bluuebunny/crossref_metadata_2025 huggingface dataset:
Terroir Traceability in Grapes, Musts and Gewürztraminer Wines from the South Tyrol Wine Region
Authors: Ferretti Carlo G. , Febbroni Stefano
Published: June 2022

This study arose from the need to relate specific terroir aspects with experienced sensory properties of Gewürztraminer wines from Tramin (northern Italy). A multidisciplinary approach was used to investigate seven vineyards’ ecological characteristics, including geology and geographical features. A geopedological method using Vineyard Geological Identity (VGI) and Solar Radiation Identity (SRI) for topoclimatic classification, as well as multi-parameter measuring stations of air and soils, elicited analytical data for qualitative and quantitative terroir characterisations. Furthermore, wide-ranging and targeted oenological and chemical analyses were conducted on grapes, musts and wines to correlate their biochemical compositions with the measured terroir conditions. The study identified strong connections between vineyard geo-identity and wine mineral fingerprint, confirming mineral traceability of Rb/Sr ratio and of some minerals common to the local geology, such as Ba, Rb, Mn and Be. In particular, the most differing geo-mineral and physical soil conditions of two studied vineyards are apparent in the oenological components, flavours and aromas of their musts and finished wines. Amino acids, primary varietal aromas and polyphenols, thiol compounds with tropical scents, phenolic compounds with spicy notes and terpenic compounds, such as geraniol and citronellol, were related differently between fine-textured, more siliceous soils of glacial origin and coarser-textured, more dolomitic soils of local debris flow origin.
Gender Differences and the Influence of Body Composition on Land and Pool-Based Assessments of Anaerobic Power and Capacity
Authors: Zera Jacquelyn N. , Nagle Elizabeth F. , Connell Emma , Curtin Erin , Marget Wilmina , Simonson Anna P. , Nagai Takashi , Abt John , Lephart Scott
Published: June 2022

Consistent differences between males and females have been shown in land-based measurements of anaerobic power and capacity. However, these differences have not been investigated for a tethered 30-s maximal swimming test (TST). The purpose of this study is to explore gender differences in land and pool-based assessments of anaerobic power (Fpeak) and capacity (Fmean), as well as the influence of body composition. Thirteen males and fifteen females completed land (Wingate (WAnT)) and pool-based (TST) measures of anaerobic power and capacity previously described in the literature. Additionally, the subjects completed assessments of body composition via air displacement plethysmography. The males produced higher force than the females for Fpeak (p < 0.001) and Fmean (p = 0.008) during the TST. However, linear regression analysis determined that lean mass significantly predicted Fpeak (p = 0.002) and Fmean (p < 0.001) during the TST, while gender was no longer significant (p = 0.694 and p = 0.136, respectively). In conclusion, increases in anaerobic power and capacity (Fpeak and Fmean) may be a function of increased lean mass in males and females, warranting future research on the impact of resistance training programs on force production and swimming performance.
A Psychoeducational Intervention in Prenatal Classes: Positive Effects on Anxiety, Self-Efficacy, and Temporal Focus in Birth Attendants
Authors: Diotaiuti Pierluigi , Valente Giuseppe , Mancone Stefania , Falese Lavinia , Corrado Stefano , Siqueira Thais Cristina , Andrade Alexandro
Published: June 2022

Background: Previous studies have reported associations between high maternal anxiety, temporal perceptions during pregnancy, and a poor sense of self-efficacy. One type of anxiety expecting mothers experience is associated with childbirth, which previous studies have shown can be reduced by antenatal training. Recent contributions have pointed out that current prenatal courses, while providing important and useful knowledge, do not devote sufficient content to the mental health of the parturient and to the psychological issues that can arise before and after the birth. Methods: In total, 80 pregnant women were provided with a special prepartum course in which ample space was devoted to topics such as maternal mental health, parenting skills and couple relationship, relaxation techniques, and assertiveness. Perception of threat, state anxiety, temporal focus, needs and expectations, and self-efficacy were assessed by comparing this psychoeducational intervention group with a traditional antenatal course group (n = 80), and a control group (n = 80). Two-way mixed ANOVAS (3 × 2) were performed for each dependent variable considered, including the time variable (pre-course–post-course) as a factor within the participants and the group variable as a factor between the subjects. Results: The psychoeducational intervention actually induced significant and positive changes primarily on four dimensions: state anxiety, perceived self-efficacy, the need for information, and reassurance of the pregnant women who participated in this trial. Conclusions: The study suggests improving the quality of prenatal classes by paying particular attention to the content and communication used within the group, in order to gratify at the highest level, the need for information, reassurance, and sharing that characterize the parturient’s request for support. The evidence collected recommends further replicating the intervention protocol described in order to improve the psychophysical well-being of women in a delicate moment such as pregnancy and preparation for childbirth, but especially in terms of the prevention and containment of the risks of psychological distress that currently affect a significant number of women after childbirth.
Tracing of Heavy Metals Embedded in Indoor Dust Particles from the Industrial City of Asaluyeh, South of Iran
Authors: Tashakor Mahsa , Behrooz Reza Dahmardeh , Asvad Seyed Reza , Kaskaoutis Dimitris G.
Published: June 2022

Assessment of indoor air quality is especially important, since people spend substantial amounts of time indoors, either at home or at work. This study analyzes concentrations of selected heavy metals in 40 indoor dust samples obtained from houses in the highly-industrialized Asaluyeh city, south Iran in spring and summer seasons (20 samples each). Furthermore, the health risk due to exposure to indoor air pollution is investigated for both children and adults, in a city with several oil refineries and petrochemical industries. The chemical analysis revealed that in both seasons the concentrations of heavy metals followed the order of Cr > Ni > Pb > As > Co > Cd. A significant difference was observed in the concentrations of potential toxic elements (PTEs) such as Cr, As and Ni, since the mean (±stdev) summer levels were at 60.2 ± 9.1 mg kg−1, 5.6 ± 2.7 mg kg−1 and 16.4 ± 1.9 mg kg−1, respectively, while the concentrations were significantly lower in spring (17.6 ± 9.7 mg kg−1, 3.0 ± 1.7 mg kg−1 and 13.5 ± 2.4 mg kg−1 for Cr, As and Ni, respectively). Although the hazard index (HI) values, which denote the possibility of non-carcinogenic risk due to exposure to household heavy metals, were generally low for both children and adults (HI < 1), the carcinogenic risks of arsenic and chromium were found to be above the safe limit of 1 × 10−4 for children through the ingestion pathway, indicating a high cancer risk due to household dust in Asaluyeh, especially in summer.
Spatial-Temporal Evolution and Driving Forces of Drying Trends on the Qinghai-Tibet Plateau Based on Geomorphological Division
Authors: Liu Yi , Ni Zhongyun , Zhao Yinbing , Zhou Guoli , Luo Yuhao , Li Shuai , Wang Dong , Zhang Shaowen
Published: June 2022

The Qinghai–Tibet Plateau (QTP) is a sensor of global climate change and regional human activities, and drought monitoring will help to achieve its ecological protection and sustainable development. In order to effectively control the geospatial scale effect, we divided the study area into eight geomorphological sub-regions, and calculated the Temperature-Vegetation Drought Index (TVDI) of each geomorphological sub-region based on MODIS Normalized Difference Vegetation Index (NDVI) and Land Surface Temperature (LST) data, and synthesized the TVDI of the whole region. We employed partial and multiple correlation analyses to identify the relationship between TVDI and temperature and precipitation. The random forest model was further used to study the driving mechanism of TVDI in each geomorphological division. The results of the study were as follows: (1) From 2000 to 2019, the QTP showed a drought trend, with the most significant drought trend in the central region. The spatial pattern of TVDI changes of QTP was consistent with the gradient changes of precipitation and temperature, both showing a gradual trend from southeast to northwest. (2) There was a risk of drought in the four seasons of the QTP, and the seasonal variation of TVDI was significant, which was characterized by being relatively dry in spring and summer and relatively humid in autumn and winter. (3) Drought in the QTP was mainly driven by natural factors, supplemented by human factors. The driving effect of temperature and precipitation factors on TVDI was stable and significant, which mainly determined the spatial distribution and variation of TVDI of the QTP. Geomorphological factors led to regional intensification and local differentiation effects of drought, especially in high mountains, flat slopes, sunny slopes and other places, which had a more significant impact on TVDI. Human activities had local point-like and linear impacts, and grass-land and cultivated land that were closely related to the relatively high impacts on TVDI of human grazing and farming activities. In view of the spatial-temporal patterns of change in TVDI in the study area, it is important to strengthen the monitoring and early warning of changes in natural factors, optimize the spatial distribution of human activities, and scientifically promote ecological protection and restoration.
Delusional Disorder in Old Age: A Hypothesis-Driven Review of Recent Work Focusing on Epidemiology, Clinical Aspects, and Outcomes
Authors: González-Rodríguez Alexandre , Seeman Mary V. , Izquierdo Eduard , Natividad Mentxu , Guàrdia Armand , Román Eloïsa , Monreal José A.
Published: June 2022

The theme, strength, and duration of a delusion are considered important in distinguishing one psychosis of old age from another. Research results, however, are mostly based on studies conducted on one form of psychosis, namely schizophrenia. The aim of this hypothesis-driven narrative review is to gather clinically important information about the psychosis identified as delusional disorder (DD), as it affects persons of senior age. We hypothesized that DD becomes relatively prevalent in old age, especially in women; and that it is associated with demonstrable brain changes, which, in turn, are associated with cognitive defects and poor pharmacological response, thus increasing the risk of aggression and suicide. Computerized searches in PubMed and ClinicalTrials.gov were conducted using the following search terms: (delusional disorder) AND (elderly OR old OR aged OR psychogeriatrics). A total of 16 recent studies (including case reports) were reviewed. Our hypotheses could not be definitively confirmed because research evidence is lacking. In order to improve eventual outcomes, our literature search demonstrates the need for more targeted, well-designed studies.
Suicidal Thoughts, Depression, Post-Traumatic Stress, and Harmful Alcohol Use Associated with Intimate Partner Violence and Rape Exposures among Female Students in South Africa
Authors: Machisa Mercilene Tanyaradzwa , Chirwa Esnat , Mahlangu Pinky , Nunze Ncediswa , Sikweyiya Yandisa , Dartnall Elizabeth , Pillay Managa , Jewkes Rachel
Published: June 2022

While ample evidence from high-income country settings indicates the prevalence and risk factors for multiple mental ill-health symptoms in student populations, evidence from low- and middle-income higher education settings remains limited. We determined the frequency, associations, and structural pathways between mental health outcomes and possible risk factors among a sample of 1292 predominantly Black African and female students ages 18–30 years, enrolled at nine purposefully selected public universities and Technical Vocational Education and Training (TVET) campuses. We measured and created a mental ill-health latent outcome consisting of depressive symptoms, post-traumatic stress disorder (PTSD), and suicidal thoughts. We also measured traumatic exposures including childhood trauma, recent intimate partner violence (IPV), non-partner rape, and other life traumatic events. We used structural equation modelling to analyse data. We found that 50% of the surveyed students binge drank, 43% reported depressive symptoms, 9% reported PTSD symptoms, and 21% had suicidal thoughts. Students’ experiences of childhood trauma, food insecurity, other traumatic events, non-partner rape, and IPV impacted the mental ill-health latent. IPV experiences mediated the relationships between experiences of childhood trauma or other trauma and the mental ill-health latent, and the relationship between binge drinking and other life traumatic events. Non-partner rape mediated the relationship between food insecurity and the mental ill-health latent. Binge drinking directly impacted non-partner rape experience. The findings substantiate the need for campus-based mental health promotion, psychosocial services and treatments, and implementation of combined interventions that address the intersections of violence against women and mental health among students in South Africa.
Post-Migration Stressors and Mental Health for African Migrants in South Australia: A Qualitative Study
Authors: Mwanri Lillian , Fauk Nelsensius Klau , Ziersch Anna , Gesesew Hailay Abrha , Asa Gregorius Abanit , Ward Paul Russell
Published: June 2022

We conducted a qualitative study involving African migrants (n = 20) and service providers (n = 10) in South Australia to explore mental health stressors, access to mental health services and how to improve mental health services for African migrant populations. This paper presents the views and experiences of African migrants about the post-migration stressors they faced in resettlement that pose mental health challenges. The participants were recruited using the snowball sampling technique. To align with the COVID-19 pandemic protocol, the data collection was conducted using one-on-one online interviews through Zoom or WhatsApp video calls. Data analysis was guided by the framework analysis. The post-migration stressors, including separation from family members and significant others, especially spouses, imposed significant difficulties on care provision and in managing children’s attitudes and behavior-related troubles at school. African cultural practices involving the community, especially elders in care provision and disciplining children, were not consistent with Australian norms, compounding the mental health stressors for all involved. The African cultural norms, that do not allow young unmarried people to live together, also contributed to child–parent conflicts, enhancing parental mental stressors. Additionally, poor economic conditions and employment-related difficulties were post-migration stressors that the participants faced. The findings indicate the need for policy and intervention programs that address the above challenges. The provision of interventions, including social support such as subsidized or free childcare services, could help leverage their time and scheduled paid employment, creating time for effective parenting and improving their mental health and wellbeing. Future studies exploring what needs to be achieved by government and non-governmental institutions to support enhanced access to social and employment opportunities for the African migrant population are also recommended.
Recording of Chronic Diseases and Adverse Obstetric Outcomes during Hospitalizations for a Delivery in the National Swiss Hospital Medical Statistics Dataset between 2012 and 2018: An Observational Cross-Sectional Study
Authors: Marxer Carole A. , Rauch Marlene , Lang Clementina , Panchaud Alice , Meier Christoph R. , Spoendlin Julia
Published: June 2022

The prevalence of chronic diseases during pregnancy and adverse maternal obstetric outcomes in Switzerland has been insufficiently studied. Data sources, which reliably capture these events, are scarce. We conducted a nationwide observational cross-sectional study (2012–2018) using data from the Swiss Hospital Medical Statistics (MS) dataset. To quantify the recording of chronic diseases and adverse maternal obstetric outcomes during delivery in hospitals or birthing centers (delivery hospitalization), we identified women who delivered a singleton live-born infant. We quantified the prevalence of 23 maternal chronic diseases (ICD-10-GM) and compared results to a nationwide Danish registry study. We further quantified the prevalence of adverse maternal obstetric outcomes (ICD-10-GM/CHOP) during the delivery hospitalization and compared the results to existing literature from Western Europe. We identified 577,220 delivery hospitalizations, of which 4.99% had a record for ≥1 diagnosis of a chronic disease (versus 15.49% in Denmark). Moreover, 13 of 23 chronic diseases seemed to be substantially under-recorded (8 of those were >10-fold more frequent in the Danish study). The prevalence of three of the chronic diseases was similar in the two studies. The prevalence of adverse maternal obstetric outcomes was comparable to other European countries. Our results suggest that chronic diseases are under-recorded during delivery hospitalizations in the MS dataset, which may be due to specific coding guidelines and aspects regarding whether a disease generates billable effort for a hospital. Adverse maternal obstetric outcomes seemed to be more completely captured.
It’s a Long Way to the Tap: Microbiome and DNA-Based Omics at the Core of Drinking Water Quality
Authors: Bruno Antonia , Agostinetto Giulia , Fumagalli Sara , Ghisleni Giulia , Sandionigi Anna
Published: June 2022

Microbial communities interact with us and affect our health in ways that are only beginning to be understood. Microorganisms have been detected in every ecosystem on Earth, as well as in any built environment that has been investigated. Drinking water sources, drinking water treatment plants and distribution systems provide peculiar microbial ecological niches, dismantling the belief of the “biological simplicity” of drinking water. Nevertheless, drinking water microbiomes are understudied compared to other microbiomes. Recent DNA sequencing and meta-omics advancements allow a deeper understanding of drinking water microbiota. Thus, moving beyond the limits of day-to-day testing for specific pathogenic microbes, new approaches aim at predicting microbiome changes driven by disturbances at the macro-scale and overtime. This will foster an effective and proactive management of water sources, improving the drinking water supply system and the monitoring activities to lower public health risk. Here, we want to give a new angle on drinking water microbiome research. Starting from a selection of 231 scientific publications on this topic, we emphasize the value of biodiversity in drinking water ecosystems and how it can be related with industrialization. We then discuss how microbiome research can support sustainable drinking water management, encouraging collaborations across sectors and involving the society through responsible research and innovation.
Match Analysis in Women’s Tennis on Clay, Grass and Hard Courts
Authors: Prieto-Lage Iván , Paramés-González Adrián , Argibay-González Juan Carlos , Reguera-López-de-la-Osa Xoana , Ordóñez-Álvarez Santiago , Gutiérrez-Santiago Alfonso
Published: June 2022

(1) Background: Performance indicators in tennis such as service effectiveness, rally length or final shots are key factors in determining the winner of the match, although there is little research in the female category. The purpose of this research is to understand the game model in female tennis based on the type of surface. (2) Methods: A total of 2759 points were analyzed from three Grand Slam tournaments from 2019 on three different surfaces. We used observational methodology. (3) Results: The effectiveness of the first service was 62.4% on clay, 64.2% on grass and 67.5% on hard court. With the second service, effectiveness reduced in 5.5%, 11.2% and 14.5% from the first service, respectively. The service direction determines the efficiency and duration of the rally. The highest efficiency occurs with first serves to the T zone or wide zone (regardless of the service side) in short rallies (from 64.9% on clay to 86.3% on hard court). Serving to the centre reduces the chances of success (between 53.1% and 69.9%) and increases the rally length. Between 64.8% (clay) and 75.9% (hard court) of points played on first serve ended in a short rally, while on second serve it was 56.2% (clay) to 61.7% (grass). (4) Conclusions: The data of the effectiveness of the sequences of specific plays can help in the trainings of professional female tennis players.
Synthesis of Indole-Coupled KYNA Derivatives via C–N Bond Cleavage of Mannich Bases
Authors: Lőrinczi Bálint , Simon Péter , Szatmári István
Published: June 2022

KYNAs, a compound with endogenous neuroprotective functions and an indole that is a building block of many biologically active compounds, such as a variety of neurotransmitters, are reacted in a transformation building upon Mannich bases. The reaction yields triarylmethane derivatives containing two biologically potent skeletons, and it may contribute to the synthesis of new, specialised neuroprotective compounds. The synthesis has been investigated via two procedures and the results were compared to those of previous studies. A possible alternative reaction route through acid catalysis has been established.
BHLHE22 Expression Is Associated with a Proinflammatory Immune Microenvironment and Confers a Favorable Prognosis in Endometrial Cancer
Authors: Darmawi  , Chen Lin-Yu , Su Po-Hsuan , Liew Phui-Ly , Wang Hui-Chen , Weng Yu-Chun , Huang Rui-Lan , Lai Hung-Cheng
Published: June 2022

Endometrial cancer (EC) rates are rising annually. Additional prediction markers need to be evaluated because only 10–20% of EC cases show an objective response to immune-checkpoint inhibitors (ICIs). Our previous methylomic study found that BHLHE22 is hypermethylated in EC tissues and can be detected using a Pap-smear sample. BHLHE22, a basic helix loop helix transcription factor family member, is known as a transcriptional repressor and is involved in cell differentiation. However, the role of BHLHE22 in EC remains poorly understood. Herein, we analyzed BHLHE22 expression in 54 paired cancer and normal endometrial tissue samples, and confirmed with databases (TCGA, GTEx, and human protein atlas). We found that BHLHE22 protein expression was significantly downregulated in EC compared with normal endometrium. High BHLHE22 expression was associated with microsatellite-instable subtype, endometrioid type, grade, and age. It showed a significant favorable survival. BHLHE22 overexpression inhibited the proliferation and migration of EC cells. Functional enrichment analysis showed that BHLHE22 was significantly associated with immune-related pathways. Furthermore, BHLHE22 was positively correlated with proinflammatory leukocyte infiltration and expression of chemokine genes in EC. In conclusion, BHLHE22 regulates immune-related pathways and modulates the immune microenvironment of EC.
Theranostic Small-Molecule Prodrug Conjugates for Targeted Delivery and Controlled Release of Toll-like Receptor 7 Agonists
Authors: Debnath Sashi , Hao Guiyang , Guan Bing , Thapa Pawan , Hao Justin , Hammers Hans , Sun Xiankai
Published: June 2022

We previously reported the design and synthesis of a small-molecule drug conjugate (SMDC) platform that demonstrated several advantages over antibody–drug conjugates (ADCs) in terms of in vivo pharmacokinetics, solid tumor penetration, definitive chemical structure, and adaptability for modular synthesis. Constructed on a tri-modal SMDC platform derived from 1,3,5-triazine (TZ) that consists of a targeting moiety (Lys-Urea-Glu) for prostate-specific membrane antigen (PSMA), here we report a novel class of chemically identical theranostic small-molecule prodrug conjugates (T-SMPDCs), [18/19F]F-TZ(PSMA)-LEGU-TLR7, for PSMA-targeted delivery and controlled release of toll-like receptor 7 (TLR7) agonists to elicit de novo immune response for cancer immunotherapy. In vitro competitive binding assay of [19F]F-TZ(PSMA)-LEGU-TLR7 showed that the chemical modification of Lys-Urea-Glu did not compromise its binding affinity to PSMA. Receptor-mediated cell internalization upon the PSMA binding of [18F]F-TZ(PSMA)-LEGU-TLR7 showed a time-dependent increase, indicative of targeted intracellular delivery of the theranostic prodrug conjugate. The designed controlled release of gardiquimod, a TLR7 agonist, was realized by a legumain cleavable linker. We further performed an in vivo PET/CT imaging study that showed significantly higher uptake of [18F]F-TZ(PSMA)-LEGU-TLR7 in PSMA+ PC3-PIP tumors (1.9 ± 0.4% ID/g) than in PSMA− PC3-Flu tumors (0.8 ± 0.3% ID/g) at 1 h post-injection. In addition, the conjugate showed a one-compartment kinetic profile and in vivo stability. Taken together, our proof-of-concept biological evaluation demonstrated the potential of our T-SMPDCs for cancer immunomodulatory therapies.
Molecular Mechanisms of Cerebrovascular Diseases
Authors: Andjelkovic Anuska V. , Keep Richard F. , Wang Michael M.
Published: June 2022

Cerebrovascular disease involves a range of conditions including ischemic and hemorrhagic stroke, vascular malformations, and vascular cognitive impairment and dementia (VCID) [...]
Spermatozoan Metabolism as a Non-Traditional Model for the Study of Huntington’s Disease
Authors: Lawlor Meghan , Zigo Michal , Kerns Karl , Cho In Ki , Easley IV Charles A. , Sutovsky Peter
Published: June 2022

Huntington’s Disease (HD) is a fatal autosomal dominant neurodegenerative disease manifested through motor dysfunction and cognitive deficits. Decreased fertility is also observed in HD animal models and HD male patients, due to altered spermatogenesis and sperm function, thus resulting in reduced fertilization potential. Although some pharmaceuticals are currently utilized to mitigate HD symptoms, an effective treatment that remedies the pathogenesis of the disease is yet to be approved by the FDA. Identification of genes and relevant diagnostic biomarkers and therapeutic target pathways including glycolysis and mitochondrial complex-I-dependent respiration may be advantageous for early diagnosis, management, and treatment of the disease. This review addresses the HD pathway in neuronal and sperm metabolism, including relevant gene and protein expression in both neurons and spermatozoa, indicated in the pathogenesis of HD. Furthermore, zinc-containing and zinc-interacting proteins regulate and/or are regulated by zinc ion homeostasis in both neurons and spermatozoa. Therefore, this review also aims to explore the comparative role of zinc in both neuronal and sperm function. Ongoing studies aim to characterize the products of genes implicated in HD pathogenesis that are expressed in both neurons and spermatozoa to facilitate studies of future treatment avenues in HD and HD-related male infertility. The emerging link between zinc homeostasis and the HD pathway could lead to new treatments and diagnostic methods linking genetic sperm defects with somatic comorbidities.
Comprehensive Analysis of N6-Methyladenosine (m6A) Writers, Erasers, and Readers in Cervical Cancer
Authors: Condic Mateja , Ralser Damian J. , Klümper Niklas , Ellinger Jörg , Qureischi Maryam , Egger Eva K. , Kristiansen Glen , Mustea Alexander , Thiesler Thore
Published: June 2022

There is growing scientific evidence for the crucial role of post-transcriptional RNA modifications in carcinogenesis, progression, metastasis, and drug resistance across various cancer entities. N6-methyladenosine (m6A) is the most abundant type of RNA modification. m6A is coordinated by a dynamic interplay of ‘writers’ (METTL3, METTL4, METTL14, WTAP, KIAA1429), ‘erasers’ (FTO, ALKBH5), and ‘readers’ (HNRNPA2B1, HNRNPC, YTHDC1, YTHDC1, YTHDF1-3). In this study, we comprehensively examined protein and mRNA expression levels of m6A writers, readers, and erasers in two cervical cancer (CC) cohorts (UHB CC cohort, N = 118; TCGA CC cohort, N = 307) with regard to clinical outcomes. In the UHB CC cohort, high protein expression levels of METTL14 (p = 0.016), WTAP (p = 0.007), KIAA1439 (p < 0.001), ALKBH5 (p < 0.001), HNRNPC (p = 0.012), YTHDC1 (p < 0.001), and YTHDF3 (p = 0.004) were significantly associated with a shorter overall survival (OS). In the TCGA CC cohort, mRNA expression levels of METTL14 (p = 0.012), WTAP (p = 0.041), KIAA1429 (p = 0.016), and YTHDC1 (p = 0.026) showed prognostic values. However, after correction for multiple testing, statistical significance remained only for m6A protein expression levels (q < 0.1). Our study points towards dysregulated m6A modification in CC. Hence, m6A might serve as a promising prognostic biomarker and therapeutical target in CC.
MicroRNA-Based Diagnosis and Therapy
Authors: Ho Phuong T. B. , Clark Ian M. , Le Linh T. T.
Published: June 2022

MicroRNAs (miRNAs) are a group of endogenous non-coding RNAs that regulate gene expression. Alteration in miRNA expression results in changes in the profile of genes involving a range of biological processes, contributing to numerous human disorders. With high stability in human fluids, miRNAs in the circulation are considered as promising biomarkers for diagnosis, as well as prognosis of disease. In addition, the translation of miRNA-based therapy from a research setting to clinical application has huge potential. The aim of the current review is to: (i) discuss how miRNAs traffic intracellularly and extracellularly; (ii) emphasize the role of circulating miRNAs as attractive potential biomarkers for diagnosis and prognosis; (iii) describe how circulating microRNA can be measured, emphasizing technical problems that may influence their relative levels; (iv) highlight some of the circulating miRNA panels available for clinical use; (v) discuss how miRNAs could be utilized as novel therapeutics, and finally (v) update those miRNA-based therapeutics clinical trials that could potentially lead to a breakthrough in the treatment of different human pathologies.
Editorial of Special Issue “The Interplay of Microbiome and Immune Response in Health and Diseases—2nd Edition”
Authors: Amedei Amedeo
Published: June 2022

The microbiota refers to the great number of microorganisms (including bacteria, fungi, viruses and parasites) that live on and in humans and has sparked a surge of recent interest [...]
Structural and Biofunctional Insights into the Cyclo(Pro-Pro-Phe-Phe-) Scaffold from Experimental and In Silico Studies: Melanoma and Beyond
Authors: Bojarska Joanna , Breza Martin , Remko Milan , Czyz Malgorzata , Gajos-Michniewicz Anna , Zimecki Michał , Kaczmarek Krzysztof , Madura Izabela D. , Wojciechowski Jakub M. , Wolf Wojciech M.
Published: June 2022

Short peptides have great potential as safe and effective anticancer drug leads. Herein, the influence of short cyclic peptides containing the Pro-Pro-Phe-Phe sequence on patient-derived melanoma cells was investigated. Cyclic peptides such as cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), called CLA, and cyclo(Pro-homoPro-β3homoPhe-Phe-), called P11, exert the cytotoxic and the cytostatic effects in melanoma cells, respectively. CLA was the most active peptide as it reduced the viability of melanoma cells to 50% of control at about 10 µM, whereas P11 at about 40 µM after 48 h incubation. Interestingly, a linear derivative of P11 did not induce any effect in melanoma cells confirming previous studies showing that cyclic peptides exert better biological activity compared to their linear counterparts. According to in silico predictions, cyclic tetrapeptides show a better pharmacokinetic and toxic profile to humans than CLA. Notably, the spatial structure of those peptides containing synthetic amino acids has not been explored yet. In the Cambridge Structural Database, there is only one such cyclic tetrapeptide, cyclo((R)-β2homoPhe-D-Pro-Lys-Phe-), while in the Protein Data Bank—none. Therefore, we report the first crystal structure of cyclo(Pro-Pro-β3homoPhe-Phe-), denoted as 4B8M, a close analog of P11, which is crucial for drug discovery. Comparative molecular and supramolecular analysis of both structures was performed. The DFT findings revealed that 4B8M is well interpreted in the water solution. The results of complex Hirshfeld surface investigations on the cooperativity of interatomic contacts in terms of electrostatic and energetic features are provided. In short, the enrichment ratio revealed O…H/H…O and C…H/H…C as privileged intercontacts in the crystals in relation to basic and large supramolecular H-bonding synthon patterns. Furthermore, the ability of self-assemble 4B8M leading to a nanotubular structure is also discussed.
Molecular Modelling Hurdle in the Next-Generation Sequencing Era
Authors: Fernandez Guerau , Yubero Dèlia , Palau Francesc , Armstrong Judith
Published: June 2022

There are challenges in the genetic diagnosis of rare diseases, and pursuing an optimal strategy to identify the cause of the disease is one of the main objectives of any clinical genomics unit. A range of techniques are currently used to characterize the genomic variability within the human genome to detect causative variants of specific disorders. With the introduction of next-generation sequencing (NGS) in the clinical setting, geneticists can study single-nucleotide variants (SNVs) throughout the entire exome/genome. In turn, the number of variants to be evaluated per patient has increased significantly, and more information has to be processed and analyzed to determine a proper diagnosis. Roughly 50% of patients with a Mendelian genetic disorder are diagnosed using NGS, but a fair number of patients still suffer a diagnostic odyssey. Due to the inherent diversity of the human population, as more exomes or genomes are sequenced, variants of uncertain significance (VUSs) will increase exponentially. Thus, assigning relevance to a VUS (non-synonymous as well as synonymous) in an undiagnosed patient becomes crucial to assess the proper diagnosis. Multiple algorithms have been used to predict how a specific mutation might affect the protein’s function, but they are far from accurate enough to be conclusive. In this work, we highlight the difficulties of genomic variability determined by NGS that have arisen in diagnosing rare genetic diseases, and how molecular modelling has to be a key component to elucidate the relevance of a specific mutation in the protein’s loss of function or malfunction. We suggest that the creation of a multi-omics data model should improve the classification of pathogenicity for a significant amount of the detected genomic variability. Moreover, we argue how it should be incorporated systematically in the process of variant evaluation to be useful in the clinical setting and the diagnostic pipeline.
Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis
Authors: Liu Zoe S. J. , Truong Trang T. T. , Bortolasci Chiara C. , Spolding Briana , Panizzutti Bruna , Swinton Courtney , Kim Jee Hyun , Kidnapillai Srisaiyini , Richardson Mark F. , Gray Laura , Dean Olivia M. , McGee Sean L. , Berk Michael , Walder Ken
Published: June 2022

Altered protein synthesis has been implicated in the pathophysiology of several neuropsychiatric disorders, particularly schizophrenia. Ribosomes are the machinery responsible for protein synthesis. However, there remains little information on whether current psychotropic drugs affect ribosomes and contribute to their therapeutic effects. We treated human neuronal-like (NT2-N) cells with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM) or vehicle control for 24 h. Transcriptomic and gene set enrichment analysis (GSEA) identified that the ribosomal pathway was altered by these drugs. We found that three of the eight drugs tested significantly decreased ribosomal gene expression, whilst one increased it. Most changes were observed in the components of cytosolic ribosomes and not mitochondrial ribosomes. Protein synthesis assays revealed that aripiprazole, clozapine and lithium all decreased protein synthesis. Several currently prescribed psychotropic drugs seem to impact ribosomal gene expression and protein synthesis. This suggests the possibility of using protein synthesis inhibitors as novel therapeutic agents for neuropsychiatric disorders.
Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review
Authors: Jang Jung Yoon , Im Eunok , Choi Yung Hyun , Kim Nam Deuk
Published: June 2022

Bile acids are major signaling molecules that play a significant role as emulsifiers in the digestion and absorption of dietary lipids. Bile acids are amphiphilic molecules produced by the reaction of enzymes with cholesterol as a substrate, and they are the primary metabolites of cholesterol in the body. Bile acids were initially considered as tumor promoters, but many studies have deemed them to be tumor suppressors. The tumor-suppressive effect of bile acids is associated with programmed cell death. Moreover, based on this fact, several synthetic bile acid derivatives have also been used to induce programmed cell death in several types of human cancers. This review comprehensively summarizes the literature related to bile acid-induced programmed cell death, such as apoptosis, autophagy, and necroptosis, and the status of drug development using synthetic bile acid derivatives against human cancers. We hope that this review will provide a reference for the future research and development of drugs against cancer.
Peripheral Ion Channel Gene Screening in Painful- and Painless-Diabetic Neuropathy
Authors: Ślęczkowska Milena , Almomani Rowida , Marchi Margherita , de Greef Bianca T. A. , Sopacua Maurice , Hoeijmakers Janneke G. J. , Lindsey Patrick , Salvi Erika , Bönhof Gidon J. , Ziegler Dan , Malik Rayaz A. , Waxman Stephen G. , Lauria Giuseppe , Faber Catharina G. , Smeets Hubert J. M. , Gerrits Monique M.
Published: June 2022

Neuropathic pain is common in diabetic peripheral neuropathy (DN), probably caused by pathogenic ion channel gene variants. Therefore, we performed molecular inversion probes-next generation sequencing of 5 transient receptor potential cation channels, 8 potassium channels and 2 calcium-activated chloride channel genes in 222 painful- and 304 painless-DN patients. Twelve painful-DN (5.4%) patients showed potentially pathogenic variants (five nonsense/frameshift, seven missense, one out-of-frame deletion) in ANO3 (n = 3), HCN1 (n = 1), KCNK18 (n = 2), TRPA1 (n = 3), TRPM8 (n = 3) and TRPV4 (n = 1) and fourteen painless-DN patients (4.6%—three nonsense/frameshift, nine missense, one out-of-frame deletion) in ANO1 (n = 1), KCNK18 (n = 3), KCNQ3 (n = 1), TRPA1 (n = 2), TRPM8 (n = 1), TRPV1 (n = 3) and TRPV4 (n = 3). Missense variants were present in both conditions, presumably with loss- or gain-of-functions. KCNK18 nonsense/frameshift variants were found in painless/painful-DN, making a causal role in pain less likely. Surprisingly, premature stop-codons with likely nonsense-mediated RNA-decay were more frequent in painful-DN. Although limited in number, painful-DN patients with ion channel gene variants reported higher maximal pain during the night and day. Moreover, painful-DN patients with TRP variants had abnormal thermal thresholds and more severe pain during the night and day. Our results suggest a role of ion channel gene variants in neuropathic pain, but functional validation is required.
Transcriptomic and Functional Evidence for Differential Effects of MCF-7 Breast Cancer Cell-Secretome on Vascular and Lymphatic Endothelial Cell Growth
Authors: Azzarito Giovanna , Visentin Michele , Leeners Brigitte , Dubey Raghvendra K.
Published: June 2022

Vascular and lymphatic vessels drive breast cancer (BC) growth and metastasis. We assessed the cell growth (proliferation, migration, and capillary formation), gene-, and protein-expression profiles of Vascular Endothelial Cells (VECs) and Lymphatic Endothelial Cells (LECs) exposed to a conditioned medium (CM) from estrogen receptor-positive BC cells (MCF-7) in the presence or absence of Estradiol. We demonstrated that MCF-7-CM stimulated growth and capillary formation in VECs but inhibited LEC growth. Consistently, MCF-7-CM induced ERK1/2 and Akt phosphorylation in VECs and inhibited them in LECs. Gene expression analysis revealed that the LECs were overall (≈10-fold) more sensitive to MCF-7-CM exposure than VECs. Growth/angiogenesis and cell cycle pathways were upregulated in VECs but downregulated in LECs. An angiogenesis proteome array confirmed the upregulation of 23 pro-angiogenesis proteins in VECs. In LECs, the expression of genes related to ATP synthesis and the ATP content were reduced by MCF-7-CM, whereas MTHFD2 gene, involved in folate metabolism and immune evasion, was upregulated. The contrasting effect of MCF-7-CM on the growth of VECs and LECs was reversed by inhibiting the TGF-β signaling pathway. The effect of MCF-7-CM on VEC growth was also reversed by inhibiting the VEGF signaling pathway. In conclusion, BC secretome may facilitate cancer cell survival and tumor growth by simultaneously promoting vascular angiogenesis and inhibiting lymphatic growth. The differential effects of BC secretome on LECs and VECs may be of pathophysiological relevance in BC.
miR-29c Increases Protein Synthesis in Skeletal Muscle Independently of AKT/mTOR
Authors: Alves Paula Ketilly Nascimento , Cruz André , Silva William J. , Labeit Siegfried , Moriscot Anselmo Sigari
Published: June 2022

microRNAs negatively regulate gene expression by blocking translation or increasing mRNA degradation. In skeletal muscle, these molecules play important roles in adaptive responses, and ongoing investigations are necessary to understand the fine-tune regulation of skeletal muscle mass. Herein we showed that skeletal muscle overexpression of miR-29c increased fiber size and force at 7 and 30 days after electrotransfer. At both time points, AKT/mTOR pathway components were downregulated, and, surprisingly, overall protein synthesis was strongly elevated at day 7, which normalized by day 30 after pCMVmiR-29c electrotransfer. These results indicate that miR-29c expression induces skeletal muscle hypertrophy and gain of function, which involves increased overall protein synthesis in spite of the deactivation of the AKT/mTOR pathway.
Cellular and Molecular Mechanisms in Mycobacterial Infection
Authors: Nieuwenhuizen Natalie E. , Evans Joanna C.
Published: June 2022

Tuberculosis (TB), caused by the bacillus Mycobacterium tuberculosis (Mtb), remains a leading cause of death by infectious disease, overshadowed only recently by the COVID-19 pandemic [...]
Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance
Authors: Nguyen Mai K. L. , Jose Jaimy , Wahba Mohamed , Bernaus-Esqué Marc , Hoy Andrew J. , Enrich Carlos , Rentero Carles , Grewal Thomas
Published: June 2022

Cancer cells undergo drastic metabolic adaptions to cover increased bioenergetic needs, contributing to resistance to therapies. This includes a higher demand for cholesterol, which often coincides with elevated cholesterol uptake from low-density lipoproteins (LDL) and overexpression of the LDL receptor in many cancers. This implies the need for cancer cells to accommodate an increased delivery of LDL along the endocytic pathway to late endosomes/lysosomes (LE/Lys), providing a rapid and effective distribution of LDL-derived cholesterol from LE/Lys to other organelles for cholesterol to foster cancer growth and spread. LDL-cholesterol exported from LE/Lys is facilitated by Niemann–Pick Type C1/2 (NPC1/2) proteins, members of the steroidogenic acute regulatory-related lipid transfer domain (StARD) and oxysterol-binding protein (OSBP) families. In addition, lysosomal membrane proteins, small Rab GTPases as well as scaffolding proteins, including annexin A6 (AnxA6), contribute to regulating cholesterol egress from LE/Lys. Here, we summarize current knowledge that links upregulated activity and expression of cholesterol transporters and related proteins in LE/Lys with cancer growth, progression and treatment outcomes. Several mechanisms on how cellular distribution of LDL-derived cholesterol from LE/Lys influences cancer cell behavior are reviewed, some of those providing opportunities for treatment strategies to reduce cancer progression and anticancer drug resistance.
Glioblastoma Treatment: State-of-the-Art and Future Perspectives
Authors: Rodríguez-Camacho Alejandro , Flores-Vázquez José Guillermo , Moscardini-Martelli Júlia , Torres-Ríos Jorge Alejandro , Olmos-Guzmán Alejandro , Ortiz-Arce Cindy Sharon , Cid-Sánchez Dharely Raquel , Pérez Samuel Rosales , Macías-González Monsserrat Del Sagrario , Hernández-Sánchez Laura Crystell , Heredia-Gutiérrez Juan Carlos , Contreras-Palafox Gabriel Alejandro , Suárez-Campos José de Jesús Emilio , Celis-López Miguel Ángel , Gutiérrez-Aceves Guillermo Axayacalt , Moreno-Jiménez Sergio
Published: June 2022

(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve overall survival, free-progression survival, and life quality in glioblastoma patients. (2) Methods: Our objective is to recap the actual state-of-the-art in glioblastoma treatment, resume the actual research and future perspectives on immunotherapy, as well as the new synthetic molecules and natural compounds that represent potential future therapies at preclinical stages. (3) Conclusions: Despite the great efforts in therapeutic research, glioblastoma management has suffered minimal changes, and the prognosis remains poor. Combined therapeutic strategies and delivery methods, including immunotherapy, synthetic molecules, natural compounds, and glioblastoma stem cell inhibition, may potentiate the standard of care therapy and represent the next step in glioblastoma management research.