bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploration of Potential Genetic Biomarkers for Heart Failure: A Systematic Review
Authors: Chair Sek-Ying , Chan Judy-Yuet-Wa , Waye Mary-Miu-Yee , Liu Ting , Law Bernard-Man-Hin , Chien Wai-Tong
Published: June 2021

Patients with heart failure (HF) often present with signs and symptoms that are often nonspecific and with a wide differential diagnosis, making diagnosis and prognosis of HF by clinical presentation alone challenging. Our knowledge on genetic diversity is rapidly evolving with high-throughput DNA sequencing technology, which makes a great potential for genetic biomarker development. The present review attempts to provide a comprehensive review on the modification of major genetic components in HF patients and to explore the potential application of these components as clinical biomarkers in the diagnosis and in monitoring the progress of HF. The literature search was conducted using six databases, resulting in the inclusion of eighteen studies in the review. The findings of these studies were summarized narratively. An appraisal of the reporting quality of the included studies was conducted using a twelve-item checklist adapted from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. The findings showed that changes in genetic components in patients with HF compared to healthy controls could be noninvasive diagnostic or prognostic tools for HF with higher specificity and sensitivity in comparison with the traditional biomarkers. This review provided evidence for the potential of developing genetic biomarkers of HF.
Effects of Nature-Based Group Art Therapy Programs on Stress, Self-Esteem and Changes in Electroencephalogram (EEG) in Non-Disabled Siblings of Children with Disabilities
Authors: Kang Soo-Ji , Kim Hyon-Suh , Baek Kwang-Hyun
Published: June 2021

The purpose of the present study was to examine changes in brain waves, stress, and self-esteem after a continuous eight-week nature-based art therapy program in the forest in non-disabled siblings of children with disabilities. A total of 29 participants participated in this study (art therapy program group, n = 18; control group, n = 11). The art therapy program group received eight weekly sessions of art therapy lasting 60 min each. Pre- and post-test results showed positive changes in the brain function index and stress levels of the participants in the art therapy program group. On the self-esteem scale, overall and social self-esteem increased significantly. In conclusion, creative activities in the forest can increase resistance to diseases through mechanisms that relieve stress and increase self-esteem. If art therapy that emphasizes somatosensory experience, creative expression, and self-motivation is accompanied by forest activities, this combined intervention can elicit positive physical and psychological changes.
Patterns, Management, and Outcome of Traumatic Femur Fracture: Exploring the Experience of the Only Level 1 Trauma Center in Qatar
Authors: Ghouri Syed Imran , Asim Mohammad , Mustafa Fuad , Kanbar Ahad , Ellabib Mohamed , Al Jogol Hisham , Muneer Mohammed , Abdurraheim Nuri , Goel Atirek Pratap , Abdelrahman Husham , Al-Thani Hassan , El-Menyar Ayman
Published: June 2021

Background: Femur is the most fractured long bone in the body that often necessitates surgical fixation; however, data on the impact of the mechanism of injury (MOI), age, and timing of intervention are lacking in our region of the Arab Middle East. We aimed to describe the patterns, management, and outcome of traumatic femoral shaft fractures. Methods: A retrospective descriptive observational study was conducted for all trauma patients admitted with femoral shaft fractures between January 2012 and December 2015 at the only level 1 trauma center and tertiary hospital in the country. Data were analyzed and compared according to the time to intervention (intramedullary nailing; IMN), MOI, and age groups. Main outcomes included in-hospital complications and mortality. Results: A total of 605 hospitalized cases with femur fractures were reviewed. The mean age was 30.7 ± 16.2 years. The majority of fractures were unilateral (96.7%) and 91% were closed fractures. Three-fourths of fractures were treated by reamed intramedullary nailing (rIMN), antegrade in 80%. The pyriform fossa nails were used in 71.6% while trochanteric entry nails were used in 28.4%. Forty-five (8.9%) fractures were treated with an external fixator, 37 (6.1%) had conservative management. Traffic-related injuries occurred more in patients aged 14–30 years, whereas fall-related injuries were significantly higher in patients aged 31–59. Thirty-one patients (7.8%) had rIMN in less than 6 h post-injury, 106 (25.5%) had rIMN after 6–12 h and 267 (66.8%) had rIMN after more than 12 h. The implant type, duration of surgery, DVT prophylaxis, in-hospital complications, and mortality were comparable among the three treatment groups. Conclusions: In our center, the frequency of femoral fracture was 11%, and it mainly affected severely injured young males due to traffic-related collisions or falls. Further multicenter studies are needed to set a consensus for an appropriate management of femur fracture based on the MOI, location, and timing of injury.
Multifactorial Landscape Parses to Reveal a Predictive Model for Knee Osteoarthritis
Authors: Singh Monica , Valecha Srishti , Khinda Rubanpal , Kumar Nitin , Singh Surinderpal , Juneja Pawan K. , Kaur Taranpal , Di Napoli Mario , Minhas Jatinder S. , Singh Puneetpal , Mastana Sarabjit
Published: June 2021

The present study attempted to investigate whether concerted contributions of significant risk variables, pro-inflammatory markers, and candidate genes translate into a predictive marker for knee osteoarthritis (KOA). The present study comprised 279 confirmed osteoarthritis patients (Kellgren and Lawrence scale ≥2) and 287 controls. Twenty SNPs within five genes (CRP, COL1A1, IL-6, VDR, and eNOS), four pro-inflammatory markers (interleukin-6 (IL-6), interleuin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and high sensitivity C-reactive protein (hsCRP)), along with significant risk variables were investigated. A receiver operating characteristic (ROC) curve was used to observe the predictive ability of the model for distinguishing patients with KOA. Multivariable logistic regression analysis revealed that higher body mass index (BMI), triglycerides (TG), poor sleep, IL-6, IL-1β, and hsCRP were independent predictors for KOA after adjusting for the confounding from other risk variables. Four susceptibility haplotypes for the risk of KOA, AGT, GGGGCT, AGC, and CTAAAT, were observed within CRP, IL-6, VDR, and eNOS genes, which showed their impact in recessive β(SE): 2.11 (0.76), recessive β(SE): 2.75 (0.59), dominant β(SE): 1.89 (0.52), and multiplicative modes β(SE): 1.89 (0.52), respectively. ROC curve analysis revealed the model comprising higher values of BMI, poor sleep, IL-6, and IL-1β was predictive of KOA (AUC: 0.80, 95%CI: 0.74–0.86, p < 0.001), and the strength of the predictive ability increased when susceptibility haplotypes AGC and GGGGCT were involved (AUC: 0.90, 95%CI: 0.87–0.95, p < 0.001).This study offers a predictive marker for KOA based on the risk scores of some pertinent genes and their genetic variants along with some pro-inflammatory markers and traditional risk variables.
Adaptation Process of Korean Fathers within Multicultural Families in Korea
Authors: Park So-Yeon , Kim Suhyun , Cho Chung Hyang-In
Published: June 2021

This study aimed to develop a grounded theory regarding the associations between factors identified in the adaptation process of 11 fathers of multicultural families. Participants were recruited purposively and data were collected through in-depth interviews. Data analysis was performed alongside data collection, following Strauss and Corbin’s grounded theory method. The following 11 categories were derived from the data: (1) a reluctantly formed multicultural family, (2) finding happiness amid confusion, (3) cultural differences, (4) economic difficulties, (5) social prejudice and alienation, (6) restrictions on the use of local services, (7) facing multiple obstacles, (8) people who provided strength and support, (9) accepting differences and moving forward, (10) growth with family, and (11) being made to stay. The core category was identified as “struggling to protect the family with a double burden.” This theory described the adaptation process of being a father in a multicultural family and participants’ reactions to the circumstances around it. Based on this theory, health policies should be developed to support not only the expansion of medical facilities in island and rural areas but also the activation of self-help groups. Future research should include the development of web-based prenatal management and parental education in immigrants’ native languages.
The Implementation of Childhood Obesity Related Policy Interventions in Malaysia—A Non Communicable Diseases Scorecard Project
Authors: Mok Wilfred Kok Hoe , Hairi Noran Naqiah , Chan Caryn Mei Hsien , Mustapha Feisul Idzwan , Saminathan Thamil Arasu , Low Wah Yun
Published: June 2021

(1) Background: The prevalence of overweight and obesity among children has increased tremendously in the ASEAN region, including Malaysia. In Malaysia, the National Strategic Plan for Non-Communicable Diseases (2015–2025) provides the overall framework for its response to the non-communicable diseases (NCD) epidemic. Preventing childhood obesity is one of the key strategies for early intervention to prevent NCDs. The objective of this research is to examine the current status of policy interventions in addressing childhood obesity in Malaysia. (2) Methods: A panel of 22 stakeholders and experts from Malaysia, representing the government, industry, academia and non-governmental organizations, were sampled using a modified Delphi technique. Data were collected using a modified NCD scorecard under four domains (governance, risk factors, surveillance and research and health systems response). A heat map was used to measure the success of the four realms of the NCD scorecard. For each domain of the NCD scorecard, the final score was grouped in quintiles. (3) Results: A total of 22 participants responded, comprising of eight (36.4%) males and 14 (63.4%) females. All the domains measured in implementing policies related to childhood obesity were of low progress. Nine governance indicators were reported as 22.5% (low progress), four in the risk factors domain, and two in the surveillance. This shows that timely and accurate monitoring, participatory review and evaluation, and effective remedies are necessary for a country’s surveillance system. (4) Conclusion: Although Malaysia has published several key strategic documents relating to childhood obesity and implemented numerous policy interventions, we have identified several gaps that must be addressed to leverage the whole-of-government and whole-of-society approach in addressing childhood obesity in the country.
Incidence of Reported Flu-Like Syndrome Cases in Brazilian Health Care Workers in 2020 (March to June)
Authors: Assunção Ada Ávila , Maia Emanuella Gomes , Jardim Renata , de Araújo Tânia Maria
Published: June 2021

Health care workers (HCWs) are at an increased risk of being exposed to COVID-19. This study aimed to characterize flu-like syndrome cases (FS) in HCWs notified in Brazil and compare them with FS cases in the general community (GC). In the Brazilian protocol, FS corresponds to a suspected case of COVID-19. The manuscript analyzed cases of FS in five Brazilian states, estimating the incidence rates of cases of FS and clinical and epidemiological characteristics. Registered cases (March to June 2020) totaled about 1,100,000 cases of FS. HCWs represented 17% of the registers, whose incidence was 20.41/100 vs. 2.15/100 in the GC. FS cases in HCWs concentrated the highest percentages in the age group of 30 to 49 years (65.15%) and among the nursing staff (46.86%). This study was the first interstate evaluation in Brazil to estimate suspected cases of FS by COVID-19 in HCWs. In order to control the spread of viral respiratory infections in HCWs, including COVID-19, it is necessary to review the management of health information to identify who they are, how many they are, and to what situations these workers are most frequently exposed, as well as in what professions they have. This information can guide specific, practical, and far-reaching actions.
Do Mobile Phone Data Provide a Better Denominator in Crime Rates and Improve Spatiotemporal Predictions of Crime?
Authors: Rummens Anneleen , Snaphaan Thom , Van de Weghe Nico , Van den Poel Dirk , Pauwels Lieven J. R. , Hardyns Wim
Published: June 2021

This article assesses whether ambient population is a more suitable population-at-risk measure for crime types with mobile targets than residential population for the purpose of intelligence-led policing applications. Specifically, the potential use of ambient population as a crime rate denominator and predictor for predictive policing models is evaluated, using mobile phone data (with a total of 9,397,473 data points) as a proxy. The results show that ambient population correlates more strongly with crime than residential population. Crime rates based on ambient population designate different problem areas than crime rates based on residential population. The prediction performance of predictive policing models can be improved by using ambient population instead of residential population. These findings support that ambient population is a more suitable population-at-risk measure, as it better reflects the underlying dynamics in spatiotemporal crime trends. Its use has therefore much as-of-yet unused potential not only for criminal research and theory testing, but also for intelligence-led policy and practice.
A Novel Heuristic Emergency Path Planning Method Based on Vector Grid Map
Authors: Yang Bowen , Yan Jin , Cai Zhi , Ding Zhiming , Li Dongze , Cao Yang , Guo Limin
Published: June 2021

Emergency path planning technology is one of the research hotspots of intelligent transportation systems. Due to the complexity of urban road networks and congested road conditions, emergency path planning is very difficult. Road congestion caused by urban emergencies directly affects the original road network structure. In this way, the static weight of the original road network is no longer suitable as the basis for path recommendation. To handle the dynamic situational road network, an equidistant grid emergency path planning framework will be designed. A novel situation grid road network model, based on situation information, is proposed and applied to an equidistant grid emergency path planning framework. A situational grid heuristic search will be proposed methodology based on this model, which can be used to detect the vehicles passing around the congestion area grid and the road to the destination in the shortest time. In the path planning methodology, a grid inspired search strategy based on quaternion function is included, which can make the algorithm converge to the target grid quickly. Three graph acceleration algorithms are proposed to improve the search efficiency of path planning algorithm. Finally, this paper will set up three experiments to verify our proposed method.
A GloVe-Based POI Type Embedding Model for Extracting and Identifying Urban Functional Regions
Authors: Zhang Chengkun , Xu Liuchang , Yan Zhen , Wu Sensen
Published: June 2021

Points-of-interest (POIs) are an important carriers of location text information in smart cities and have been widely used to extract and identify urban functional regions. However, it is difficult to model the relationship between POIs and urban functional types using existing methods due to insufficient POIs information mining. In this study, we propose a Global Vectors (GloVe)-based, POI type embedding model (GPTEM) to extract and identify urban functional regions at the scale of traffic analysis zones (TAZs) by integrating the co-occurrence information and spatial context of POIs. This method has three main steps. First, we utilize buffer zones centered on each POI to construct the urban functional corpus. Second, we use the constructed corpus and GPTEM to train POI type vectors. Third, we cluster the TAZs and annotate the urban functional types in clustered regions by calculating enrichment factors. The results are evaluated by comparing them against manual annotations and food takeout delivery data, showing that the overall identification accuracy of the proposed method (78.44%) is significantly higher than that of a baseline method based on word2vec. Our work can assist urban planners to efficiently evaluate the development of and changes in the functions of various urban regions.
Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors
Authors: Luise Chiara , Robaa Dina , Regenass Pierre , Maurer David , Ostrovskyi Dmytro , Seifert Ludwig , Bacher Johannes , Burgahn Teresa , Wagner Tobias , Seitz Johannes , Greschik Holger , Park Kwang-Su , Xiong Yan , Jin Jian , Schüle Roland , Breit Bernhard , Jung Manfred , Sippl Wolfgang
Published: June 2021

The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings.
The FtsHi Enzymes of Arabidopsis thaliana: Pseudo-Proteases with an Important Function
Authors: Mishra Laxmi S. , Funk Christiane
Published: June 2021

FtsH metalloproteases found in eubacteria, animals, and plants are well-known for their vital role in the maintenance and proteolysis of membrane proteins. Their location is restricted to organelles of endosymbiotic origin, the chloroplasts, and mitochondria. In the model organism Arabidopsis thaliana, there are 17 membrane-bound FtsH proteases containing an AAA+ (ATPase associated with various cellular activities) and a Zn2+ metalloprotease domain. However, in five of those, the zinc-binding motif HEXXH is either mutated (FtsHi1, 2, 4, 5) or completely missing (FtsHi3), rendering these enzymes presumably inactive in proteolysis. Still, homozygous null mutants of the pseudo-proteases FtsHi1, 2, 4, 5 are embryo-lethal. Homozygous ftshi3 or a weak point mutant in FTSHi1 are affected in overall plant growth and development. This review will focus on the findings concerning the FtsHi pseudo-proteases and their involvement in protein import, leading to consequences in embryogenesis, seed growth, chloroplast, and leaf development and oxidative stress management.
Tellurium: A Rare Element with Influence on Prokaryotic and Eukaryotic Biological Systems
Authors: Vávrová Silvia , Struhárňanská Eva , Turňa Ján , Stuchlík Stanislav
Published: June 2021

Metalloid tellurium is characterized as a chemical element belonging to the chalcogen group without known biological function. However, its compounds, especially the oxyanions, exert numerous negative effects on both prokaryotic and eukaryotic organisms. Recent evidence suggests that increasing environmental pollution with tellurium has a causal link to autoimmune, neurodegenerative and oncological diseases. In this review, we provide an overview about the current knowledge on the mechanisms of tellurium compounds’ toxicity in bacteria and humans and we summarise the various ways organisms cope and detoxify these compounds. Over the last decades, several gene clusters conferring resistance to tellurium compounds have been identified in a variety of bacterial species and strains. These genetic determinants exhibit great genetic and functional diversity. Besides the existence of specific resistance mechanisms, tellurium and its toxic compounds interact with molecular systems, mediating general detoxification and mitigation of oxidative stress. We also discuss the similarity of tellurium and selenium biochemistry and the impact of their compounds on humans.
Changes in Phenotypes and DNA Methylation of In Vitro Aging Sperm in Common Carp Cyprinus carpio
Authors: Cheng Yu , Vechtova Pavlina , Fussy Zoltan , Sterba Jan , Linhartová Zuzana , Rodina Marek , Tučková Vladimíra , Gela David , Samarin Azin Mohagheghi , Lebeda Ievgen , Xin Miaomiao , Zhang Songpei , Rahi Deepali , Linhart Otomar
Published: June 2021

The purpose of the current study was to analyze phenotypic and functional characteristics of common carp (Cyprinus carpio) spermatozoa during in vitro aging and to investigate whether global DNA methylation is affected by sperm aging. Milt was collected from five individual males, stored in vitro on ice in a refrigerator for up to 96 h post stripping (HPS) and used to fertilize eggs with intervals of 1, 24 and 96 h. Computer-assisted sperm analysis and a S3e Cell Sorter was employed to determine the spermatozoa phenotypic characteristics (motility, velocity, concentration and viability). In addition, pH and osmolality of the seminal fluid and the capacity of the spermatozoa to fertilize, hatching rate and health of the resulting embryos were examined at different aging times. Whole-genome bisulfite sequencing was used to compare the global and gene-specific DNA methylation in fresh and aged spermatozoa. The results demonstrated that spermatozoa aging in common carp significantly affects their performance and thus the success of artificial fertilization. The methylation level at the cytosine-phosphate-guanine (CpG) sites increased significantly with 24 HPS spermatozoa compared to the fresh group at 1 HPS and then decreased significantly at 96 HPS. A more detailed investigation of gene specific differences in the DNA methylation was hindered by incomplete annotation of the C. carpio genome in the public databases.
Spontaneous Fusion of MSC with Breast Cancer Cells Can Generate Tumor Dormancy
Authors: Melzer Catharina , von der Ohe Juliane , Luo Tianjiao , Hass Ralf
Published: June 2021

Direct cellular interactions of MDA-MB-231cherry breast cancer cells with GFP-transduced human mesenchymal stroma/stem-like cells (MSCGFP) in a co-culture model resulted in spontaneous cell fusion by the generation of MDA-MSC-hyb5cherry GFP breast cancer hybrid cells. The proliferative capacity of MDA-MSC-hyb5 cells was enhanced about 1.8-fold when compared to the parental MDA-MB-231cherry breast cancer cells. In contrast to a spontaneous MDA-MB-231cherry induced tumor development in vivo within 18.8 days, the MDA-MSC-hyb5 cells initially remained quiescent in a dormancy-like state. At distinct time points after injection, NODscid mice started to develop MDA-MSC-hyb5 cell-induced tumors up to about a half year later. Following tumor initiation, however, tumor growth and formation of metastases in various different organs occurred rapidly within about 10.5 days. Changes in gene expression levels were evaluated by RNA-microarray analysis and revealed certain increase in dormancy-associated transcripts in MDA-MSC-hyb5. Chemotherapeutic responsiveness of MDA-MSC-hyb5 cells was partially enhanced when compared to MDA-MB-231 cells. However, some resistance, e.g., for taxol was detectable in cancer hybrid cells. Moreover, drug response partially changed during the tumor development of MDA-MSC-hyb5 cells; this suggests the presence of unstable in vivo phenotypes of MDA-hyb5 cells with increased tumor heterogeneity.
(5′S) 5′,8-cyclo-2′-deoxyadenosine Cannot Stop BER. Clustered DNA Lesion Studies
Authors: Karwowski Boleslaw T.
Published: June 2021

As a result of external and endocellular physical-chemical factors, every day approximately ~105 DNA lesions might be formed in each human cell. During evolution, living organisms have developed numerous repair systems, of which Base Excision Repair (BER) is the most common. 5′,8-cyclo-2′-deoxyadenosine (cdA) is a tandem lesion that is removed by the Nucleotide Excision Repair (NER) mechanism. Previously, it was assumed that BER machinery was not able to remove (5′S)cdA from the genome. In this study; however, it has been demonstrated that, if (5′S)cdA is a part of a single-stranded clustered DNA lesion, it can be removed from ds-DNA by BER. The above is theoretically possible in two cases: (A) When, during repair, clustered lesions form Okazaki-like fragments; or (B) when the (5′S)cdA moiety is located in the oligonucleotide strand on the 3′-end side of the adjacent DNA damage site, but not when it appears at the opposite 5′-end side. To explain this phenomenon, pure enzymes involved in BER were used (polymerase β (Polβ), a Proliferating Cell Nuclear Antigen (PCNA), and the X-Ray Repair Cross-Complementing Protein 1 (XRCC1)), as well as the Nuclear Extract (NE) from xrs5 cells. It has been found that Polβ can effectively elongate the primer strand in the presence of XRCC1 or PCNA. Moreover, supplementation of the NE from xrs5 cells with Polβ (artificial Polβ overexpression) forced oligonucleotide repair via BER in all the discussed cases.
Probing of Interactions of Magnetite Nanoparticles Coated with Native and Aminated Starch with a DPPC Model Membrane
Authors: Piosik Emilia , Zaryczniak Aleksandra , Mylkie Kinga , Ziegler-Borowska Marta
Published: June 2021

Understanding the mechanism of interactions between magnetite nanoparticles and phospholipids that form cellular membranes at the molecular level is of crucial importance for their safe and effective application in medicine (e.g., magnetic resonance imaging, targeted drug delivery, and hyperthermia-based anticancer therapy). In these interactions, their surface coating plays a crucial role because even a small modification to its structure can cause significant changes to the behaviour of the magnetite nanoparticles that come in contact with a biomembrane. In this work, the influence of the magnetite nanoparticles functionalized with native and aminated starch on the thermodynamics, morphology, and dilatational elasticity of the model cell membranes was studied. The model cell membranes constituted the Langmuir monolayers formed at the air–water interface of dipalmitoylphosphatidylcholine (DPPC). The surface of the aminated starch-coated nanoparticles was enriched in highly reactive amino groups, which allowed more effective binding of drugs and biomolecules suitable for specific nano–bio applications. The studies indicated that the presence of these groups also reduced to some extent the disruptive effect of the magnetite nanoparticles on the model membranes and improved their adsorption.
Interfacial Modeling of Fibrinogen Adsorption onto LiNbO3 Single Crystal–Single Domain Surfaces
Authors: Cross Jeffrey S. , Kubota Yasuhiro , Chatterjee Abhijit , Unni Samir , Ikoma Toshiyuki , Tagaya Motohiro
Published: June 2021

For the development of next-generation protein-based biosensor surfaces, it is important to understand how functional proteins, such as fibrinogen (FBG), interact with polar substrate surfaces in order to prepare highly sensitive points of medical care diagnostics. FBG, which is a fibrous protein with an extracellular matrix, has both positively and negatively charged regions on its 3-dimensional surface, which makes interpreting how it effectively binds to polarized surfaces challenging. In this study, single-crystal LiNbO3 (LNO) substrates that have surface charges were used to investigate the adsorption of FBG protruding polar fragments on the positively and negatively charged LNO surfaces. We performed a combination of experiments and multi-scale molecular modeling to understand the binding of FBG in vacuum and water-solvated surfaces of LNO. XPS measurements showed that the FBG adsorption on LNO increased with increment in solution concentration on surfaces independent of charges. Multi-scale molecular modeling employing Quantum Mechanics, Monte Carlo, and Molecular Mechanics addressed the phenomenon of FBG fragment bonding on LNO surfaces. The binding simulation validated the experimental observation using zeta potential measurements which showed presence of solvated medium influenced the adsorption phenomenon due to the negative surface potential.
Novel Approach for the Synthesis of Chlorophosphazene Cycles with a Defined Size via Controlled Cyclization of Linear Oligodichlorophosphazenes [Cl(PCl2=N)n–PCl3]+[PCl6]−
Authors: Gorlov Mikhail , Bredov Nikolay , Esin Andrey , Sirotin Igor , Soldatov Mikhail , Oberemok Volodymyr , Kireev Vyacheslav V.
Published: June 2021

Despite a significant number of investigations in the field of phosphazene chemistry, the formation mechanism of this class of cyclic compounds is still poorly studied. At the same time, a thorough understanding of this process is necessary, both for the direct production of phosphazene rings of a given size and for the controlled cyclization reaction when it is secondary and undesirable. We synthesized a series of short linear phosphazene oligomers with the general formula Cl[PCl2=N]n–PCl3+PCl6– and studied their tendency to form cyclic structures under the influence of elevated temperatures or in the presence of nitrogen-containing agents, such as hexamethyldisilazane (HMDS) or ammonium chloride. It was established that linear oligophosphazenes are inert when heated in the absence of the mentioned cyclization agents, and the formation of cyclic products occurs only when these agents are involved in the process. The ability to obtain the desired size phosphazene cycle from corresponding linear chains is shown for the first time. Known obstacles, such as side interaction with the PCl6– counterion and a tendency of longer chains to undergo crosslinking elongation instead of cyclization are still relevant, and ways to overcome them are being discussed.
A Comparative Study to Decipher the Structural and Dynamics Determinants Underlying the Activity and Thermal Stability of GH-11 Xylanases
Authors: Vucinic Jelena , Novikov Gleb , Montanier Cédric , Dumon Claire , Schiex Thomas , Barbe Sophie
Published: June 2021

With the growing need for renewable sources of energy, the interest for enzymes capable of biomass degradation has been increasing. In this paper, we consider two different xylanases from the GH-11 family: the particularly active GH-11 xylanase from Neocallimastix patriciarum, NpXyn11A, and the hyper-thermostable mutant of the environmentally isolated GH-11 xylanase, EvXyn11TS. Our aim is to identify the molecular determinants underlying the enhanced capacities of these two enzymes to ultimately graft the abilities of one on the other. Molecular dynamics simulations of the respective free-enzymes and enzyme–xylohexaose complexes were carried out at temperatures of 300, 340, and 500 K. An in-depth analysis of these MD simulations showed how differences in dynamics influence the activity and stability of these two enzymes and allowed us to study and understand in greater depth the molecular and structural basis of these two systems. In light of the results presented in this paper, the thumb region and the larger substrate binding cleft of NpXyn11A seem to play a major role on the activity of this enzyme. Its lower thermal stability may instead be caused by the higher flexibility of certain regions located further from the active site. Regions such as the N-ter, the loops located in the fingers region, the palm loop, and the helix loop seem to be less stable than in the hyper-thermostable EvXyn11TS. By identifying molecular regions that are critical for the stability of these enzymes, this study allowed us to identify promising targets for engineering GH-11 xylanases. Eventually, we identify NpXyn11A as the ideal host for grafting the thermostabilizing traits of EvXyn11TS.
Resveratrol Attenuates the Proliferation of Prostatic Stromal Cells in Benign Prostatic Hyperplasia by Regulating Cell Cycle Progression, Apoptosis, Signaling Pathways, BPH Markers, and NF-κB Activity
Authors: Jang Jowon , Song Junhui , Lee Jiyun , Moon Sung-Kwon , Moon Bokyung
Published: June 2021

Resveratrol can inhibit cell proliferation and metastasis and induce apoptosis. However, the mechanisms of action through which resveratrol inhibits the abnormal proliferation of prostate stromal cells, causing prostatic hyperplasia, have not been fully elucidated. Here, we evaluated the inhibitory effects of resveratrol on cell proliferation associated with prostatic hyperplasia using WPMY-1 cells. Our results showed that resveratrol inhibited the proliferation of WPMY-1 cells via the induction of G0/G1-phase cell cycle arrest, which was caused by downregulated expression of cyclins and cyclin-dependent kinases regulated by increased p21WAF1 and p27KIP1 expression level. In addition, resveratrol treatment suppressed the phosphorylation of phosphatidylinositol 3-kinase/AKT and extracellular signal-regulated kinase 1/2. The expression levels of molecular markers affecting prostate development were also reduced by treatment with resveratrol. Finally, resveratrol attenuated the binding activity of the transcription factor nuclear factor-κB in WPMY-1 cells, and accelerated apoptotic cell death via intrinsic cascade pathway. These results indicate that resveratrol may be useful for the prevention or treatment of prostatic hyperplasia.
Kcnj16 (Kir5.1) Gene Ablation Causes Subfertility and Increases the Prevalence of Morphologically Abnormal Spermatozoa
Authors: Poli Giulia , Hasan Sonia , Belia Silvia , Cenciarini Marta , Tucker Stephen J. , Imbrici Paola , Shehab Safa , Pessia Mauro , Brancorsini Stefano , D'Adamo Maria Cristina
Published: June 2021

The ability of spermatozoa to swim towards an oocyte and fertilize it depends on precise K+ permeability changes. Kir5.1 is an inwardly-rectifying potassium (Kir) channel with high sensitivity to intracellular H+ (pHi) and extracellular K+ concentration [K+]o, and hence provides a link between pHi and [K+]o changes and membrane potential. The intrinsic pHi sensitivity of Kir5.1 suggests a possible role for this channel in the pHi-dependent processes that take place during fertilization. However, despite the localization of Kir5.1 in murine spermatozoa, and its increased expression with age and sexual maturity, the role of the channel in sperm morphology, maturity, motility, and fertility is unknown. Here, we confirmed the presence of Kir5.1 in spermatozoa and showed strong expression of Kir4.1 channels in smooth muscle and epithelial cells lining the epididymal ducts. In contrast, Kir4.2 expression was not detected in testes. To examine the possible role of Kir5.1 in sperm physiology, we bred mice with a deletion of the Kcnj16 (Kir5.1) gene and observed that 20% of Kir5.1 knock-out male mice were infertile. Furthermore, 50% of knock-out mice older than 3 months were unable to breed. By contrast, 100% of wild-type (WT) mice were fertile. The genetic inactivation of Kcnj16 also resulted in smaller testes and a greater percentage of sperm with folded flagellum compared to WT littermates. Nevertheless, the abnormal sperm from mutant animals displayed increased progressive motility. Thus, ablation of the Kcnj16 gene identifies Kir5.1 channel as an important element contributing to testis development, sperm flagellar morphology, motility, and fertility. These findings are potentially relevant to the understanding of the complex pHi- and [K+]o-dependent interplay between different sperm ion channels, and provide insight into their role in fertilization and infertility.
Valproic Acid Reduces Vasospasm through Modulation of Akt Phosphorylation and Attenuates Neuronal Apoptosis in Subarachnoid Hemorrhage Rats
Authors: Wu Chieh-Hsin , Tsai Yi-Cheng , Tsai Tai-Hsin , Kuo Keng-Liang , Su Yu-Feng , Chang Chih-Hui , Lin Chih-Lung
Published: June 2021

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating emergent event associated with high mortality and morbidity. Survivors usually experience functional neurological sequelae caused by vasospasm-related delayed ischemia. In this study, male Sprague-Dawley rats were randomly assigned to five groups: sham (non-SAH) group, SAH group, and three groups with SAH treated with different doses of valproic acid (VPA) (10, 20, 40 mg/kg, once-daily, for 7 days). The severity of vasospasm was determined by the ratio of cross-sectional areas to intima-media thickness of the basilar arteries (BA) on the seventh day after SAH. The BA showed decreased expression of phospho-Akt proteins. The dentate gyrus showed increased expression of cleaved caspase-3 and Bax proteins and decreased expression of Bcl-2, phospho-ERK 1/2, phospho-Akt and acetyl-histone H3 proteins. The incidence of SAH-induced vasospasm was significantly lower in the SAH group treated with VPA 40 mg/kg (p < 0.001). Moreover, all groups treated with VPA showed reversal of the above-mentioned protein expression in BA and the dentate gyrus. Treatment with VPA upregulated histone H3 acetylation and conferred anti-vasospastic and neuro-protective effects by enhancing Akt and/or ERK phosphorylation. This study demonstrated that VPA could alleviate delayed cerebral vasospasm induced neuro-apoptosis after SAH.
Can Human Oral Mucosa Stem Cells Differentiate to Corneal Epithelia?
Authors: López Sonia , Hoz Lía , Tenorio Eda Patricia , Buentello Beatriz , Magaña Fátima Sofía , Wintergerst Ana , Navas Alejandro , Garfias Yonathan , Arzate Higinio
Published: June 2021

Human oral mucosa stem cells (hOMSCs) arise from the neural crest, they can self-renew, proliferate, and differentiate to several cell lines and could represent a good source for application in tissue engineering. Because of their anatomical location, hOMSCs are easy to isolate, have multilineage differentiation capacity and express embryonic stem cells markers such as—Sox2, Oct3/4 and Nanog. We have used SHEM (supplemented hormonal epithelial medium) media and cultured hOMSCs over human amniotic membrane and determined the cell’s capacity to differentiate to an epithelial-like phenotype and to express corneal specific epithelial markers—CK3, CK12, CK19, Pan-cadherin and E-cadherin. Our results showed that hOMSCs possess the capacity to attach to the amniotic membrane and express CK3, CK19, Pan-Cadherin and E-Cadherin without induction with SHEM media and expressed CK12 or changed the expression pattern of E-Cadherin to a punctual-like feature when treated with SHEM media. The results observed in this study show that hOMSCs possess the potential to differentiate toward epithelial cells. In conclusion, our results revealed that hOMSCs readily express markers for corneal determination and could provide the ophthalmology field with a therapeutic alternative for tissue engineering to achieve corneal replacement when compared with other techniques. Nevertheless, further studies are needed to develop a predictable therapeutic alternative for cornea replacement.
The Enigmatic Metallothioneins: A Case of Upward-Looking Research
Authors: Abdin Ahmad Yaman , Jacob Claus , Kästner Lena
Published: June 2021

In the mid-1950s, Bert Lester Vallee and his colleague Marvin Margoshes discovered a molecule referred to today as metallothionein (MT). Meanwhile, MTs have been shown to be common in many biological organisms. Despite their prevalence, however, it remains unclear to date what exactly MTs do and how they contribute to the biological function of an organism or organ. We investigate why biochemical research has not yet been able to pinpoint the function(s) of MTs. We shall systematically examine both the discovery of and recent research on Dr. Vallee’s beloved family of MT proteins utilizing tools from philosophy of science. Our analysis highlights that Vallee’s initial work exhibited features prototypical of a developing research tradition: it was upward-looking, exploratory, and utilized mere interactions. Since the 1960s, MT research has increasingly become intervention- and hypothesis-based while it remained largely upward-looking in character. Whilst there is no reason to think that upward-looking research cannot successfully yield structure-function mappings, it has not yet been successful in the case of MTs. Thus, we suggest it might be time to change track and consider other research strategies looking into the evolution of MTs. Recent studies in mollusks render research in this direction worthy of pursuit.
Nrf2 Activation Attenuates Acrylamide-Induced Neuropathy in Mice
Authors: Davuljigari Chand Basha , Ekuban Frederick Adams , Zong Cai , Fergany Alzahraa A. M. , Morikawa Kota , Ichihara Gaku
Published: June 2021

Acrylamide is a well characterized neurotoxicant known to cause neuropathy and encephalopathy in humans and experimental animals. To investigate the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in acrylamide-induced neuropathy, male C57Bl/6JJcl adult mice were exposed to acrylamide at 0, 200 or 300 ppm in drinking water and co-administered with subcutaneous injections of sulforaphane, a known activator of the Nrf2 signaling pathway at 0 or 25 mg/kg body weight daily for 4 weeks. Assessments for neurotoxicity, hepatotoxicity, oxidative stress as well as messenger RNA-expression analysis for Nrf2-antioxidant and pro-inflammatory cytokine genes were conducted. Relative to mice exposed only to acrylamide, co-administration of sulforaphane protected against acrylamide-induced neurotoxic effects such as increase in landing foot spread or decrease in density of noradrenergic axons as well as hepatic necrosis and hemorrhage. Moreover, co-administration of sulforaphane enhanced acrylamide-induced mRNA upregulation of Nrf2 and its downstream antioxidant proteins and suppressed acrylamide-induced mRNA upregulation of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase (iNOS) in the cerebral cortex. The results demonstrate that activation of the Nrf2 signaling pathway by co-treatment of sulforaphane provides protection against acrylamide-induced neurotoxicity through suppression of oxidative stress and inflammation. Nrf2 remains an important target for the strategic prevention of acrylamide-induced neurotoxicity.
Protease–Antiprotease Imbalance in Bronchiectasis
Authors: Oriano Martina , Amati Francesco , Gramegna Andrea , De Soyza Anthony , Mantero Marco , Sibila Oriol , Chotirmall Sanjay H. , Voza Antonio , Marchisio Paola , Blasi Francesco , Aliberti Stefano
Published: June 2021

Airway inflammation plays a central role in bronchiectasis. Protease–antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases’ over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease–antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.
Elevated CO2 Impacts on Plant–Pollinator Interactions: A Systematic Review and Free Air Carbon Enrichment Field Study
Authors: Crowley Liam M. , Sadler Jonathan P. , Pritchard Jeremy , Hayward Scott A. L.
Published: June 2021

The impact of elevated CO2 (eCO2) on plant–pollinator interactions is poorly understood. This study provides the first systematic review of this topic and identifies important knowledge gaps. In addition, we present field data assessing the impact of eCO2 (150 ppm above ambient) on bluebell (Hyacinthoides non-scripta)–pollinator interactions within a mature, deciduous woodland system. Since 1956, only 71 primary papers have investigated eCO2 effects on flowering time, floral traits and pollination, with a mere 3 studies measuring the impact on pollination interactions. Our field experiment documented flowering phenology, flower visitation and seed production, as well as the abundance and phenology of dominant insect pollinators. We show that first and mid-point flowering occurred 6 days earlier under eCO2, but with no change in flowering duration. Syrphid flies and bumble bees were the dominant flower visitors, with peak activity recorded during mid- and late-flowering periods. Whilst no significant difference was recorded in total visitation or seed set between eCO2 and ambient treatments, there were clear patterns of earlier flowering under eCO2 accompanied by lower pollinator activity during this period. This has implications for potential loss of synchrony in pollination systems under future climate scenarios, with associated long-term impacts on abundance and diversity.
Eriophyid Mites in Classical Biological Control of Weeds: Progress and Challenges
Authors: Marini Francesca , Weyl Philip , Vidović Biljana , Petanović Radmila , Littlefield Jeffrey , Simoni Sauro , de Lillo Enrico , Cristofaro Massimo , Smith Lincoln
Published: June 2021

A classical biological control agent is an exotic host-specific natural enemy, which is intentionally introduced to obtain long-term control of an alien invasive species. Among the arthropods considered for this role, eriophyid mites are likely to possess the main attributes required: host specificity, efficacy, and long-lasting effects. However, so far, only a few species have been approved for release. Due to their microscopic size and the general lack of knowledge regarding their biology and behavior, working with eriophyids is particularly challenging. Furthermore, mites disperse in wind, and little is known about biotic and abiotic constraints to their population growth. All these aspects pose challenges that, if not properly dealt with, can make it particularly difficult to evaluate eriophyids as prospective biological control agents and jeopardize the general success of control programs. We identified some of the critical aspects of working with eriophyids in classical biological control of weeds and focused on how they have been or may be addressed. In particular, we analyzed the importance of accurate mite identification, the difficulties faced in the evaluation of their host specificity, risk assessment of nontarget species, their impact on the weed, and the final steps of mite release and post-release monitoring.