bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancement of Countermovement Jump Performance Using a Heavy Load with Velocity-Loss Repetition Control in Female Volleyball Players
Authors: Krzysztofik Michal , Kalinowski Rafal , Trybulski Robert , Filip-Stachnik Aleksandra , Stastny Petr
Published: November 2021

Although velocity control in resistance training is widely studied, its utilization in eliciting post-activation performance enhancement (PAPE) responses receives little attention. Therefore, this study aimed to evaluate the effectiveness of heavy-loaded barbell squats (BS) with velocity loss control conditioning activity (CA) on PAPE in subsequent countermovement jump (CMJ) performance. Sixteen resistance-trained female volleyball players participated in this study (age: 24 ± 5 yrs.; body mass: 63.5 ± 5.2 kg; height: 170 ± 6 cm; relative BS one-repetition maximum (1RM): 1.45 ± 0.19 kg/body mass). Each participant performed two different conditions: a set of the BS at 80% 1 RM with repetitions performed until a mean velocity loss of 10% as the CA or a control condition without CA (CNTRL). To assess changes in jump height (JH) and relative mean power output (MP), the CMJ was performed 5 min before and throughout the 10 min after the CA. The two-way analysis of variance with repeated measures showed a significant main effect of condition (p = 0.008; η2 = 0.387) and time (p < 0.0001; η2 = 0.257) for JH. The post hoc test showed a significant decrease in the 10th min in comparison to the value from baseline (p < 0.006) for the CNTRL condition. For the MP, a significant interaction (p = 0.045; η2 = 0.138) was found. The post hoc test showed a significant decrease in the 10th min in comparison to the values from baseline (p < 0.006) for the CNTRL condition. No significant differences were found between all of the time points and the baseline value for the CA condition. The CA used in the current study fails to enhance subsequent countermovement jump performance in female volleyball players. However, the individual analysis showed that 9 out of the 16 participants (56%) responded positively to the applied CA, suggesting that the PAPE effect may be individually dependent and should be carefully verified before implementation in a training program.
Role of SatO2, PaO2/FiO2 Ratio and PaO2 to Predict Adverse Outcome in COVID-19: A Retrospective, Cohort Study
Authors: Sartini Stefano , Massobrio Laura , Cutuli Ombretta , Campodonico Paola , Bernini Cristina , Sartini Marina , Cristina Maria Luisa , Castellani Luca , Ceschi Ludovica , Spadaro Marzia , Gratarola Angelo , Barbera Paolo
Published: November 2021

COVID-19 respiratory failure is a life-threatening condition. Oxygenation targets were evaluated in a non-ICU setting. In this retrospective, observational study, we enrolled all patients admitted to the University Hospital of Genoa, Italy, between 1 February and 31 May 2020 with an RT-PCR positive for SARS-CoV-2. PaO2, PaO2/FiO2 and SatO2% were collected and analyzed at time 0 and in case of admission, patients who required or not C-PAP (groups A and B) were categorized. Each measurement was correlated to adverse outcome. A total of 483 patients were enrolled, and 369 were admitted to hospital. Of these, 153 required C-PAP and 266 had an adverse outcome. Patients with PaO2 <60 and >100 had a higher rate of adverse outcome at time 0, in groups A and B (OR 2.52, 3.45, 2.01, respectively). About the PaO2/FiO2 ratio, the OR for < 300 was 3.10 at time 0, 4.01 in group A and 4.79 in group B. Similar odds were found for < 200 in any groups and < 100 except for group B (OR 11.57). SatO2 < 94% showed OR 1.34, 3.52 and 19.12 at time 0, in groups A and B, respectively. PaO2 < 60 and >100, SatO2 < 94% and PaO2/FiO2 ratio < 300 showed at least two- to three-fold correlation to adverse outcome. This may provide simple but clear targets for clinicians facing COVID-19 respiratory failure in a non ICU-setting.
Point-of-Interest (POI) Data Validation Methods: An Urban Case Study
Authors: Yeow Lih Wei , Low Raymond , Tan Yu Xiang , Cheah Lynette
Published: November 2021

Point-of-interest (POI) data from map sources are increasingly used in a wide range of applications, including real estate, land use, and transport planning. However, uncertainties in data quality arise from the fact that some of this data are crowdsourced and proprietary validation workflows lack transparency. Comparing data quality between POI sources without standardized validation metrics is a challenge. This study reviews and implements the available POI validation methods, working towards identifying a set of metrics that is applicable across datasets. Twenty-three validation methods were found and categorized. Most methods evaluated positional accuracy, while logical consistency and usability were the least represented. A subset of nine methods was implemented to assess four real-world POI datasets extracted for a highly urbanized neighborhood in Singapore. The datasets were found to have poor completeness with errors of commission and omission, although spatial errors were reasonably low (<60 m). Thematic accuracy in names and place types varied. The move towards standardized validation metrics depends on factors such as data availability for intrinsic or extrinsic methods, varying levels of detail across POI datasets, the influence of matching procedures, and the intended application of POI data.
Volumetric Representation and Sphere Packing of Indoor Space for Three-Dimensional Room Segmentation
Authors: Yang Fan , Che Mingliang , Zuo Xinkai , Li Lin , Zhang Jiyi , Zhang Chi
Published: November 2021

Room segmentation is a basic task for the semantic enrichment of point clouds. Recent studies have mainly projected single-floor point clouds to binary images to realize two-dimensional room segmentation. However, these methods have difficulty solving semantic segmentation problems in complex 3D indoor environments, including cross-floor spaces and rooms inside rooms; this is the bottleneck of indoor 3D modeling for non-Manhattan worlds. To make full use of the abundant geometric and spatial structure information in 3D space, a novel 3D room segmentation method that realizes room segmentation directly in 3D space is proposed in this study. The method utilizes volumetric representation based on a VDB data structure and packs an indoor space with a set of compact spheres to form rooms as separated connected components. Experimental results on different types of indoor point cloud datasets demonstrate the efficiency of the proposed method.
Editorial on the Citizen Science and Geospatial Capacity Building
Authors: Kocaman Sultan , Saran Sameer , Durmaz Murat , Kumar Senthil
Published: November 2021

This article introduces the Special Issue on “Citizen Science and Geospatial Capacity Building” and briefly evaluates the future trends in this field. This Special Issue was initiated for emphasizing the importance of citizen science (CitSci) and volunteered geographic information (VGI) in various stages of geodata collection, processing, analysis and visualization; and for demonstrating the capabilities and advantages of both approaches. The topic falls well within the main focus areas of ISPRS Commission V on Education and Outreach. The articles collected in the issue have shown the enormously wide application fields of geospatial technologies, and the need of CitSci and VGI support for efficient information extraction and synthesizing. They also pointed out various problems encountered during these processes. The needs and future research directions in this subject can broadly be categorized as; (a) data quality issues especially in the light of big data; (b) ontology studies for geospatial data suited for diverse user backgrounds, data integration, and sharing; (c) development of machine learning and artificial intelligence based online tools for pattern recognition and object identification using existing repositories of CitSci and VGI projects; and (d) open science and open data practices for increasing the efficiency, decreasing the redundancy, and acknowledgement of all stakeholders.
The Entorhinal Cortex and Adult Neurogenesis in Major Depression
Authors: Kim Il Bin , Park Seon-Cheol
Published: November 2021

Depression is characterized by impairments in adult neurogenesis. Reduced hippocampal function, which is suggestive of neurogenesis impairments, is associated with depression-related phenotypes. As adult neurogenesis operates in an activity-dependent manner, disruption of hippocampal neurogenesis in depression may be a consequence of neural circuitry impairments. In particular, the entorhinal cortex is known to have a regulatory effect on the neural circuitry related to hippocampal function and adult neurogenesis. However, a comprehensive understanding of how disruption of the neural circuitry can lead to neurogenesis impairments in depression remains unclear with respect to the regulatory role of the entorhinal cortex. This review highlights recent findings suggesting neural circuitry-regulated neurogenesis, with a focus on the potential role of the entorhinal cortex in hippocampal neurogenesis in depression-related cognitive and emotional phenotypes. Taken together, these findings may provide a better understanding of the entorhinal cortex-regulated hippocampal neurogenesis model of depression.
Adolescent Intermittent Ethanol (AIE) Enhances the Dopaminergic Response to Ethanol within the Mesolimbic Pathway during Adulthood: Alterations in Cholinergic/Dopaminergic Genes Expression in the Nucleus Accumbens Shell
Authors: Hauser Sheketha R. , Mulholland Patrick J. , Truitt William A. , Waeiss R. Aaron , Engleman Eric A. , Bell Richard L. , Rodd Zachary A.
Published: November 2021

A consistent preclinical finding is that exposure to alcohol during adolescence produces a persistent hyperdopaminergic state during adulthood. The current experiments determine that effects of Adolescent Intermittent Ethanol (AIE) on the adult neurochemical response to EtOH administered directly into the mesolimbic dopamine system, alterations in dendritic spine and gene expression within the nucleus accumbens shell (AcbSh), and if treatment with the HDACII inhibitor TSA could normalize the consequences of AIE. Rats were exposed to the AIE (4 g/kg ig; 3 days a week) or water (CON) during adolescence, and all testing occurred during adulthood. CON and AIE rats were microinjected with EtOH directly into the posterior VTA and dopamine and glutamate levels were recorded in the AcbSh. Separate groups of AIE and CON rats were sacrificed during adulthood and Taqman arrays and dendritic spine morphology assessments were performed. The data indicated that exposure to AIE resulted in a significant leftward and upward shift in the dose-response curve for an increase in dopamine in the AcbSh following EtOH microinjection into the posterior VTA. Taqman array indicated that AIE exposure affected the expression of target genes (Chrna7, Impact, Chrna5). The data indicated no alterations in dendritic spine morphology in the AcbSh or any alteration in AIE effects by TSA administration. Binge-like EtOH exposure during adolescence enhances the response to acute ethanol challenge in adulthood, demonstrating that AIE produces a hyperdopaminergic mesolimbic system in both male and female Wistar rats. The neuroadaptations induced by AIE in the AcbSh could be part of the biological basis of the observed negative consequences of adolescent binge-like alcohol exposure on adult drug self-administration behaviors.
Enhancing the Efficiency of Distraction Osteogenesis through Rate-Varying Distraction: A Computational Study
Authors: Fu Ruisen , Feng Yili , Bertrand David , Du Tianming , Liu Youjun , Willie Bettina M. , Yang Haisheng
Published: November 2021

Distraction osteogenesis (DO) is a mechanobiological process of producing new bone and overlying soft tissues through the gradual and controlled distraction of surgically separated bone segments. The process of bone regeneration during DO is largely affected by distraction parameters. In the present study, a distraction strategy with varying distraction rates (i.e., “rate-varying distraction”) is proposed, with the aim of shortening the distraction time and improving the efficiency of DO. We hypothesized that faster and better healing can be achieved with rate-varying distractions, as compared with constant-rate distractions. A computational model incorporating the viscoelastic behaviors of the callus tissues and the mechano-regulatory tissue differentiation laws was developed and validated to predict the bone regeneration process during DO. The effect of rate-varying distraction on the healing outcomes (bony bridging time and bone formation) was examined. Compared to the constant low-rate distraction, a low-to-high rate-varying distraction provided a favorable mechanical environment for angiogenesis and bone tissue differentiation, throughout the distraction and consolidation phase, leading to an improved healing outcome with a shortened healing time. These results suggest that a rate-varying clinical strategy could reduce the overall treatment time of DO and decrease the risk of complications related to the external fixator.
Stem Cells and Their Derivatives—Implications for Alveolar Bone Regeneration: A Comprehensive Review
Authors: Hollý Dušan , Klein Martin , Mazreku Merita , Zamborský Radoslav , Polák Štefan , Danišovič Ľuboš , Csöbönyeiová Mária
Published: November 2021

Oral and craniofacial bone defects caused by congenital disease or trauma are widespread. In the case of severe alveolar bone defect, autologous bone grafting has been considered a “gold standard”; however, the procedure has several disadvantages, including limited supply, resorption, donor site morbidity, deformity, infection, and bone graft rejection. In the last few decades, bone tissue engineering combined with stem cell-based therapy may represent a possible alternative to current bone augmentation techniques. The number of studies investigating different cell-based bone tissue engineering methods to reconstruct alveolar bone damage is rapidly rising. As an interdisciplinary field, bone tissue engineering combines the use of osteogenic cells (stem cells/progenitor cells), bioactive molecules, and biocompatible scaffolds, whereas stem cells play a pivotal role. Therefore, our work highlights the osteogenic potential of various dental tissue-derived stem cells and induced pluripotent stem cells (iPSCs), the progress in differentiation techniques of iPSCs into osteoprogenitor cells, and the efforts that have been made to fabricate the most suitable and biocompatible scaffold material with osteoinductive properties for successful bone graft generation. Moreover, we discuss the application of stem cell-derived exosomes as a compelling new form of “stem-cell free” therapy.
Understanding Drivers of Ocular Fibrosis: Current and Future Therapeutic Perspectives
Authors: Mallone Fabiana , Costi Roberta , Marenco Marco , Plateroti Rocco , Minni Antonio , Attanasio Giuseppe , Artico Marco , Lambiase Alessandro
Published: November 2021

Ocular fibrosis leads to severe visual impairment and blindness worldwide, being a major area of unmet need in ophthalmology and medicine. To date, the only available treatments are antimetabolite drugs that have significant potentially blinding side effects, such as tissue damage and infection. There is thus an urgent need to identify novel targets to prevent/treat scarring and postsurgical fibrosis in the eye. In this review, the latest progress in biological mechanisms underlying ocular fibrosis are discussed. We also summarize the current knowledge on preclinical studies based on viral and non-viral gene therapy, as well as chemical inhibitors, for targeting TGFβ or downstream effectors in fibrotic disorders of the eye. Moreover, the role of angiogenetic and biomechanical factors in ocular fibrosis is discussed, focusing on related preclinical treatment approaches. Moreover, we describe available evidence on clinical studies investigating the use of therapies targeting TGFβ-dependent pathways, angiogenetic factors, and biomechanical factors, alone or in combination with other strategies, in ocular tissue fibrosis. Finally, the recent progress in cell-based therapies for treating fibrotic eye disorders is discussed. The increasing knowledge of these disorders in the eye and the promising results from testing of novel targeted therapies could offer viable perspectives for translation into clinical use.
Oxidative Transformations of 3,4-Dihydroxyphenylacetaldehyde Generate Potential Reactive Intermediates as Causative Agents for Its Neurotoxicity
Authors: Ito Shosuke , Tanaka Hitomi , Ojika Makoto , Wakamatsu Kazumasa , Sugumaran Manickam
Published: November 2021

Neurogenerative diseases, such as Parkinson’s disease, are associated, not only with the selective loss of dopamine (DA), but also with the accumulation of reactive catechol-aldehyde, 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is formed as the immediate oxidation product of cytoplasmic DA by monoamine oxidase. DOPAL is well known to exhibit toxic effects on neuronal cells. Both catecholic and aldehyde groups seem to be associated with the neurotoxicity of DOPAL. However, the exact cause of toxicity caused by this compound remains unknown. Since the reactivity of DOPAL could be attributed to its immediate oxidation product, DOPAL-quinone, we examined the potential reactions of this toxic metabolite. The oxidation of DOPAL by mushroom tyrosinase at pH 5.3 produced conventional DOPAL-quinone, but oxidation at pH 7.4 produced the tautomeric quinone-methide, which gave rise to 3,4-dihydroxyphenylglycolaldehyde and 3,4-dihydroxybenzaldehyde as products through a series of reactions. When the oxidation reaction was performed in the presence of ascorbic acid, two additional products were detected, which were tentatively identified as the cyclized products, 5,6-dihydroxybenzofuran and 3,5,6-trihydroxybenzofuran. Physiological concentrations of Cu(II) ions could also cause the oxidation of DOPAL to DOPAL-quinone. DOPAL-quinone exhibited reactivity towards the cysteine residues of serum albumin. DOPAL-oligomer, the oxidation product of DOPAL, exhibited pro-oxidant activity oxidizing GSH to GSSG and producing hydrogen peroxide. These results indicate that DOPAL-quinone generates several toxic compounds that could augment the neurotoxicity of DOPAL.
Off-Target Effect of Lovastatin Disrupts Dietary Lipid Uptake and Dissemination through Pro-Drug Inhibition of the Mesenteric Lymphatic Smooth Muscle Cell Contractile Apparatus
Authors: Stephens Matthew , Roizes Simon , von der Weid Pierre-Yves
Published: November 2021

Previously published, off-target effects of statins on skeletal smooth muscle function have linked structural characteristics within this drug class to myopathic effects. However, the effect of these drugs on lymphatic vascular smooth muscle cell function, and by proxy dietary cholesterol uptake, by the intestinal lymphatic network has not been investigated. Several of the most widely prescribed statins (Atorvastatin, Pravastatin, Lovastatin, and Simvastatin) were tested for their in-situ effects on smooth muscle contractility in rat mesenteric collecting lymphatic vessels. Lovastatin and Simvastatin had a concentration-dependent effect of initially increasing vessel contraction frequency before flatlining the vessel, a phenomenon which was found to be a lactone-ring dependent phenomenon and could be ameliorated through use of Lovastatin- or Simvastatin-hydroxyacid (HA). Simvastatin treatment further resulted in mitochondrial depolymerization within primary-isolated rat lymphatic smooth muscle cells (LMCs) while Lovastatin was found to be acting in a mitochondrial-independent manner, increasing the function of RhoKinase. Lovastatin’s effect on RhoKinase was investigated through pharmacological testing and in vitro analysis of increased MLC and MYPT1 phosphorylation within primary isolated LMCs. Finally, acute in vivo treatment of rats with Lovastatin, but not Lovastatin-HA, resulted in a significantly decreased dietary lipid absorption in vivo through induced disfunction of mesenteric lymph uptake and trafficking.
Identification of DNA Damage Repair-Associated Prognostic Biomarkers for Prostate Cancer Using Transcriptomic Data Analysis
Authors: Teng Pai-Chi , Huang Shu-Pin , Liu Chia-Hsin , Lin Ting-Yi , Cho Yi-Chun , Lai Yo-Liang , Wang Shu-Chi , Yeh Hsin-Chih , Chuu Chih-Pin , Chen Deng-Neng , Cheng Wei-Chung , Li Chia-Yang
Published: November 2021

In the recent decade, the importance of DNA damage repair (DDR) and its clinical application have been firmly recognized in prostate cancer (PC). For example, olaparib was just approved in May 2020 to treat metastatic castration-resistant PC with homologous recombination repair-mutated genes; however, not all patients can benefit from olaparib, and the treatment response depends on patient-specific mutations. This highlights the need to understand the detailed DDR biology further and develop DDR-based biomarkers. In this study, we establish a four-gene panel of which the expression is significantly associated with overall survival (OS) and progression-free survival (PFS) in PC patients from the TCGA-PRAD database. This panel includes DNTT, EXO1, NEIL3, and EME2 genes. Patients with higher expression of the four identified genes have significantly worse OS and PFS. This significance also exists in a multivariate Cox regression model adjusting for age, PSA, TNM stages, and Gleason scores. Moreover, the expression of the four-gene panel is highly correlated with aggressiveness based on well-known PAM50 and PCS subtyping classifiers. Using publicly available databases, we successfully validate the four-gene panel as having the potential to serve as a prognostic and predictive biomarker for PC specifically based on DDR biology.
A Review on the Role of Stem Cells against SARS-CoV-2 in Children and Pregnant Women
Authors: Sanie-Jahromi Fatemeh , NejatyJahromy Yaser , Jahromi Rahim Raoofi
Published: November 2021

Since the COVID-19 outbreak was acknowledged by the WHO on 30 January 2020, much research has been conducted to unveil various features of the responsible SARS-CoV-2 virus. Different rates of contagion in adults, children, and pregnant women may guide us to understand the underlying infection conditions of COVID-19. In this study, we first provide a review of recent reports of COVID-19 clinical outcomes in children and pregnant women. We then suggest a mechanism that explains the curious case of COVID-19 in children/pregnant women. The unique stem cell molecular signature, as well as the very low expression of angiotensin-converting enzyme 2 and the lower ACE/ACE2 ratio in stem cells of children/pregnant women compared to adults might be the cause of milder symptoms of COVID-19 in them. This study provides the main molecular keys on how stem cells can function properly and exert their immunomodulatory and regenerative effects in COVID-19-infected children/pregnant women, while failing to replicate their role in adults. This can lay the groundwork for both predicting the pattern of spread and severity of the symptoms in a population and designing novel stem cell-based treatment and prevention strategies for COVID-19.
Chronic Systemic Curcumin Administration Antagonizes Murine Sarcopenia and Presarcopenia
Authors: Gorza Luisa , Germinario Elena , Tibaudo Lucia , Vitadello Maurizio , Tusa Chiara , Guerra Irene , Bondì Michela , Salmaso Stefano , Caliceti Paolo , Vitiello Libero , Danieli-Betto Daniela
Published: November 2021

Curcumin administration attenuates muscle disuse atrophy, but its effectiveness against aging-induced, selective loss of mass or force (presarcopenia or asthenia/dynopenia), or combined loss (sarcopenia), remains controversial. A new systemic curcumin treatment was developed and tested in 18-month-old C57BL6J and C57BL10ScSn male mice. The effects on survival, liver toxicity, loss of muscle mass and force, and satellite cell responsivity and commitment were evaluated after 6-month treatment. Although only 24-month-old C57BL10ScSn mice displayed age-related muscle impairment, curcumin significantly increased survival of both strains (+20–35%), without signs of liver toxicity. Treatment prevented sarcopenia in soleus and presarcopenia in EDL of C57BL10ScSn mice, whereas it did not affect healthy-aged muscles of C57BL6J. Curcumin-treated old C57BL10ScSn soleus preserved type-1 myofiber size and increased type-2A one, whereas EDL maintained adult values of total myofiber number and fiber-type composition. Mechanistically, curcumin only partially prevented the age-related changes in protein level and subcellular distribution of major costamere components and regulators. Conversely, it affected satellite cells, by maintaining adult levels of myofiber maturation in old regenerating soleus and increasing percentage of isolated, MyoD-positive satellite cells from old hindlimb muscles. Therefore, curcumin treatment successfully prevents presarcopenia and sarcopenia development by improving satellite cell commitment and recruitment.
Autoantibodies from Patients with Scleroderma Renal Crisis Promote PAR-1 Receptor Activation and IL-6 Production in Endothelial Cells
Authors: Simon Michèle , Lücht Christian , Hosp Isa , Zhao Hongfan , Wu Dashan , Heidecke Harald , Witowski Janusz , Budde Klemens , Riemekasten Gabriela , Catar Rusan
Published: November 2021

Background. Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc). Autoantibodies (Abs) against endothelial cell antigens have been implicated in SSc and SRC. However, their detailed roles remain poorly defined. Pro-inflammatory cytokine interleukin-6 (IL-6) has been found to be increased in SSc, but its role in SRC is unclear. Here, we aimed to determine how the autoantibodies from patients with SSc and SRC affect IL-6 secretion by micro-vascular endothelial cells (HMECs). Methods. Serum IgG fractions were isolated from either SSc patients with SRC (n = 4) or healthy individuals (n = 4) and then each experiment with HMECs was performed with SSc-IgG from a separate patient or separate healthy control. IL-6 expression and release by HMECs was assessed by quantitative reverse transcription and quantitative PCR (RT-qPCR) and immunoassays, respectively. The mechanisms underlying the production of IL-6 were analyzed by transient HMEC transfections with IL-6 promoter constructs, electrophoretic mobility shift assays, Western blots and flow cytometry. Results. Exposure of HMECs to IgG from SSc patients, but not from healthy controls, resulted in a time- and dose-dependent increase in IL-6 secretion, which was associated with increased AKT, p70S6K, and ERK1/2 signalling, as well as increased c-FOS/AP-1 transcriptional activity. All these effects could be reduced by the blockade of the endothelial PAR-1 receptor and/or c-FOS/AP-1silencing. Conclusions. Autoantibodies against PAR-1 found in patients with SSc and SRC induce IL-6 production by endothelial cells through signalling pathways controlled by the AP-1 transcription factor. These observations offer a greater understanding of adverse endothelial cell responses to autoantibodies present in patients with SRC.
PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action
Authors: Surmiak Ewa , Magiera-Mularz Katarzyna , Musielak Bogdan , Muszak Damian , Kocik-Krol Justyna , Kitel Radoslaw , Plewka Jacek , Holak Tad A. , Skalniak Lukasz
Published: November 2021

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.
Effects of Acute 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure on the Circulating and Cecal Metabolome Profile
Authors: Dopkins Nicholas , Neameh Wurood Hantoosh , Hall Alina , Lai Yunjia , Rutkovsky Alex , Gandy Alexa Orr , Lu Kun , Nagarkatti Prakash S. , Nagarkatti Mitzi
Published: November 2021

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a polyhalogenated planar hydrocarbon belonging to a group of highly toxic and persistent environmental contaminants known as “dioxins”. TCDD is an animal teratogen and carcinogen that is well characterized for causing immunosuppression through activation of aryl hydrocarbon receptor (AHR). In this study, we investigated the effect of exposure of mice to an acute dose of TCDD on the metabolic profile within the serum and cecal contents to better define the effects of TCDD on host physiology. Our findings demonstrated that within the circulating metabolome following acute TCDD exposure, there was significant dysregulation in the metabolism of bioactive lipids, amino acids, and carbohydrates when compared with the vehicle (VEH)-treated mice. These widespread changes in metabolite abundance were identified to regulate host immunity via modulating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated protein kinase (ERK1/2) activity and work as biomarkers for a variety of organ injuries and dysfunctions that follow TCDD exposure. Within the cecal content of mice exposed to TCDD, we were able to detect changes in inflammatory markers that regulate NF-κB, markers of injury-related inflammation, and changes in lysine degradation, nicotinamide metabolism, and butanoate metabolism, which collectively suggested an immediate suppression of broad-scale metabolic processes in the gastrointestinal tract. Collectively, these results demonstrate that acute TCDD exposure results in immediate irregularities in the circulating and intestinal metabolome, which likely contribute to TCDD toxicity and can be used as biomarkers for the early detection of individual exposure.
Omega-3 Polyunsaturated Fatty Acid Attenuates Uremia-Induced Brain Damage in Mice
Authors: Kim Eun-Ji , Ham Young Rok , Shin Jin Ah , Jeong Jin Young , Na Ki Ryang , Lee Kang Wook , Kim Jwa-Jin , Choi Dae Eun
Published: November 2021

Although the cause of neurological disease in patients with chronic kidney disease (CKD) has not been completely identified yet, recent papers have identified accumulated uremic toxin as its main cause. Additionally, omega-3 polyunsaturated fatty acid (ω-3 PUFA) plays an important role in maintaining normal nerve function, but its protective effects against uremic toxin is unclear. The objective of this study was to identify brain damage caused by uremic toxicity and determine the protective effects of ω-3 PUFA against uremic toxin. We divided mice into the following groups: wild-type (wt) sham (n = 8), ω-3 PUFA sham (n = 8), Fat-1 sham (n = 8), ischemia-reperfusion (IR) (n = 20), and ω-3 PUFA+IR (n = 20) Fat-1+IR (n = 20). Brain tissue, kidney tissue, and blood were collected three days after the operation of mice (sham and IR operation). This study showed that Ki67 and neuronal nuclei (NeuN) decreased in the brain of uremic mice as compared to wt mice brain, but increased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. The pro-apoptotic protein expressions were increased, whereas anti-apoptotic protein expression decreased in the brain of uremic mice as compared to wt mice brain. However, apoptotic protein expression decreased in the ω-3 PUFA-treated uremic mice and the brain of uremic Fat-1 mice as compared to the brain of uremic mice. Furthermore, the brain of ω-3 PUFA-treated uremic mice and uremic Fat-1 mice showed increased expression of p-PI3K, p-PDK1, and p-Akt as compared to the brain of uremic mice. We confirm that uremic toxin damages the brain and causes cell death. In these injuries, ω-3 PUFA plays an important role in neuroprotection through PI(3)K-Akt signaling.
Hydroxylation of the Acetyltransferase NAA10 Trp38 Is Not an Enzyme-Switch in Human Cells
Authors: Ree Rasmus , Krogstad Karoline , McTiernan Nina , Jakobsson Magnus E. , Arnesen Thomas
Published: November 2021

NAA10 is a major N-terminal acetyltransferase (NAT) that catalyzes the cotranslational N-terminal (Nt-) acetylation of 40% of the human proteome. Several reports of lysine acetyltransferase (KAT) activity by NAA10 exist, but others have not been able to find any NAA10-derived KAT activity, the latter of which is supported by structural studies. The KAT activity of NAA10 towards hypoxia-inducible factor 1α (HIF-1α) was recently found to depend on the hydroxylation at Trp38 of NAA10 by factor inhibiting HIF-1α (FIH). In contrast, we could not detect hydroxylation of Trp38 of NAA10 in several human cell lines and found no evidence that NAA10 interacts with or is regulated by FIH. Our data suggest that NAA10 Trp38 hydroxylation is not a switch in human cells and that it alters its catalytic activity from a NAT to a KAT.
Unexpected Interacting Effects of Physical (Radiation) and Chemical (Bisphenol A) Treatments on Male Reproductive Functions in Mice
Authors: Wieckowski Margaux , Ranga Stéphanie , Moison Delphine , Messiaen Sébastien , Abdallah Sonia , Granon Sylvie , Habert René , Rouiller-Fabre Virginie , Livera Gabriel , Guerquin Marie-Justine
Published: November 2021

For decades, numerous chemical pollutants have been described to interfere with endogenous hormone metabolism/signaling altering reproductive functions. Among these endocrine disrupting substances, Bisphenol A (BPA), a widely used compound, is known to negatively impact germ and somatic cells in the testis. Physical agents, such as ionizing radiation, were also described to perturb spermatogenesis. Despite the fact that we are constantly exposed to numerous environmental chemical and physical compounds, very few studies explore the impact of combined exposure to chemical and physical pollutants on reproductive health. The aim of this study was to describe the impact of fetal co-exposure to BPA and IR on testicular function in mice. We exposed pregnant mice to 10 µM BPA (corresponding to 0.5 mg/kg/day) in drinking water from 10.5 dpc until birth, and we irradiated mice with 0.2 Gy (γ-ray, RAD) at 12.5 days post-conception. Co-exposure to BPA and γ-ray induces DNA damage in fetal germ cells in an additive manner, leading to a long-lasting decrease in germ cell abundance. We also observed significant alteration of adult steroidogenesis by RAD exposure independently of the BPA exposure. This is illustrated by the downregulation of steroidogenic genes and the decrease of the number of adult Leydig cells. As a consequence, courtship behavior is modified, and male ultrasonic vocalizations associated with courtship decreased. In conclusion, this study provides evidence for the importance of broadening the concept of endocrine disruptors to include physical agents, leading to a reevaluation of risk management and regulatory decisions.
Immunomodulatory Lectin-like Peptides for Fish Erythrocytes-Targeting as Potential Antiviral Drug Delivery Platforms
Authors: Salvador-Mira Maria , Chico Veronica , Arostica Monica , Guzmán Fanny , Roher Nerea , Perez Luis , Ortega-Villaizan Maria del Mar
Published: November 2021

One of the challenges of science in disease prevention is optimizing drug and vaccine delivery. Until now, many strategies have been employed in this sector, but most are quite complex and labile. To overcome these limitations, great efforts are directed to coupling drugs to carriers, either of natural or synthetic origin. Among the most studied cell carriers are antigen-presenting cells (APCs), however, red blood cells (RBCs) are positioned as attractive carriers in drug delivery due to their abundance and availability in the body. Furthermore, fish RBCs have a nucleus and have been shown to have a strong involvement in modulating the immune response. In this study, we evaluated the binding of three peptides to rainbow trout RBCs, two lectin-like peptides and another derived from Plasmodium falciparum membrane protein, in order to take advantage of this peptide-RBCs binding to generate tools to improve the specificity, efficacy, immunostimulatory effect, and safety of the antiviral therapeutic or prophylactic administration systems currently used.
Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line
Authors: Jee Ha-yeon , Lee Yoon-Gyeong , Lee Sol , Elvira Rosalie , Seo Hye-eun , Lee Ji-Yeon , Han Jaeseok , Lee Kyungho
Published: November 2021

Protein synthesis is important for maintaining cellular homeostasis under various stress responses. In this study, we screened an anticancer drug library to select compounds with translational repression functions. AZD8055, an ATP-competitive mechanistic target of rapamycin complex 1/2 (mTORC1/2) inhibitor, was selected as a translational suppressor. AZD8055 inhibited protein synthesis in mouse embryonic fibroblasts and hepatocellular carcinoma HepG2 cells. Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) were activated during the early phase of mTORC1/2 inhibition by AZD8055 treatment. Combined treatment of AZD8055 with the MAPK kinase1/2 (MEK1/2) inhibitor refametinib or the p38 inhibitor SB203580 markedly decreased translation in HepG2 cells. Thus, the inhibition of ERK1/2 or p38 may enhance the efficacy of AZD8055-mediated inhibition of protein synthesis. In addition, AZD8055 down-regulated the phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), and AZD8055-induced phosphorylation of ERK1/2 and p38 had no effect on phosphorylation status of 4E-BP1. Interestingly, AZD8055 modulated the 4E-BP1 mRNA pool by up-regulating ERK1/2 and p38 pathways. Together, these results suggest that AZD8055-induced activation of MAPKs interferes with inhibition of protein synthesis at an early stage of mTORC1/2 inhibition, and that it may contribute to the development of resistance to mTORC1/2 inhibitors.
Distinct Exosomal miRNA Profiles from BALF and Lung Tissue of COPD and IPF Patients
Authors: Kaur Gagandeep , Maremanda Krishna Prahlad , Campos Michael , Chand Hitendra S. , Li Feng , Hirani Nikhil , Haseeb M. A. , Li Dongmei , Rahman Irfan
Published: November 2021

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic, progressive lung ailments that are characterized by distinct pathologies. Early detection biomarkers and disease mechanisms for these debilitating diseases are lacking. Extracellular vesicles (EVs), including exosomes, are small, lipid-bound vesicles attributed to carry proteins, lipids, and RNA molecules to facilitate cell-to-cell communication under normal and diseased conditions. Exosomal miRNAs have been studied in relation to many diseases. However, there is little to no knowledge regarding the miRNA population of bronchoalveolar lavage fluid (BALF) or the lung-tissue-derived exosomes in COPD and IPF. Here, we determined and compared the miRNA profiles of BALF- and lung-tissue-derived exosomes of healthy non-smokers, smokers, and patients with COPD or IPF in independent cohorts. Results: Exosome characterization using NanoSight particle tracking and TEM demonstrated that the BALF-derived exosomes were ~89.85 nm in size with a yield of ~2.95 × 1010 particles/mL in concentration. Lung-derived exosomes were larger in size (~146.04 nm) with a higher yield of ~2.38 × 1011 particles/mL. NGS results identified three differentially expressed miRNAs in the BALF, while there was one in the lung-derived exosomes from COPD patients as compared to healthy non-smokers. Of these, miR-122-5p was three- or five-fold downregulated among the lung-tissue-derived exosomes of COPD patients as compared to healthy non-smokers and smokers, respectively. Interestingly, there were a large number (55) of differentially expressed miRNAs in the lung-tissue-derived exosomes of IPF patients compared to non-smoking controls. Conclusions: Overall, we identified lung-specific miRNAs associated with chronic lung diseases that can serve as potential biomarkers or therapeutic targets.
Effect of Epigallocatechin-3-Gallate on EGFR Signaling and Migration in Non-Small Cell Lung Cancer
Authors: Minnelli Cristina , Cianfruglia Laura , Laudadio Emiliano , Mobbili Giovanna , Galeazzi Roberta , Armeni Tatiana
Published: November 2021

The epidermal growth factor receptor (EGFR) is one of the most well-studied molecular targets in non-small cell lung cancer (NSCLC) and tyrosine kinase inhibitors have been shown to be effective in the treatment of advanced NSCLC. Nevertheless, the efficacy of tyrosine kinase inhibitors could be compromised by additional mutations in EGFR and compensatory activations of other pathways. Epigallocatechin-3-gallate (EGCG), the main bioactive molecule in green tea, acts as a tyrosine kinase inhibitor toward cancer cells overexpressing EGFR (wild-type). However, little information has been reported on the effect of EGCG on EGFR with activating mutations. In this study, we evaluated the ability of EGCG to inhibit EGFR signaling activation in three different NSCLC cell lines containing wild-type EGFR or EGFR with additional mutations. The effect on proliferation, apoptosis, migration, and vinculin expression was then studied. Overall, our results demonstrate that EGCG polyphenol inhibits cell proliferation and migration in NSCLC cell lines, although with different efficacy and mechanisms. These data may be of interest for an evaluation of the use of EGCG as an adjunct to NSCLC therapies.
Sustainable UV-Crosslinkable Acrylic Pressure-Sensitive Adhesives for Medical Application
Authors: Ossowicz-Rupniewska Paula , Bednarczyk Paulina , Nowak Małgorzata , Nowak Anna , Duchnik Wiktoria , Kucharski Łukasz , Rokicka Joanna , Klimowicz Adam , Czech Zbigniew
Published: November 2021

This study aimed to investigate the potential of photoreactive acrylate patches as systems for transdermal drug delivery, in particular, using more renewable alternatives and more environmentally friendly synthesis routes of transdermal patches. Therefore, the aim of this study was to develop a transdermal patch containing ibuprofen and investigate its performance in vitro through the pigskin. Transparent patches were prepared using four acrylate copolymers with an incorporated photoinitiator. Two types of transdermal patches based on the photocrosslinking acrylic prepolymers with isobornyl methacrylate as biocomponent and monomer increasing Tg (“hard”) were manufactured. The obtained patches were characterized for their adhesive properties and tested for permeability of the active substance. It turns out that patches whose adhesive matrix is photoreactive polyacrylate copolymers have a higher cohesion than patches from commercial adhesives, while the modification of the copolymers with isobornyl methacrylate resulted in an improvement in adhesion and tack. This study demonstrates the feasibility of developing photoreactive acrylic-based transdermal patches that contain biocomponents that can deliver a therapeutically relevant dose of ibuprofen.
Heterotrimeric G Proteins in Plants: Canonical and Atypical Gα Subunits
Authors: Maruta Natsumi , Trusov Yuri , Jones Alan M. , Botella Jose R.
Published: November 2021

Heterotrimeric GTP-binding proteins (G proteins), consisting of Gα, Gβ and Gγ subunits, transduce signals from a diverse range of extracellular stimuli, resulting in the regulation of numerous cellular and physiological functions in Eukaryotes. According to the classic G protein paradigm established in animal models, the bound guanine nucleotide on a Gα subunit, either guanosine diphosphate (GDP) or guanosine triphosphate (GTP) determines the inactive or active mode, respectively. In plants, there are two types of Gα subunits: canonical Gα subunits structurally similar to their animal counterparts and unconventional extra-large Gα subunits (XLGs) containing a C-terminal domain homologous to the canonical Gα along with an extended N-terminal domain. Both Gα and XLG subunits interact with Gβγ dimers and regulator of G protein signalling (RGS) protein. Plant G proteins are implicated directly or indirectly in developmental processes, stress responses, and innate immunity. It is established that despite the substantial overall similarity between plant and animal Gα subunits, they convey signalling differently including the mechanism by which they are activated. This review emphasizes the unique characteristics of plant Gα subunits and speculates on their unique signalling mechanisms.
Dynamic Hormone Gradients Regulate Wound-Induced de novo Organ Formation in Tomato Hypocotyl Explants
Authors: Larriba Eduardo , Sánchez-García Ana Belén , Justamante María Salud , Martínez-Andújar Cristina , Albacete Alfonso , Pérez-Pérez José Manuel
Published: November 2021

Plants have a remarkable regenerative capacity, which allows them to survive tissue damage after biotic and abiotic stresses. In this study, we use Solanum lycopersicum ‘Micro-Tom’ explants as a model to investigate wound-induced de novo organ formation, as these explants can regenerate the missing structures without the exogenous application of plant hormones. Here, we performed simultaneous targeted profiling of 22 phytohormone-related metabolites during de novo organ formation and found that endogenous hormone levels dynamically changed after root and shoot excision, according to region-specific patterns. Our results indicate that a defined temporal window of high auxin-to-cytokinin accumulation in the basal region of the explants was required for adventitious root formation and that was dependent on a concerted regulation of polar auxin transport through the hypocotyl, of local induction of auxin biosynthesis, and of local inhibition of auxin degradation. In the apical region, though, a minimum of auxin-to-cytokinin ratio is established shortly after wounding both by decreasing active auxin levels and by draining auxin via its basipetal transport and internalization. Cross-validation with transcriptomic data highlighted the main hormonal gradients involved in wound-induced de novo organ formation in tomato hypocotyl explants.
Functional Genomics for Plant Breeding
Authors: Maghuly Fatemeh , Myśków Beata , Till Bradley J.
Published: November 2021

To face the rapidly growing world human population, an increase in agricultural productivity and production is necessary to overcome the enhanced food demand [...]