bluuebunny/crossref_metadata_2025 huggingface dataset:
The Psychological Impact of the Coronavirus Disease 2019 Pandemic on Pregnant Women in China
Authors: Zheng Zheng , Zhang Ruoxi , Liu Tao , Cheng Pei , Zhou Yanhong , Lu Weicong , Xu Guiyun , So Kwok-Fai , Lin Kangguang
Published: July 2021

Background: The coronavirus disease 2019 (COVID-19) pandemic has been reported to have negative psychological impact on mental health. Nonetheless, there are few studies investigating the impacts on pregnant women. This study investigated the psychological impact of COVID-19 pandemic on pregnant women, and the associated risk factors that moderated this impact.

Methods and Materials: A total of 2,798 pregnant participants were recruited from the Guangzhou Women and Children's Medical Center. The Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) and Insomnia Severity Index (ISI) were used to assess depression, generalized anxiety disorder and insomnia, respectively, during and before the COVID-19 pandemic. The Impact of Event Scale-Revised (IES-R) was used to assess psychological stress during the COVID-19 pandemic.

Results: During the COVID-19 pandemic, over one third of pregnant participants reported mild depression, around 20% experienced mild generalized anxiety, about one third reported problems with sleeping, and more than 15% felt mild psychological stress. The occurrence of psychological problems was significantly higher during the COVID-19 pandemic when compared to before the outbreak. The previously described pattern that pregnant women in the first trimester are more likely to report depression, and those in the third trimester are more likely to report insomnia and psychological stress, was also recognized in our study population. Mental health issues existing before the outbreak were risk factors, while family support was a protective factor in the occurrence of the measured mental health problems during the COVID-19 pandemic.

Conclusion: Our data suggest pregnant women's mental health is inevitably affected during the COVID-19 pandemic. Pregnant women in the first and third trimester and those who experienced mental issues before the outbreak may be particularly affected.
Victims of the Terrorist Attacks in Belgium and Professional Mental Health Aid Barriers: A Qualitative Study
Authors: Van Overmeire Roel , Muysewinkel Emilie , Van Keer Rose-Lima , Vesentini Lara , Bilsen Johan
Published: July 2021

Introduction: Terrorist attacks can cause short and long-term stress-reactions, anxiety, and depression among those exposed. Sometimes, professional mental health aid, meaning all types of professional psychotherapy, would be appropriate, but victims often delay or never access mental health aid, even up to a decade after the initial event. Little is known about the barriers terrorist-victims encounter when they try to access professional mental health aid.

Method: Using a qualitative design, 27 people exposed to the 22/03/2016 terrorist attack in Belgium were interviewed using half-structured, in-depth interviews, on their experiences with professional mental health aid. A reflexive thematic analysis was employed.

Results: Five main barriers for professional mental health aid seeking by victims were found. First, their perception of a lack of expertise of mental health aid professionals. Second, the lack of incentives to overcome their uncertainty to contact a professional. Third, social barriers: people did not feel supported by their social network, feared stigma, or trusted that the support of their social network would be enough to get them through any difficulties. Fourth, a lack of mental health literacy, which seems to be needed to recognize the mental health issues they are facing. Finally, there are financial barriers. The cost of therapy is often too high to begin or continue therapy.

Conclusions: This study showed that the barriers for seeking professional mental health aid are diverse and not easily overcome. More mental health promotion is needed, so that there is a societal awareness of possible consequences of being exposed to terrorist attacks, which might result in less stigma, and a quicker realization of possible harmful stress reactions due to a disaster.
Study Protocol—Coping With the Pandemics: What Works Best to Reduce Anxiety and Depressive Symptoms
Authors: Fortea Lydia , Solanes Aleix , Pomarol-Clotet Edith , Garcia-Leon Maria Angeles , Fortea Adriana , Torrent Carla , Varo Cristina , Bonnin C. Mar , Montejo Laura , Alonso Jordi , Carmona Susana , Soldevila-Matías Pau , Alustiza Irene , Arbós Daniel , Hidalgo-Mazzei Diego , Grande Iria , Vieta Eduard , Fullana Miquel Àngel , Radua Joaquim
Published: July 2021

Background: The coronavirus disease 2019 (COVID-19) pandemic and lockdown might increase anxiety and depressive symptoms in most individuals. Health bodies recommend several coping behaviors to protect against such symptoms, but evidence on the relationship between these behaviors and symptoms mostly comes from cross-sectional studies in convenience samples. We will conduct a prospective longitudinal study of the associations between coping behaviors and subsequent anxiety and depressive symptoms during the COVID-19 pandemic in a representative sample of the Spanish general adult population.

Methods: We will recruit 1,000 adult participants from all autonomous communities of Spain and with sex, age, and urbanicity distributions similar to those of their populations and assess anxiety and depressive symptoms and coping behaviors using fortnightly questionnaires and real-time methods (ecological momentary assessments) for 1 year. The fortnightly questionnaires will inquire about anxiety and depressive symptoms [General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9)] and the frequency of 10 potential coping behaviors (e.g., follow a routine) during the past 2 weeks. In addition, we will collect several variables that could confound or moderate these associations. These will include subjective well-being [International Positive and Negative Affect Schedule Short Form (I-PANAS-SF) and Satisfaction with Life Scale (SWLS)], obsessive-compulsive symptoms [Obsessive Compulsive Inventory-Revised (OCI-R)], personality and emotional intelligence [International Personality Item Pool (IPIP) and Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF)], sociodemographic factors (e.g., work status, housing-built environment), and COVID-19 pandemic-related variables (e.g., hospitalizations or limitations in social gatherings). Finally, to analyze the primary relationship between coping behaviors and subsequent anxiety and depressive symptoms, we will use autoregressive moving average (ARMA) models.

Discussion: Based on the study results, we will develop evidence-based, clear, and specific recommendations on coping behaviors during the COVID-19 pandemic and lockdown. Such suggestions might eventually help health bodies or individuals to manage current or future pandemics.
Safety and Preliminary Efficacy of Lorcaserin for Cocaine Use Disorder: A Phase I Randomized Clinical Trial
Authors: Johns Sade E. , Keyser-Marcus Lori , Abbate Antonio , Boone Edward , Van Tassell Benjamin , Cunningham Kathryn A. , Anastasio Noelle C. , Poklis Justin L. , Ramey Tatiana , Moeller F. Gerard
Published: July 2021

Background and Objectives: Preclinical studies show serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonists reduce cocaine-seeking and cocaine intake. This study examined safety of the 5-HT2CR agonist lorcaserin administered with cocaine in participants with cocaine use disorder (CocUD). Secondarily, subjective response to cocaine and choice of cocaine vs. money were examined.

Methods: A double-blind, randomized, placebo-controlled trial of 25 inpatient non-treatment seeking participants with CocUD. Participants were randomized to either lorcaserin (n = 17) or placebo (n = 8). Primary outcome measures included cardiovascular measures and plasma cocaine levels. Secondary measures of subjective response to cocaine were assessed using a visual analog scale (VAS) and cocaine vs. money progressive ratio choice sessions.

Results: Thirteen randomized participants were included in the final analysis. No serious or unexpected adverse events were related to lorcaserin. There were no significant interactions between cocaine and lorcaserin on cardiovascular measures, plasma cocaine, or subjective ratings. After multiple comparisons correction, cocaine significantly increased blood pressure, heart rate, and QTc. Lorcaserin significantly decreased VAS ratings of “feel irritable,” “feel hungry,” and “I am craving.” For the cocaine vs. money choice procedure, there was a significant interaction between choice (cocaine vs. money) and lorcaserin. Participants treated with lorcaserin were more likely to choose cocaine.

Discussion and Conclusions: This study showed safety of lorcaserin administered with cocaine but lack of efficacy to reduce the reinforcing effects of cocaine.

Scientific Significance: This study is the first to show a disconnect between effects of 5-HT2CR agonists on craving and cocaine choice in human cocaine users.
Threat-Modulation of Executive Functions—A Novel Biomarker of Depression?
Authors: Peräkylä Jari , Järventausta Kaija , Haapaniemi Piia , Camprodon Joan A. , Hartikainen Kaisa M.
Published: July 2021

Background: Alterations in executive functions, emotion regulation, and their interaction are common concomitants of depression. Executive dysfunction frequently lingers after treatment, has adverse effects on daily life, and predisposes to recurrence of depression. Yet, sensitive measures of executive function for reliable assessment of cognitive outcomes are still lacking in clinical practice. To better understand the impact of depression and its most effective treatment, electroconvulsive therapy (ECT), on cognition, we assessed executive functions pre- and post-ECT and whether objective measures reflecting alterations in emotion–executive function interaction correlate with depression severity or with cognitive outcome.

Methods: Executive functions were assessed in 21 patients with major depressive disorder (MDD) before and after ECT using subjective measures from the Behavior Rating Inventory of Executive Function—Adult version (BRIEF-A) and objective cognitive performance measures derived from computer-based test of executive function, Executive Reaction Time (RT) Test. In addition, we created novel indices reflecting emotional modulation of cognitive performance by subtracting different performance measures in the context of neutral distractors from those in the context of threat-related distractors. We correlated these indices with Beck Depression Inventory (BDI) and BRIEF-A scores.

Results: Depression was significantly alleviated, and executive functions improved post-ECT, as seen in reduced BDI scores, BRIEF-A scores, and number of errors in Executive RT Test. Pre-ECT BDI scores correlated with threat modulation of RT (tmRT) and threat modulation of working memory (tmWM). Post-ECT tmRT correlated with several Behavioral Regulation scales and tmWM with several Metacognition scales of BRIEF-A.

Conclusion: While caution is warranted, results from both subjective and objective measures suggest that ECT significantly improves executive functions and emotion regulation along with alleviation of depression. Novel indices derived from threat modulation of executive function and working memory show promise as objective biomarkers of depression severity pre-ECT and cognitive outcome post-ECT with potential for guiding depression treatments.
Cognition and Frailty in Patients With Heart Failure: A Systematic Review of the Association Between Frailty and Cognitive Impairment
Authors: Faulkner Kenneth M. , Uchmanowicz Izabella , Lisiak Magdalena , Cichoń Ewelina , Cyrkot Tomasz , Szczepanowski Remigiusz
Published: July 2021

Background/Aim: Pathological processes associated with aging increase the risk of cognitive deficits. Frailty syndrome may significantly accelerate these pathological processes in elderly patients with heart failure. The objective of this review was to better understand the association between frailty syndrome and co-occurring cognitive decline in patients with heart failure.

Methods: We conducted a systematic review based on PubMed/MEDLINE, Scopus, EMBASE, and CINAHL as databases. The search followed the method described by Webb and Roe. For inclusions, the studies were selected employing cross-sectional and longitudinal designs. The included studies had to evaluate frailty syndrome and cognitive impairments among participants with heart failure. As we were interested in older adults, the search was limited to individuals >65 years of age. The search was limited to primary research articles written in English published since the year 2000.

Results: Of the 1,245 studies retrieved by the systematic review, 8 relevant studies were enclosed for the full-text review. Our review revealed that most studies of patients with HF demonstrated evidence of an association between greater frailty and cognitive impairment. In particular, six studies reported evidence for the significant association between higher levels of frailty and cognitive impairment in patients with heart failure. The remaining two studies failed to find an association between frailty and cognitive impairment.

Conclusions: The development of frailty and cognitive impairment in heart failure is particularly important because this cardiovascular disease is a common cause of both morbidity and mortality in the world. The results of this review fill the existing gap in the literature related to the identification of clinical factors linked with frailty syndrome that contribute to cognitive impairment in patients with a diagnosis of heart failure. The prevalence of overlapping frailty and cognitive impairment in patients with heart failure, therefore, necessitates a routine assessment of these components in the care of patients with cardiovascular disease.
Urban Air Pollution and Mental Stress: A Nationwide Study of University Students in China
Authors: Zhang Weifang , Peng Sihui , Fu Jialu , Xu Ke , Wang Huihui , Jin Yu , Yang Tingzhong , Cottrell Randall R.
Published: July 2021

Background: Studies exploring the relationship between air pollution levels and mental stress have rarely been done, and no studies have been done comparing university student mental stress levels based on regional air pollution levels.

Objectives: The objective of this study was to evaluate the association between air pollution and mental stress among university students.

Methods: Participants were 11,942 students, who were identified through a multistage survey sampling process conducted in 50 universities. Regional air pollution levels were retrieved from a national database, and mental stress was measured using a perceived stress scale. Both unadjusted and adjusted methods were utilized in the data analyses.

Results: Mental stress prevalence was 36.9% (95% Confidence Interval: 24.4–49.5%). The final model indicated that regional air pollution levels were positively associated with students' mental stress.

Conclusions: This study provided new and direct evidence of the health hazards of air pollution. The findings underscore the need to develop and implement stringent environmental protection policies, while simultaneously raising public awareness of environmental protection.
A Review of SMA-Based Actuators for Bidirectional Rotational Motion: Application to Origami Robots
Authors: Hu Kejun , Rabenorosoa Kanty , Ouisse Morvan
Published: July 2021

Shape memory alloys (SMAs) are a group of metallic alloys capable of sustaining large inelastic strains that can be recovered when subjected to a specific process between two distinct phases. Regarding their unique and outstanding properties, SMAs have drawn considerable attention in various domains and recently became appropriate candidates for origami robots, that require bi-directional rotational motion actuation with limited operational space. However, longitudinal motion-driven actuators are frequently investigated and commonly mentioned, whereas studies in SMA-based rotational motion actuation is still very limited in the literature. This work provides a review of different research efforts related to SMA-based actuators for bi-directional rotational motion (BRM), thus provides a survey and classification of current approaches and design tools that can be applied to origami robots in order to achieve shape-changing. For this purpose, analytical tools for description of actuator behaviour are presented, followed by characterisation and performance prediction. Afterward, the actuators’ design methods, sensing, and controlling strategies are discussed. Finally, open challenges are discussed.
To Observe, or Not to Observe, Quantum-Coherent Dark Matter in the Milky Way, That is a Question
Authors: Rindler-Daller Tanja
Published: July 2021

In recent years, Bose-Einstein-condensed dark matter (BEC-DM) has become a popular alternative to standard, collisionless cold dark matter (CDM). This BEC-DM -also called scalar field dark matter (SFDM)- can suppress structure formation and thereby resolve the small-scale crisis of CDM for a range of boson masses. However, these same boson masses also entail implications for BEC-DM substructure within galaxies, especially within our own Milky Way. Observational signature effects of BEC-DM substructure depend upon its unique quantum-mechanical features and have the potential to reveal its presence. Ongoing efforts to determine the dark matter substructure in our Milky Way will continue and expand considerably over the next years. In this contribution, we will discuss some of the existing constraints and potentially new ones with respect to the impact of BEC-DM onto baryonic tracers. Studying dark matter substructure in our Milky Way will soon resolve the question, whether dark matter behaves classical or quantum on scales of≲1 kpc.
A Mobile-Based System for Detecting Plant Leaf Diseases Using Deep Learning
Authors: Ahmed Ahmed Abdelmoamen , Reddy Gopireddy Harshavardhan
Published: July 2021

Plant diseases are one of the grand challenges that face the agriculture sector worldwide. In the United States, crop diseases cause losses of one-third of crop production annually. Despite the importance, crop disease diagnosis is challenging for limited-resources farmers if performed through optical observation of plant leaves’ symptoms. Therefore, there is an urgent need for markedly improved detection, monitoring, and prediction of crop diseases to reduce crop agriculture losses. Computer vision empowered with Machine Learning (ML) has tremendous promise for improving crop monitoring at scale in this context. This paper presents an ML-powered mobile-based system to automate the plant leaf disease diagnosis process. The developed system uses Convolutional Neural networks (CNN) as an underlying deep learning engine for classifying 38 disease categories. We collected an imagery dataset containing 96,206 images of plant leaves of healthy and infected plants for training, validating, and testing the CNN model. The user interface is developed as an Android mobile app, allowing farmers to capture a photo of the infected plant leaves. It then displays the disease category along with the confidence percentage. It is expected that this system would create a better opportunity for farmers to keep their crops healthy and eliminate the use of wrong fertilizers that could stress the plants. Finally, we evaluated our system using various performance metrics such as classification accuracy and processing time. We found that our model achieves an overall classification accuracy of 94% in recognizing the most common 38 disease classes in 14 crop species.
A Review of Omics Technologies and Bioinformatics to Accelerate Improvement of Papaya Traits
Authors: Zainal-Abidin Rabiatul-Adawiah , Ruhaizat-Ooi Insyirah-Hannah , Harun Sarahani
Published: July 2021

Papaya (Carica papaya) is an economically important fruit crop that is mostly planted in tropical and subtropical regions. Major diseases of papaya, such as the papaya dieback disease (PDD), papaya ringspot virus (PRSV) disease, and papaya sticky disease (PSD), have caused large yield and economic losses in papaya-producing countries worldwide. Postharvest losses have also contributed to the decline in papaya production. Hence, there is an urgent need to secure the production of papaya for a growing world population. Integration of omics resources in crop breeding is anticipated in order to facilitate better-designed crops in the breeding programme. In papaya research, the application of omics and bioinformatics approaches are gradually increased and are underway. Hence, this review focuses on addressing omics technologies and bioinformatics that are used in papaya research. To date, four traits of the papaya have been studied using omics and bioinformatics approaches, which include its ripening process, abiotic stress, disease resistance, and fruit quality (i.e., sweetness, fruit shape, and fruit size). This review also highlights the potential of genetics and genomics data, as well as the systems biology approach that can be applied in a papaya-breeding programme in the near future.
Expert Perspectives on the Performance of Explosive Detection Canines: Performance Degrading Factors
Authors: Farr Brian D. , Otto Cynthia M. , Szymczak Julia E.
Published: July 2021

The explosive detection canine (EDC) team is currently the best available mobile sensor capability in the fight against explosive threats. While the EDC can perform at a high level, the EDC team faces numerous factors during the search process that may degrade performance. Understanding these factors is key to effective selection, training, assessment, deployment, and operationalizable research. A systematic description of these factors is absent from the literature. This qualitative study leveraged the perspectives of expert EDC handlers, trainers, and leaders (n = 17) to determine the factors that degrade EDC performance. The participants revealed factors specific to utilization, the EDC team, and the physical, climate, operational, and explosive odor environments. Key results were the reality of performance degradation, the impact of the handler, and the importance of preparation. This study’s results can help improve EDC selection, training, assessment, and deployment and further research into sustaining EDC performance.
Evaluation of the Feasibility, Reliability, and Repeatability of Welfare Indicators in Free-Roaming Horses: A Pilot Study
Authors: Harley Jessica J. , Stack J. David , Braid Helen , McLennan Krista M. , Stanley Christina R.
Published: July 2021

Validated assessment protocols have been developed to quantify welfare states for intensively managed sport, pleasure, and working horses. There are few protocols for extensively managed or free-roaming populations. Here, we trialed welfare indicators to ascertain their feasibility, reliability, and repeatability using free-roaming Carneddau Mountain ponies as an example population. The project involved (1) the identification of animal and resource-based measures of welfare from both the literature and discussion with an expert group; (2) testing the feasibility and repeatability of a modified body condition score and mobility score on 34 free-roaming and conservation grazing Carneddau Mountain ponies; and (3) testing a prototype welfare assessment template comprising 12 animal-based and 6 resource-based welfare indicators, with a total of 20 questions, on 35 free-roaming Carneddau Mountain ponies to quantify inter-assessor reliability and repeatability. This pilot study revealed that many of the indicators were successfully repeatable and had good levels of inter-assessor reliability. Some of the indicators could not be verified for reliability due to low/absent occurrence. The results indicated that many animal and resource-based indicators commonly used in intensively managed equine settings could be measured in-range with minor modifications. This study is an initial step toward validating a much-needed tool for the welfare assessment of free-roaming and conservation grazing ponies.
Carnosine Content and Its Association with Carnosine-Related Gene Expression in Breast Meat of Thai Native and Black-Bone Chicken
Authors: Khumpeerawat Panuwat , Duangjinda Monchai , Phasuk Yupin
Published: July 2021

This study aimed to investigate the carnosine content and ATP-grasp domain-containing protein 1 (CARNS1) gene expression and their relationship with breast meat of Black Chinese (BC), KU-Phuparn (KP), Pradu Hang Dam (PD), and Black Chinese × Pradu Hang Dam (Sri Mok: SM) to aid in the selection and mating programs for developing functional meat in Thai chicken populations. The results show that the carnosine content in each breed and breed group varied from 428.08 to 553.93 mg/100 g, whereas the relative expression of CARNS1 ranged from 0.84 to 1.56. The BC and KP chicken breeds had a higher carnosine content (p < 0.01) and higher CARNS1 expression level (p < 0.05) than the SM and PD chicken breeds. The carnosine content and relative gene expression for each age ranged from 423.02 to 577.83 mg/100 g and 0.68 to 1.83, respectively. At 4 weeks of age, the carnosine content (p < 0.01) and gene expression (p < 0.05) were the highest. However, they decreased as chicken age increased further. The carnosine content and gene expression linearly decreased as chicken age increased (p < 0.01). The correlation coefficient between the level of gene expression and carnosine content was moderately positive. The results from this study showed that different breeds and ages of chickens have different amounts of carnosine, and CARNS1 could act as a biomarker to study marker-assisted selection to improve functional meat in the chicken population in Thailand.
The Influence of Instrumental Line Shape Degradation on Gas Retrievals and Observation of Greenhouse Gases in Maoming, China
Authors: Liu Dandan , Huang Yinbo , Cao Zhensong , Lu Xingji , Liu Xiangyuan
Published: July 2021

The instrument line shape (ILS), as a very important parameter, has a significant influence on the inversion of trace gas concentration. Different levels of ILS degradation for H2O, CO2, CH4, and CO gases were investigated, and the influence of ILS on the inversion of column-averaged dry air mole fractions (DMFs) was assessed. Our results indicate that the averages of XH2O, XCH4, and XCO with modulation efficiency (ME) amplitude values have a positive correlation, the correlation coefficients are 0.9925, 0.9968, and 0.9981 respectively, whereas the relationship between the average of XCO2 and ME is a negative correlation with 0.986 correlation coefficient. For a typical ILS degradation, a decrease of 5% in the modulation efficiency amplitude value results in the average of XCO2 changing by 0.744%, XCH4 and XH2O are less sensitive species, with average values of −0.206% and −0.464%, whereas XCO shows the strongest intraday variability with an average value of −0.238%. However, with a decrease of 2‰ in the phase error (PE) value, the average of XCO changed by −0.150%, XCO2 and XH2O almost coincided with the same average value of −0.141%, whereas XCH4 was the least sensitive species with an average value of −0.133%. At the same time, we measured the ILS for EM27/SUN spectrometers—the mean values of modulation efficiency amplitudes and phase errors were 0.9611 and 0.00593. Compared with standard values, the modulation efficiency amplitudes and the phase error deviations were 2.450% and 0.433%. During the observation period, the daily average of XCO2 ranged from 415.09 to 421.78 ppm. XCH4 ranged from 1.96 to 2.02 ppm with a mean of 1.982 ppm, and the daily average of XCO ranged from 0.118 to 0.157 ppm with a mean of 0.137 ppm. For the relationship between XCO2 and XCH4, the linear regression line shows a good correlation with the correlation coefficient R2 ≥ 0.5. Especially, for the correlation coefficient R2 = 0.82 on 8 October, our studies found a weak correlation in the variation of CO2 and CO during the observations. The correlation coefficient R2 ≥ 0.5 was only found on 30 September and 3 October. The trajectories dram at a height of 10 km give a hint of trace gas transport from the bay of western India, Bengal, and the Arabian Sea, whereas for the trajectories dram boundary layer height, trace gases were transported from southwest and east of China. These results provide a theoretical basis to understand the time and space distribution and the changes of greenhouse gas in the atmosphere as well as providing a theoretical basis for calculations of atmospheric radiation transmission.
New Hybrid Compounds Combining Fragments of Usnic Acid and Monoterpenoids for Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibition
Authors: Dyrkheeva Nadezhda S. , Filimonov Aleksandr S. , Luzina Olga A. , Zakharenko Alexandra L. , Ilina Ekaterina S. , Malakhova Anastasia A. , Medvedev Sergey P. , Reynisson Jóhannes , Volcho Konstantin P. , Zakian Suren M. , Salakhutdinov Nariman F. , Lavrik Olga I.
Published: July 2021

Usnic acid (UA) is a secondary metabolite of lichens that exhibits a wide range of biological activities. Previously, we found that UA derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1 (TDP1). It can remove covalent complex DNA-topoisomerase 1 (TOP1) stabilized by the TOP1 inhibitor topotecan, neutralizing the effect of the drugs. TDP1 removes damage at the 3′ end of DNA caused by other anticancer agents. Thus, TDP1 is a promising therapeutic target for the development of drug combinations with topotecan, as well as other drugs for cancer treatment. Ten new UA enamino derivatives with variation in the terpene fragment and substituent of the UA backbone were synthesized and tested as TDP1 inhibitors. Four compounds, 11a-d, had IC50 values in the 0.23–0.40 μM range. Molecular modelling showed that 11a-d, with relatively short aliphatic chains, fit to the important binding domains. The intrinsic cytotoxicity of 11a-d was tested on two human cell lines. The compounds had low cytotoxicity with CC50 ≥ 60 μM for both cell lines. 11a and 11c had high inhibition efficacy and low cytotoxicity, and they enhanced topotecan’s cytotoxicity in cancerous HeLa cells but reduced it in the non-cancerous HEK293A cells. This “protective” effect from topotecan on non-cancerous cells requires further investigation.
Stress Intensity Factor of Reinforced Concrete Beams in Bending
Authors: Nuguzhinov Zhmagul , Bakirov Zhetpisbay , Vatin Nikolai , Bakirov Madi , Kurokhtina Irina , Tokanov Daniyar , Khabidolda Omirkhan
Published: July 2021

The stress values at the crack tip in bending reinforced concrete beams are considered. The stress state is analytically determined with an initial and propagating crack. Equations of the equilibrium of a part of the beam cut along the crack line are compiled. These equations are reduced to a system of two nonlinear algebraic equations using the plane-sections hypothesis. The equations determine the stress zone’s height and the nominal stress at the crack tip for a beam with an initial crack and the crack length. The rest of the stress state parameters are expressed regarding the zone stress height and the nominal stress or crack length. The same equation system determines the external moment starting from which the crack length increases. The analytical method for determining the stress intensity factor (SIF) with an initial and growing crack in bent reinforced concrete beams is proposed. The method is based on the assumption that the size of the stress concentration zone at the crack tip is determined by the equality of the nominal and local stresses at the end of this zone. The method determines the value of the external moment starting from which the crack length increases. The stress zone’s size is determined by the coincidence of the local stress with the nominal stress. The same problem is solved in a three-dimensional formulation by the FE method, considering the stress field’s peculiarities at the crack tip. The calculation results coincide with the analytical solutions.
Haploinsufficiency Interactions between RALBP1 and p53 in ERBB2 and PyVT Models of Mouse Mammary Carcinogenesis
Authors: Singh Sharda P. , Lee Jihyun , Bose Chhanda , Li Hongzhi , Yuan Yate-Ching , Hindle Ashly , Singhal Sharad S. , Kopel Jonathan , Palade Philip T. , Jones Catherine , Rahman Rakhshanda L. , Awasthi Sanjay
Published: July 2021

We recently reported that loss of one or both alleles of Ralbp1, which encodes the stress-protective protein RLIP76 (Rlip), exerts a strong dominant negative effect on both the inherent cancer susceptibility and the chemically inducible cancer susceptibility of mice lacking one or both alleles of the tumor suppressor p53. In this paper, we examined whether congenital Rlip deficiency could prevent genetically-driven breast cancer in two transgenic mouse models: the MMTV-PyVT model, which expresses the polyomavirus middle T antigen (PyVT) under control of the mouse mammary tumor virus promoter (MMTV) and the MMTV-Erbb2 model which expresses MMTV-driven erythroblastic leukemia viral oncogene homolog 2 (Erbb2, HER2/Neu) and frequently acquires p53 mutations. We found that loss of either one or two Rlip alleles had a suppressive effect on carcinogenesis in Erbb2 over-expressing mice. Interestingly, Rlip deficiency did not affect tumor growth but significantly reduced the lung metastatic burden of breast cancer in the viral PyVT model, which does not depend on either Ras or loss of p53. Furthermore, spontaneous tumors of MMTV-PyVT/Rlip+/+ mice showed no regression following Rlip knockdown. Finally, mice lacking one or both Rlip alleles differentially expressed markers for apoptotic signaling, proliferation, angiogenesis, and cell cycling in PyVT and Erbb2 breast tumors. Our results support the efficacy of Rlip depletion in suppressing p53 inactivated cancers, and our findings may yield novel methods for prevention or treatment of cancer in patients with HER2 mutations or tumor HER2 expression.
Differential Regulation of Lacto-/Neolacto- Glycosphingolipid Biosynthesis Pathway Reveals Transcription Factors as Potential Candidates in Triple-Negative Breast Cancer
Authors: Zeng Ruichao , Mohamed Ahmed , Khanna Kum Kum , Hill Michelle M.
Published: July 2021

Triple-negative breast cancer (TNBC) is an aggressive breast cancer with limited treatment options. Glycosylation has been implicated in cancer development, but TNBC-specific glycosylation pathways have not been examined. Here, we applied bioinformatic analyses on public datasets to discover TNBC-specific glycogenes and pathways, as well as their upstream regulatory mechanisms. Unsupervised clustering of 345 glycogene expressions in breast cancer datasets revealed a relative homogenous expression pattern in basal-like TNBC subtype. Differential expression analyses of the 345 glycogenes between basal-like TNBC (hereafter termed TNBC) and other BC subtypes, or normal controls, revealed 84 differential glycogenes in TNBC. Pathway enrichment showed two common TNBC-enriched pathways across all three datasets, cell cycle and lacto-/neolacto- glycosphingolipid (GSL) biosynthesis, while a total of four glycosylation-related pathways were significantly enriched in TNBC. We applied a selection criterion of the top 50% differential anabolic/catabolic glycogenes in the enriched pathways to define 34 TNBC-specific glycogenes. The lacto-/neolacto- GSL biosynthesis pathway was the most highly enriched, with seven glycogenes all up-regulated in TNBC. This data led us to investigate the hypothesis that a common upstream mechanism in TNBC up-regulates the lacto-/neolacto-GSL biosynthesis pathway. Using public multi-omic datasets, we excluded the involvement of copy-number alteration and DNA methylation, but identified three transcription factors (AR, GATA3 and ZNG622) that each target three candidate genes in the lacto-/neolacto- GSL biosynthesis pathway. Interestingly, a subset of TNBC has been reported to express AR and GATA3, and AR antagonists are being trialed for TNBC. Our findings suggest that AR and GATA3 may contribute to TNBC via GSL regulation, and provide a list of candidate glycogenes for further investigation.
Organ-Specific, Fibroblast-Derived Matrix as a Tool for Studying Breast Cancer Metastasis
Authors: Jensen Adina R. D. , Horton Edward R. , Blicher Lene H. , Pietras Elin J. , Steinhauer Cornelia , Reuten Raphael , Schoof Erwin M. , Erler Janine T.
Published: July 2021

During the metastatic process, breast cancer cells must come into contact with the extra-cellular matrix (ECM) at every step. The ECM provides both structural support and biochemical cues, and cell–ECM interactions can lead to changes in drug response. Here, we used fibroblast-derived ECM (FDM) to perform high throughput drug screening of 4T1 breast cancer cells on metastatic organ ECM (lung), and we see that drug response differs from treatment on plastic. The FDMs that we can produce from different organs are abundant in and contains a complex mixture of ECM proteins. We also show differences in ECM composition between the primary site and secondary organ sites. Furthermore, we show that global kinase signalling of 4T1 cells on the ECM is relatively unchanged between organs, while changes in signalling compared to plastic are significant. Our study highlights the importance of context when testing drug response in vitro, showing that consideration of the ECM is critically important.
Colorectal Cancer Patients Have Four Specific Bacterial Species in Oral and Gut Microbiota in Common—A Metagenomic Comparison with Healthy Subjects
Authors: Uchino Yoshinori , Goto Yuichi , Konishi Yusuke , Tanabe Kan , Toda Hiroko , Wada Masumi , Kita Yoshiaki , Beppu Mahiro , Mori Shinichiro , Hijioka Hiroshi , Otsuka Takao , Natsugoe Shoji , Hara Eiji , Sugiura Tsuyoshi
Published: July 2021

Oral microbiota is reportedly associated with gut microbiota and influences colorectal cancer (CRC) progression; however, the details remain unclear. This study aimed to evaluate the role of oral microbiota in CRC progression. Fifty-two patients with CRC and 51 healthy controls were included. Saliva and stool samples were collected, and microbiota were evaluated using 16S rRNA analysis and next-generation sequencing. Comparative analysis was performed on both groups. Linear discriminant analysis effect size (LEfSe) revealed the presence of indigenous oral bacteria, such as Peptostreptococcus, Streptococcus, and Solobacterium spp., at a significantly higher relative abundance in saliva and stool samples of CRC patients compared with controls. Next, CRC patients were divided into early stage (Stage I, II; n = 26; 50%) and advanced stage (Stage III, IV; n = 26; 50%) disease. LEfSe revealed that S. moorei was present at a significantly higher relative abundance in the advanced-stage group compared with the early-stage group, again consistent for both saliva and stool samples. Among bacterial species with significantly higher relative abundance in CRC patients, P. stomatis, S. anginosus, S. koreensis, and S. moorei originated from the oral cavity, suggesting indigenous oral bacteria may have promoted initiation of CRC carcinogenesis. Furthermore, S. moorei may influence CRC progression.
The Analysis of Inflammation-Related Proteins in a Cargo of Exosomes Derived from the Serum of Uveal Melanoma Patients Reveals Potential Biomarkers of Disease Progression
Authors: Wróblewska Joanna Patrycja , Lach Michał Stefan , Kulcenty Katarzyna , Galus Łukasz , Suchorska Wiktoria Maria , Rösel Daniel , Brábek Jan , Marszałek Andrzej
Published: July 2021

Background: Uveal melanoma (UM) is the most common intraocular tumour in adults with a poor prognosis and extremely high mortality rate due to the development of metastatic disease. However, despite relatively good knowledge about the histological and genetic risk factors for metastasis development, there is no specific biomarker that would allow early detection of UM progression. Recently, exosomes and their molecular cargo have been widely studied in the search for potential biomarkers in several cancers. The purpose of this study was to analyze the inflammation-related protein cargo of exosomes derived from the serum of primary and metastatic UM patients and healthy donors. Methods: The exosomes were isolated from the serum of primary and metastatic UM patients and healthy donors. Using multiplex immunoassay technology, we analyzed the concentration of 37 inflammation-related proteins in obtained exosomes. Results: The analysis of protein cargo showed several molecules related to inflammation, such as interferon-gamma, interleukin 2, 22 and 12(p40), Pentraxin-3, TNFSF13B and TNFSF8 which were significantly enriched in metastatic UM exosomes. We showed a significant correlation between the disease stage and the concentration of these inflammation-related proteins from exosomal cargo. Conclusions: Based on the obtained results, we propose the panel of exosomal proteins for early detection of uveal melanoma progression into metastatic disease.
The Immune Microenvironment of Chordomas: An Immunohistochemical Analysis
Authors: Dridi Maroa , Krebs-Drouot Lila , Meyronet David , Dumollard Jean Marc , Vassal François , Jouanneau Emmanuel , Jacquesson Timothée , Barrey Cédric , Grange Sylvain , Boutonnat Jean , Péoc’h Michel , Karpathiou Georgia
Published: July 2021

Chordomas are rare sarcomas that are usually treated by surgery and/or radiotherapy since these are chemo-resistant tumors, but immunotherapy could be a possible option for chordoma patients. However, few reports investigating the composition of the chordoma immune microenvironment exist. We immunohistochemically studied 81 chordomas regarding their immune microenvironment factors and compared them with clinicopathological data. Macrophages and CD4 cells were the most prominent inflammatory cell populations, followed by CD8 T cells, while CD20 B cells and high endothelial venules (MECA-79+) were less frequently found. PD-L1 (22C3) expression by inflammatory cells was found in 21 (26%) tumors and was associated with a larger tumor size. None of the cases showed the expression of PD-L1 by tumor cells. Survival analysis showed that younger patients had a better overall survival. Considering the immunohistochemical factors studied, higher CD8, the presence of PD-L1+ immune cells, and higher vascular density were adverse prognostic factors, but in multivariate analysis, only PD-L1+ immune cells retained prognostic significance. To conclude, chordoma tumor cells do not express PD-L1, but PD-L1+ immune cells seem to play a negative prognostic role, supporting the need for further studies in this field and the possible beneficial role of immunotherapy in these patients.
ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins
Authors: Alcon Clara , Gómez Tejeda Zañudo Jorge Gómez Tejeda , Albert Reka , Wagle Nikhil , Scaltriti Maurizio , Letai Anthony , Samitier Josep , Montero Joan
Published: July 2021

Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.
NLRP3 Triggers Attenuate Lipocalin-2 Expression Independent with Inflammasome Activation
Authors: Ahn Huijeong , Lee Gilyoung , Kim Jeongeun , Park Jeongho , Kang Seung Goo , Yoon Sung-Il , Lee Eunsong , Lee Geun-Shik
Published: July 2021

Lipocalin-2 (LCN2), a small secretory glycoprotein, is upregulated by toll-like receptor (TLR) signaling in various cells and tissues. LCN2 inhibits bacterial growth by iron sequestration and regulates the innate immune system. Inflammasome activates the inflammatory caspases leading to pyroptosis and cytokine maturation. This study examined the effects of inflammasome activation on LCN2 secretion in response to TLR signaling. The triggers of NLRP3 inflammasome activation attenuated LCN2 secretion while it induced interleukin-1β in mouse macrophages. In mice, NLRP3 inflammasome activation inhibited TLR-mediated LCN2 secretion. The inhibition of NLRP3 triggers on LCN2 secretion was caused by the inhibited transcription and translation of LCN2. At the same time, no changes in the other cytokines and IκBζ, a well-known transcriptional factor of Lcn2 transcription, were observed. Overall, NLRP3 triggers are a regulator of LCN2 expression suggesting a new linkage of inflammasome activation and LCN2 secretion in the innate immunity.
Extensive Phenotype of Human Inflammatory Monocyte-Derived Dendritic Cells
Authors: Coutant Frédéric , Pin Jean-Jacques , Miossec Pierre
Published: July 2021

Inflammatory monocyte-derived dendritic cells (Mo-DCs) have been described in several chronic inflammatory disorders, such as rheumatoid arthritis (RA), and are suspected to play a detrimental role by fueling inflammation and skewing adaptive immune responses. However, the characterization of their phenotype is still limited, as well as the comprehension of the factors that govern their differentiation. Here, we show that inflammatory Mo-DCs generated in vitro expressed a large and atypical panel of C-type lectin receptors, including isoforms of CD209 and CD206, CD303 and CD207, as well as intracellular proteins at their surfaces such as the lysosomal protein CD208. Combination of these markers allowed us to identify cells in the synovial fluid of RA patients with a close phenotype of inflammatory Mo-DCs generated in vitro. Finally, we found in coculture experiments that RA synoviocytes critically affected the phenotypic differentiation of monocytes into Mo-DCs, suggesting that the crosstalk between infiltrating monocytes and local mesenchymal cells is decisive for Mo-DCs generation.