bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting Spatiotemporal Demand of Dockless E-Scooter Sharing Services with a Masked Fully Convolutional Network
Authors: Phithakkitnukooon Santi , Patanukhom Karn , Demissie Merkebe Getachew
Published: November 2021

Dockless electric scooters (e-scooter) have emerged as a green alternative to automobiles and a solution to the first- and last-mile problems. Demand anticipation, or being able to accurately predict spatiotemporal demand of e-scooter usage, is one supply–demand balancing strategy. In this paper, we present a dockless e-scooter demand prediction model based on a fully convolutional network (FCN) coupled with a masking process and a weighted loss function, namely, masked FCN (or MFCN). The MFCN model handles the sparse e-scooter usage data with its masking process and weighted loss function. The model is trained with highly correlated features through our feature selection process. Next-hour and next 24-h prediction schemes have been tested for both pick-up and drop-off demands. Overall, the proposed MFCN outperforms other baseline models including a naïve forecasting, linear regression, and convolutional long short-term memory networks with mean absolute errors of 0.0434 and 0.0464 for the next-hour pick-up and drop-off demand prediction, respectively, and the errors of 0.0491 and 0.0501 for the next 24-h pick-up and drop-off demand prediction, respectively. The developed MFCN expands the collection of deep learning techniques that can be applied in the transportation domain, especially spatiotemporal demand prediction.
Trip Purpose Imputation Using GPS Trajectories with Machine Learning
Authors: Gao Qinggang , Molloy Joseph , Axhausen Kay W.
Published: November 2021

We studied trip purpose imputation using data mining and machine learning techniques based on a dataset of GPS-based trajectories gathered in Switzerland. With a large number of labeled activities in eight categories, we explored location information using hierarchical clustering and achieved a classification accuracy of 86.7% using a random forest approach as a baseline. The contribution of this study is summarized below. Firstly, using information from GPS trajectories exclusively without personal information shows a negligible decrease in accuracy (0.9%), which indicates the good performance of our data mining steps and the wide applicability of our imputation scheme in case of limited information availability. Secondly, the dependence of model performance on the geographical location, the number of participants, and the duration of the survey is investigated to provide a reference when comparing classification accuracy. Furthermore, we show the ensemble filter to be an excellent tool in this research field not only because of the increased accuracy (93.6%), especially for minority classes, but also the reduced uncertainties in blindly trusting the labeling of activities by participants, which is vulnerable to class noise due to the large survey response burden. Finally, the trip purpose derivation accuracy across participants reaches 74.8%, which is significant and suggests the possibility of effectively applying a model trained on GPS trajectories of a small subset of citizens to a larger GPS trajectory sample.
The Dynamic Influence of High-Speed Rail on the Spatial Structure of Economic Networks and the Underlying Mechanisms in Northeastern China
Authors: He Sanwei , Mei Lei , Wang Lei
Published: November 2021

Drawing on 185 cities in the northeastern region of China, this paper improves the radiation model by incorporating the accessibility index to characterize the asymmetric process of economic linkages before HSR in 2007 and after HSR in 2016. Then social network analysis is utilized to examine the impact of HSR on the spatial structure of economic networks, including nodal centrality and community structures. Finally, spatial econometric models are employed to explore the driving factors of nodal centrality in economic networks and some policy implications are proposed. The major findings of this paper are the following. First, HSR services can weaken the core-peripheral inequality of economic linkages and a corridor economy is evident in northeastern China. Second, HSR services have significantly improved the out-degree centrality of prefecture-level cities but have slightly decreased the in-degree centrality of Liaoning. Third, there was a slight decline of coherence in the economic network after the construction of HSR and the within-modular connections were strengthened by HSR. Four, the spatial error model (SEM) is more desirable for explaining the distribution of in-degree centrality. GDP, fixed asset investment, education, population, and fiscal expenditure are important contributors to the in-degree centrality in economic networks. These findings give significant insights into city system planning, integrated transport and land use development, formulating regional poles and the coordinated development across administrative boundaries in northeastern China.
A GIS-Based Multi-Criterion Decision-Making Method to Select City Fire Brigade: A Case Study of Wuhan, China
Authors: Jiang Yuncheng , Lv Aifeng , Yan Zhigang , Yang Zhen
Published: November 2021

Rapid urban expansion has brought new challenges to firefighting, with the speed of firefighting rescue being crucial for the safety of property and life. Thus, fire prevention and rescuing people in distress have become more challenging for city managers and emergency responders. Unfortunately, existing research does not consider the negative effects of the current spatial distribution of fire-risk areas, land cover, location, and traffic congestion. To address these shortcomings, we use multiple methods (including geographic information system, multi-criterion decision-making, and location–allocation (L-A)) and multi-source geospatial data (including land cover, point-of-interest, drive time, and statistical yearbooks) to identify suitable areas for fire brigades. We propose a method for identifying potential fire-risk areas and to select suitable fire brigade zones. In this method, we first remove exclusion criteria to identify spatially undeveloped zones and use kernel density methods to evaluate the various fire-risk zones. Next, we use analytic hierarchy processes (AHPs) to comprehensively evaluate the undeveloped areas according to the location, orography, and potential fire-risk zones. In addition, based on the multi-time traffic situation, the average traffic speed during rush hour of each road is calculated, a traffic network model is established, and the travel time is calculated. Finally, the L-A model and network analysis are used to map the spatial coverage of the fire brigades, which is optimized by combining various objectives, such as the coverage rate of high-fire-risk zones, the coverage rate of building construction, and the maintenance of a sub-five-minute drive time between the proposed fire brigade and the demand point. The result shows that the top 50% of fire-risk zones in the central part of Wuhan are mainly concentrated to the west of the Yangtze River. Good overall rescue coverage is obtained with existing fire brigades, but the fire brigades in the north, south, southwest, and eastern areas of the study area lack rescue capabilities. The optimized results show that, to cover the high-fire-risk zones and building constructions, nine fire brigades should be added to increase the service coverage rate from 93.28% to 99.01%. The proposed method combines the viewpoint of big data, which provides new ideas and technical methods for the fire brigade site-selection model.
Assessing Potential Climatic and Human Pressures in Indonesian Coastal Ecosystems Using a Spatial Data-Driven Approach
Authors: Fauzi Adam Irwansyah , Sakti Anjar Dimara , Robbani Balqis Falah , Ristiyani Mita , Agustin Rahiska Tisa , Yati Emi , Nuha Muhammad Ulin , Anika Nova , Putra Raden , Siregar Diyanti Isnani , Prasetyo Budhi Agung , Julzarika Atriyon , Wikantika Ketut
Published: November 2021

Blue carbon ecosystems are key for successful global climate change mitigation; however, they are one of the most threatened ecosystems on Earth. Thus, this study mapped the climatic and human pressures on the blue carbon ecosystems in Indonesia using multi-source spatial datasets. Data on moderate resolution imaging spectroradiometer (MODIS) ocean color standard mapped images, VIIRS (visible, infrared imaging radiometer suite) boat detection (VBD), global artificial impervious area (GAIA), MODIS surface reflectance (MOD09GA), MODIS land surface temperature (MOD11A2), and MODIS vegetation indices (MOD13A2) were combined using remote sensing and spatial analysis techniques to identify potential stresses. La Niña and El Niño phenomena caused sea surface temperature deviations to reach −0.5 to +1.2 °C. In contrast, chlorophyll-a deviations reached 22,121 to +0.5 mg m−3. Regarding fishing activities, most areas were under exploitation and relatively sustained. Concerning land activities, mangrove deforestation occurred in 560.69 km2 of the area during 2007–2016, as confirmed by a decrease of 84.9% in risk-screening environmental indicators. Overall, the potential pressures on Indonesia’s blue carbon ecosystems are varied geographically. The framework of this study can be efficiently adopted to support coastal and small islands zonation planning, conservation prioritization, and marine fisheries enhancement.
Immunohistochemical Evaluation of Adaptor Protein FAM159B Expression in Normal and Neoplastic Human Tissues
Authors: Beyer Anna-Sophia Lieselott , Kaemmerer Daniel , Sänger Jörg , Evert Katja , Lupp Amelie
Published: November 2021

FAM159B is a so-called adaptor protein. These proteins are essential components in numerous cell signalling pathways. However, little is known regarding FAM159B expression in normal and neoplastic human tissues. The commercially available rabbit polyclonal anti-human FAM159B antibody HPA011778 was initially characterised for its specificity using Western blot analyses and immunocytochemistry and then applied to a large series of formalin-fixed, paraffin-embedded normal and neoplastic human tissue samples. Confirmation of FAM159B’s predicted size and antibody specificity was achieved in BON-1 cells, a neuroendocrine tumour cell line endogenously expressing FAM159B, using targeted siRNA. Immunocytochemical experiments additionally revealed cytoplasmic expression of the adaptor protein. Immunohistochemical staining detected FAM159B expression in neuronal and neuroendocrine tissues such as the cortex, the trigeminal ganglia, dorsal root and intestinal ganglia, the pancreatic islets and the neuroendocrine cells of the bronchopulmonary and gastrointestinal tract, but also in the syncytiotrophoblasts of the placenta. FAM159B was also expressed in many of the 28 tumour entities investigated, with high levels in medullary and anaplastic thyroid carcinomas, parathyroid adenomas, lung and ovarian carcinomas, lymphomas and neuroendocrine tumours of different origins. The antibody HPA011778 can act as a useful tool for basic research and identifying FAM159B expression in tissue samples.
Enhanced Muscle Strength in Dyslipidemic Mice and Its Relation to Increased Capacity for Fatty Acid Oxidation
Authors: Tomczyk Marta , Braczko Alicja , Jablonska Patrycja , Mika Adriana , Przyborowski Kamil , Jedrzejewska Agata , Krol Oliwia , Kus Filip , Sledzinski Tomasz , Chlopicki Stefan , Slominska Ewa M. , Smolenski Ryszard T.
Published: November 2021

Dyslipidemia is commonly linked to skeletal muscle dysfunction, accumulation of intramyocellular lipids, and insulin resistance. However, our previous research indicated that dyslipidemia in apolipoprotein E and low-density lipoprotein receptor double knock-out mice (ApoE/LDLR -/-) leads to improvement of exercise capacity. This study aimed to investigate in detail skeletal muscle function and metabolism in these dyslipidemic mice. We found that ApoE/LDLR -/- mice showed an increased grip strength as well as increased troponins, and Mhc2 levels in skeletal muscle. It was accompanied by the increased skeletal muscle mitochondria numbers (judged by increased citrate synthase activity) and elevated total adenine nucleotides pool. We noted increased triglycerides contents in skeletal muscles and increased serum free fatty acids (FFA) levels in ApoE/LDLR -/- mice. Importantly, Ranolazine mediated inhibition of FFA oxidation in ApoE/LDLR -/- mice led to the reduction of exercise capacity and total adenine nucleotides pool. Thus, this study demonstrated that increased capacity for fatty acid oxidation, an adaptive response to dyslipidemia leads to improved cellular energetics that translates to increased skeletal muscle strength and contributes to increased exercise capacity in ApoE/LDLR -/- mice.
Genomic Instability and Cancer Risk Associated with Erroneous DNA Repair
Authors: Yoshioka Ken-ichi , Kusumoto-Matsuo Rika , Matsuno Yusuke , Ishiai Masamichi
Published: November 2021

Many cancers develop as a consequence of genomic instability, which induces genomic rearrangements and nucleotide mutations. Failure to correct DNA damage in DNA repair defective cells, such as in BRCA1 and BRCA2 mutated backgrounds, is directly associated with increased cancer risk. Genomic rearrangement is generally a consequence of erroneous repair of DNA double-strand breaks (DSBs), though paradoxically, many cancers develop in the absence of DNA repair defects. DNA repair systems are essential for cell survival, and in cancers deficient in one repair pathway, other pathways can become upregulated. In this review, we examine the current literature on genomic alterations in cancer cells and the association between these alterations and DNA repair pathway inactivation and upregulation.
Control of Chromatin Organization and Chromosome Behavior during the Cell Cycle through Phase Separation
Authors: Li Jiaxiang , Gao Jinmin , Wang Ruoxi
Published: November 2021

Phase-separated condensates participate in various biological activities. Liquid–liquid phase separation (LLPS) can be driven by collective interactions between multivalent and intrinsically disordered proteins. The manner in which chromatin—with various morphologies and activities—is organized in a complex and small nucleus still remains to be fully determined. Recent findings support the claim that phase separation is involved in the regulation of chromatin organization and chromosome behavior. Moreover, phase separation also influences key events during mitosis and meiosis. This review elaborately dissects how phase separation regulates chromatin and chromosome organization and controls mitotic and meiotic chromosome behavior.
The GTPase Arf1 Is a Determinant of Yeast Vps13 Localization to the Golgi Apparatus
Authors: Kolakowski Damian , Rzepnikowska Weronika , Kaniak-Golik Aneta , Zoladek Teresa , Kaminska Joanna
Published: November 2021

VPS13 proteins are evolutionarily conserved. Mutations in the four human genes (VPS13A-D) encoding VPS13A-D proteins are linked to developmental or neurodegenerative diseases. The relationship between the specific localization of individual VPS13 proteins, their molecular functions, and the pathology of these diseases is unknown. Here we used a yeast model to establish the determinants of Vps13′s interaction with the membranes of Golgi apparatus. We analyzed the different phenotypes of the arf1-3 arf2Δ vps13∆ strain, with reduced activity of the Arf1 GTPase, the master regulator of Golgi function and entirely devoid of Vps13. Our analysis led us to propose that Vps13 and Arf1 proteins cooperate at the Golgi apparatus. We showed that Vps13 binds to the Arf1 GTPase through its C-terminal Pleckstrin homology (PH)-like domain. This domain also interacts with phosphoinositol 4,5-bisphosphate as it was bound to liposomes enriched with this lipid. The homologous domain of VPS13A exhibited the same behavior. Furthermore, a fusion of the PH-like domain of Vps13 to green fluorescent protein was localized to Golgi structures in an Arf1-dependent manner. These results suggest that the PH-like domains and Arf1 are determinants of the localization of VPS13 proteins to the Golgi apparatus in yeast and humans.
Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies
Authors: Cieślik Paulina , Siekierzycka Anna , Radulska Adrianna , Płoska Agata , Burnat Grzegorz , Brański Piotr , Kalinowski Leszek , Wierońska Joanna M.
Published: November 2021

MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.
Treatment of HT29 Human Colorectal Cancer Cell Line with Nanocarrier-Encapsulated Camptothecin Reveals Histone Modifier Genes in the Wnt Signaling Pathway as Important Molecular Cues for Colon Cancer Targeting
Authors: Farhana Aisha , Koh Avin Ee-Hwan , Kothandan Sangeetha , Alsrhani Abdullah , Mok Pooi Ling , Subbiah Suresh Kumar
Published: November 2021

Cancer cells are able to proliferate in an unregulated manner. There are several mechanisms involved that propel such neoplastic transformations. One of these processes involves bypassing cell death through changes in gene expression and, consequently, cell growth. This involves a complex epigenetic interaction within the cell, which drives it towards oncogenic transformations. These epigenetic events augment cellular growth by potentially altering chromatin structures and influencing key gene expressions. Therapeutic mechanisms have been developed to combat this by taking advantage of the underlying oncogenic mechanisms through chemical modulation. Camptothecin (CPT) is an example of this type of drug. It is a selective topoisomerase I inhibitor that is effective against many cancers, such as colorectal cancer. Previously, we successfully formulated a magnetic nanocarrier-conjugated CPT with β-cyclodextrin and iron NPs (Fe3O4) cross-linked using EDTA (CPT-CEF). Compared to CPT alone, it boasts higher efficacy due to its selective targeting and increased solubility. In this study, we treated HT29 colon cancer cells with CPT-CEF and attempted to investigate the cytotoxic effects of the formulation through an epigenetic perspective. By using RNA-Seq, several differentially expressed genes were obtained (p < 0.05). Enrichr was then used for the over-representation analysis, and the genes were compared to the epigenetic roadmap and histone modification database. The results showed that the DEGs had a high correlation with epigenetic modifications involving histone H3 acetylation. Furthermore, a subset of these genes was shown to be associated with the Wnt/β-catenin signaling pathway, which is highly upregulated in a large number of cancer cells. These genes could be investigated as downstream therapeutic targets against the uncontrolled proliferation of cancer cells. Further interaction analysis of the identified genes with the key genes of the Wnt/β-catenin signaling pathway in colorectal cancer identified the direct interactors and a few transcription regulators. Further analysis in cBioPortal confirmed their genetic alterations and their distribution across patient samples. Thus, the findings of this study reveal that colorectal cancer could be reversed by treatment with the CPT-CEF nanoparticle-conjugated nanocarrier through an epigenetic mechanism.
A Deep Learning Approach with Data Augmentation to Predict Novel Spider Neurotoxic Peptides
Authors: Lee Byungjo , Shin Min Kyoung , Hwang In-Wook , Jung Junghyun , Shim Yu Jeong , Kim Go Woon , Kim Seung Tae , Jang Wonhee , Sung Jung-Suk
Published: November 2021

As major components of spider venoms, neurotoxic peptides exhibit structural diversity, target specificity, and have great pharmaceutical potential. Deep learning may be an alternative to the laborious and time-consuming methods for identifying these peptides. However, the major hurdle in developing a deep learning model is the limited data on neurotoxic peptides. Here, we present a peptide data augmentation method that improves the recognition of neurotoxic peptides via a convolutional neural network model. The neurotoxic peptides were augmented with the known neurotoxic peptides from UniProt database, and the models were trained using a training set with or without the generated sequences to verify the augmented data. The model trained with the augmented dataset outperformed the one with the unaugmented dataset, achieving accuracy of 0.9953, precision of 0.9922, recall of 0.9984, and F1 score of 0.9953 in simulation dataset. From the set of all RNA transcripts of Callobius koreanus spider, we discovered neurotoxic peptides via the model, resulting in 275 putative peptides of which 252 novel sequences and only 23 sequences showing homology with the known peptides by Basic Local Alignment Search Tool. Among these 275 peptides, four were selected and shown to have neuromodulatory effects on the human neuroblastoma cell line SH-SY5Y. The augmentation method presented here may be applied to the identification of other functional peptides from biological resources with insufficient data.
Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer
Authors: Scheidemann Erin R. , Shajahan-Haq Ayesha N.
Published: November 2021

Estrogen receptor-positive (ER+) breast cancer is the most common form of breast cancer. Antiestrogens were the first therapy aimed at treating this subtype, but resistance to these warranted the development of a new treatment option. CDK4/6 inhibitors address this problem by halting cell cycle progression in ER+ cells, and have proven to be successful in the clinic. Unfortunately, both intrinsic and acquired resistance to CDK4/6 inhibitors are common. Numerous mechanisms of how resistance occurs have been identified to date, including the activation of prominent growth signaling pathways, the loss of tumor-suppressive genes, and noncanonical cell cycle function. Many of these have been successfully targeted and demonstrate the ability to overcome resistance to CDK4/6 inhibitors in preclinical and clinical trials. Future studies should focus on the development of biomarkers so that patients likely to be resistant to CDK4/6 inhibition can initially be given alternative methods of treatment.
Bridging Radiotherapy to Immunotherapy: The IFN–JAK–STAT Axis
Authors: Shi Lewis Zhichang , Bonner James A.
Published: November 2021

The unprecedented successes of immunotherapies (IOs) including immune checkpoint blockers (ICBs) and adoptive T-cell therapy (ACT) in patients with late-stage cancer provide proof-of-principle evidence that harnessing the immune system, in particular T cells, can be an effective approach to eradicate cancer. This instills strong interests in understanding the immunomodulatory effects of radiotherapy (RT), an area that was actually investigated more than a century ago but had been largely ignored for many decades. With the “newly” discovered immunogenic responses from RT, numerous endeavors have been undertaken to combine RT with IOs, in order to bolster anti-tumor immunity. However, the underlying mechanisms are not well defined, which is a subject of much investigation. We therefore conducted a systematic literature search on the molecular underpinnings of RT-induced immunomodulation and IOs, which identified the IFN–JAK–STAT pathway as a major regulator. Our further analysis of relevant studies revealed that the signaling strength and duration of this pathway in response to RT and IOs may determine eventual immunological outcomes. We propose that strategic targeting of this axis can boost the immunostimulatory effects of RT and radiosensitizing effects of IOs, thereby promoting the efficacy of combination therapy of RT and IOs.
Acetylenic Synthetic Betulin Derivatives Inhibit Akt and Erk Kinases Activity, Trigger Apoptosis and Suppress Proliferation of Neuroblastoma and Rhabdomyosarcoma Cell Lines
Authors: Król Sylwia K. , Bębenek Ewa , Dmoszyńska-Graniczka Magdalena , Sławińska-Brych Adrianna , Boryczka Stanisław , Stepulak Andrzej
Published: November 2021

Neuroblastoma (NB) and rhabdomyosarcoma (RMS), the most common pediatric extracranial solid tumors, still represent an important clinical challenge since no effective treatment is available for metastatic and recurrent disease. Hence, there is an urgent need for the development of new chemotherapeutics to improve the outcome of patients. Betulin (Bet), a triterpenoid from the bark of birches, demonstrated interesting anti-cancer potential. The modification of natural phytochemicals with evidenced anti-tumor activity, including Bet, is one of the methods of receiving new compounds for potential implementation in oncological treatment. Here, we showed that two acetylenic synthetic Bet derivatives (ASBDs), EB5 and EB25/1, reduced the viability and proliferation of SK-N-AS and TE671 cells, as measured by MTT and BrdU tests, respectively. Moreover, ASBDs were also more cytotoxic than temozolomide (TMZ) and cisplatin (cis-diaminedichloroplatinum [II], CDDP) in vitro, and the combination of EB5 with CDDP enhanced anti-cancer effects. We also showed the slowdown of cell cycle progression at S/G2 phases mediated by EB5 using FACS flow cytometry. The decreased viability and proliferation of pediatric cancers cells after treatment with ASBDs was linked to the reduced activity of kinases Akt, Erk1/2 and p38 and the induction of apoptosis, as investigated using Western blotting and FACS. In addition, in silico analyses of the ADMET profile found EB5 to be a promising anti-cancer drug candidate that would benefit from further investigation.
Olfactory Receptor OR7A17 Expression Correlates with All-Trans Retinoic Acid (ATRA)-Induced Suppression of Proliferation in Human Keratinocyte Cells
Authors: Kim Hyeyoun , Park See-Hyoung , Oh Sae Woong , Kwon Kitae , Park Se Jung , Yu Eunbi , Yang Seyoung , Park Jung Yoen , Choi Seoyoung , Yang Seoyoun , Han Su Bin , Song Minkyung , Cho Jae Youl , Lee Jongsung
Published: November 2021

Olfactory receptors (ORs), which belong to the G-protein-coupled receptor family, have been widely studied as ectopically expressed receptors in various human tissues, including the skin. However, the physiological functions of only a few OR types have been elucidated in skin cells. All-trans retinoic acid (ATRA) is a well-known medication for various skin diseases. However, many studies have shown that ATRA can have adverse effects, resulting from the suppression of cell proliferation. Here, we investigated the involvement of OR7A17 in the ATRA-induced suppression of human keratinocyte (HaCaT) proliferation. We demonstrated that OR7A17 is expressed in HaCaT keratinocytes, and its expression was downregulated by ATRA. The ATRA-induced downregulation of OR7A17 was attenuated via RAR α or RAR γ antagonist treatment, indicating that the effects of ATRA on OR7A17 expression were mediated through nuclear retinoic acid receptor signaling. Moreover, we found that the overexpression of OR7A17 induced the proliferation of HaCaT cells while counteracting the antiproliferative effect of ATRA. Mechanistically, OR7A17 overexpression reversed the ATRA-induced attenuation of Ca2+ entry. Our findings indicated that ATRA suppresses cell proliferation through the downregulation of OR7A17 via RAR α- and γ-mediated retinoid signaling. Taken together, OR7A17 is a potential therapeutic target for ameliorating the anti-proliferative effects of ATRA.
Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension
Authors: Shanks Julia , Ramchandra Rohit
Published: November 2021

The renin–angiotensin–aldosterone system (RAAS) impacts cardiovascular homeostasis via direct actions on peripheral blood vessels and via modulation of the autonomic nervous system. To date, research has primarily focused on the actions of the RAAS on the sympathetic nervous system. Here, we review the critical role of the RAAS on parasympathetic nerve function during normal physiology and its role in cardiovascular disease, focusing on hypertension. Angiotensin (Ang) II receptors are present throughout the parasympathetic nerves and can modulate vagal activity via actions at the level of the nerve endings as well as via the circumventricular organs and as a neuromodulator acting within brain regions. There is tonic inhibition of cardiac vagal tone by endogenous Ang II. We review the actions of Ang II via peripheral nerve endings as well as via central actions on brain regions. We review the evidence that Ang II modulates arterial baroreflex function and examine the pathways via which Ang II can modulate baroreflex control of cardiac vagal drive. Although there is evidence that Ang II can modulate parasympathetic activity and has the potential to contribute to impaired baseline levels and impaired baroreflex control during hypertension, the exact central regions where Ang II acts need further investigation. The beneficial actions of angiotensin receptor blockers in hypertension may be mediated in part via actions on the parasympathetic nervous system. We highlight important unknown questions about the interaction between the RAAS and the parasympathetic nervous system and conclude that this remains an important area where future research is needed.
Inhibitory Potential of New Phenolic Hydrazide-Hydrazones with a Decoy Substrate Fragment towards Laccase from a Phytopathogenic Fungus: SAR and Molecular Docking Studies
Authors: Maniak Halina , Talma Michał , Giurg Mirosław
Published: November 2021

Laccase from pathogenic fungi participates in both the delignification and neutralization of phytoantibiotics. Furthermore, it interferes with the hormone signaling in plants and catalyzes melanization. Infections of these pathogens contribute to loss in forestry, agriculture, and horticulture. As there is still a need to expand knowledge on efficient defense strategies against phytopathogenic fungi, the present study aimed to reveal more information on the molecular mechanisms of laccase inhibition with natural and natural-like carboxylic acid semi-synthetic derivatives. A set of hydrazide-hydrazones derived from carboxylic acids, generally including electron-rich arene units that serve as a decoy substrate, was synthesized and tested with laccase from Trametes versicolor. The classic synthesis of the title inhibitors proceeded with good to almost quantitative yield. Ninety percent of the tested molecules were active in the range of KI = 8–233 µM and showed different types of action. Such magnitude of inhibition constants qualified the hydrazide-hydrazones as strong laccase inhibitors. Molecular docking studies supporting the experimental data explained the selected derivatives’ interactions with the enzyme. The results are promising in developing new potential antifungal agents mitigating the damage scale in the plant cultivation, gardening, and horticulture sectors.
Efficacy of Cord Blood Cell Therapy for Hutchinson–Gilford Progeria Syndrome—A Case Report
Authors: Suh Mi Ri , Lim Ikhyun , Kim Jongwook , Yang Pil-Sung , Choung Jin Seung , Sim Hye Ryeong , Ha Sung Chan , Kim MinYoung
Published: November 2021

Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare premature aging disorder characterized by short stature and atherosclerosis-induced death within teenage years. A 13-year-old male diagnosed with HGPS was administered three intravenous infusions of allogeneic cord blood (CB) cells from unrelated donors at four-month intervals to evaluate the safety and its therapeutic efficacy. Adverse events were monitored in addition to height, weight, laboratory blood tests, joint range of motion (ROM), and carotid Doppler. Cytokine and receptor assays were also performed. The patient exhibited an increase in growth rate for both height and weight. One year after therapy initiation, evident amelioration in pulse wave velocity, bilateral maximal intima-media thickness, and dyslipidemic status were observed, which were in abrupt aggravation prior to treatment. Further, an increase in flexibility occurred in some joints of the upper extremities. No serious adverse events were observed throughout the study period and one year beyond. A molecular assay revealed downregulation of proinflammatory and atherosclerosis, representing cytokine expressions following the administration of CB cells. This is the first reported case of an allogeneic CB trial in a patient with HGPS showing therapeutic effects of CB with improvements in anthropometric measures, joint ROM with amelioration of atherosclerosis, and dyslipidemia induced by anti-inflammatory and anti-atherosclerotic responses.
Genome-Wide Identification of GDSL-Type Esterase/Lipase Gene Family in Dasypyrum villosum L. Reveals That DvGELP53 Is Related to BSMV Infection
Authors: Zhang Heng , Zhang Xu , Zhao Jia , Sun Li , Wang Haiyan , Zhu Ying , Xiao Jin , Wang Xiue
Published: November 2021

GDSL-type esterase/lipase proteins (GELPs) characterized by a conserved GDSL motif at their N-terminus belong to the lipid hydrolysis enzyme superfamily. In plants, GELPs play an important role in plant growth, development and stress response. The studies of the identification and characterization of the GELP gene family in Triticeae have not been reported. In this study, 193 DvGELPs were identified in Dasypyrum villosum and classified into 11 groups (clade A–K) by means of phylogenetic analysis. Most DvGELPs contain only one GDSL domain, only four DvGELPs contain other domains besides the GDSL domain. Gene structure analysis indicated 35.2% DvGELP genes have four introns and five exons. In the promoter regions of the identified DvGELPs, we detected 4502 putative cis-elements, which were associated with plant hormones, plant growth, environmental stress and light responsiveness. Expression profiling revealed 36, 44 and 17 DvGELPs were highly expressed in the spike, the root and the grain, respectively. Further investigation of a root-specific expressing GELP, DvGELP53, indicated it was induced by a variety of biotic and abiotic stresses. The knockdown of DvGELP53 inhibited long-distance movement of BSMV in the tissue of D. villosum. This research provides a genome-wide glimpse of the D. villosum GELP genes and hints at the participation of DvGELP53 in the interaction between virus and plants.
Transcriptomic Changes in Internode Explants of Stinging Nettle during Callogenesis
Authors: Xu Xuan , Legay Sylvain , Berni Roberto , Hausman Jean-Francois , Guerriero Gea
Published: November 2021

Callogenesis, the process during which explants derived from differentiated plant tissues are subjected to a trans-differentiation step characterized by the proliferation of a mass of cells, is fundamental to indirect organogenesis and the establishment of cell suspension cultures. Therefore, understanding how callogenesis takes place is helpful to plant tissue culture, as well as to plant biotechnology and bioprocess engineering. The common herbaceous plant stinging nettle (Urtica dioica L.) is a species producing cellulosic fibres (the bast fibres) and a whole array of phytochemicals for pharmacological, nutraceutical and cosmeceutical use. Thus, it is of interest as a potential multi-purpose plant. In this study, callogenesis in internode explants of a nettle fibre clone (clone 13) was studied using RNA-Seq to understand which gene ontologies predominate at different time points. Callogenesis was induced with the plant growth regulators α-napthaleneacetic acid (NAA) and 6-benzyl aminopurine (BAP) after having determined their optimal concentrations. The process was studied over a period of 34 days, a time point at which a well-visible callus mass developed on the explants. The bioinformatic analysis of the transcriptomic dataset revealed specific gene ontologies characterizing each of the four time points investigated (0, 1, 10 and 34 days). The results show that, while the advanced stage of callogenesis is characterized by the iron deficiency response triggered by the high levels of reactive oxygen species accumulated by the proliferating cell mass, the intermediate and early phases are dominated by ontologies related to the immune response and cell wall loosening, respectively.
Dissimilar Ligands Bind in a Similar Fashion: A Guide to Ligand Binding-Mode Prediction with Application to CELPP Studies
Authors: Xu Xianjin , Zou Xiaoqin
Published: November 2021

The molecular similarity principle has achieved great successes in the field of drug design/discovery. Existing studies have focused on similar ligands, while the behaviors of dissimilar ligands remain unknown. In this study, we developed an intercomparison strategy in order to compare the binding modes of ligands with different molecular structures. A systematic analysis of a newly constructed protein–ligand complex structure dataset showed that ligands with similar structures tended to share a similar binding mode, which is consistent with the Molecular Similarity Principle. More importantly, the results revealed that dissimilar ligands can also bind in a similar fashion. This finding may open another avenue for drug discovery. Furthermore, a template-guiding method was introduced for predicting protein–ligand complex structures. With the use of dissimilar ligands as templates, our method significantly outperformed the traditional molecular docking methods. The newly developed template-guiding method was further applied to recent CELPP studies.
To Discover the Efficient and Novel Drug Targets in Human Cancers Using CRISPR/Cas Screening and Databases
Authors: Onishi Iichiroh , Yamamoto Kouhei , Kinowaki Yuko , Kitagawa Masanobu , Kurata Morito
Published: November 2021

CRISPR/Cas has emerged as an excelle nt gene-editing technology and is used worldwide for research. The CRISPR library is an ideal tool for identifying essential genes and synthetic lethality targeted for cancer therapies in human cancers. Synthetic lethality is defined as multiple genetic abnormalities that, when present individually, do not affect function or survival, but when present together, are lethal. Recently, many CRISPR libraries are available, and the latest libraries are more accurate and can be applied to few cells. However, it is easier to efficiently search for cancer targets with their own screenings by effectively using databases of CRISPR screenings, such as Depmap portal, PICKLES (Pooled In-Vitro CRISPR Knockout Library Essentiality Screens), iCSDB, Project Score database, and CRISP-view. This review will suggest recent optimal CRISPR libraries and effective databases for Novel Approaches in the Discovery and Design of Targeted Therapies.
Intrauterine L-NAME Exposure Weakens the Development of Sympathetic Innervation and Induces the Remodeling of Arterial Vessels in Two-Week-Old Rats
Authors: Selivanova Ekaterina K. , Shvetsova Anastasia A. , Borzykh Anna A. , Gaynullina Dina K. , Kiryukhina Oxana O. , Lukoshkova Elena V. , Potekhina Viktoria M. , Kuzmin Vladislav S. , Tarasova Olga S.
Published: November 2021

Nitric oxide (NO) has been shown to stimulate differentiation and increase the survival of ganglionic sympathetic neurons. The proportion of neuronal NOS-immunoreactive sympathetic preganglionic neurons is particularly high in newborn rats and decreases with maturation. However, the role of NO in the development of vascular sympathetic innervation has never been studied before. We tested the hypothesis that intrauterine NO deficiency weakened the development of vascular sympathetic innervation and thereby changed the contractility of peripheral arteries and blood pressure level in two-week-old offspring. Pregnant rats consumed NOS inhibitor L-NAME (250 mg/L in drinking water) from gestational day 10 until delivery. Pups in the L-NAME group had a reduced body weight and blood level of NO metabolites at 1–2 postnatal days. Saphenous arteries from two-week-old L-NAME offspring demonstrated a lower density of sympathetic innervation, a smaller inner diameter, reduced maximal active force and decreased α-actin/β-actin mRNA expression ratio compared to the controls. Importantly, pups in the L-NAME group exhibited decreased blood pressure levels before, but not after, ganglionic blockade with chlorisondamine. In conclusion, intrauterine L-NAME exposure is followed by the impaired development of the sympathetic nervous system in early postnatal life, which is accompanied by the structural and functional remodeling of arterial blood vessels.
Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects
Authors: Ulloa-Aguirre Alfredo , Zariñán Teresa , Jardón-Valadez Eduardo
Published: November 2021

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.
What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment
Authors: Palicelli Andrea , Croci Stefania , Bisagni Alessandra , Zanetti Eleonora , De Biase Dario , Melli Beatrice , Sanguedolce Francesca , Ragazzi Moira , Zanelli Magda , Chaux Alcides , Cañete-Portillo Sofia , Bonasoni Maria Paola , Soriano Alessandra , Ascani Stefano , Zizzo Maurizio , Castro Ruiz Carolina , De Leo Antonio , Giordano Guido , Landriscina Matteo , Carrieri Giuseppe , Cormio Luigi , Berney Daniel M. , Gandhi Jatin , Copelli Valerio , Bernardelli Giuditta , Santandrea Giacomo , Bonacini Martina
Published: November 2021

The tumor microenvironment (TME) includes immune (T, B, NK, dendritic), stromal, mesenchymal, endothelial, adipocytic cells, extracellular matrix, and cytokines/chemokines/soluble factors regulating various intracellular signaling pathways (ISP) in tumor cells. TME influences the survival/progression of prostate cancer (PC), enabling tumor cell immune-evasion also through the activation of the PD-1/PD-L1 axis. We have performed a systematic literature review according to the PRISMA guidelines, to investigate how the PD-1/PD-L1 pathway is influenced by TME and ISPs. Tumor immune-escape mechanisms include suppression/exhaustion of tumor infiltrating cytotoxic T lymphocytes, inhibition of tumor suppressive NK cells, increase in immune-suppressive immune cells (regulatory T, M2 macrophagic, myeloid-derived suppressor, dendritic, stromal, and adipocytic cells). IFN-γ (the most investigated factor), TGF-β, TNF-α, IL-6, IL-17, IL-15, IL-27, complement factor C5a, and other soluble molecules secreted by TME components (and sometimes increased in patients’ serum), as well as and hypoxia, influenced the regulation of PD-L1. Experimental studies using human and mouse PC cell lines (derived from either androgen-sensitive or androgen-resistant tumors) revealed that the intracellular ERK/MEK, Akt-mTOR, NF-kB, WNT and JAK/STAT pathways were involved in PD-L1 upregulation in PC. Blocking the PD-1/PD-L1 signaling by using immunotherapy drugs can prevent tumor immune-escape, increasing the anti-tumor activity of immune cells.
Artificial Intelligence in Translational Medicine
Authors: Brogi Simone , Calderone Vincenzo
Published: November 2021

The huge advancement in Internet web facilities as well as the progress in computing and algorithm development, along with current innovations regarding high-throughput techniques, enable the scientific community to gain access to biological datasets, clinical data and several databases containing billions of pieces of information concerning scientific knowledge. Consequently, during the last decade the system for managing, analyzing, processing and extrapolating information from scientific data has been considerably modified in several fields, including the medical one. As a consequence of the mentioned scenario, scientific vocabulary was enriched by novel lexicons such as machine learning (ML)/deep learning (DL) and overall artificial intelligence (AI). Beyond the terminology, these computational techniques are revolutionizing the scientific research in drug discovery pitch, from the preclinical studies to clinical investigation. Interestingly, between preclinical and clinical research, translational research is benefitting from computer-based approaches, transforming the design and execution of translational research, resulting in breakthroughs for advancing human health. Accordingly, in this review article, we analyze the most advanced applications of AI in translational medicine, providing an up-to-date outlook regarding this emerging field.