bluuebunny/crossref_metadata_2025 huggingface dataset:
Volunteers’ Support of Carers of Rural People Living with Dementia to Use a Custom-Built Application
Authors: Wilding Clare , Davis Hilary , Rasekaba Tshepo , Hamiduzzaman Mohammad , Royals Kayla , Greenhill Jennene , O’Connell Megan E. , Perkins David , Bauer Michael , Morgan Debra , Blackberry Irene
Published: September 2021

There is great potential for human-centred technologies to enhance wellbeing for people living with dementia and their carers. The Virtual Dementia Friendly Rural Communities (Verily Connect) project aimed to increase access to information, support, and connection for carers of rural people living with dementia, via a co-designed, integrated website/mobile application (app) and Zoom videoconferencing. Volunteers were recruited and trained to assist the carers to use the Verily Connect app and videoconferencing. The overall research design was a stepped wedge open cohort randomized cluster trial involving 12 rural communities, spanning three states of Australia, with three types of participants: carers of people living with dementia, volunteers, and health/aged services staff. Data collected from volunteers (n = 39) included eight interviews and five focus groups with volunteers, and 75 process memos written by research team members. The data were analyzed using a descriptive evaluation framework and building themes through open coding, inductive reasoning, and code categorization. The volunteers reported that the Verily Connect app was easy to use and they felt they derived benefit from volunteering. The volunteers had less volunteering work than they desired due to low numbers of carer participants; they reported that older rural carers were partly reluctant to join the trial because they eschewed using online technologies, which was the reason for involving volunteers from each local community.
The Effect of High-Intensity Accelerations and Decelerations on Match Outcome of an Elite English League Two Football Team
Authors: Rhodes David , Valassakis Stephen , Bortnik Lukasz , Eaves Richard , Harper Damian , Alexander Jill
Published: September 2021

Objectives: Previous research has highlighted the frequency of high-intensity accelerations and decelerations in elite football. The influence of these actions on match performance outcomes has not been established. The aim of the present study was to identify the influence of high-intensity accelerations and decelerations on match performance outcomes (i.e., win, draw, lost). Comparisons were also made between team and positional high-intensity accelerations and decelerations recorded within the games. Methods: 26 elite outfield footballers from an elite English Football League (EFL) Two team completed the present study. Global Positioning System (GPS) technology was utilised to quantify high-intensity accelerations and decelerations during 45 games in a competitive season. Magnitude analysis and the effects of results, positions and fixture periods were observed. Results: Significant effects of results, periods and positions were observed (p ≤ 0.05), with the highest outputs observed in games won. Positionally, fullbacks and centre forwards in a 4–3–3 formation exhibited the greatest frequency of high-intensity accelerations and decelerations. Very large differences were observed between the frequency of high-intensity decelerations compared to accelerations in games won (g = 2.37), drawn (g = 2.99) and lost (g = 3.59). The highest team frequencies of high-intensity accelerations (n = 3330) and decelerations (n = 6482) were completed in games won. Conclusions: The frequency of high-intensity accelerations and decelerations has a significant impact on match performance outcomes in an elite English League Two football team. Consideration needs to be given to specific conditioning and recovery strategies to optimise high-intensity acceleration and deceleration performance in games. Caution should be taken as these findings are representative of one team within the EFL.
‘You Learn How to Hate’: Adapting a Healthy Relationship Curriculum Using a Trauma-Informed Race Equity Lens
Authors: Guillot-Wright Shannon , Torres Elizabeth D. , Obinyan Bianca , Temple Jeff R.
Published: September 2021

Teen dating violence is a public health concern that can lead to short- and long-term mental and physical health consequences, including depression, anxiety, risky behaviors, and unhealthy future relationships. Research shows that social and structural determinants of health, such as racism, low socio-economic status, and neighborhood conditions, may predispose certain communities to violence. To better understand methods to reduce TDV among ethnically and economically diverse populations, we used a trauma-informed race equity lens to adapt an efficacious prevention program known as Fourth R. This universal program has been shown to reduce some dating violence, substance use, and risky sexual behaviors, but there remains room for improvement. Specifically, more attention to trauma and the importance of societal risk and protective factors may improve the program’s effectiveness. Thus, focus group discussions were conducted with students and we then adapted Fourth R lessons specific to trauma, racism, and discrimination. Major themes discussed are that Fourth R and other prevention programs should focus attention on social and structural issues, such as racism and discrimination.
Awareness of Endometriosis Symptoms—A Cross Sectional Survey among Polish Women
Authors: Kotowska Maja , Urbaniak Justyna , Falęcki Wojciech J. , Łazarewicz Piotr , Masiak Mateusz , Szymusik Iwona
Published: September 2021

Background: Endometriosis is a chronic inflammatory condition characterized by the presence of endometrial-like tissue outside of the uterine cavity. It affects approximately 6–12% among reproductive-age women. Laparoscopy is still the gold standard for diagnosing it. Since an average of couple of years elapses from the onset of symptoms to the definitive diagnosis, analysis of symptoms could serve as a non-invasive diagnostic tool. Methods: An anonymous survey was distributed online in November 2019. It contained 23 closed questions, which covered two areas: knowledge and awareness of endometriosis symptoms and its presence among respondents. Results: A total of 3319 women completed the survey, of which 328 were diagnosed with endometriosis (9.9%). The symptoms of endometriosis most often indicated by the general population were infertility and dysmenorrhea. In contrast, those least frequently indicated were painful defecation and dysuria. Respondents suffering from endometriosis indicated that they often or sometimes experienced dysmenorrhea (83%, n = 273), pelvic pain not related to menstruation (72%, n = 235), dyspareunia (68%, n = 223) and painful defecation or dysuria (40%, n = 132). Conclusions: Since the search for a non-invasive diagnostic endometriosis marker has been conducted for many years without success so far, it seems that awareness of the clinical presentation and reported symptoms may help to provide earlier diagnoses.
Environmental Risk Perception and Preventive Behavior during the COVID-19 Pandemic in Central Taiwan
Authors: Hsu Kuo-Wei , Chao Jen-Chih , Hsu Ching-Yi
Published: September 2021

Due to traffic and industrial and seasonal air pollution, wearing masks outside the home has long been a daily habit for many people in Taiwan. After the emergence of the novel coronavirus (COVID-19), which has an incubation period of up to 14 days, wearing masks and maintaining social distancing was advised to reduce exposure to this new environmental risk. This study investigates open and semi-open spaces in three districts in central Taiwan, using a non-participant observation method, with the aim of understanding people’s mask-wearing behavior. The results indicate that mask-wearing rates were higher in urban areas than in rural ones and among females than males. By age cohort, mask-wearing was most prevalent among young adults and middle-aged people and least prevalent among minors, with the elderly occupying a middle position. Masks were also more likely to be worn in semi-open spaces than in open ones. This study enriches our understanding of environmental risk perception of the pandemic and of public perceptions, which are vital to increasing the adoption of preventative measures.
Between- and within-Group Differences in Fruit and Vegetable Purchases, Consumption, and BMI among Hispanic Farmers’ Market Shoppers Who Use SNAP
Authors: Sawyer-Morris Ginnie , Grajeda Sara , Tracy Tara , Karpyn Allison
Published: September 2021

(1) Background: Despite considerable efforts to increase farmers’ market access (FM) and improve household fruit and vegetable (FV) purchasing in low-income communities, little is known about the FV purchasing and consumption characteristics of low-income Hispanic farmers’ market shoppers. (2) Methods: A secondary analysis of baseline data from a farmers’ market study conducted between 2015 and 2017 (n = 2825) was performed. Participants who also received supplemental nutrition assistance program (SNAP) completed a 31-item online survey assessing demographics, health characteristics, and FV purchasing and consumption habits. Descriptive statistics and bivariate analyses were used to assess between- and within-group differences amongst Hispanic and non-Hispanic households. Regression analyses were used to examine associations among BMI, FV purchasing and consumption, and household size for Hispanic and non-Hispanic households as well as for Hispanic subgroups. (3) Results: The sample included 515 Hispanic and 2310 non-Hispanic SNAP-using FM shoppers in 13 states. Despite experiencing significantly higher food insecurity (89% vs. 81%, non-Hispanic), Hispanic shoppers consumed similar amounts of FV (3.04 cups/day) and spent less doing so. Significant subgroup differences were identified for FV purchasing. (4) Conclusions: Findings emphasize the importance of food insecurity and household size in FV interventions and underscore the capacity of Hispanic families to maintain FV consumption.
Application of Pandemic Intelligence in Dynamic Data in Taiwan
Authors: Chang Tzu-Yin , Su Wen-Ray , Chen Hongey , Huang Ming-Wey , Chen Lu-Yen A.
Published: September 2021

Taiwan was successful in containing the spread of the novel coronavirus (COVID-19) in 2020. One major factor in this success was the compilation and provision of comprehensive information about the pandemic. The present study proposes a pandemic intelligence system that provides data on the number of epidemic prevention professionals in each county and city, as well as daily confirmed cases, the demographics of the confirmed cases, and available resources (negative-pressure room beds and artificial ventilation apparatuses) in hospitals. Furthermore, the system provides the location of pharmacies selling masks and their current inventories, as well as the distribution of crowds at popular tourist destinations and social-distance monitoring. The most frequently used map layer in the thematic map of the pandemic is that of crowd distribution during the study period from March 2020 until the end of the same year. The case study used in this investigation for applying the system is represented by the 4-day weekend for Tomb-Sweeping Day of 2020. Through the real-time analysis of dynamic data and the integration of intelligence, the system offers a clear insight into changes in relevant information and, thus, enables the preemptive deployment of control measures by the county/city governments regarding pandemic management.
Challenges Associated with Parenting While Incarcerated: A Review
Authors: Dargis Monika , Mitchell-Somoza Arielle
Published: September 2021

Of the 2.5 million people who are incarcerated in the United States, over half are parents. While it is well-established that incarceration has a detrimental impact on the children of incarcerated parents, less is known regarding the psychological impact of incarceration on parents themselves. The present review summarizes existing literature on the impact of incarceration on parents retrieved via online databases. Published articles were classified according to their overall themes and summarized. Pertinent studies include the psychological and emotional consequences of incarceration on parents, the experience of parenting while incarcerated, including barriers to parenting, the utility of parenting program interventions during periods of incarceration, and how these results differ for mothers and fathers. While the existing evidence introduces these issues, there is a need for additional research on the impact of incarceration on parents. These areas for future research as well as clinical implications are discussed.
Impact of Two Different Recruitment Procedures (Random vs. Volunteer Selection) on the Results of Seroepidemiological Study (SARS-CoV-2)
Authors: Gajda Maksymilian , Kowalska Małgorzata , Zejda Jan Eugeniusz
Published: September 2021

The proper recruitment of subjects for population-based epidemiological studies is critical to the external validity of the studies and, above all, to the sound and correct interpretation of the findings. Since 2020, the novel coronavirus SARS-CoV-2 pandemic has been a new factor that has been, additionally, hindering studies. Therefore, the aim of our study is to compare demographic, socio-economic, health-related characteristics and the frequency of SARS-CoV-2 infection occurrence among the randomly selected group and the group composed of volunteers. We compare two groups of participants from the cross-sectional study assessing the seroprevalence of SARS-CoV-2 coronavirus, which was conducted in autumn 2020, in three cities of the Silesian Voivodeship in Poland. The first group consisted of a randomly selected, nationally representative, age-stratified sample of subjects (1167 participants, “RG” group) and was recruited using personal invitation letters and postal addresses obtained from a national registry. The second group (4321 volunteers, “VG” group) included those who expressed their willingness to participate in response to an advertisement published in the media. Compared with RG subjects, volunteers were more often females, younger and professionally active, more often had a history of contact with a COVID-19 patient, post-contact nasopharyngeal swab, fewer comorbidities, as well as declared the occurrence of symptoms that might suggest infection with SARS-CoV-2. Additionally, in the VG group the percentage of positive IgG results and tuberculosis vaccination were higher. The findings of the study confirm that surveys limited to volunteers are biased. The presence of the bias may seriously affect and distort inference and make the generalizability of the results more than questionable. Although effective control over selection bias in surveys, including volunteers, is virtually impossible, its impact on the survey results is impossible to predict. However, whenever possible, such surveys could include a small component of a random sample to assess the presence and potential effects of selection bias.
Anxiety, Depression and Risk of Post-Traumatic Stress Disorder in Health Workers: The Relationship with Burnout during COVID-19 Pandemic in Italy
Authors: Ghio Lucio , Patti Sara , Piccinini Giulia , Modafferi Cinzia , Lusetti Eleonora , Mazzella Massimo , Del Sette Massimo
Published: September 2021

During the COVID-19 pandemic, healthcare workers (HW) have faced an extremely difficult work environment, with an increased workload and traumatic events. Our study aimed to investigate the impact of COVID-19 pandemic on HW’s mental wellbeing. We analyzed the correlations between levels of burnout and other mental health disorders and we searched for the presence of specific risk factors of post-traumatic symptomatology related to the pandemic. A structured an on-line questionnaire and validated instruments were completed by a sample of HW from some hospitals in Genoa, Italy. Anxious, depressive, post-traumatic and other psychological symptoms were assessed and risk factors, related to the pandemic, were considered. Then, we investigated the correlation between levels of burnout and the risk of developing psychopathology. A total of 731 HW were screened, and we found increased levels of anxiety (61%), depression (62%), PTSD (34%) and high levels of burnout; especially emotional exhaustion (37%). A statistically significant association between burnout and insomnia, depression, anxiety, and post-traumatic symptoms was demonstrated. This study indicates that during the COVID-19 pandemic, HW showed high levels of psychological distress and that burnout is an important predictor of sufferance. These findings support the idea to provide psychological and psychiatric support for HW.
Specific Engineered G Protein Coupling to Histamine Receptors Revealed from Cellular Assay Experiments and Accelerated Molecular Dynamics Simulations
Authors: Höring Carina , Conrad Marcus , Söldner Christian A. , Wang Jinan , Sticht Heinrich , Strasser Andrea , Miao Yinglong
Published: September 2021

G protein-coupled receptors (GPCRs) are targets of extracellular stimuli and hence occupy a key position in drug discovery. By specific and not yet fully elucidated coupling profiles with α subunits of distinct G protein families, they regulate cellular responses. The histamine H2 and H4 receptors (H2R and H4R) are prominent members of Gs- and Gi-coupled GPCRs. Nevertheless, promiscuous G protein and selective Gi signaling have been reported for the H2R and H4R, respectively, the molecular mechanism of which remained unclear. Using a combination of cellular experimental assays and Gaussian accelerated molecular dynamics (GaMD) simulations, we investigated the coupling profiles of the H2R and H4R to engineered mini-G proteins (mG). We obtained coupling profiles of the mGs, mGsi, or mGsq proteins to the H2R and H4R from the mini-G protein recruitment assays using HEK293T cells. Compared to H2R–mGs expressing cells, histamine responses were weaker (pEC50, Emax) for H2R–mGsi and –mGsq. By contrast, the H4R selectively bound to mGsi. Similarly, in all-atom GaMD simulations, we observed a preferential binding of H2R to mGs and H4R to mGsi revealed by the structural flexibility and free energy landscapes of the complexes. Although the mG α5 helices were consistently located within the HR binding cavity, alternative binding orientations were detected in the complexes. Due to the specific residue interactions, all mG α5 helices of the H2R complexes adopted the Gs-like orientation toward the receptor transmembrane (TM) 6 domain, whereas in H4R complexes, only mGsi was in the Gi-like orientation toward TM2, which was in agreement with Gs- and Gi-coupled GPCRs structures resolved by X-ray/cryo-EM. These cellular and molecular insights support (patho)physiological profiles of the histamine receptors, especially the hitherto little studied H2R function in the brain, as well as of the pharmacological potential of H4R selective drugs.
Discovery of a Non-Nucleoside SETD2 Methyltransferase Inhibitor against Acute Myeloid Leukemia
Authors: Bajusz Dávid , Bognár Zsolt , Ebner Jessica , Grebien Florian , Keserű György M.
Published: September 2021

Histone methyltransferases (HMTs) have attracted considerable attention as potential targets for pharmaceutical intervention in various malignant diseases. These enzymes are known for introducing methyl marks at specific locations of histone proteins, creating a complex system that regulates epigenetic control of gene expression and cell differentiation. Here, we describe the identification of first-generation cell-permeable non-nucleoside type inhibitors of SETD2, the only mammalian HMT that is able to tri-methylate the K36 residue of histone H3. By generating the epigenetic mark H3K36me3, SETD2 is involved in the progression of acute myeloid leukemia. We developed a structure-based virtual screening protocol that was first validated in retrospective studies. Next, prospective screening was performed on a large library of commercially available compounds. Experimental validation of 22 virtual hits led to the discovery of three compounds that showed dose-dependent inhibition of the enzymatic activity of SETD2. Compound C13 effectively blocked the proliferation of two acute myeloid leukemia (AML) cell lines with MLL rearrangements and led to decreased H3K36me3 levels, prioritizing this chemotype as a viable chemical starting point for drug discovery projects.
Synaptic Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders
Authors: Czapski Grzegorz A. , Babiec Lidia , Jęśko Henryk , Gąssowska-Dobrowolska Magdalena , Cieślik Magdalena , Matuszewska Marta , Frontczak-Baniewicz Małgorzata , Zajdel Karolina , Adamczyk Agata
Published: September 2021

Tuberous sclerosis complex (TSC) is a rare, multi-system genetic disease with serious neurological and mental symptoms, including autism. Mutations in the TSC1/TSC2 genes lead to the overactivation of mTOR signalling, which is also linked to nonsyndromic autism. Our aim was to analyse synaptic pathology in a transgenic model of TSC: two-month-old male B6;129S4-Tsc2tm1Djk/J mice with Tsc2 haploinsufficiency. Significant brain-region-dependent alterations in the expression of several synaptic proteins were identified. The most prominent changes were observed in the immunoreactivity of presynaptic VAMP1/2 (ca. 50% increase) and phospho-synapsin-1 (Ser62/67) (ca. 80% increase). Transmission electron microscopy demonstrated serious ultrastructural abnormalities in synapses such as a blurred structure of synaptic density and a significantly increased number of synaptic vesicles. The impairment of synaptic mitochondrial ultrastructure was represented by excessive elongation, swelling, and blurred crista contours. Polyribosomes in the cytoplasm and swollen Golgi apparatus suggest possible impairment of protein metabolism. Moreover, the delamination of myelin and the presence of vacuolar structures in the cell nucleus were observed. We also report that Tsc2+/− mice displayed increased brain weights and sizes. The behavioural analysis demonstrated the impairment of memory function, as established in the novel object recognition test. To summarise, our data indicate serious synaptic impairment in the brains of male Tsc2+/− mice.
Long-term Interactions of Circulating Neutrophils with Titanium Implants, the Role of Platelets in Regulation of Leukocyte Function
Authors: Zdziennicka Joanna , Junkuszew Andrzej , Latalski Michał , Świeca Michał , Wessely-Szponder Joanna
Published: September 2021

Despite the fact that different biomaterials are widely used in many biomedical applications, they can still cause side effects. Therefore, our aim was to assess neutrophil activity during the inflammatory phase of the repair process and long-term interactions between circulating neutrophils and Titanium (Ti) implants. Additionally, neutrophil in vitro response after stimulation by the extract of antimicrobial peptides (AMP extract), pentoxifylline (PTX) and some platelet-rich (L-PRP and PURE PRP) and platelet-poor (PPP) concentrates were tested. The study was conducted on eight sheep after Ti implant insertion into the tibia and revealed that the Ti implant did not cause any side effects during the course of experiment. After addition of L-PRP into neutrophils, culture activity of these cells significantly increased (p < 0.01), whereas treatment with AMP extract, PURE PRP, PPP or PTX caused decrease in neutrophil enzymatic response (on the basis of elastase, myeloperoxidase and alkaline phosphatase release) and free radical generation. These effects were observed in neutrophils isolated during the inflammatory phase as well as 4 and 10 months after implantation. Obtained results will be useful in regulation of inflammatory response during implantation of biomaterial and create possibility to modulate the cells response towards pro- or anti-inflammatory to reduce host tissue damage.
Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment
Authors: Mao Na , Yang Honghao , Yin Jie , Li Yaqian , Jin Fuyu , Li Tian , Yang Xinyu , Sun Ying , Liu Heliang , Xu Hong , Yang Fang
Published: September 2021

Glycolytic reprogramming is an important metabolic feature in the development of pulmonary fibrosis. However, the specific mechanism of glycolysis in silicosis is still not clear. In this study, silicotic models and silica-induced macrophage were used to elucidate the mechanism of glycolysis induced by silica. Expression levels of the key enzymes in glycolysis and macrophage activation indicators were analyzed by Western blot, qRT-PCR, IHC, and IF analyses, and by using a lactate assay kit. We found that silica promotes the expression of the key glycolysis enzymes HK2, PKM2, LDHA, and macrophage activation factors iNOS, TNF-α, Arg-1, IL-10, and MCP1 in silicotic rats and silica-induced NR8383 macrophages. The enhancement of glycolysis and macrophage activation induced by silica was reduced by Ac-SDKP or siRNA-Ldha treatment. This study suggests that Ac-SDKP treatment can inhibit glycolytic reprogramming in silica-induced lung macrophages and silicosis.
Vitreoretinal Surgery in the Prevention and Treatment of Toxic Tumour Syndrome in Uveal Melanoma: A Systematic Review
Authors: Romano Mario R. , Catania Fiammetta , Confalonieri Filippo , Zollet Piero , Allegrini Davide , Sergenti Jessica , Lanza Francesco B. , Ferrara Mariantonia , Angi Martina
Published: September 2021

Toxic tumour syndrome (TTS) is a particularly aggressive form of secondary vasculopathy occurring after radiation therapy of uveal melanoma due to the persistence of the necrotic tumour mass inside the eye. The development of TTS confers a particularly unfavourable functional and anatomical ocular prognosis, ultimately requiring enucleation in most cases if untreated. Vitreoretinal (VR) surgery has been successfully applied for treatment and prevention of TTS using both resecting and non-resecting techniques. In this systematic review, we aim to define characteristics of uveal melanomas benefiting the most from secondary VR surgery and to outline the optimal type and timing of VR intervention in such cases. Analysis of the literature reveals that endoresection should be performed within 3 months after radiotherapy to tumours thicker than 7 mm and with a largest basal diameter between 8 mm and 15 mm with post-equatorial location, especially after proton beam treatment. Alternatively, endodrainage remains a valid therapeutic option in eyes with macula-off retinal detachment, tumour diameter larger than 15 mm or ciliary body involvement. VR surgery can be successful in the management of TTS following radiotherapy for uveal melanoma when timing and indication are appropriately evaluated.
Dimerization of Human Angiogenin and of Variants Involved in Neurodegenerative Diseases
Authors: Fasoli Sabrina , Bettin Ilaria , Montioli Riccardo , Fagagnini Andrea , Peterle Daniele , Laurents Douglas V. , Gotte Giovanni
Published: September 2021

Human Angiogenin (hANG, or ANG, 14.1 kDa) promotes vessel formation and is also called RNase 5 because it is included in the pancreatic-type ribonuclease (pt-RNase) super-family. Although low, its ribonucleolytic activity is crucial for angiogenesis in tumor tissues but also in the physiological development of the Central Nervous System (CNS) neuronal progenitors. Nevertheless, some ANG variants are involved in both neurodegenerative Parkinson disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Notably, some pt-RNases acquire new biological functions upon oligomerization. Considering neurodegenerative diseases correlation with massive protein aggregation, we analyzed the aggregation propensity of ANG and of three of its pathogenic variants, namely H13A, S28N, and R121C. We found no massive aggregation, but wt-ANG, as well as S28N and R121C variants, can form an enzymatically active dimer, which is called ANG-D. By contrast, the enzymatically inactive H13A-ANG does not dimerize. Corroborated by a specific cross-linking analysis and by the behavior of H13A-ANG that in turn lacks one of the two His active site residues necessary for pt-RNases to self-associate through the three-dimensional domain swapping (3D-DS), we demonstrate that ANG actually dimerizes through 3D-DS. Then, we deduce by size exclusion chromatography (SEC) and modeling that ANG-D forms through the swapping of ANG N-termini. In light of these novelties, we can expect future investigations to unveil other ANG determinants possibly related with the onset and/or development of neurodegenerative pathologies.
Maize WRKY Transcription Factor ZmWRKY79 Positively Regulates Drought Tolerance through Elevating ABA Biosynthesis
Authors: Gulzar Faiza , Fu Jingye , Zhu Chenying , Yan Jie , Li Xinglin , Meraj Tehseen Ahmad , Shen Qinqin , Hassan Beenish , Wang Qiang
Published: September 2021

Drought stress causes heavy damages to crop growth and productivity under global climatic changes. Transcription factors have been extensively studied in many crops to play important roles in plant growth and defense. However, there is a scarcity of studies regarding WRKY transcription factors regulating drought responses in maize crops. Previously, ZmWRKY79 was identified as the regulator of maize phytoalexin biosynthesis with inducible expression under different elicitation. Here, we elucidated the function of ZmWRKY79 in drought stress through regulating ABA biosynthesis. The overexpression of ZmWRKY79 in Arabidopsis improved the survival rate under drought stress, which was accompanied by more lateral roots, lower stomatal aperture, and water loss. ROS scavenging was also boosted by ZmWRKY79 to result in less H2O2 and MDA accumulation and increased antioxidant enzyme activities. Further analysis detected more ABA production in ZmWRKY79 overexpression lines under drought stress, which was consistent with up-regulated ABA biosynthetic gene expression by RNA-seq analysis. ZmWRKY79 was observed to target ZmAAO3 genes in maize protoplast through acting on the specific W-boxes of the corresponding gene promoters. Virus-induced gene silencing of ZmWRKY79 in maize resulted in compromised drought tolerance with more H2O2 accumulation and weaker root system architecture. Together, this study substantiates the role of ZmWRKY79 in the drought-tolerance mechanism through regulating ABA biosynthesis, suggesting its broad functions not only as the regulator in phytoalexin biosynthesis against pathogen infection but also playing the positive role in abiotic stress response, which provides a WRKY candidate gene to improve drought tolerance for maize and other crop plants.
Burn Injury Induces Proinflammatory Plasma Extracellular Vesicles That Associate with Length of Hospital Stay in Women: CRP and SAA1 as Potential Prognostic Indicators
Authors: Maile Robert , Willis Micah L. , Herring Laura E. , Prevatte Alex , Mahung Cressida , Cairns Bruce , Wallet Shannon , Coleman Leon G.
Published: September 2021

Severe burn injury is a devastating form of trauma that results in persistent immune dysfunction with associated morbidity and mortality. The underlying drivers of this immune dysfunction remain elusive, and there are no prognostic markers to identify at-risk patients. Extracellular vesicles (EVs) are emerging as drivers of immune dysfunction as well as biomarkers. We investigated if EVs after burn injury promote macrophage activation and assessed if EV contents can predict length of hospital stay. EVs isolated early from mice that received a 20% total body surface area (TBSA) burn promoted proinflammatory responses in cultured splenic macrophages. Unbiased LC-MS/MS proteomic analysis of early EVs (<72 h post-injury) from mice and humans showed some similarities including enrichment of acute phase response proteins such as CRP and SAA1. Semi-unbiased assessment of early human burn patient EVs found alterations consistent with increased proinflammatory signaling and loss of inhibition of CRP expression. In a sample of 50 patients with large burn injury, EV SAA1 and CRP were correlated with TBSA injury in both sexes and were correlated with length of hospital stay in women. These findings suggest that EVs are drivers of immune responses after burn injury and their content may predict hospital course.
Lipid Self-Assemblies under the Atomic Force Microscope
Authors: García-Arribas Aritz B. , Goñi Félix M. , Alonso Alicia
Published: September 2021

Lipid model membranes are important tools in the study of biophysical processes such as lipid self-assembly and lipid–lipid interactions in cell membranes. The use of model systems to adequate and modulate complexity helps in the understanding of many events that occur in cellular membranes, that exhibit a wide variety of components, including lipids of different subfamilies (e.g., phospholipids, sphingolipids, sterols…), in addition to proteins and sugars. The capacity of lipids to segregate by themselves into different phases at the nanoscale (nanodomains) is an intriguing feature that is yet to be fully characterized in vivo due to the proposed transient nature of these domains in living systems. Model lipid membranes, instead, have the advantage of (usually) greater phase stability, together with the possibility of fully controlling the system lipid composition. Atomic force microscopy (AFM) is a powerful tool to detect the presence of meso- and nanodomains in a lipid membrane. It also allows the direct quantification of nanomechanical resistance in each phase present. In this review, we explore the main kinds of lipid assemblies used as model membranes and describe AFM experiments on model membranes. In addition, we discuss how these assemblies have extended our knowledge of membrane biophysics over the last two decades, particularly in issues related to the variability of different model membranes and the impact of supports/cytoskeleton on lipid behavior, such as segregated domain size or bilayer leaflet uncoupling.
Pathogenesis and Molecular Mechanisms of Anderson–Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies
Authors: Tuttolomondo Antonino , Simonetta Irene , Riolo Renata , Todaro Federica , Di Chiara Tiziana , Miceli Salvatore , Pinto Antonio
Published: September 2021

Anderson–Fabry disease (AFD) is a rare disease with an incidenceof approximately 1:117,000 male births. Lysosomal accumulation of globotriaosylceramide (Gb3) is the element characterizing Fabry disease due to a hereditary deficiency α-galactosidase A (GLA) enzyme. The accumulation of Gb3 causes lysosomal dysfunction that compromises cell signaling pathways. Deposition of sphingolipids occurs in the autonomic nervous system, dorsal root ganglia, kidney epithelial cells, vascular system cells, and myocardial cells, resulting in organ failure. This manuscript will review the molecular pathogenetic pathways involved in Anderson–Fabry disease and in its organ damage. Some studies reported that inhibition of mitochondrial function and energy metabolism plays a significant role in AFD cardiomyopathy and in kidney disease of AFD patients. Furthermore, mitochondrial dysfunction has been reported as linked to the dysregulation of the autophagy–lysosomal pathway which inhibits the mechanistic target of rapamycin kinase (mTOR) mediated control of mitochondrial metabolism in AFD cells. Cerebrovascular complications due to AFD are caused by cerebral micro vessel stenosis. These are caused by wall thickening resulting from the intramural accumulation of glycolipids, luminal occlusion or thrombosis. Other pathogenetic mechanisms involved in organ damage linked to Gb3 accumulation are endocytosis and lysosomal degradation of endothelial calcium-activated intermediate-conductance potassium ion channel 3.1 (KCa3.1) via a clathrin-dependent process. This process represents a crucial event in endothelial dysfunction. Several studies have identified the deacylated form of Gb3, globotriaosylsphingosine (Lyso-Gb3), as the main catabolite that increases in plasma and urine in patients with AFD. The mean concentrations of Gb3 in all organs and plasma of Galactosidase A knockout mice were significantly higher than those of wild-type mice. The distributions of Gb3 isoforms vary from organ to organ. Various Gb3 isoforms were observed mainly in the kidneys, and kidney-specific Gb3 isoforms were hydroxylated. Furthermore, the action of Gb3 on the KCa3.1 channel suggests a possible contribution of this interaction to the Fabry disease process, as this channel is expressed in various cells, including endothelial cells, fibroblasts, smooth muscle cells in proliferation, microglia, and lymphocytes. These molecular pathways could be considered a potential therapeutic target to correct the enzyme in addition to the traditional enzyme replacement therapies (ERT) or drug chaperone therapy.
Netrin-1 as a Multitarget Barrier Stabilizer in the Peripheral Nerve after Injury
Authors: Chen Jeremy Tsung-Chieh , Schmidt Lea , Schürger Christina , Hankir Mohammed K. , Krug Susanne M. , Rittner Heike L.
Published: September 2021

The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain.
Functional Activity of Recombinant Forms of Amh and Synergistic Action with Fsh in European Sea Bass Ovary
Authors: Zapater Cinta , Rocha Ana , Molés Gregorio , Mascoli Alessia , Ibañez Soledad , Zanuy Silvia , Gómez Ana
Published: September 2021

Although anti-Müllerian hormone (AMH) has classically been correlated with the regression of Müllerian ducts in male mammals, involvement of this growth factor in other reproductive processes only recently come to light. Teleost is the only gnathostomes that lack Müllerian ducts despite having amh orthologous genes. In adult teleost gonads, Amh exerts a role in the early stages of germ cell development in both males and females. Mechanisms involving the interaction of Amh with gonadotropin- and growth factor-induced functions have been proposed, but our overall knowledge regarding Amh function in fish gonads remains modest. In this study, we report on Amh actions in the European sea bass ovary. Amh and type 2 Amh receptor (Amhr2) are present in granulosa and theca cells of both early and late-vitellogenic follicles and cannot be detected in previtellogenic ovaries. Using the Pichia pastoris system a recombinant sea bass Amh has been produced that is endogenously processed to generate a 12–15 kDa bioactive mature protein. Contrary to previous evidence in lower vertebrates, in explants of previtellogenic sea bass ovaries, mature Amh has a synergistic effect on steroidogenesis induced by the follicle-stimulating hormone (Fsh), increasing E2 and cyp19a1a levels.
Sodium 4-Phenylbutyrate Reduces Ocular Hypertension by Degrading Extracellular Matrix Deposition via Activation of MMP9
Authors: Maddineni Prabhavathi , Kasetti Ramesh B. , Kodati Bindu , Yacoub Sam , Zode Gulab S.
Published: September 2021

Ocular hypertension (OHT) is a serious adverse effect of the widely prescribed glucocorticoid (GC) therapy and, if left undiagnosed, it can lead to glaucoma and complete blindness. Previously, we have shown that the small chemical chaperone, sodium-4-phenylbutyrate (PBA), rescues GC-induced OHT by reducing ocular endoplasmic reticulum (ER) stress. However, the exact mechanism of how PBA rescues GC-induced OHT is not completely understood. The trabecular meshwork (TM) is a filter-like specialized contractile tissue consisting of TM cells embedded within extracellular matrix (ECM) that controls intraocular pressure (IOP) by constantly regulating aqueous humor (AH) outflow. Induction of abnormal ECM deposition in TM is a hallmark of GC-induced OHT. Here, we investigated whether PBA reduces GC-induced OHT by degrading abnormal ECM deposition in TM using mouse model of GC-induced OHT, ex vivo cultured human TM tissues and primary human TM cells. We show that topical ocular eye drops of PBA (1%) significantly lowers elevated IOP in mouse model of GC-induced OHT. Importantly, PBA prevents synthesis and deposition of GC-induced ECM in TM. We report for the first time that PBA can degrade existing abnormal ECM in normal human TM cells/tissues by inducing matrix metalloproteinase (MMP)9 expression and activity. Furthermore, inhibition of MMPs activity by chemical-inhibitor (minocycline) abrogated PBA’s effect on ECM reduction and its associated ER stress. Our study indicates a non-chaperone activity of PBA via activation of MMP9 that degrades abnormal ECM accumulation in TM.
Hydrogen Sulfide Reduces Ischemia and Reperfusion Injury in Neuronal Cells in a Dose- and Time-Dependent Manner
Authors: Scheid Stefanie , Goeller Max , Baar Wolfgang , Wollborn Jakob , Buerkle Hartmut , Schlunck Günther , Lagrèze Wolf , Goebel Ulrich , Ulbrich Felix
Published: September 2021

Background: The ischemia-reperfusion injury (IRI) of neuronal tissue, such as the brain and retina, leads to possible cell death and loss of function. Current treatment options are limited, but preliminary observations suggest a protective effect of hydrogen sulfide (H2S). However, the dosage, timing, and mechanism of inhaled H2S treatment after IRI requires further exploration. Methods: We investigated possible neuroprotective effects of inhaled H2S by inducing retinal ischemia–reperfusion injury in rats for the duration of 1 h (120 mmHg), followed by the administration of hydrogen sulfide (H2S) for 1 h at different time points (0, 1.5, and 3 h after the initiation of reperfusion) and at different H2S concentrations (120, 80, and 40 ppm). We quantified the H2S effect by conducting retinal ganglion cell counts in fluorogold-labeled animals 7 days after IRI. The retinal tissue was harvested after 24 h for molecular analysis, including qPCR and Western blotting. Apoptotic and inflammatory mediators, transcription factors, and markers for oxidative stress were investigated. Histological analyses of the retina and the detection of inflammatory cytokines in serum assays were also performed. Results: The effects of inhaled H2S were most evident at a concentration of 80 ppm administered 1.5 h after IRI. H2S treatment increased the expression of anti-apoptotic Bcl-2, decreased pro-apoptotic Bax expression, reduced the release of the inflammatory cytokines IL-1β and TNF-α, attenuated NF-κB p65, and enhanced Akt phosphorylation. H2S also downregulated NOX4 and cystathionine β-synthase. Histological analyses illustrated a reduction in TNF-α in retinal ganglion cells and lower serum levels of TNF-α in H2S-treated animals after IRI. Conclusion: After neuronal IRI, H2S mediates neuroprotection in a time- and dose-dependent manner. The H2S treatment modulated transcription factor NF-κB activation and reduced retinal inflammation.
Can We Predict the Isosymmetric Phase Transition? Application of DFT Calculations to Study the Pressure Induced Transformation of Chlorothiazide
Authors: Szeleszczuk Łukasz , Mazurek Anna Helena , Milcarz Katarzyna , Napiórkowska Ewa , Pisklak Dariusz Maciej
Published: September 2021

Isosymmetric structural phase transition (IPT, type 0), in which there are no changes in the occupation of Wyckoff positions, the number of atoms in the unit cell, and the space group symmetry, is relatively uncommon. Chlorothiazide, a diuretic agent with a secondary function as an antihypertensive, has been proven to undergo pressure-induced IPT of Form I to Form II at 4.2 GPa. For that reason, it has been chosen as a model compound in this study to determine if IPT can be predicted in silico using periodic DFT calculations. The transformation of Form II into Form I, occurring under decompression, was observed in geometry optimization calculations. However, the reverse transition was not detected, although the calculated differences in the DFT energies and thermodynamic parameters indicated that Form II should be more stable at increased pressure. Finally, the IPT was successfully simulated using ab initio molecular dynamics calculations.
Cell-Penetrating Delivery of Nitric Oxide by Biocompatible Dinitrosyl Iron Complex and Its Dermato-Physiological Implications
Authors: Chen Yu-Chieh , Chen Yi-Hong , Chiu Han , Ko Yi-Hsuan , Wang Ruei-Ting , Wang Wei-Ping , Chuang Yung-Jen , Huang Chieh-Cheng , Lu Tsai-Te
Published: September 2021

After the discovery of endogenous dinitrosyl iron complexes (DNICs) as a potential biological equivalent of nitric oxide (NO), bioinorganic engineering of [Fe(NO)2] unit has emerged to develop biomimetic DNICs [(NO)2Fe(L)2] as a chemical biology tool for controlled delivery of NO. For example, water-soluble DNIC [Fe2(μ-SCH2CH2OH)2(NO)4] (DNIC-1) was explored for oral delivery of NO to the brain and for the activation of hippocampal neurogenesis. However, the kinetics and mechanism for cellular uptake and intracellular release of NO, as well as the biocompatibility of synthetic DNICs, remain elusive. Prompted by the potential application of NO to dermato-physiological regulations, in this study, cellular uptake and intracellular delivery of DNIC [Fe2(μ-SCH2CH2COOH)2(NO)4] (DNIC-2) and its regulatory effect/biocompatibility toward epidermal cells were investigated. Upon the treatment of DNIC-2 to human fibroblast cells, cellular uptake of DNIC-2 followed by transformation into protein-bound DNICs occur to trigger the intracellular release of NO with a half-life of 1.8 ± 0.2 h. As opposed to the burst release of extracellular NO from diethylamine NONOate (DEANO), the cell-penetrating nature of DNIC-2 rationalizes its overwhelming efficacy for intracellular delivery of NO. Moreover, NO-delivery DNIC-2 can regulate cell proliferation, accelerate wound healing, and enhance the deposition of collagen in human fibroblast cells. Based on the in vitro and in vivo biocompatibility evaluation, biocompatible DNIC-2 holds the potential to be a novel active ingredient for skincare products.
Biotransformation of the Phenolic Constituents from Licorice and Cytotoxicity Evaluation of Their Metabolites
Authors: Xiao Yina , Han Fubo , Lee Ik-Soo
Published: September 2021

Biotransformation of four bioactive phenolic constituents from licorice, namely licoisoflavanone (1), glycyrrhisoflavone (2), echinatin (3), and isobavachalcone (4), was performed by the selected fungal strain Aspergillus niger KCCM 60332, leading to the isolation of seventeen metabolites (5–21). Structures of the isolated compounds were determined on the basis of extensive spectroscopic methods, twelve of which (5–7, 10–17 and 19) have been previously undescribed. A series of reactions including hydroxylation, hydrogenation, epoxidation, hydrolysis, reduction, cyclization, and alkylation was observed in the biotransformation process. All compounds were tested for their cytotoxic activities against three different human cancer cell lines including A375P, MCF-7, and HT-29. Compounds 1 and 12 exhibited most considerable cytotoxic activities against all the cell lines investigated, while compounds 2 and 4 were moderately cytotoxic. These findings will contribute to expanding the chemical diversity of phenolic compounds, and compounds 1 and 12 may serve as leads for the development of potential cancer chemopreventive agents.