bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical Inference for Odds Ratio of Two Proportions in Bilateral Correlated Data
Authors: Li Zhiming , Ma Changxing
Published: September 2022

Bilateral correlated data frequently arise in medical clinical studies such as otolaryngology and ophthalmology. Based on an equal correlation coefficient model, this paper mainly aimed to investigate the statistical inference for the odds ratio of two proportions in bilateral correlated data, including not only three test procedures but also four confidence interval (CI) constructions. Through iterative algorithms, all unknown parameters are estimated in order to construct the likelihood ratio, score and Wald-type tests. Furthermore, the profile likelihood CI, score CI, and Wald-type CI are obtained by the bisection root-finding algorithm. We provided another Wald-type CI based on an asymptotic normality property. The performance of the proposed tests were investigated with regard to empirical type I error rate and power, and CI methods were compared in terms of mean coverage probability and mean interval width. Numerical simulations show that the score test is more robust, and has higher power than other tests. The score CI also has a shorter interval width, and its coverage probability is closer to 0.95. A real example is used to illustrate the proposed methods.
Agglomeration-Free and Air-Inert Garnet for Upgrading PEO/Garnet Composite Solid State Electrolyte
Authors: Cheng Jun , Zhang Hongqiang , Li Deping , Li Yuanyuan , Zeng Zhen , Ji Fengjun , Wei Youri , Xu Xiao , Sun Qing , Wang Shang , Lu Jingyu , Ci Lijie
Published: September 2022

Due to the intrinsically high ionic conductivity and good interfacial stability towards lithium, garnet-type solid electrolytes are usually introduced into polymer electrolytes as fillers to prepare polymer/garnet composite electrolytes, which can improve the ionic conductivity and enhance the mechanical strength to suppress Li dendrites. However, the surface Li2CO3 and/or LiOH passive layers which form when garnet is exposed to the air greatly reduce the enhancement effect of garnet on the composite electrolyte. Furthermore, compared with micro-size particles, nano-size garnet fillers exhibit a better effect on enhancing the performance of composite solid electrolytes. Nevertheless, inferior organic/inorganic interphase compatibility and high specific surface energy of nanofillers inevitably cause agglomeration, which severely hinders the effect of nanoparticles for promoting composite solid electrolytes. Herein, a cost-effective amphipathic 3-Aminopropyltriethoxysilane coupling agent is introduced to modify garnet fillers, which effectively expands the air stability of garnet and greatly improves the dispersion of garnet fillers in the polymer matrix. The well-dispersed garnet filler/polymer interface is intimate through the bridging effect of the silane coupling agent, resulting in boosted ionic conductivity (0.72 × 10−4 S/cm at room temperature) of the composite electrolyte, enhanced stability against lithium dendrites (critical current density > 0.5 mA/cm2), and prolonged cycling life of LFP/Li full cells.
A Unified Power Converter for Solar PV and Energy Storage in dc Microgrids
Authors: Coelho Sergio , Monteiro Vitor , Sousa Tiago J. C. , Barros Luis A. M. , Pedrosa Delfim , Couto Carlos , Afonso Joao L.
Published: September 2022

This paper deals with the development and experimental validation of a unified power converter for application in dc microgrids, contemplating the inclusion of solar photovoltaic (PV) panels and energy storage systems (ESS), namely batteries. Considering the limitations presented by the current structure of the power grid, mostly highlighted by the accentuated integration of emerging technologies (ESS, renewables, electric vehicles, and electrical appliances that natively operate in dc), it is extremely pertinent to adopt new topologies, architectures, and paradigms. In particular, decentralized power systems, unified topologies, and correspondent control algorithms are representative of a new trend towards a reduction in the number of power converters. Thus, the developed solution is designed to operaSAVE-15te at a nominal power of 3.6 kW, with a switching frequency of 100 kHz, and in four operation modes concerning power flow: (i) solar PV panels to batteries (PV2B); (ii) solar PV panels to dc grid (PV2G); (iii) batteries to dc grid (B2G); (iv) dc grid to batteries (G2B). Moreover, a dual active bridge converter guarantees galvanic isolation, while two back-end dc–dc converters are responsible for interfacing solar PV panels and batteries. The experimental validation of the proposed unified power converter proves its application value to self-consumption production units.
FT-IR Analysis of Structural Changes in Ketoprofen Lysine Salt and KiOil Caused by a Pulsed Magnetic Field
Authors: Pullano Salvatore Andrea , Marcianò Gianmarco , Bianco Maria Giovanna , Oliva Giuseppe , Rania Vincenzo , Vocca Cristina , Cione Erika , De Sarro Giovambattista , Gallelli Luca , Romeo Pietro , La Gatta Antonio , Fiorillo Antonino S.
Published: September 2022

High-intensity, low-frequency magnetic fields (MFs) have been widely used in the treatment of diseases and in drug delivery, even though they could induce structural changes in pharmacological molecules. Morphological changes in ketoprofen and KiOil were investigated through Fourier-transform infrared spectroscopy (FT-IR). Unsupervised principal component analysis was carried out for data clustering. Clinical validation on 22 patients with lower back pain was managed using diamagnetic therapy plus topical ketoprofen or KiOil. The Numerical Rating Scale (NRS) and Short-Form Health Survey 36 (SF-36) were used to evaluate clinical and functional response. Ketoprofen showed clear clustering among samples exposed to MF (4000–650 cm−1), and in the narrow frequency band (1675–1475 cm−1), results evidenced structural changes which involved other excipients than ketoprofen. KiOil has evidenced structural modifications in the subcomponents of the formulation. Clinical treatment with ketoprofen showed an average NRS of 7.77 ± 2.25 before and an average NRS of 2.45 ± 2.38 after MF treatment. There was a statistically significant reduction in NRS (p = 0.003) and in SF-36 (p < 0.005). Patients treated with KiOil showed an average NRS of 7.59 ± 2.49 before treatment and an average NRS of 1.90 ± 2.26 after treatment (p < 0.005). SF-36 showed statistical significance for all items except limitations due to emotional problems. A high-intensity pulsed magnetic field is an adjunct to topical treatment in patients with localized pain, and the effect of MF does not evidence significant effects on the molecules.
Optimization of Propagation of the Polish Strain of Aldrovanda vesiculosa in Tissue Culture
Authors: Parzymies Marzena , Pogorzelec Magdalena , Świstowska Alicja
Published: September 2022

Aldrovanda vesiculosa is a rare and critically endangered carnivorous plant species. Its populations have declined worldwide, so there is a need to protect the species from extinction. The research was conducted to establish an effective method of in vitro propagation of the species in order to obtain plants for reintroduction in the wild. The procedures included disinfection, multiplication, and acclimatization of plants. Contamination-free in vitro cultures were established using shoots and turions, which were disinfected with 0.25% sodium hypochlorite. The shoots were first defoliated. The explants regenerated better in liquid 1/5 MS medium than in solidified one. The optimum medium for the multiplication phase contained MS macro- and microelements diluted to 1/10. Plants cultivated in that medium were of good quality, long, and branched. The advantageous effect of medium was also confirmed by the content of photosynthetic pigments in the plant material. The content of chlorophyll a was highest in plants cultivated in 1/5 or 1/10 MS medium. The plants obtained were acclimatized to ex vitro conditions and reintroduced in the wild.
Evaluation of the Antifungal Activity of Bacillus amyloliquefaciens and B. velezensis and Characterization of the Bioactive Secondary Metabolites Produced against Plant Pathogenic Fungi
Authors: Soliman Shereen A. , Khaleil Mona M. , Metwally Rabab A.
Published: September 2022

Endophytic bacteria are plant-beneficial bacteria with a broad host range. They provide numerous benefits to their hosts, helping them tolerate several biotic and abiotic stresses. An interest has recently been developed in endophytic bacteria which are producing bioactive compounds that contribute to the biological control of various phytopathogens. This research paper aimed to investigate the potentiality of new local strains of endophytic bacteria such as Bacillus amyloliquefaciens and B. velezensis and the production of several antimicrobial metabolites associated with the biocontrol of Alternaria sp., which cause serious diseases and affect important vegetable crops in Egypt. Twenty-five endophytic bacteria isolates were obtained from different plants cultivated in El-Sharkia Governorate, Egypt. Dual culture technique was used to evaluate the bacterial isolates’ antagonistic potentiality against Alternaria sp. and Helminthosporium sp. The most active bacterial isolates obtained were selected for further screening. The antifungal activity of the most active endophytic bacterial isolate was assessed in vivo on pepper seedlings as a biocontrol agent against Alternaria sp. A significant antifungal activity was recorded with isolates C1 and T5 against Alternaria sp. and Helminthosporium sp. The bacterial endophyte discs of C1 and T5 showed the highest inhibitory effect against Alternaria sp. at 4.7 and 3.1 cm, respectively, and Helminthosporium sp. at 3.9 and 4.0 cm, respectively. The most active endophytic isolates C1 and T5 were identified and the 16S rRNA sequence was submitted to the NCBI GenBank database with accession numbers: MZ945930 and MZ945929 for Bacillus amyloliquefaciens and Bacillus velezensis, respectively. The deformity of pathogenic fungal mycelia of Alternaria sp. and Helminthosporium sp. was studied under the biotic stress of bacteria. The culture filtrates of B. amyloliquefaciens and B. velezensis were extracted with different solvents, and the results indicated that hexane was the most efficient. Gas Chromatography-Mass Spectrometry revealed that Bis (2-ethylhexyl) phthalate, Bis (2-ethylhexyl) ester, and N,N-Dimethyldodecylamine were major constituents of the endophytic crude extracts obtained from B. amyloliquefaciens and B. velezensis. The in vivo results showed that Alternaria sp. infection caused the highest disease incidence, leading to a high reduction in plant height and in the fresh and dry weights of pepper plants. With B. amyloliquefaciens application, DI significantly diminished compared to Alternaria sp. infected pepper plants, resulting in an increase in their morphological parameters. Our findings allow for a reduction of chemical pesticide use and the control of some important plant diseases.
Nuclear Molecular Imaging of Disease Burden and Response to Treatment for Cardiac Amyloidosis
Authors: Zhao Min , Calabretta Raffaella , Yu Josef , Binder Patrick , Hu Shuo , Hacker Marcus , Li Xiang
Published: September 2022

Cardiac amyloidosis (CA) is a heterogeneous group of diseases in which extracellular insoluble amyloid proteins are deposited in specific organs and tissues locally or systemically, thereby interfering with physiological function. Transthyretin protein (TTR) and light chain (AL) amyloidosis are the most common types of cardiac amyloidosis. Radionuclide bone scintigraphy has recently become the most common non-invasive test for the diagnosis of TTR-CA but is of limited value for the diagnosis of AL-CA. PET has proved promising for the diagnosis of CA and its applications are expected to expand in the future. This review summarizes the current bone scintigraphy and amyloid-targeting Positron emission tomography (PET) imaging, the binding imaging properties of radiotracers, and the values of diagnosis, prognosis, and monitoring therapy response in CA.
Development of Genetic Tools in Glucoamylase-Hyperproducing Industrial Aspergillus niger Strains
Authors: Liu Dandan , Liu Qian , Guo Wenzhu , Liu Yin , Wu Min , Zhang Yongli , Li Jingen , Sun Wenliang , Wang Xingji , He Qun , Tian Chaoguang
Published: September 2022

The filamentous fungus Aspergillus niger is widely exploited by the fermentation industry for the production of enzymes, particularly glucoamylase. Although a variety of genetic techniques have been successfully used in wild-type A. niger, the transformation of industrially used strains with few conidia (e.g., A. niger N1) or that are even aconidial (e.g., A. niger O1) remains laborious. Herein, we developed genetic tools, including the protoplast-mediated transformation and Agrobacterium tumefaciens-mediated transformation of the A. niger strains N1 and O1 using green fluorescent protein as a reporter marker. Following the optimization of various factors for protoplast release from mycelium, the protoplast-mediated transformation efficiency reached 89.3% (25/28) for N1 and 82.1% (32/39) for O1. The A. tumefaciens-mediated transformation efficiency was 98.2% (55/56) for N1 and 43.8% (28/64) for O1. We also developed a marker-free CRISPR/Cas9 genome editing system using an AMA1-based plasmid to express the Cas9 protein and sgRNA. Out of 22 transformants, 9 albA deletion mutants were constructed in the A. niger N1 background using the protoplast-mediated transformation method and the marker-free CRISPR/Cas9 system developed here. The genome editing methods improved here will accelerate the elucidation of the mechanism of glucoamylase hyperproduction in these industrial fungi and will contribute to the use of efficient targeted mutation in other industrial strains of A. niger.
WDR73 Depletion Destabilizes PIP4K2C Activity and Impairs Focal Adhesion Formation in Galloway–Mowat Syndrome
Authors: Li Hongyan , Liu Fang , Kuang Hanzhe , Teng Hua , Chen Siyi , Zeng Sijing , Zhou Qimin , Li Zhaokai , Liang Desheng , Li Zhuo , Wu Lingqian
Published: September 2022

(1) Background: Galloway–Mowat syndrome (GAMOS) is a rare genetic disease, classically characterized by a combination of various neurological symptoms and nephrotic syndrome. WDR73 is the pathogenic gene responsible for GAMOS1. However, the pathological and molecular mechanisms of GAMOS1, especially nephrotic syndrome caused by WDR73 deficiency, remain unknown. (2) Methods and Results: In this study, we first observed remarkable cellular morphological changes including impaired cell adhesion, decreased pseudopodia, and G2/M phase arrest in WDR73 knockout (KO) HEK 293 cells. The differentially expressed genes in WDR73 KO cells were enriched in the focal adhesion (FA) pathway. Additionally, PIP4K2C, a phospholipid kinase also involved in the FA pathway, was subsequently validated to interact with WDR73 via protein microarray and GST pulldown. WDR73 regulates PIP4K2C protein stability through the autophagy–lysosomal pathway. The stability of PIP4K2C was significantly disrupted by WDR73 KO, leading to a remarkable reduction in PIP2 and thus weakening the FA formation. In addition, we found that podocyte-specific conditional knockout (Wdr73 CKO) mice showed high levels of albuminuria and podocyte foot process injury in the ADR-induced model. FA formation was impaired in primary podocytes derived from Wdr73 CKO mice. (3) Conclusions: Since FA has been well known for its critical roles in maintaining podocyte structures and function, our study indicated that nephrotic syndrome in GAMOS1 is associated with disruption of FA caused by WDR73 deficiency.
The Interaction Effect of Laser Irradiation and 6-Benzylaminopurine Improves the Chemical Composition and Biological Activities of Linseed (Linum usitatissimum) Sprouts
Authors: Zrig Ahlem , Najar Basma , Magdy Korany Shereen , Hassan Abdelrahim H. A. , Alsherif Emad A. , Ali Shah Anis , Fahad Shah , Selim Samy , AbdElgawad Hamada
Published: September 2022

Even though laser light (LL) and 6-benzylaminopurine (BAP) priming are well-known as promising strategies for increasing the growth and nutritional value of several plants, no previous studies have investigated their synergistic effect. Herein, we investigated the effects of laser light, 6-benzylaminopurine (BAP) priming, and combined LL-BAP treatment on the nutritional value, chemical composition, and the biological activity of Linum usitatissimum sprouts. The fresh weight, leaf pigments, primary and secondary metabolites, enzymes, and antimicrobial activities were determined. A substantial enhancement was observed in the growth characteristics and leaf pigments of laser-irradiated and BAP-primed sprouts. Furthermore, the combined treatments improved the accumulation of minerals, vitamins, and amino acids, and also enhanced the N-metabolism more than LL or BAP alone. Furthermore, the combined priming boosted the antioxidant capacity by increasing the contents of fatty acids, phenols, and flavonoids. Antimicrobial activity and the highest increase in bioactive compounds were recorded in linseed sprouts simultaneously treated with LL and BAP. This work suggests that priming L. usitatissimum sprouts with laser light and BAP is a promising approach that can improve the nutritional value and health-promoting impacts of L. usitatissimum sprouts.
Late Miocene Leaves and Endocarps of Choerospondias (Anacardiaceae) from Zhejiang, Eastern China: Implications for Paleogeography and Paleoclimate
Authors: Xiao Liang , Wu Zeling , Guo Liyan , Li Xiangchuan , Ji Deshuang , Xia Xiaoyuan , Wang Jianan , Liang Jiaqi , Sun Nan
Published: September 2022

Choerospondias (Anacardiaceae), characterized by radially arranged germination pores near the top, is a monotypic genus mainly distributed in subtropical and tropical eastern Asia, while fossil records indicate a wide distribution throughout Eurasia during the Cenozoic. In this study, we reported three-dimensionally preserved Choerospondias endocarps, and the associated compressed leaves from the late Miocene Shengxian Formation in Tiantai, Zhejiang, eastern China. The plant remains were assigned to two new fossil species. The endocarps were identified as Choerospondiastiantaiensis sp. nov., and the leaves were identified as Choerospondias mioaxillaris sp. nov. Based on fossil records and climate fluctuation during the Cenozoic, we conclude that Choerospondias may have originated from Europe in the early Eocene and then spread to Asia along the coast and island chains of the Tethys and Paratethys oceans. The distribution position of the current fossils was adjacent to the northern boundary of the modern distribution of Choerospondias in East Asia, indicating that the distribution pattern of Choerospondias in East Asia likely formed no later than the late Miocene. We reconstructed the late Miocene paleoclimate of eastern Zhejiang by using the method of climate analysis of endemic species (CAES), and then compared it to the data reconstructed in previous studies. The results indicate that the late Miocene climate in eastern Zhejiang was similar to or warmer and more humid than the modern climate in this region.
Correction: Wang et al. TERT Promoter Revertant Mutation Inhibits Melanoma Growth through Intrinsic Apoptosis. Biology 2022, 11, 141
Authors: Wang Yanbing , Chen Yiwu , Li Chang , Xiao Zhiwei , Yuan Hongming , Zhang Yuanzhu , Pang Daxin , Tang Xiaochun , Li Mengjing , Ouyang Hongsheng
Published: September 2022

The authors would like to make the following correction to the published paper [...]
Biomechanical Analysis on Skilled Badminton Players during Take-Off Phase in Forehand Overhead Strokes: A Pilot Study
Authors: Cui Xinze , Lam Wing Kai , Gao Qiang , Wang Xin , Zhao Tianyu
Published: September 2022

Different movement speeds can contribute to different joint loading in sports. Joint contact force is the actual force acting on the articular surface, which could predict performance and injury, but is rarely reported for badminton overhead strokes. Through an approach using musculoskeletal modelling, six male elite badminton players performed forehand overhead strokes at different movement speeds (fast (100%) vs. moderate (90%)). The synchronized kinematics and ground reaction force (GRF) data were measured using a motion capturing system and a force platform. All kinematics and GRF information were input into the AnyBody musculoskeletal modelling to determine the three-dimensional hip, knee and ankle contact forces. Paired t-tests were performed to assess the significant differences among the GRF, joint kinematics and contact force variables between the movement speed conditions. The results showed that when compared with the moderate movement condition, participants performing faster stroke movements induced larger first and second vertical peaks and larger first horizontal peak but lower second horizontal peak, and it also led to higher peak ankle lateral and distal contact forces, knee lateral and distal contact forces, and hip distal contact forces. Additionally, fast movements corresponded with distinct joint angles and velocities at the instant of initial contact, peak and take-off among the hip, knee and ankle joints compared with moderate movement speeds. The current results suggest that changes in joint kinematics and loading could contribute to changes in movement speeds. However, the relationship between lower limb joint kinematics and contact forces during overhead stroke is unclear and requires further investigation.
PHLPP Inhibitor NSC74429 Is Neuroprotective in Rodent Models of Cardiac Arrest and Traumatic Brain Injury
Authors: Jackson Travis C. , Dezfulian Cameron , Vagni Vincent A. , Stezoski Jason , Janesko-Feldman Keri , Kochanek Patrick M.
Published: September 2022

Pleckstrin homology domain and leucine rich repeat protein phosphatase (PHLPP) knockout mice have improved outcomes after a stroke, traumatic brain injury (TBI), and decreased maladaptive vascular remodeling following vascular injury. Thus, small-molecule PHLPP inhibitors have the potential to improve neurological outcomes in a variety of conditions. There is a paucity of data on the efficacy of the known experimental PHLPP inhibitors, and not all may be suited for targeting acute brain injury. Here, we assessed several PHLPP inhibitors not previously explored for neuroprotection (NSC13378, NSC25247, and NSC74429) that had favorable predicted chemistries for targeting the central nervous system (CNS). Neuronal culture studies in staurosporine (apoptosis), glutamate (excitotoxicity), and hydrogen peroxide (necrosis/oxidative stress) revealed that NSC74429 at micromolar concentrations was the most neuroprotective. Subsequent testing in a rat model of asphyxial cardiac arrest, and in a mouse model of severe TBI, showed that serial dosing of 1 mg/kg of NSC74429 over 3 days improved hippocampal survival in both models. Taken together, NSC74429 is neuroprotective across multiple insult mechanisms. Future pharmacokinetic and pharmacodynamic (PK/PD) studies are warranted to optimize dosing, and mechanistic studies are needed to determine the percentage of neuroprotection mediated by PHLPP1/2 inhibition, or potentially from the modulation of PHLPP-independent targets.
A Study on the Nature of SARS-CoV-2 Using the Shell Disorder Models: Reproducibility, Evolution, Spread, and Attenuation
Authors: Goh Gerard Kian-Meng , Dunker A. Keith , Foster James A. , Uversky Vladimir N.
Published: September 2022

The basic tenets of the shell disorder model (SDM) as applied to COVID-19 are that the harder outer shell of the virus shell (lower PID—percentage of intrinsic disorder—of the membrane protein M, PIDM) and higher flexibility of the inner shell (higher PID of the nucleocapsid protein N, PIDN) are correlated with the contagiousness and virulence, respectively. M protects the virion from the anti-microbial enzymes in the saliva and mucus. N disorder is associated with the rapid replication of the virus. SDM predictions are supported by two experimental observations. The first observation demonstrated lesser and greater presence of the Omicron particles in the lungs and bronchial tissues, respectively, as there is a greater level of mucus in the bronchi. The other observation revealed that there are lower viral loads in 2017-pangolin-CoV, which is predicted to have similarly low PIDN as Omicron. The abnormally hard M, which is very rarely seen in coronaviruses, arose from the fecal–oral behaviors of pangolins via exposure to buried feces. Pangolins provide an environment for coronavirus (CoV) attenuation, which is seen in Omicron. Phylogenetic study using M shows that COVID-19-related bat-CoVs from Laos and Omicron are clustered in close proximity to pangolin-CoVs, which suggests the recurrence of interspecies transmissions. Hard M may have implications for long COVID-19, with immune systems having difficulty degrading viral proteins/particles.
Pulmonary Thrombosis Promotes Tumorigenesis via Myeloid Hypoxia-Inducible Factors
Authors: Lu Xiao , Prodger Alice , Sim Jingwei , Evans Colin E.
Published: September 2022

Cancer patients have a greater risk of thrombosis than individuals without cancer. Conversely, thrombosis is a diagnostic predictor of cancer, but the mechanisms by which thrombosis promotes tumor propagation are incompletely understood. Our previous studies showed that hypoxia-inducible factors (HIF) 1α and HIF2α are stabilized in myeloid cells of murine thrombi. We also previously showed that pulmonary thrombosis increases the levels of HIF1α and HIF2α in murine lungs, enhances the levels of tumorigenic factors in the circulation, and promotes pulmonary tumorigenesis. In this study, we aimed to investigate the regulation of thrombosis-induced tumorigenesis by myeloid cell-specific HIFs (i.e., HIF1 and HIF2 in neutrophils and macrophages). Our in vitro studies showed that multiple tumorigenic factors are upregulated in the secretome of hypoxic versus normoxic neutrophils and macrophages, which promotes lung cancer cell proliferation and migration in a myeloid-HIF-dependent manner. Next, we used a mouse model of pulmonary microvascular occlusion to study the impact of pulmonary thrombosis and myeloid HIFs on lung tumorigenesis. Experiments on mice lacking either HIF1α or HIF2α in myeloid cells demonstrated that loss of either factor eliminates the advantage given to pulmonary tumor formation by thrombotic insult. The myeloid HIF-dependent and tumorigenic impact of pulmonary thrombosis on tumor burden may be partly driven by paracrine thymidine phosphorylase (TP), given that TP levels were increased by hypoxia in neutrophil and macrophage supernates, and that plasma TP levels were positively correlated with multiple measures of tumor progression in wild type mice but not myeloid cell-specific HIF1α or HIF2α knockout mice. These data together demonstrate the importance of thrombotic insult in a model of pulmonary tumorigenesis and the essential role of myeloid HIFs in mediating tumorigenic success.
Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of Mycobacterium tuberculosis
Authors: Bajrai Leena Hussein , Khateb Aiah M. , Alawi Maha M. , Felemban Hashim R. , Sindi Anees A. , Dwivedi Vivek Dhar , Azhar Esam Ibraheem
Published: September 2022

Due to the concerning rise in the number of multiple- and prolonged-drug-resistant (MDR and XDR) Mycobacterium tuberculosis (Mtb) strains, unprecedented demand has been created to design and develop novel therapeutic drugs with higher efficacy and safety. In this study, with a focused view on implementing an in silico drug design pipeline, a diverse set of glycosylated flavonoids were screened against the Mtb cytochrome-P450 enzyme 121 (CYP121), which is established as an approved drug target for the treatment of Mtb infection. A total of 148 glycosylated flavonoids were screened using structure-based virtual screening against the crystallized ligand, i.e., the L44 inhibitor, binding pocket in the Mtb CYP121 protein. Following this, only the top six compounds with the highest binding scores (kcal/mol) were considered for further intermolecular interaction and dynamic stability using 100 ns classical molecular dynamics simulation. These results suggested a considerable number of hydrogen and hydrophobic interactions and thermodynamic stability in comparison to the reference complex, i.e., the CYP121-L44 inhibitor. Furthermore, binding free energy via the MMGBSA method conducted on the last 10 ns interval of MD simulation trajectories revealed the substantial affinity of glycosylated compounds with Mtb CYP121 protein against reference complex. Notably, both the docked poses and residual energy decomposition via the MMGBSA method demonstrated the essential role of active residues in the interactions with glycosylated compounds by comparison with the reference complex. Collectively, this study demonstrates the viability of these screened glycosylated flavonoids as potential inhibitors of Mtb CYP121 for further experimental validation to develop a therapy for the treatment of drug-resistant Mtb strains.
The Role of Autophagy in Osteoarthritic Cartilage
Authors: Kao Wei-Chun , Chen Jian-Chih , Liu Ping-Cheng , Lu Cheng-Chang , Lin Sung-Yen , Chuang Shu-Chun , Wu Shun-Cheng , Chang Ling-hua , Lee Mon-Juan , Yang Chung-Da , Lee Tien-Ching , Wang Ying-Chun , Li Jhong-You , Wei Chun-Wang , Chen Chung-Hwan
Published: September 2022

Osteoarthritis (OA) is one of the most common diseases leading to physical disability, with age being the main risk factor, and degeneration of articular cartilage is the main focus for the pathogenesis of OA. Autophagy is a crucial intracellular homeostasis system recycling flawed macromolecules and cellular organelles to sustain the metabolism of cells. Growing evidences have revealed that autophagy is chondroprotective by regulating apoptosis and repairing the function of damaged chondrocytes. Then, OA is related to autophagy depending on different stages and models. In this review, we discuss the character of autophagy in OA and the process of the autophagy pathway, which can be modulated by some drugs, key molecules and non-coding RNAs (microRNAs, long non-coding RNAs and circular RNAs). More in-depth investigations of autophagy are needed to find therapeutic targets or diagnostic biomarkers through in vitro and in vivo situations, making autophagy a more effective way for OA treatment in the future. The aim of this review is to introduce the concept of autophagy and make readers realize its impact on OA. The database we searched in is PubMed and we used the keywords listed below to find appropriate article resources.
Investigating the Role of Zinc in Atherosclerosis: A Review
Authors: Shen Tong , Zhao Qing , Luo Yumin , Wang Tao
Published: September 2022

Zinc, an indispensable micronutrient for human health, might play an important role in the development of atherosclerosis. Zinc could be involved in the atherogenic process through interaction with atherogenic cells, such as endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and immune cells. In addition, zinc also exerts important positive or negative functions in various atherosclerosis-related risk factors, including lipid metabolism, glucose metabolism, and blood pressure. Currently, evidence focusing on the relationship between zinc status and atherogenic risk factors has been well established, while the direct interaction between zinc and atherosclerosis has not been fully understood. In this review, we aimed to summarize the association between zinc and atherosclerosis and explore current findings on how zinc and zinc homeostasis-associated proteins act in the atherogenic processes.
Antipsychotic Drug Fluphenazine against Human Cancer Cells
Authors: Duarte Diana , Vale Nuno
Published: September 2022

Drug repurposing is a strategy that can speed up and find novel clinical uses for already-approved drugs for several diseases, such as cancer. This process is accelerated compared to the development of new drugs because these compounds have already been tested in clinical trials and data related to their pharmacokinetics is already described, reducing the costs and time associated with the development of new anticancer therapeutics. Several studies suggest that the repurposing of fluphenazine for cancer therapy may be a promising approach, as this drug proved to reduce the viability of diverse cancer cell lines. In this review, intensive research of the literature was performed related to the anticancer potential of fluphenazine in different human cancer cells. We have found several research articles on the cytotoxic effect of fluphenazine in lung, breast, colon, liver, brain, leukemia, oral, ovarian, and skin cancer and have summarized the main findings in this review. Taken together, these findings suggest that fluphenazine may regulate the cell cycle, reduce cell proliferation, and cause apoptosis in several types of cancer cells, besides being an established calmodulin inhibitor. It was also found that this drug is able to target cancer-related proteins, such as ABCB1 and P-glycoprotein as well as to regulate the Akt and Wnt signaling pathways. Some studies also refer this drug causes DNA alterations and interferes with cell invasion and migration ability as well as with ROS generation. Collectively, these results imply that fluphenazine may be a favorable compound for further research in oncologic therapy.
Assessment of Lipid Quality in Commercial Omega-3 Supplements Sold in the French Market
Authors: Pasini Federica , Gómez-Caravaca Ana Maria , Blasco Thierry , Cvejić Jelena , Caboni Maria Fiorenza , Verardo Vito
Published: September 2022

Supplementation of omega-3 fatty acids is considered a valuable strategy to supply the low intake of these fatty acids. Thus, the safety of the supplements is an important milestone. Because of that, we analyzed 20 unflavored supplements sold in the French market for fatty acid and triglyceride composition, for EPA and DHA, and for tocol content, as well as for oxidative status. This study found that only 2.5% of the supplements did not meet their label claims for omega-3 content. TAG analysis showed high variability among the triglyceride distribution, and the same trend was also noticed for the tocol content; in fact, a high variability of the distribution of the six tocols (four tocopherols and two tocotrienols) was found among the samples. Of the tested products, all of them complied with peroxide value, p-anisidine value, and Totox values established by the Global Organization for EPA and DHA Omega-3s (GOED) and were not oxidized.
Liposomal Entrapment or Chemical Modification of Relaxin2 for Prolongation of Its Stability and Biological Activity
Authors: Kogkos George , Gkartziou Foteini , Mourtas Spyridon , Barlos Kostas K. , Klepetsanis Pavlos , Barlos Kleomenis , Antimisiaris Sophia G.
Published: September 2022

Relaxin (RLX) is a protein that is structurally similar to insulin and has interesting biological activities. As with all proteins, preservation of RLX’s structural integrity/biological functionality is problematic. Herein, we investigated two methods for increasing the duration of relaxin-2’s (RLX2) biological activity: synthesis of a palmitoyl RLX2 conjugate (P-RLX2) with the use of a Palmitoyl-l-Glu-OtBu peptide modifier, and encapsulation into liposomes of P-RLX2, RLX2, and its oxidized form (O-RLX2). For liposomal encapsulation thin-film hydration and DRV methods were applied, and different lipid compositions were tested for optimized protein loading. RLX2 and O-RLX2 were quantified by HPLC. The capability of the peptides/conjugate to stimulate transfected cells to produce cyclic adenosine monophosphate (cAMP) was used as a measure of their biological activity. The stability and bioactivity of free and liposomal RLX2 types were monitored for a 30 d period, in buffer (in some cases) and bovine serum (80%) at 37 °C. The results showed that liposome encapsulation substantially increased the RLX2 integrity in buffer; PEGylated liposomes demonstrated a higher protection. Liposome encapsulation also increased the stability of RLX2 and O-RLX2 in serum. Considering the peptide’s biological activity, cAMP production of RLX2 was higher than that of the oxidized form and the P-RLX2 conjugate (which demonstrated a similar activity to O-RLX2 when measured in buffer, but lower when measured in the presence of serum proteins), while liposome encapsulation resulted in a slight decrease of bioactivity initially, but prolonged the peptide bioactivity during incubation in serum. It was concluded that liposome encapsulation of RLX2 and synthetic modification to P-RLX2 can both prolong RLX2 peptide in vitro stability; however, the applied chemical conjugation results in a significant loss of bioactivity (cAMP production), whereas the effect of liposome entrapment on RLX2 activity was significantly lower.
Prostate Cancer-Associated miRNAs in Saliva: First Steps to an Easily Accessible and Reliable Screening Tool
Authors: Luedemann Christoph , Reinersmann Jan-Ludwig , Klinger Claudia , Degener Stephan , Dreger Nici Markus , Roth Stephan , Kaufmann Michael , Savelsbergh Andreas
Published: September 2022

Background: Common diagnostic tools for prostate cancer—prostate-specific antigen and transrectal biopsy—show only low predictive value and poor sensitivity. This study examines circulating miRNA in saliva to explore the possibility of a non-invasive and easy-to-execute diagnostic tool for prostate cancer screenings. Methods: 16 miRNAs were extracted from salivary exosomes and analyzed via the delta-CT method. The presented method enables an application of the test in any health institution and even outpatient sector. Recruited participants were suspected to suffer from prostate cancer due to elevated PSA serum levels. Of these participants, 43 were diagnosed with prostate cancer, while 31 suffered from benign diseases and served as control group. Results: hsa-mir-331-3p and hsa-mir-200b were significantly reduced in prostate cancer patients compared to the control group. ROC curve analysis revealed a reliable differentiation strength (AUC > 0.6) for both miRNAs with positive predictive values of 71% indicating prostate cancer. Differentiation of both groups based on PSA serum measurements was insufficient. The other 14 examined miRNAs showed no significant group differences. Conclusions: The presented method and miRNA are promising non-invasive tools to augment the current prostate cancer screening, thereby improving screening sensitivity and reducing numbers of false positive cancer suspects admitted to further invasive diagnostic and therapeutic steps.
Localized Perivascular Therapeutic Approaches to Inhibit Venous Neointimal Hyperplasia in Arteriovenous Fistula Access for Hemodialysis Use
Authors: Barcena Allan John R. , Perez Joy Vanessa D. , Liu Olivia , Mu Amy , Heralde Francisco M. , Huang Steven Y. , Melancon Marites P.
Published: September 2022

An arteriovenous fistula (AVF) is the preferred vascular access for chronic hemodialysis, but high failure rates restrict its use. Optimizing patients’ perioperative status and the surgical technique, among other methods for preventing primary AVF failure, continue to fall short in lowering failure rates in clinical practice. One of the predominant causes of AVF failure is neointimal hyperplasia (NIH), a process that results from the synergistic effects of inflammation, hypoxia, and hemodynamic shear stress on vascular tissue. Although several systemic therapies have aimed at suppressing NIH, none has shown a clear benefit towards this goal. Localized therapeutic approaches may improve rates of AVF maturation by providing direct structural and functional support to the maturating fistula, as well as by delivering higher doses of pharmacologic agents while avoiding the adverse effects associated with systemic administration of therapeutic agents. Novel materials—such as polymeric scaffolds and nanoparticles—have enabled the development of different perivascular therapies, such as supportive mechanical devices, targeted drug delivery, and cell-based therapeutics. In this review, we summarize various perivascular therapeutic approaches, available data on their effectiveness, and the outlook for localized therapies targeting NIH in the setting of AVF for hemodialysis use. Highlights: Most systemic therapies do not improve AVF patency outcomes; therefore, localized therapeutic approaches may be beneficial. Locally delivered drugs and medical devices may improve AVF patency outcomes by providing biological and mechanical support. Cell-based therapies have shown promise in suppressing NIH by delivering a more extensive array of bioactive substances in response to the biochemical changes in the AVF microenvironment.
Elevated Extracellular HSP72 and Blunted Heat Shock Response in Severe COVID-19 Patients
Authors: Borges Russo Mariana Kras , Kowalewski Lucas Stahlhöfer , da Natividade Gabriella Richter , de Lemos Muller Carlos Henrique , Schroeder Helena Trevisan , Bock Patrícia Martins , Ayres Layane Ramos , Cardoso Bernardo Urbano , Zanotto Caroline , Schein Julia Tsao , Rech Tatiana Helena , Crispim Daisy , Canani Luis Henrique , Friedman Rogério , Leitão Cristiane Bauermann , Gerchman Fernando , Krause Mauricio
Published: September 2022

Aims: We hypothesized that critically ill patients with SARS-CoV-2 infection and insulin resistance would present a reduced Heat Shock Response (HSR), which is a pathway involved in proteostasis and anti-inflammation, subsequently leading to worse outcomes and higher inflammation. In this work we aimed: (i) to measure the concentration of extracellular HSP72 (eHSP72) in patients with severe COVID-19 and in comparison with noninfected patients; (ii) to compare the HSR between critically ill patients with COVID-19 (with and without diabetes); and (iii) to compare the HSR in these patients with noninfected individuals. Methods: Sixty critically ill adults with acute respiratory failure with SARS-CoV-2, with or without diabetes, were selected. Noninfected subjects were included for comparison (healthy, n = 19 and patients with diabetes, n = 22). Blood samples were collected to measure metabolism (glucose and HbA1c); oxidative stress (lypoperoxidation and carbonyls); cytokine profile (IL-10 and TNF); eHSP72; and the HSR (in vitro). Results: Patients with severe COVID-19 presented higher plasma eHSP72 compared with healthy individuals and noninfected patients with diabetes. Despite the high level of plasma cytokines, no differences were found between critically ill patients with COVID-19 with or without diabetes. Critically ill patients, when compared to noninfected, presented a blunted HSR. Oxidative stress markers followed the same pattern. No differences in the HSR (extracellular/intracellular level) were found between critically ill patients, with or without diabetes. Conclusions: We demonstrated that patients with severe COVID-19 have elevated plasma eHSP72 and that their HSR is blunted, regardless of the presence of diabetes. These results might explain the uncontrolled inflammation and also provide insights on the increased risk in developing type 2 diabetes after SARS-CoV-2 infection.
Toxic and Essential Metals in Human Health and Disease 2021
Authors: Aaseth Jan O.
Published: September 2022

The Special Issue of Biomolecules called “Toxic and Essential Metals in Human Health and Disease 2021” represents a follow-up of the previous Special Issue with the name of “Toxic and Essential Metals in Human Health and Disease” [...]
Therapeutic Potential of Adipose Stem Cell-Derived Conditioned Medium on Scar Contraction Model
Authors: Imai Yukiko , Mori Nobuhito , Nihashi Yuma , Kumagai Yutaro , Shibuya Yoichiro , Oshima Junya , Sasaki Masahiro , Sasaki Kaoru , Aihara Yukiko , Sekido Mitsuru , Kida Yasuyuki S.
Published: September 2022

Scars are composed of stiff collagen fibers, which contract strongly owing to the action of myofibroblasts. To explore the substances that modulate scar contracture, the fibroblast-populated collagen lattice (FPCL) model has been used. However, the molecular signature of the patient-derived FPCL model has not been verified. Here, we examined whether the patient-derived keloid FPCL model reflects scar contraction, analyzing detailed gene expression changes using comprehensive RNA sequencing and histological morphology, and revealed that these models are consistent with the changes during human scar contracture. Moreover, we examined whether conditioned media derived from adipose stem cells (ASC-CM) suppress the scar contracture of the collagen disc. Detailed time-series measurements of changes in disc area showed that the addition of ASC-CM significantly inhibited the shrinkage of collagen discs. In addition, a deep sequencing data analysis revealed that ASC-CM suppressed inflammation-related gene expression in the early phase of contraction; in the later phase, this suppression was gradually replaced by extracellular matrix (ECM)-related gene expression. These lines of data suggested the effectiveness of ASC-CM in suppressing scar contractures. Therefore, the molecular analysis of the ASC-CM actions found in this study will contribute to solving medical problems regarding pathological scarring in wound prognosis.
Genetic Variations miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G and the Risk of Recurrent Pregnancy Loss in Korean Women
Authors: An Hui-Jeong , Cho Sung-Hwan , Park Han-Sung , Kim Ji-Hyang , Kim Young-Ran , Lee Woo-Sik , Lee Jung-Ryeol , Joo Seong-Soo , Ahn Eun-Hee , Kim Nam-Keun
Published: September 2022

This study investigated the genetic association between recurrent pregnancy loss (RPL) and microRNA (miRNA) polymorphisms in miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G in Korean women. Blood samples were collected from 381 RPL patients and 281 control participants, and genotyping of miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G was carried out by TaqMan miRNA RT-Real Time polymerase chain reaction (PCR). Four polymorphisms were identified, including miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G. MiR-10a dominant model (AA vs. AT + TT) and miR-499bGG genotypes were associated with increased RPL risk (adjusted odds ratio [AOR] = 1.520, 95% confidence interval [CI] = 1.038–2.227, p = 0.032; AOR = 2.956, 95% CI = 1.168–7.482, p = 0.022, respectively). Additionally, both miR-499 dominant (AA vs. AG + GG) and recessive (AA + AG vs. GG) models were significantly associated with increased RPL risk (AOR = 1.465, 95% CI = 1.062–2.020, p = 0.020; AOR = 2.677, 95% CI = 1.066–6.725, p = 0.036, respectively). We further propose that miR-10aA>T, miR-30cA>G, and miR-499bA>G polymorphisms effects could contribute to RPL and should be considered during RPL patient evaluation.
Cholesterol Chip for the Study of Cholesterol–Protein Interactions Using SPR
Authors: He Peng , Faris Shannon , Sagabala Reddy Sudheer , Datta Payel , Xu Zihan , Callahan Brian , Wang Chunyu , Boivin Benoit , Zhang Fuming , Linhardt Robert J.
Published: September 2022

Cholesterol, an important lipid in animal membranes, binds to hydrophobic pockets within many soluble proteins, transport proteins and membrane bound proteins. The study of cholesterol–protein interactions in aqueous solutions is complicated by cholesterol’s low solubility and often requires organic co-solvents or surfactant additives. We report the synthesis of a biotinylated cholesterol and immobilization of this derivative on a streptavidin chip. Surface plasmon resonance (SPR) was then used to measure the kinetics of cholesterol interaction with cholesterol-binding proteins, hedgehog protein and tyrosine phosphatase 1B.