bluuebunny/crossref_metadata_2025 huggingface dataset:
An Ounce of Prevention, a Pound of Complications: A Case of Statin-Induced Necrotizing Myopathy in a Frail Elderly Patient
Authors: Stens Oleg , Neutel Bradley , Goodman Elizabeth L.
Published: March 2022

The use of statins for primary prevention in older adults remains controversial. In this manuscript, we present a case of an 81-year-old woman with a history of HTN, HLD, Alzheimer’s dementia and osteoporosis, who presented to a geriatrics clinic with profound muscle weakness accompanied by new functional deficits in the setting of taking double her prescribed dose of atorvastatin. She was admitted to the hospital where she was found to have rhabdomyolysis. Muscle biopsy and serologic work up revealed anti-HMG statin co-reductase myopathy as the cause of her symptoms. The patient was treated with steroids IVIG and immunomodulators with marked improvement in her weakness; however, her course was complicated by delirium and multiple falls, resulting in several fragility fractures. This case highlights the need to conduct a risk–benefit analysis prior to initiating new therapies in patients with limited life expectancy, including the consideration of the potential for medication errors.
From the Light Chain Sequence to the Tissue Microenvironment: Contribution of the Mesangial Cells to Glomerular Amyloidosis
Authors: Del Pozo-Yauner Luis , Turbat-Herrera Elba A. , Pérez-Carreón Julio I. , Herrera Guillermo A.
Published: March 2022

Studies carried out in the last three decades have significantly advanced our knowledge about the structural factors that drive the amyloid aggregation of the immunoglobulin light chains. Solid-state nuclear magnetic resonance and cryo-electron microscopy studies have resulted in huge progress in our knowledge about the AL fibril structure. Now, it is known that the assembly of the light chain into AL fibrils implies an extensive conformational rearrangement that converts the beta-sandwich fold of the protein into a near flat structure. On the other hand, there has also been significant progress made in understanding the role that some cell types play as facilitators of AL formation. Such a role has been studied in glomerular amyloidosis, where mesangial cells play an important role in the mechanism of AL deposition, as well as for the pathogenic mechanisms that result in glomerular/renal damage. This review addresses what we currently know about why and how certain light chains are prone to forming amyloid. It also summarizes the most recent publications on the structure of AL fibrils and analyzes the structural bases of this type of aggregate, including the origin of its structural diversity. Finally, the most relevant findings on the role of mesangial cells in the amyloid deposition of light chains in the glomerular space are summarized.
Associations between a Universal Free Breakfast Policy and School Breakfast Program Participation, School Attendance, and Weight Status: A District-Wide Analysis
Authors: Bullock Sally Lawrence , Dawson-McClure Spring , Truesdale Kimberly Parker , Ward Dianne Stanton , Aiello Allison E. , Ammerman Alice S.
Published: March 2022

Breakfast consumption among youth is associated with improved diet quality, weight, cognition, and behavior. However, not all youth in the United States consume breakfast. Participation in the School Breakfast Program (SBP) is also low relative to the lunch program. Universal free breakfast (UFB) policies have been implemented to increase breakfast participation by reducing cost and stigma associated with the SBP. This study examined whether a UFB policy implemented in a school district in the Southeast US was associated with changes in breakfast participation, school attendance, and student weight. A longitudinal study of secondary data was conducted, and a mixed modeling approach was used to assess patterns of change in SBP participation. General linear models were used to assess attendance and student weight change. On average, across schools in the district, there was an increase in breakfast participation of 4.1 percentage points following the implementation of the policy. The change in breakfast participation in schools differed by the percent of students in the school who received school meals for free or at a reduced price, the percent of students of color, and the grade level of the school. Increases in SBP participation were not associated with significant changes in attendance or weight. UFB policies may be effective in increasing participation in the SBP.
Quality of Spontaneous Reports of Adverse Drug Reactions Sent to a Regional Pharmacovigilance Unit
Authors: Salvador Mário Rui , Monteiro Cristina , Pereira Luísa , Duarte Ana Paula
Published: March 2022

Spontaneous reports (SRs) of adverse drug reactions (ADRs) remain the basis of pharmacovigilance systems. The main objective of this study was to evaluate the quality of SRs received by the Pharmacovigilance Unit of Beira Interior, in Central Portugal. The second objective was to identify factors associated with complete SRs. SRs received between 1 January 2017 and 31 October 2019 were analyzed. SR information was classified as “mandatory” or “recommended” criteria. SR were then grouped into three categories (well, slightly, and poorly documented). Association between “well documented” SR and confounding variables was estimated using a multiple logistic regression model. The results showed 22.4% of SRs are “well documented”, and 41.2% are “poorly documented”. Most of the complete SRs correspond to non-serious ADRs (55.8%), with a negative association between complete SRs and serious ADRs (OR = 0.595, [95% CI 0.362–0.977], p = 0.040). There is also a significant association between complete SRs and e-mail notification (OR = 1.876, [95% CI 1.060–3.321], p = 0.002). The results highlight the small amount of SR documentation sent to pharmacovigilance systems. There is an association between non-serious ADRs and complete SRs. These results reinforce the need for training for notification of ADRs and that these SRs include as much information as possible for an effective drug risk management.
Evaluation of Occupational Health Risk Management and Performance in China: A Case Study of Gas Station Workers
Authors: Mohsin Muhammad , Yin Hengbin , Huang Weilun , Zhang Shijun , Zhang Luyao , Mehak Ana
Published: March 2022

China has a large number of gas stations, with which thousands of workers are associated. There is abundant online literature documenting the various occupational health risks these workers face. However, this literature has many flaws to address, and it falls short of suggesting measures to manage these risks. This study strives to fill that gap, and aims to improve the occupational health of gas station workers through comprehensive risk management and performance analysis. To this end, a reasonable volume of reliable data, i.e., 208 completed questionnaires, were analyzed through current statistical routines, viz., fuzzy Analytical Hierarchy Process (AHP) and Importance Performance Analysis (IPA). These methods were employed to hierarchically organize the main factors and sub-factors of physical risk management, chemical risk management, biological risk management, physiological risk management and psychological risk management according to their appraised importance, and screen out the risk management stratagem for priority improvement. Research findings reveal that chemical risk and biological risk response schemes have the lowest performance, and need to be prioritized for improvement. Furthermore, this study argues that we can safeguard the occupational health of gas station workers through appropriate risk management strategies. It also elaborates on implications, limitations and future research directions.
Predictors of eHealth Literacy and Its Associations with Preventive Behaviors, Fear of COVID-19, Anxiety, and Depression among Undergraduate Nursing Students: A Cross-Sectional Survey
Authors: Tran Ha T. T. , Nguyen Minh H. , Pham Thu T. M. , Kim Giang B. , Nguyen Hiep T. , Nguyen Ngoc-Minh , Dam Hoa T. B. , Duong Thai H. , Nguyen Yen H. , Do Thao T. , Nguyen Thao T. P. , Le Thuy T. , Do Hien T. T. , Nguyen Tham T. , Pham Khue M. , Duong Tuyen Van
Published: March 2022

Background: The infodemic has been co-existing with the COVID-19 pandemic with an influx of misinformation and conspiracy theories. These affect people’s psychological health and adherence to preventive measures. eHealth literacy (eHEALS) may help with alleviating the negative effects of the infodemic. As nursing students are future healthcare professionals, having adequate eHEALS skills is critically important in their clinical practice, safety, and health. This study aimed to (1) explore the eHEALS level and its associated factors, and (2) examine the associations of eHEALS with preventive behaviors, fear of COVID-19 (FCV-19S), anxiety, and depression among nursing students. Methods: We surveyed 1851 nursing students from 7 April to 31 May 2020 from eight universities across Vietnam. Data were collected, including demographic characteristics, eHEALS, adherence to preventive behaviors (handwashing, mask-wearing, physical distancing), FCV-19S, anxiety, and depression. Linear and logistic regression analyses were performed appropriately to examine associations. Results: The mean score of eHEALS was 31.4 ± 4.4. The eHEALS score was significantly higher in males (unstandardized regression coefficient, B, 0.94; 95% confidence interval, 95% CI, 0.15 to 1.73; p = 0.019), and students with a better ability to pay for medication (B, 0.79; 95% CI, 0.39 to 1.19; p < 0.001), as compared to their counterparts. Nursing students with a higher eHEALS score had a higher likelihood of adhering to hand-washing (odds ratio, OR, 1.18; 95% CI, 1.15 to 1.22; p < 0.001), mask-wearing (OR, 1.15; 95% CI, 1.12 to 1.19; p < 0.001), keeping a safe physical distance (OR, 1.20; 95% CI, 1.15 to 1.25; p < 0.001), and had a lower anxiety likelihood (OR, 0.95; 95% CI, 0.92 to 0.99; p = 0.011). Conclusions: Nursing students who were men and with better ability to pay for medication had higher eHEALS scores. Those with higher eHEALS scores had better adherence to preventive measures, and better psychological health. The development of strategies to improve eHEALS of nursing students may contribute to COVID-19 containment and improve their psychological health.
Education in Radiation Oncology—Current Challenges and Difficulties
Authors: Mireștean Camil Ciprian , Iancu Roxana Irina , Iancu Dragoș Petru Teodor
Published: March 2022

The evolution and development of radiotherapy in the last two decades has meant that postgraduate medical training has not kept up with this rapid progress both in terms of multidisciplinary clinical approaches and especially in terms of technological advances. Education in radiation oncology is a major priority in the context of the rapid development of radiotherapy, including advanced knowledge of radiobiology, radiation physics and clinical oncology, anatomy, tumor biology and advanced medical imaging. In this context, the lack of training in radiation oncology in the curricula of medical faculties may have detrimental consequences for the training of residents in radiotherapy but also in their choice of specialty after completing their university studies. There is a clear gap between resident physicians’ actual and required knowledge of radiotherapy, and this requires urgent remediation. In the context of technical advances in imaging-guided radiotherapy (IGRT) and new radiobiology data, a balanced approach divided equally between general oncology, clinical radiation oncology, radiation oncology technology, medical physics and radiobiology, anatomy and multimodal imaging, including mentorship could bring educational and career choice benefits for students of radiation oncology.
Pediatric Dental Emergency Visits and Treatment during Lockdown in the COVID-19 Pandemic: A Retrospective Study
Authors: Elalouf Amir , Moran Rubanenko , Yaron Bernstein , Oman Michal
Published: March 2022

The COVID-19 pandemic has affected all the professions of life, particularly the healthcare sector. In dentistry, prevention of viral spread among healthcare professionals and patients was a substantial challenge. The virus can directly or indirectly infect dentists during dental procedures. This study focuses on the purpose of pediatric patients’ emergency visits to dental clinics and the treatments practiced during the lockdown. It compares the purpose of emergency pediatric patient visits in dental clinics and their treatments before, during, and after the lockdown periods. Computerized data for two consecutive years (2019 and 2020), between 19 March and 30 April and after the lockdown period from 1 May to 12 June 2020, were collected from five random dental clinics in Israel. The emergency visits of patients under 18 years before, during, and after the lockdown was organized into demographic characteristics, the purpose of the visits, and the treatments with medication or dental procedures. Categorical variables were compared and correlated with the chi-squared test and Pearson’s test, respectively, by using SPSS version 21. During the lockdown, emergency cases got appointments for a physical checkup. Herein, we found higher cases of emergency visits of pediatric patients with pain (n = 281, 32.6%) than trauma (n = 18, 24.7%), followed by infection (n = 31, 28.4%) and treatment continuation (n = 7, 20.6%) during the lockdown period, compared to before and after the lockdown periods. The patients treated with medication and dental procedures during lockdown were significantly different (p < 0.001) than before and after the lockdown. Extraction (n = 81, 41.5%), filling (n = 84, 50.6%), fluoride (n = 13, 92.9%), and pulp treatment (n = 92, 42.6%) were substantially practiced in pediatric patients during the lockdown. Further, this study confirmed the rapid adaptation of professional dentists to deal with non-vaccinated pediatric patients and reinforced the better preparation and requirements for such challenges in the future.
Adolescents’ Self-Esteem and Life Satisfaction: Communication with Peers as a Mediator
Authors: Szcześniak Małgorzata , Bajkowska Iga , Czaprowska Anna , Sileńska Aleksandra
Published: March 2022

The main goal of this study was to verify whether the relationship between adolescents’ self-esteem and life satisfaction is mediated by peer communication. The rationale behind this choice was the fact that while we know a lot about the association between self-esteem and life satisfaction in adolescents, we know far less about the mechanisms that may regulate this direct relationship. The research was conducted among high school students in one of the Polish provincial capitals (N = 429). The Rosenberg Self-Esteem Scale, the Satisfaction with Life Scale, and the Scale of Communication of Adolescents with Peers were used. In line with the hypotheses, self-esteem correlated positively with life satisfaction and openness, and negatively with difficulty in communication with peers. Open peer communication was positively associated with life satisfaction, and difficult peer communication was negatively correlated with life satisfaction. Moreover, the association between self-esteem and life satisfaction was mediated by openness and difficulty in peer communication. The mediatory effect of peer communication suggests that the simple bivariate relationship between adolescents’ evaluation of the self and a subjective assessment of their overall quality of life may be more complex.
The Effect of a Masticatory Muscle Training Program on Chewing Efficiency and Bite Force in People with Dementia
Authors: Jockusch Julia , Hahnel Sebastian , Sobotta Bernhard B. A. J. , Nitschke Ina
Published: March 2022

Until now, no study has investigated the effects of masticatory muscle training on chewing function in people with dementia. This study aimed to investigate whether physiotherapeutic exercises for the masticatory muscles have an influence on chewing efficiency and bite force in people with dementia. In a clinical trial with stratified randomization subjects were assigned to three groups based on the Mini Mental State Examination (MMSE: group 1—28–30, group 2—25–27, group 3—18–24). Each group was divided into an experimental (ExpG, intervention) and control group (ConG, no intervention). As intervention a Masticatory Muscle Training (MaMuT) (part 1: three physiotherapeutic treatments and daily home exercises, part 2: daily home exercises only) was carried out. Chewing efficiency and bite force were recorded. The MaMuT influenced the masticatory performance regardless of the cognitive state. Bite force increased in ExpG 1 and 2. Without further training, however, the effect disappeared. Chewing efficiency increased in all ExpG. After completion of the training, the ExpG 2 and 3 showed a decrease to initial values. Subjects of ExpG 1 showed a training effect at the final examination, but a tendency toward the initial values was observed. ExpG 3 seemed to benefit most from the physiotherapeutic exercises in terms of improving chewing efficiency by the end of the intervention phase. ExpG 1 showed the greatest gain in bite force. The MaMuT program is a potential method of improving masticatory performance in people with cognitive impairment or dementia when used on a daily basis.
Workplace Intervention for Heat Stress: Essential Elements of Design, Implementation, and Assessment
Authors: Glaser Jason , Wegman David H. , Arias-Monge Esteban , Pacheco-Zenteno Felipe , Prince Heath , Chavarria Denis , Martinez-Cuadra William Jose , Jakobsson Kristina , Hansson Erik , Lucas Rebekah A. I. , Weiss Ilana , Wesseling Catharina
Published: March 2022

Heat stress is associated with numerous health effects that potentially harm workers, especially in a warming world. This investigation occurred in a setting where laborers are confronted with occupational heat stress from physically demanding work in high environmental temperatures. Collaboration with a major Nicaraguan sugarcane producer offered the opportunity to study interventions to prevent occupational heat-stress-related kidney disease. Two aims for this study of a rest-shade-water intervention program were: (1) describe the evolving intervention, summarize findings that motivated proposed improvements, assess impact of those improvements, and identify challenges to successful implementation and (2) extract primary lessons learned about intervention research that have both general relevance to investigations of work-related disease prevention and specific relevance to this setting. The learning curve for the various stakeholders as well as the barriers to success demonstrate that effectiveness of an intervention cannot be adequately assessed without considerations of implementation. Designing, effectively implementing, and assessing both health impacts and implementation quality is a resource-intensive endeavor requiring a transdisciplinary approach. Both general and specific lessons learned are presented for decisions on study design and study elements, implementation assessment, and management engagement in understanding how productivity and health can be successfully balanced and for building effective communication between investigators and all levels of management.
The Impact of the COVID-19 Virus Pandemic on the Incidence of First Psychotic Spectrum Disorders
Authors: Łoś Kacper , Kulikowska Joanna , Waszkiewicz Napoleon
Published: March 2022

The effects of COVID-19 on the human body are not yet understood enough. Medical history provides information on cases of psychiatric symptoms during viral infections in the 20th century, such as the influenza pandemic. Currently, it is observed that there is an increasing number of new psychiatric disorders in previously healthy individuals. In addition, because of the decreased amount of reporting to health care providers, including psychiatrists, many physicians suggest that the number of neuropsychiatric disorders may be underestimated. In this paper, we review available studies on the occurrence of first-time psychotic spectrum disorder (PSD) in individuals related to SARS-CoV-2 infection. The reviewed studies suggest that first-time psychotic disorder in COVID-19 patients is statistically significantly more frequent compared to influenza, as well as to other respiratory infections. The emergence of new PSDs is explained by direct neurotropism of the virus on the one hand and by immunological mechanisms on the other. The main conclusions of this review should be treated with caution, and future research on this topic is needed. The authors recognize the particular need to develop standardized laboratory panels that include inflammatory markers (IL-6, TNF-α), cerebrospinal fluid (CSF) testing, and SARS-CoV-2 antibody assays to entirely understand the etiology of neuropsychiatric complications of SARS-CoV-2 infections and the pandemic itself. In addition, public health efforts are required to promote mental health, especially during COVID-19.
Active Commuting and Healthy Behavior among Adolescents in Neighborhoods with Varying Socioeconomic Status: The NESLA Study
Authors: Buli Benti Geleta , Tillander Annika , Fell Terence , Bälter Katarina
Published: March 2022

(1) Background: The World Health Organization recommends active commuting as a source of physical activity. Active commuting is determined by various factors, including the socioeconomic status (SES) of families and neighborhoods, distance to schools, perceived neighborhood safety, lifestyles and availability of walkways and biking paths. This study aimed to assess factors associated with modes of transportation to and from school among adolescents aged 16–19 living in a middle-sized city in Sweden. (2) Method: Three hundred and fourteen students, of whom 55% were females, from schools in the city of Västerås participated in the study. Printed as well as web-based self-administered questionnaires were used to collect the data. (3) Results: Adolescents living in high SES neighborhoods were 80% more likely to bike or walk to school (OR = 1.80; CI: 1.01, 3.20) than adolescents living in low SES neighborhoods. Furthermore, active commuting was associated with higher consumption of fruits and vegetables (OR = 1.77; CI: 1.05, 2.97) and less consumption of junk foods (OR = 0.43; CI: 0.26, 0.71), as compared to passive commuting. (4) Conclusions: Active commuting is a cost-effective and sustainable source of regular physical activity and should be encouraged at a societal level.
Fusion Scheme and Implementation Based on SRTM1, ASTER GDEM V3, and AW3D30
Authors: Zhao Shangmin , Liu Jiao , Cheng Weiming , Zhou Chenghu
Published: March 2022

Multi-source data fusion can help to weaken the original data’s shortcomings while improving data accuracy. The experimental area in this research is Taiyuan City in Shanxi Province, China. Using SRTM1 DEM, ASTER GDEM V3, and AW3D30 DEM, the optimal resolution of the Fused DEM in the research area is determined by analyzing the topographic factor information entropy. Then the optimally weighted fusion coefficient of the DEM with root mean square error (RMSE) as the criterion under different slope classes is determined by traversal exploration and quantitatively evaluates the fusion effect. The results show that the optimal resolution of the Fused DEM is 40 m under the terrain feature constraint of Taiyuan city. The fused DEM decreases by 33.8%, 57.9%, and 11.5% for mean absolute error (MAE), 36.3%, 54.6%, and 1.4% for standard deviation (STD), and 32.8%, 54.2%, and 9.7% for root mean square error (RMSE) compared with SRTM1, ASTER GDEM V3, and AW3D30. The weighted average fusion of multiple intensities increased the accuracy of the original data. The reduced topographic factor errors, such as slope, profile curvature, and TPI, improved the Fused DEM’s topographic representation capacity. Furthermore, the results confirm the high accuracy of Fused DEM in complex mountainous regions.
Use of Photodynamic Therapy Associated with Antimicrobial Peptides for Bacterial Control: A Systematic Review and Meta-Analysis
Authors: Dias Luana Mendonça , Ferrisse Túlio Morandin , Medeiros Karine Sousa , Cilli Eduardo Maffud , Pavarina Ana Claudia
Published: March 2022

Considering the challenges related to antimicrobial resistance, other strategies for controlling infections have been suggested, such as antimicrobial photodynamic therapy (aPDT) and antimicrobial peptides (AMP). This study aims to perform a systematic review and meta-analysis to obtain evidence on the antimicrobial effectiveness of aPDT associated with AMP and establish in vitro knowledge on this topic for further study designs. The PubMed, Scopus, Web of Science, Science Direct, Scielo, and Cochrane Library databases were searched. Two independent and calibrated researchers (Kappa = 0.88) performed all the systematic steps according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The odds ratio (OR) was used as the effect measure. The Peto method was used to perform the meta-analysis due to the sparse data. Twenty studies were included in the present review. The result was significant (OR = 0.14/p = 0.0235/I-squared = 0%), showing better outcomes of aPDT associated with peptides than those of aPDT alone for controlling the microbial load. Only 20% of the studies included evaluated this approach in a biofilm culture. Combined treatment with aPDT and AMP highly increased the ability of microbial reduction of Gram-positive and Gram-negative bacteria. However, additional blind studies are required to evaluate the efficacy of this therapy on microbial biofilms.
Molecular Mechanisms Involved in Hypoxia-Induced Alterations in Bone Remodeling
Authors: Usategui-Martín Ricardo , Rigual Ricardo , Ruiz-Mambrilla Marta , Fernández-Gómez José-María , Dueñas Antonio , Pérez-Castrillón José Luis
Published: March 2022

Bone is crucial for the support of muscles and the protection of vital organs, and as a reservoir of calcium and phosphorus. Bone is one of the most metabolically active tissues and is continuously renewed to adapt to the changes required for healthy functioning. To maintain normal cellular and physiological bone functions sufficient oxygen is required, as evidence has shown that hypoxia may influence bone health. In this scenario, this review aimed to analyze the molecular mechanisms involved in hypoxia-induced bone remodeling alterations and their possible clinical consequences. Hypoxia has been associated with reduced bone formation and reduced osteoblast matrix mineralization due to the hypoxia environment inhibiting osteoblast differentiation. A hypoxic environment is involved with increased osteoclastogenesis and increased bone resorptive capacity of the osteoclasts. Clinical studies, although with contradictory results, have shown that hypoxia can modify bone remodeling.
The Transcription Factor SpoVG Is of Major Importance for Biofilm Formation of Staphylococcus epidermidis under In Vitro Conditions, but Dispensable for In Vivo Biofilm Formation
Authors: Benthien Hannah , Fresenborg Beate , Pätzold Linda , Elhawy Mohamed Ibrahem , Huc-Brandt Sylvaine , Beisswenger Christoph , Krasteva-Christ Gabriela , Becker Sören L. , Molle Virginie , Knobloch Johannes K. , Bischoff Markus
Published: March 2022

Staphylococcus epidermidis is a common cause of device related infections on which pathogens form biofilms (i.e., multilayered cell populations embedded in an extracellular matrix). Here, we report that the transcription factor SpoVG is essential for the capacity of S. epidermidis to form such biofilms on artificial surfaces under in vitro conditions. Inactivation of spoVG in the polysaccharide intercellular adhesin (PIA) producing S. epidermidis strain 1457 yielded a mutant that, unlike its parental strain, failed to produce a clear biofilm in a microtiter plate-based static biofilm assay. A decreased biofilm formation capacity was also observed when 1457 ΔspoVG cells were co-cultured with polyurethane-based peripheral venous catheter fragments under dynamic conditions, while the cis-complemented 1457 ΔspoVG::spoVG derivative formed biofilms comparable to the levels seen with the wild-type. Transcriptional studies demonstrated that the deletion of spoVG significantly altered the expression of the intercellular adhesion (ica) locus by upregulating the transcription of the ica operon repressor icaR and down-regulating the transcription of icaADBC. Electrophoretic mobility shift assays (EMSA) revealed an interaction between SpoVG and the icaA-icaR intergenic region, suggesting SpoVG to promote biofilm formation of S. epidermidis by modulating ica expression. However, when mice were challenged with the 1457 ΔspoVG mutant in a foreign body infection model, only marginal differences in biomasses produced on the infected catheter fragments between the mutant and the parental strain were observed. These findings suggest that SpoVG is critical for the PIA-dependent biofilm formation of S. epidermis under in vitro conditions, but is largely dispensable for biofilm formation of this skin commensal under in vivo conditions.
Artificial Intelligence Technologies for COVID-19 De Novo Drug Design
Authors: Floresta Giuseppe , Zagni Chiara , Gentile Davide , Patamia Vincenzo , Rescifina Antonio
Published: March 2022

The recent covid crisis has provided important lessons for academia and industry regarding digital reorganization. Among the fascinating lessons from these times is the huge potential of data analytics and artificial intelligence. The crisis exponentially accelerated the adoption of analytics and artificial intelligence, and this momentum is predicted to continue into the 2020s and beyond. Drug development is a costly and time-consuming business, and only a minority of approved drugs generate returns exceeding the research and development costs. As a result, there is a huge drive to make drug discovery cheaper and faster. With modern algorithms and hardware, it is not too surprising that the new technologies of artificial intelligence and other computational simulation tools can help drug developers. In only two years of covid research, many novel molecules have been designed/identified using artificial intelligence methods with astonishing results in terms of time and effectiveness. This paper reviews the most significant research on artificial intelligence in de novo drug design for COVID-19 pharmaceutical research.
ABPP-HT*—Deep Meets Fast for Activity-Based Profiling of Deubiquitylating Enzymes Using Advanced DIA Mass Spectrometry Methods
Authors: Jones Hannah B. L. , Heilig Raphael , Davis Simon , Fischer Roman , Kessler Benedikt M. , Pinto-Fernández Adán
Published: March 2022

Activity-based protein profiling (ABPP) uses a combination of activity-based chemical probes with mass spectrometry (MS) to selectively characterise a particular enzyme or enzyme class. ABPP has proven invaluable for profiling enzymatic inhibitors in drug discovery. When applied to cell extracts and cells, challenging the ABP-enzyme complex formation with a small molecule can simultaneously inform on potency, selectivity, reversibility/binding affinity, permeability, and stability. ABPP can also be applied to pharmacodynamic studies to inform on cellular target engagement within specific organs when applied to in vivo models. Recently, we established separate high depth and high throughput ABPP (ABPP-HT) protocols for the profiling of deubiquitylating enzymes (DUBs). However, the combination of the two, deep and fast, in one method has been elusive. To further increase the sensitivity of the current ABPP-HT workflow, we implemented state-of-the-art data-independent acquisition (DIA) and data-dependent acquisition (DDA) MS analysis tools. Hereby, we describe an improved methodology, ABPP-HT* (enhanced high-throughput-compatible activity-based protein profiling) that in combination with DIA MS methods, allowed for the consistent profiling of 35–40 DUBs and provided a reduced number of missing values, whilst maintaining a throughput of 100 samples per day.
Role of Extracellular High-Mobility Group Box-1 as a Therapeutic Target of Gastric Cancer
Authors: Takaki Wataru , Konishi Hirotaka , Matsubara Daiki , Shoda Katsutoshi , Arita Tomohiro , Kataoka Satoshi , Shibamoto Jun , Furuke Hirotaka , Takabatake Kazuya , Shimizu Hiroki , Komatsu Shuhei , Shiozaki Atsushi , Kubota Takeshi , Okamoto Kazuma , Otsuji Eigo
Published: March 2022

Background: High-mobility group box-1 (HMGB1) is involved in the tumorigenesis and metastasis of various cancers. The present study investigated the roles of extracellular HMGB1 in the progression of gastric cancer (GC) and the therapeutic effects of recombinant human soluble thrombomodulin (rTM) targeting HMGB1. Methods: The effects of extracellular HMGB1 and rTM on GC cells were assessed using proliferation and Transwell assays. Their effects on local tumor growth and metastasis were evaluated using subcutaneous tumor and liver metastasis mouse models, respectively. Plasma HMGB1 concentrations in GC patients were measured using ELISA. The relationships between plasma HMGB1 concentrations and the prognosis and clinicopathological factors of patients were also investigated. Results: GC proliferation, migration, and invasion abilities were promoted by increases in extracellular HMGB1 concentrations and alleviated by rTM. In the subcutaneous tumor model, local tumor growth was promoted by the addition of rhHMGB1 and alleviated by rTM. Similar changes occurred in the liver metastasis model. Recurrence-free survival (p < 0.01) and overall survival (p = 0.01) were significantly worse in patients with high plasma HMGB1 concentrations. Conclusion: Plasma HMGB1 concentrations are a prognostic marker in GC patients. Extracellular HMGB1 promotes cancer progression and has potential as a novel treatment target in GC cells for rTM.
Innovative Approaches for Crop Improvement and Sustainable Management of Plant Disease in the Post-Genomic Era
Authors: Fambrini Marco , Pugliesi Claudio , Pecchia Susanna
Published: March 2022

Safeguarding food supply in a world environment subject to sudden climate change, reducing the use of anthropogenic sources of pollution as much as possible, and using crops that must necessarily be increasingly resilient to biotic and abiotic stresses is a mandatory and ambitious necessity for the foreseeable future [...]
Chitosan Hydrogel Supplemented with Metformin Promotes Neuron–like Cell Differentiation of Gingival Mesenchymal Stem Cells
Authors: Cai Shanglin , Lei Tong , Bi Wangyu , Sun Shutao , Deng Shiwen , Zhang Xiaoshuang , Yang Yanjie , Xiao Zhuangzhuang , Du Hongwu
Published: March 2022

Human gingival mesenchymal stem cells (GMSCs) are derived from migratory neural crest stem cells and have the potential to differentiate into neurons. Metformin can inhibit stem–cell aging and promotes the regeneration and development of neurons. In this study, we investigated the potential of metformin as an enhancer on neuronal differentiation of GMSCs in the growth environment of chitosan hydrogel. The crosslinked chitosan/β–glycerophosphate hydrogel can form a perforated microporous structure that is suitable for cell growth and channels to transport water and macromolecules. GMSCs have powerful osteogenic, adipogenic and chondrogenic abilities in the induction medium supplemented with metformin. After induction in an induction medium supplemented with metformin, Western blot and immunofluorescence results showed that GMSCs differentiated into neuron–like cells with a significantly enhanced expression of neuro–related markers, including Nestin (NES) and β–Tubulin (TUJ1). Proteomics was used to construct protein profiles in neural differentiation, and the results showed that chitosan hydrogels containing metformin promoted the upregulation of neural regeneration–related proteins, including ATP5F1, ATP5J, NADH dehydrogenase (ubiquinone) Fe–S protein 3 (NDUFS3), and Glutamate Dehydrogenase 1 (GLUD1). Our results help to promote the clinical application of stem–cell neural regeneration.
Anti-Inflammatory Characteristics of Local Anesthetics: Inhibition of TNF-α Secretion of Lipopolysaccharide-Stimulated Leucocytes in Human Blood Samples
Authors: Weinschenk Stefan , Weiss Carsten , Benrath Justus , von Baehr Volker , Strowitzki Thomas , Feißt Manuel
Published: March 2022

Background. Local anesthetics (LAs) have potent anti-inflammatory properties. Inflammatory down-regulation is crucial in diseases with overactive immune reactions, such as acute respiratory distress syndrome (ARDS) and chronic inflammation. We investigated the influence of four LAs, procaine, lidocaine, mepivacaine, and bupivacaine, on the reduction of tumor necrosis factor-alpha (TNF-α) secretion in lipopolysaccharide (LPS)-activated human leucocytes. Methods. Blood samples of 28 individuals were stimulated with LPS. The reduction of TNF-α production by each of the four LAs added (0.5 mg/mL) was measured and correlated with biometric variables. A response was defined as reduction to <85% of initial levels. Results. All four LAs down-regulated the TNF-α secretion in 44–61%: Bupivacaine (44.4%), lidocaine (61.5%), mepivacaine (44.4%), and procaine (50% of the individuals, “responders”). The TNF-α secretion was reduced to 67.4, 68.0, 63.6, and 67.1% of the initial values in responders. The effects in both patients and healthy persons were the same. Interindividual responses to LAs were not correlated with the duration or type of complaints, basal TNF-α serum level, sex, BMI, or age of responders. Conclusions. Four clinically relevant LAs (amid-LA and ester-LA) attenuate the inflammatory response provoked by LPS. They are potential candidates for drug repositioning in treating overactive immune reactions and chronic inflammation.
Disruption of Membrane Integrity as a Molecular Initiating Event Determines the Toxicity of Polyhexamethylene Guanidine Phosphate Depending on the Routes of Exposure
Authors: Song Jeongah , Jung Kyung-Jin , Yang Mi-Jin , Kim Woojin , Lee Byoung-Seok , Choe Seong-Kyu , Kim Seong-Jin , Hwang Jeong-Ho
Published: March 2022

Polyhexamethylene guanidine phosphate (PHMG-P), a cationic biocide, is widely used in household products due to its strong bactericidal activity and low toxicity. However, it causes fatal lung damage when inhaled. In this study, we investigated why PHMG-P causes fatal lung injury when inhaled, and demonstrated that the disruption of membrane integrity through ionic interaction—a molecular initiating event of PHMG-P—determines toxicity. Mice were injected intravenously with 0.9 or 7.2 mg/kg PHMG-P (IV group), or instilled intratracheally with 0.9 mg/kg PHMG-P (ITI group); they were euthanatized at 4 h and on days 1 and 7 after treatment. Increased total BAL cell count and proinflammatory cytokine production, along with fibrotic changes in the lungs, were detected in the ITI group only. Levels of hepatic enzymes and hepatic serum amyloid A mRNA expression were markedly upregulated in the 7.2 mg/kg IV and ITI groups at 4 h or day 1 after treatment, but returned to baseline. No pathological findings were detected in the heart, liver, or kidneys. To simulate the IV injection, A549, THP-1, and HepG2 cells were treated with PHMG-P in cell culture media supplemented with different serum concentrations. Increased serum concentration was associated with an increase in cell viability. These results support the idea that direct contact between PHMG-P and cell membranes is necessary for PHMG-induced toxicity.
Preclinical Evaluation of BMP-9-Treated Human Bone-like Substitutes for Alveolar Ridge Preservation following Tooth Extraction
Authors: Kawecki Fabien , Jann Jessica , Fortin Michel , Auger François A. , Faucheux Nathalie , Fradette Julie
Published: March 2022

The success of dental implant treatment after tooth extraction is generally maximized by preserving the alveolar ridge using cell-free biomaterials. However, these treatments can be associated with inflammatory reactions, leading to additional bone volume loss hampering dental implant positioning. Our group developed a self-assembled bone-like substitute constituted of osteogenically induced human adipose-derived stromal/stem cells (hASCs). We hypothesized that a bone morphogenetic protein (BMP) supplementation could improve the in vitro osteogenic potential of the bone-like substitute, which would subsequently translate into enhanced alveolar bone healing after tooth extraction. ASCs displayed a better osteogenic response to BMP-9 than to BMP-2 in monolayer cell culture, as shown by higher transcript levels of the osteogenic markers RUNX2, osterix (OSX/SP7), and alkaline phosphatase after three and six days of treatment. Interestingly, BMP-9 treatment significantly increased OSX transcripts and alkaline phosphatase activity, as well as pro-angiogenic angiopoietin-1 gene expression, in engineered bone-like substitutes after 21 days of culture. Alveolar bone healing was investigated after molar extraction in nude rats. Microcomputed tomography and histological evaluations revealed similar, or even superior, global alveolar bone preservation when defects were filled with BMP-9-treated bone-like substitutes for ten weeks compared to a clinical-grade biomaterial, with adequate gingival re-epithelialization in the absence of resorption.
Short-Chain Fatty Acid Receptors and Cardiovascular Function
Authors: Lymperopoulos Anastasios , Suster Malka S. , Borges Jordana I.
Published: March 2022

Increasing experimental and clinical evidence points toward a very important role for the gut microbiome and its associated metabolism in human health and disease, including in cardiovascular disorders. Free fatty acids (FFAs) are metabolically produced and utilized as energy substrates during almost every biological process in the human body. Contrary to long- and medium-chain FFAs, which are mainly synthesized from dietary triglycerides, short-chain FFAs (SCFAs) derive from the gut microbiota-mediated fermentation of indigestible dietary fiber. Originally thought to serve only as energy sources, FFAs are now known to act as ligands for a specific group of cell surface receptors called FFA receptors (FFARs), thereby inducing intracellular signaling to exert a variety of cellular and tissue effects. All FFARs are G protein-coupled receptors (GPCRs) that play integral roles in the regulation of metabolism, immunity, inflammation, hormone/neurotransmitter secretion, etc. Four different FFAR types are known to date, with FFAR1 (formerly known as GPR40) and FFAR4 (formerly known as GPR120) mediating long- and medium-chain FFA actions, while FFAR3 (formerly GPR41) and FFAR2 (formerly GPR43) are essentially the SCFA receptors (SCFARs), responding to all SCFAs, including acetic acid, propionic acid, and butyric acid. As with various other organ systems/tissues, the important roles the SCFARs (FFAR2 and FFAR3) play in physiology and in various disorders of the cardiovascular system have been revealed over the last fifteen years. In this review, we discuss the cardiovascular implications of some key (patho)physiological functions of SCFAR signaling pathways, particularly those regulating the neurohormonal control of circulation and adipose tissue homeostasis. Wherever appropriate, we also highlight the potential of these receptors as therapeutic targets for cardiovascular disorders.
CCL2 Inhibition of Pro-Resolving Mediators Potentiates Neuroinflammation in Astrocytes
Authors: Gutiérrez Irene L. , Novellino Fabiana , Caso Javier R. , García-Bueno Borja , Leza Juan C. , Madrigal José L. M.
Published: March 2022

The chemokine CCL2 participates in multiple neuroinflammatory processes, mainly through the recruitment of glial cells. However, CCL2 has also been proven to exert different types of actions on these cells, including the modification of their response to inflammatory stimuli. In the present study we analyzed the effect of CCL2 on the resolution of inflammation in astrocytes. We observed that genetic removal of CCL2 increases the expression of the enzymes responsible for the synthesis of specialized pro-resolving mediators arachidonate 15-lipoxygenase and arachidonate 5-lipoxygenase in the brain cortex of 5xFAD mice. The expression of FPR2 receptor, known to mediate the activity of pro-resolving mediators was also increased in mice lacking CCL2.The downregulation of these proteins by CCL2 was also observed in cultured astrocytes. This suggests that CCL2 inhibition of the resolution of inflammation could facilitate the progression of neuroinflammatory processes. The production of the pro-inflammatory cytokine IL-1beta by astrocytes was analyzed, and allowed us to confirm that CCL2 potentiates the activation of astrocytes trough the inhibition of pro-resolving pathways mediated by Resolvin D1. In addition, the analysis of the expression of TNFalpha, MIP1alpha and NOS2 further confirmed CCL2 inhibition of inflammation resolution in astrocytes.
Systematic Discovery of FBXW7-Binding Phosphodegrons Highlights Mitogen-Activated Protein Kinases as Important Regulators of Intracellular Protein Levels
Authors: Singh Neha , Zeke András , Reményi Attila
Published: March 2022

A FBXW7 is an F-box E3 ubiquitin-ligase affecting cell growth by controlling protein degradation. Mechanistically, its effect on its substrates depends on the phosphorylation of degron motifs, but the abundance of these phosphodegrons has not been systematically explored. We used a ratiometric protein degradation assay geared towards the identification of FBXW7-binding degron motifs phosphorylated by mitogen-activated protein kinases (MAPKs). Most of the known FBXW7 targets are localized in the nucleus and function as transcription factors. Here, in addition to more transcription affecting factors (ETV5, KLF4, SP5, JAZF1, and ZMIZ1 CAMTA2), we identified phosphodegrons located in proteins involved in chromatin regulation (ARID4B, KMT2E, KMT2D, and KAT6B) or cytoskeletal regulation (MAP2, Myozenin-2, SMTL2, and AKAP11), and some other proteins with miscellaneous functions (EIF4G3, CDT1, and CCAR2). We show that the protein level of full-length ARID4B, ETV5, JAZF1, and ZMIZ1 are affected by different MAPKs since their FBXW7-mediated degradation was diminished in the presence of MAPK-specific inhibitors. Our results suggest that MAPK and FBXW7 partnership plays an important cellular role by directly affecting the level of key regulatory proteins. The data also suggest that the p38α-controlled phosphodegron in JAZF1 may be responsible for the pathological regulation of the cancer-related JAZF1-SUZ12 fusion construct implicated in endometrial stromal sarcoma.
Aberrant Notch Signaling Pathway as a Potential Mechanism of Central Precocious Puberty
Authors: Shim Young Suk , Lee Hae Sang , Hwang Jin Soon
Published: March 2022

The Notch signaling pathway is highly conserved during evolution. It has been well documented that Notch signaling regulates cell proliferation, migration, and death in the nervous, cardiac, and endocrine systems. The Notch pathway is relatively simple, but its activity is regulated by numerous complex mechanisms. Ligands bind to Notch receptors, inducing their activation and cleavage. Various post-translational processes regulate Notch signaling by affecting the synthesis, secretion, activation, and degradation of Notch pathway-related proteins. Through such post-translational regulatory processes, Notch signaling has versatile effects in many tissues, including the hypothalamus. Recently, several studies have reported that mutations in genes related to the Notch signaling pathway were found in patients with central precocious puberty (CPP). CPP is characterized by the early activation of the hypothalamus–pituitary–gonadal (HPG) axis. Although genetic factors play an important role in CPP development, few associated genetic variants have been identified. Aberrant Notch signaling may be associated with abnormal pubertal development. In this review, we discuss the current knowledge about the role of the Notch signaling pathway in puberty and consider the potential mechanisms underlying CPP.