutrophil-activating capacity and hence their proinflammatory properties. Our research managed to confirm this hypothesis. Human serum albumin (HSA) was glycated with methylglyoxal (MG), and HSA-MG was adsorbed onto mineral microparticles composed of calcium carbonate nanocrystals (vaterite polymorph, CC) or hydroxyapatite nanowires (CP). As scopoletin fluorescence has shown, H2O2 generation by neutrophils stimulated with HSA-MG was inhibited with diphenyleneiodonium chloride, wortmannin, genistein and EDTA, indicating a key role for NADPH-oxidase, protein tyrosine kinase, phosphatidylinositol 3-kinase and divalent ions (presumably Ca2+) in HSA-MG-induced neutrophil respiratory burst. Superoxide anion generation assessed by lucigenin-enhanced chemiluminescence (Luc-CL) was significantly enhanced by free HSA-MG and by both CC-HSA-MG and CP-HSA-MG microparticles. Comparing the concentrations of CC-bound and free HSA-MG, one could see that adsorption enhanced the neutrophil-activating capacity of HSA-MG.
Pathogenesis and Therapeutic Strategies Related to Non-Alcoholic Fatty Liver Disease
Authors: Teng Tieshan , Qiu Shuai , Zhao Yiming , Zhao Siyuan , Sun Dequan , Hou Lingzhu , Li Yihang , Zhou Ke , Yu Xixi , Yang Changyong , Li Yanzhang
Published: July 2022

Non-alcoholic fatty liver disease (NAFLD), one of the most common types of chronic liver disease, is strongly correlated with obesity, insulin resistance, metabolic syndrome, and genetic components. The pathological progression of NAFLD, consisting of non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and liver cirrhosis, is characterized by a broad spectrum of clinical phenotypes. Although patients with mild NAFL are considered to show no obvious clinical symptoms, patients with long-term NAFL may culminate in NASH and further liver fibrosis. Even though various drugs are able to improve NAFLD, there are no FDA-approved medications that directly treat NAFLD. In this paper, the pathogenesis of NAFLD, the potential therapeutic targets, and their underlying mechanisms of action were reviewed.
Effects of GH on the Aging Process in Several Organs: Mechanisms of Action
Authors: Tresguerres Jesús Á. F. , Fernández-Tresguerres Isabel , Viña José , Rancan Lisa , Paredes Sergio D. , Linillos-Pradillo Beatriz , Vara Elena
Published: July 2022

In order to investigate the possible beneficial effects of GH administration on the aging process, 24-month-old rats of both sexes and 10-month-old SAMP8 mice were used. Male rats showed increased fat content and decreased lean body mass together with enhanced vasoconstriction and reduced vasodilation of their aortic rings compared to young adult animals. Chronic GH treatment for 10 weeks increased lean body mass and reduced fat weight together with inducing an enhancement of the vasodilatory response by increasing eNOS and a reduction of the constrictory responses. Old SAMP8 male mice also showed insulin resistance together with a decrease in insulin production by the endocrine pancreas and a reduced expression of differentiation parameters. GH treatment decreased plasma levels and increased pancreatic production of insulin and restored differentiation parameters in these animals. Ovariectomy plus low calcium diet in rabbits induced osteoporosis Titanium implants inserted into these rabbit tibiae showed after one month lesser bone to implant (BIC) surface and bone mineral density (BMD). Local application of GH in the surgical opening was able to increase BIC in the osteoporotic group. The hippocampus of old rats showed a reduction in the number of neurons and also in neurogenesis compared to young ones, together with an increase of caspases and a reduction of Bcl-2. GH treatment was able to enhance significantly only the total number of neurons. In conclusion, GH treatment was able to show beneficial effects in old animals on all the different organs and metabolic functions studied.
Integrated Workflow for the Label-Free Isolation and Genomic Analysis of Single Circulating Tumor Cells in Pancreatic Cancer
Authors: Rupp Brittany , Owen Sarah , Ball Harrison , Smith Kaylee Judith , Gunchick Valerie , Keller Evan T. , Sahai Vaibhav , Nagrath Sunitha
Published: July 2022

As pancreatic cancer is the third deadliest cancer in the U.S., the ability to study genetic alterations is necessary to provide further insight into potentially targetable regions for cancer treatment. Circulating tumor cells (CTCs) represent an especially aggressive subset of cancer cells, capable of causing metastasis and progressing the disease. Here, we present the Labyrinth–DEPArray pipeline for the isolation and analysis of single CTCs. Established cell lines, patient-derived CTC cell lines and freshly isolated CTCs were recovered and sequenced to reveal single-cell copy number variations (CNVs). The resulting CNV profiles of established cell lines showed concordance with previously reported data and highlight several gains and losses of cancer-related genes such as FGFR3 and GNAS. The novel sequencing of patient-derived CTC cell lines showed gains in chromosome 8q, 10q and 17q across both CTC cell lines. The pipeline was used to process and isolate single cells from a metastatic pancreatic cancer patient revealing a gain of chromosome 1q and a loss of chromosome 5q. Overall, the Labyrinth-DEPArray pipeline offers a validated workflow combining the benefits of antigen-free CTC isolation with single cell genomic analysis.
Cytochrome P450 27C1 Level Dictates Lung Cancer Tumorigenicity and Sensitivity towards Multiple Anticancer Agents and Its Potential Interplay with the IGF-1R/Akt/p53 Signaling Pathway
Authors: Mo Hai-Ying , Wei Qi-Yao , Zhong Qiu-Hua , Zhao Xiao-Yun , Guo Dan , Han Jin , Noracharttiyapot Wachiraporn , Visser Lydia , van den Berg Anke , Xu Yan-Ming , Lau Andy T. Y.
Published: July 2022

Cytochrome P450 enzymes (CYP450s) exert mighty catalytic actions in cellular metabolism and detoxication, which play pivotal roles in cell fate determination. Preliminary data shows differential expression levels of CYP27C1, one of the “orphan P450s” in human lung cancer cell lines. Here, we study the functions of CYP27C1 in lung cancer progression and drug endurance, and explore its potential to be a diagnostic and therapeutic target for lung cancer management. Quantitative real-time PCR and immunoblot assays were conducted to estimate the transcription and protein expression level of CYP27C1 in human lung cancer cell lines, which was relatively higher in A549 and H1975 cells, but was lower in H460 cells. Stable CYP27C1-knockdown A549 and H1975 cell lines were established, in which these cells showed enhancement in cell proliferation, colony formation, and migration. In addition, aberrant IGF-1R/Akt/p53 signal transduction was also detected in stable CYP27C1-knockdown human lung cancer cells, which exhibited greater tolerance towards the treatments of anticancer agents (including vinorelbine, picropodophyllin, pacritinib, and SKLB610). This work, for the first time, reveals that CYP27C1 impacts lung cancer cell development by participating in the regulation of the IGF-1R/Akt/p53 signaling pathway, and the level of CYP27C1 plays indispensable roles in dictating the cellular sensitivity towards multiple anticancer agents.
A Perspective on Studies of Phage DNA Packaging Dynamics
Authors: Serwer Philip
Published: July 2022

The Special Issue “DNA Packaging Dynamics of Bacteriophages” is focused on an event that is among the physically simplest known events with biological character. Thus, phage DNA (and RNA) packaging is used as a relatively accessible model for physical analysis of all biological events. A similar perspective motivated early phage-directed work, which was a major contributor to early molecular biology. However, analysis of DNA packaging encounters the limitation that phages vary in difficulty of observing various aspects of their packaging. If a difficult-to-access aspect arises while using a well-studied phage, a counterstrategy is to (1) look for and use phages that provide a better access “window” and (2) integrate multi-phage-accessed information with the help of chemistry and physics. The assumption is that all phages are characterized by the same evolution-derived themes, although with variations. Universal principles will emerge from the themes. A spin-off of using this strategy is the isolation and characterization of the diverse phages needed for biomedicine. Below, I give examples in the areas of infectious disease, cancer, and neurodegenerative disease.
Muscle Fiber Composition Changes after Selective Nerve Innervation
Authors: Watanabe Shiho , Ochiai Hiroko , Sakuma Hisashi , Mori Taisuke , Yazawa Masaki , Oka Aiko , Kishi Kazuo
Published: July 2022

Facial nerve paralysis interferes with mimetic muscle function. To reconstruct natural facial movement, free muscle flaps are transplanted as new muscles. However, it is difficult to maintain resting tonus. A dual innervation technique in which other nerves such as the hypoglossal nerve or contralateral facial nerve are added is often applied. Using 10-week-old rats (n = 10), the masseteric and hypoglossal nerves were cut, and the distal stump of the masseteric nerve and the proximal stump of the hypoglossal nerve were then sutured (suture group). In the other group, the masseteric nerve was cut and cauterized (cut group). Immunohistochemistry and microarray were performed on the extracted masseter muscle. The immunohistochemistry results suggested that the muscles in the suture group obtained oxidative characteristics. The microarray showed the genes involved in mitochondrial function, including Perm1. In summary, our data support the validity of the dualinnervation technique for facial paralysis treatment.
Role of Signaling Pathways in the Viral Life Cycle 2.0
Authors: Moens Ugo
Published: July 2022

Viral infections can lead to the generation of new virus particles, whereas other viruses behave as chameleons by camouflaging themselves to evade or mislead the immune system of the host, thereby establishing a latent infection [...]
PagGRF11 Overexpression Promotes Stem Development and Dwarfing in Populus
Authors: Tian Yanting , Zhao Ye , Sun Yuhan , El-Kassaby Yousry A. , Song Guoyong , Mi Yueqi , Han Juan , Li Yun
Published: July 2022

Poplar is not only an important woody plant, but also a model species for molecular plant studies. We identified PagGRF11 (pAxG07Gg0005700), a homolog of the Arabidopsis AtGRF1 (AT4G37740) and AtGRF2 (AT2G22840) gene. We transformed the poplar clone “84K” with PagGRF11, and the transgenic overexpressed plants (PagGRF11-OE) showed plant height reduction (dwarfing), stem diameter increase, internode shortening, and larger leaf area. The Arabidopsis overexpression line grf-oe (Overexpression of PagGRF11 in Arabidopsis), mutant line atgrf (a loss-of-function mutant of the AtGRF1 gene of Arabidopsis thaliana), and mutant trans-complementary line atgrf+oe (overexpression of PagGRF11 in mutant plants (atgrf)) also showed different leaf size phenotypes. Further, tissue sections revealed that increased xylem production was the main cause of stem thickening. Transcriptome differential expression analysis of PagGRF11 overexpressed and control plants showed that PagGRF11 promoted CCCH39(C3H39) expression. The expression profile of CCCH39 in different tissues showed that it was highly expressed in xylem. Yeast single hybrid and instantaneous double luciferase assay results showed that PagGRF11 directly transcribed and activated CCCH39 expression through interaction with cis-acting element GARE (TCTGTTG), thus promoting xylem development. This is the first finding that GRF positively regulates xylem development through CCCH39 expression activation and further suggests that PagGRF11 is a potential target for increasing wood yield.
NK Cells and Other Cytotoxic Innate Lymphocytes in Colorectal Cancer Progression and Metastasis
Authors: Fionda Cinzia , Scarno Gianluca , Stabile Helena , Molfetta Rosa , Di Censo Chiara , Gismondi Angela , Paolini Rossella , Sozzani Silvano , Santoni Angela , Sciumè Giuseppe
Published: July 2022

Colorectal cancer (CRC) is one of the most common malignancies and leading causes of cancer-related deaths worldwide. Despite its complex pathogenesis and progression, CRC represents a well-fitting example of how the immune contexture can dictate the disease outcome. The presence of cytotoxic lymphocytes, both CD8+ T cells and natural killer (NK) cells, represents a relevant prognostic factor in CRC and is associated with a better overall survival. Together with NK cells, other innate lymphocytes, namely, innate lymphoid cells (ILCs), have been found both in biopsies of CRC patients and in murine models of intestinal cancer, playing both pro- and anti-tumor activities. In particular, several type 1 innate lymphoid cells (ILC1) with cytotoxic functions have been recently described, and evidence in mice shows a role for both NK cells and ILC1 in controlling CRC metastasis. In this review, we provide an overview of the features of NK cells and the expanding spectrum of innate lymphocytes with cytotoxic functions. We also comment on both the described and the potential roles these innate lymphocytes can play during the progression of intestinal cancer leading to metastasis. Finally, we discuss recent advances in the molecular mechanisms underlying the functional regulation of cytotoxic innate lymphocytes in CRC.