bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Experienced Thermoregulation in Depression—No Evidence for an Effect of Early Life Stress
Authors: von Salis Sarina , Ehlert Ulrike , Fischer Susanne
Published: July 2021

Objectives: Accumulating evidence suggests that individuals with depression are characterised by difficulties in thermoregulatory cooling. The aim of this study was to investigate, for the first time, whether depressed individuals are aware of these alterations, what their physical consequences are and whether they may be rooted in early life stress.

Methods: A total of N = 672 medically healthy individuals from the general population were recruited to participate in an online survey. Participants were divided into depressed vs. non-depressed using the Patient Health Questionnaire. Experienced autonomic and behavioural thermoregulation as well as vigilance problems in response to temperature increases were assessed by the Experienced Temperature Sensitivity and Regulation Survey. The Childhood Trauma Questionnaire was administered to assess early life stress.

Results: Controlling for age, sex, body mass index, and physical activity, depressed vs. non-depressed individuals did not differ in their experienced autonomic and behavioural responses to temperature increases. However, the depressed individuals reported comparably greater difficulties in concentrating and drowsiness/fatigue in warm environments (p = 0.029), during physical exertion (p = 0.029), and during stress (p < 0.001). There were no differences in the experienced thermoregulation between depressed individuals with vs. without early life stress.

Conclusions: Depressed individuals experienced more severe physical impairments (i.e., greater vigilance problems) in response to intense warmth when compared to non-depressed individuals. These differences were not attributable to comorbid illnesses, the intake of medication, or physical deconditioning. Further enquiries in clinical populations are warranted to investigate to what extent the observed alterations map onto specific symptoms of depression (e.g., sleep disturbances).
The Heterogeneity of Longitudinal Cognitive Decline in Euthymic Bipolar I Disorder With Clinical Characteristics and Functional Outcomes
Authors: Chen Wen-Yin , Huang Ming-Chyi , Lee Ya-Chin , Chang Chiao-Erh , Lin Shih-Ku , Chiu Chih Chiang , Liu Hsing-Cheng , Kuo Chian-Jue , Weng Shih-Han , Chen Po-Yu , Kuo Po-Hsiu
Published: July 2021

We characterized the heterogeneity and risk factors of cognitive decline in euthymic bipolar disorder (BD), and their magnitude of associations with subjective daily functions. In this retrospective cohort, BD type I patients (N = 128) were followed for an average of 6.5 years. Intelligence quotient (IQ) at index date was recorded, and premorbid IQ was estimated. We used Brief Assessment of Cognition in Affective Disorders (BAC-A) to assess cognition at follow-up. We evaluated current functions with World Health Organization Disability Assessment Schedule 2.0. Clinical and sociodemographic factors were examined for their independent effects on longitudinal cognitive decline. In addition, we employed multivariate adaptive regression spline to detect inflection points for the nature of slope changes in cognitive decline among BD patients. During follow-up years, 21 BD patients (16.4%) showed longitudinal cognitive decline. In cognitive decline group, all cognitive domains of BAC-A were significantly worsened. We found that density of episodes with psychotic features was an independent risk factor for cognitive decline after adjusted for age, gender and dose of mood stabilizer. After the age of 42 years, a steeper cognitive change was observed in the cognitive decline group. The correlation pattern between cognitive domains and functional outcomes differed between patients with and without cognitive decline. The present study characterized cognitive heterogeneity longitudinally in BD patients. As density of episodes play roles for cognitive decline, our results emphasize the importance of relapse prevention. Our findings provide hints for future personalized interventions and facilitating genetic and biological studies for dissecting the heterogeneity of bipolar illness.
Community Health Representative Workforce: Meeting the Moment in American Indian Health Equity
Authors: Sabo Samantha , O'Meara Louisa , Russell Kim , Hemstreet Corey , Nashio J. T. , Bender Brook , Hamilton Joyce , Begay Mae-Gilene
Published: July 2021

In 2018, the Community Health Representative (CHR) workforce celebrated their 50th year and serve as the oldest and only federally funded Community Health Worker (CHW) workforce in the United States. CHRs are a highly trained, well-established standardized workforce serving the medical and social needs of American Indian communities. Nationally, the CHR workforce consists of ~1,700 CHRs, representing 264 Tribes. Of the 22 Tribes of Arizona, 19 Tribes operate a CHR Program and employ ~250 CHRs, equivalent to ~30% of the total CHW workforce in the state. Since 2015, Tribal CHR Programs of Arizona have come together for annual CHR Policy Summits to dialogue and plan for the unique issues and opportunities facing CHR workforce sustainability and advancement. Overtime, the Policy Summits have resulted in the Arizona CHR Workforce Movement, which advocates for inclusion of CHRs in state and national level dialogue regarding workforce standardization, certification, training, supervision, and financing. This community case study describes the impetus, collaborative process, and selected results of a 2019–2020 multi-phase CHR workforce assessment. Specifically, we highlight CHR core roles and competencies, contributions to the social determinant of health and well-being and the level to which CHRs are integrated within systems and teams. We offer recommendations for strengthening the workforce, increasing awareness of CHR roles and competencies, integrating CHRs within teams and systems, and mechanism for sustainability.
Paricalcitol versus Calcitriol + Cinacalcet for the Treatment of Secondary Hyperparathyroidism in Chronic Kidney Disease in China: A Cost-Effectiveness Analysis
Authors: Zhang Zhuolin , Cai Lele , Wu Hong , Xu Xinglu , Fang Wenqing , He Xuan , Wang Xiao , Li Xin
Published: July 2021

Background: Chronic Kidney Disease (CKD) is a global chronic disease with increasing prevalence in recent years, particularly CKD accompanied by Secondary Hyperparathyroidism (SHPT) leads to reduced quality of life, increased mortality, a considerable economic burden for patients and society. The aim of this study was to investigate the cost-effectiveness analysis of paricalcitol vs. calcitriol + cinacalcet for CKD patients with SHPT in China in 2020.

Methods: A Markov model was conducted employing data derived from published literature, clinical trials, official sources, and tertiary public hospital data in China, based on a 10-year horizon from the perspective of the healthcare system. Calcitriol + Cinacalcet was used as the reference group. CKD stage 5 (CKD-5) dialysis patients suffering from SHPT were included in the study. Effectiveness was measured in quality-adjusted life years (QALYs). The discount rate (5%) was applied to costs and effectiveness. Sensitivity analysis was performed to confirm the robustness of the findings.

Results: The base case analysis demonstrated that Patients treated with paricalcitol could gain an increase in utility (0.183 QALYs) and require fewer expenditures (6925.612 yuan). One-way sensitivity analysis was performed to showed that impact factors were the price of cinacalcet, the hospitalization costs of patients with paricalcitol and calcitriol, the costs and utilities of hemodialysis and the costs of calcitriol, the costs of paricalcitol regardless of period. Probabilistic simulation analysis displayed when willingness-to-pay was ¥217113, the probability that Paricalcitol was dominant is 96.20%.

Conclusion: The results showed that paricalcitol administrated to treat patients diagnosed with Secondary hyperparathyroidism in Chronic Kidney Disease, compared to calcitriol and cinacalcet, might be dominant in China.
Reflections on Binary Sex/Gender Categorization in Magnetic Resonance Tomography and its Future Challenges
Authors: Fitsch Hannah
Published: July 2021

This paper examines the role of technical, methodological conditions in functional magnetic imaging (fMRI) in the production of binary sex/gender differences. The aim is to investigate the scanning process with a focus on the statistical parameter of gendered markers within the technology, in order to make visible the problems entangled in typical research routines. It is especially important to elaborate this because the computer models currently being used and Big Data studies are reproducing and reapplying outdated and rigid concepts of sex/gender differences with the goal of improving science considerably. Therefore, the paper discusses the empirical methodologies and epistemic underpinnings of differentiation through statistics, and argues that counter-counting, weighing and sizing might not help to substantiate the idea of “equality” (not only for the sex/gender category) in brain studies. In relation to the topic of this special issue, I argue that in order to develop an interdisciplinary approach to criticizing dimorphism and differentiation by groups, a wider understanding of the technical and theoretical foundations used in brain research is needed.
Allocating Students to Industry Placements Using Integer Programming and Ant Colony Optimisation
Authors: Thiruvady Dhananjay , Morgan Kerri , Bedingfield Susan , Nazari Asef
Published: July 2021

The increasing demand for work-ready students has heightened the need for universities to provide work integrated learning programs to enhance and reinforce students’ learning experiences. Students benefit most when placements meet their academic requirements and graduate aspirations. Businesses and community partners are more engaged when they are allocated students that meet their industry requirements. In this paper, both an integer programming model and an ant colony optimisation heuristic are proposed, with the aim of automating the allocation of students to industry placements. The emphasis is on maximising student engagement and industry partner satisfaction. As part of the objectives, these methods incorporate diversity in industry sectors for students undertaking multiple placements, gender equity across placement providers, and the provision for partners to rank student selections. The experimental analysis is in two parts: (a) we investigate how the integer programming model performs against manual allocations and (b) the scalability of the IP model is examined. The results show that the IP model easily outperforms the previous manual allocations. Additionally, an artificial dataset is generated which has similar properties to the original data but also includes greater numbers of students and placements to test the scalability of the algorithms. The results show that integer programming is the best option for problem instances consisting of less than 3000 students. When the problem becomes larger, significantly increasing the time required for an IP solution, ant colony optimisation provides a useful alternative as it is always able to find good feasible solutions within short time-frames.
Water Table Fluctuation and Methane Emission in Pineapples (Ananas comosus (L.) Merr.) Cultivated on a Tropical Peatland
Authors: Luta Wendy , Ahmed Osumanu Haruna , Omar Latifah , Heng Roland Kueh Jui , Choo Liza Nuriati Lim Kim , Jalloh Mohamadu Boyie , Musah Adiza Alhassan , Abdu Arifin
Published: July 2021

Inappropriate drainage and agricultural development on tropical peatland may lead to an increase in methane (CH4) emission, thus expediting the rate of global warming and climate change. It was hypothesized that water table fluctuation affects CH4 emission in pineapple cultivation on tropical peat soils. The objectives of this study were to: (i) quantify CH4 emission from a tropical peat soil cultivated with pineapple and (ii) determine the effects of water table depth on CH4 emission from a peat soil under simulated water table fluctuation. Soil CH4 emissions from an open field pineapple cultivation system and field lysimeters were determined using the closed chamber method. High-density polyethylene field lysimeters were set up to simulate the natural condition of cultivated drained peat soils under different water table fluctuations. The soil CH4 flux was measured at five time intervals to obtain a 24 h CH4 emission in the dry and wet seasons during low- and high-water tables. Soil CH4 emissions from open field pineapple cultivation were significantly lower compared with field lysimeters under simulated water table fluctuation. Soil CH4 emissions throughout the dry and wet seasons irrespective of water table fluctuation were not affected by soil temperature but emissions were influenced by the balance between methanogenic and methanotrophic microorganisms controlling CH4 production and consumption, CH4 transportation through molecular diffusion via peat pore spaces, and non-microbial CH4 production in peat soils. Findings from the study suggest that water table fluctuation at the soil–water interface relatively controls the soil CH4 emission from lysimeters under simulated low- and high-water table fluctuation. The findings of this study provide an understanding of the effects of water table fluctuation on CH4 emission in a tropical peatland cultivated with pineapple.
Morphological Characterization of Southern Jalisco, Mexico, Pomegranate Genotypes Using AFLP Markers
Authors: Tapia-Campos Ernesto , del Pilar Ramírez-Anaya Jessica , Cavazos-Garduño Adriana , Serrano-Niño Julio C. , Fragoso-Jiménez Javier Cuauhtémoc , Castañeda-Saucedo Ma. Claudia
Published: July 2021

Pomegranate is gaining popularity because of its proved nutraceutical properties and is highly adaptable to different climates. In southern Jalisco, Mexico, 18 genotypes were characterized on the basis of fruit characteristics (21 traits) and AFLP (Amplified Fragment length polymorphism) markers. The first three components of a principal components analysis (PCA) explained 71.5% of the variation. The most important variables were related to fruit size and weight. Fruit weight, equatorial diameter, polar diameter, and rind and membrane weight were the variables that most contributed to principal component one (PC1) 46.4%. The variables juice per fruit, edible proportion, proportion of rind and membrane, and seed length contributed most to principal component two (PC2) 15.2%, while juice pH, weight of one seed, and aril width contributed the most to principal component three (PC3) 9.9%. With the six combinations of AFLP primers, 315 fragments were obtained (an average of 52.5 fragments per primer); of these, 229 were polymorphic (72.7% polymorphism). Grouping by both morphological traits and AFLP markers separated all the evaluated individuals so that there were no repeated genotypes. In both analyses, the grouping did not obey geographic origin of the genotypes (r = −0.35), suggesting that both techniques were useful and complementary in the characterization of pomegranate genotypes. The commercial cultivars Wonderful and Apaseo had low levels of similarity to genotypes from southern Jalisco. The level of polymorphism found and compared with the results obtained by other authors suggests that the pomegranate genotypes evaluated are highly polymorphic. We found broad genetic diversity that can be used in breeding programs.
Softening of Processed Plant Virus Infected Cucumis sativus L. Fruits
Authors: Kersten Anne-Katrin , Scharf Sabrina , Bandte Martina , Martin Peer , Meurer Peter , Lentzsch Peter , Büttner Carmen
Published: July 2021

Texture softening of pickled cucumbers does not meet consumers’ quality expectations and leads to economic losses. The factor(s) triggering this phenomenon is still unknown. We investigated the importance of plant viruses such as Cucumber green mottle mosaic tobamovirus (CGMMV) and Zucchini yellow mosaic potyvirus (ZYMV) in the context of softening of pickles. Cucumber plants (Cucumis sativus) were infected by mechanical inoculation, grown under greenhouse conditions and tested positive for the viral infection by ELISA. The severity of virus infection was reflected in yield and symptom expression. Histological and morphological alterations were observed. All fruits were pasteurized, separately stored in jars and subjected to texture measurements after four, six and 12 months. CGMMV-infections were asymptomatic or caused mild symptoms on leaves and fruit, and texture quality was comparable to control. At the same time, fruits of ZYMV-infected plants showed severe symptoms like deformations and discoloration, as well as a reduction in firmness and crunchiness after pasteurization. In addition, histological alterations were detected in such fruits, possibly causing textural changes. We conclude that plant viruses could have a considerable influence on the firmness and crunchiness of pickled cucumbers after pasteurization. It is possible that the severity of symptom expression has an influence on texture properties.
Optimizing Sowing Date and Planting Density Can Mitigate the Impacts of Future Climate on Maize Yield: A Case Study in the Guanzhong Plain of China
Authors: Xu Fang , Wang Bin , He Chuan , Liu De Li , Feng Puyu , Yao Ning , Zhang Renhe , Xu Shutu , Xue Jiquan , Feng Hao , Yu Qiang , He Jianqiang
Published: July 2021

We used the APSIM-Maize model to simulate maize potential yield (Yp) and rain-fed yield (Yw) when adaptation options of sowing date and planting density were adopted under Representative Concentration Pathway (RCP) 4.5 and 8.5 in the Guanzhong Plain of China. The results showed that Yp would decrease by 10.6–14.9% and 15.0–31.4% under RCP4.5 and RCP8.5 for summer maize, and 13.9–19.7% and 18.5–36.3% for spring maize, respectively. The Yw would decrease by 17.1–19.0% and 23.6–41.1% under RCP4.5 and RCP8.5 for summer maize, and 20.9–24.5% and 27.8–45.5% for spring maize, respectively. The loss of Yp and Yw could be reduced by 2.6–9.7% and 0–9.9%, respectively, under future climate for summer maize through countermeasures. For spring maize, the loss of Yp was mitigated by 14.0–25.0% and 2.0–21.8% for Yw. The contribution of changing sowing date and plant density on spring maize yield was more than summer maize, and the optimal adaptation options were more effective for spring maize. Additionally, the influences of changing sowing date and planting density on yields become weak as climate changes become more severe. Therefore, it is important to investigate the potential of other adaptation measures to cope with climate change in the Guanzhong Plain of China.
Evidence of Another Anthropic Impact on Iguana delicatissima from the Lesser Antilles: The Presence of Antibiotic Resistant Enterobacteria
Authors: Di Lallo Gustavo , D’Andrea Marco Maria , Sennati Samanta , Thaller Maria Cristina , Migliore Luciana , Gentile Gabriele
Published: July 2021

The improper use of antibiotics by humans may promote the dissemination of resistance in wildlife. The persistence and spread of acquired antibiotic resistance and human-associated bacteria in the environment, while representing a threat to wildlife, can also be exploited as a tool to monitor the extent of human impact, particularly on endangered animal species. Hence, we investigated both the associated enterobacterial species and the presence of acquired resistance traits in the cloacal microbiota of the critically endangered lesser Antillean iguana (Iguana delicatissima), by comparing two separate populations living in similar climatic conditions but exposed to different anthropic pressures. A combination of techniques, including direct plating, DNA sequencing and antimicrobial susceptibility testing allowed us to characterize the dominant enterobacterial populations, the antibiotic resistant strains and their profiles. A higher frequency of Escherichia coli was found in the samples from the more anthropized site, where multi-drug resistant strains were also isolated. These results confirm how human-associated bacteria as well as their antibiotic-resistance determinants may be transferred to wildlife, which, in turn, may act as a reservoir of antibiotic resistance.
Impact of Dental Model Height on Thermoformed PET-G Aligner Thickness—An In Vitro Micro-CT Study
Authors: Ihssen Benjamin Alexander , Kerberger Robert , Rauch Nicole , Drescher Dieter , Becker Kathrin
Published: July 2021

The aim of the present study was to investigate whether base height of 3D-printed dental models has an impact on local thickness values from polyethylene terephthalate glycol (PET-G) aligners. A total of 20 aligners were thermoformed on dental models from the upper jaw exhibiting either a 5 mm high (H) or narrow (N), i.e., 0 mm, base height. The aligners were digitized using micro-CT, segmented, and local thickness values were computed utilizing a 3D-distance transform. The mean thickness values and standard deviations were assessed for both groups, and local thickness values at pre-defined reference points were also recorded. The statistical analysis was performed using R. Aligners in group H were significantly thinner and more homogenous compared to group N (p < 0.001). Significant differences in thickness values were observed among tooth types between both groups. Whereas thickness values were comparable at cusp tips and occlusal/incisal/cervical measurement locations, facial and palatal surfaces were significantly thicker in group N compared to group H (p < 0.01). Within the limits of the study, the base height of 3D-printed models impacts on local thickness values of thermoformed aligners. The clinician should consider potential implication on exerted forces at the different tooth types, and at facial as well as palatal surfaces.
Lateral Resistance Requirement of Girder-Sleeper Fastener for CWR Track on an Open-Deck Steel Plate Girder Bridge
Authors: Lee Hyeoung-Deok , Choi Sanghyun , Moon Jiho
Published: July 2021

For an open-deck steel plate girder railway bridge with rail joints, frequent damage to the bridge members and a high level of noise and vibration occur. By installing continuous welded rail (CWR) to the bridge, it is possible to reduce the noise and impact force of the bridge. However, current girder–sleeper fasteners have low lateral resistance in nature and track buckling can occur when CWR is used on such a bridge. Therefore, a new girder-sleeper fastener with proper lateral resistance to prevent CWR track buckling is needed. In this study, the lateral resistance requirements of a girder-sleeper fastener are investigated through a series of finite element (FE) analyses and parametric study. The effect of peak lateral resistance of the fastener, curve radius, girder length, and lateral displacement of girder are examined. From the analysis results, the peak lateral resistance criterion of the girder–sleeper fastener is proposed for the design of a new fastener for CWR tracks on an open-deck steel plate girder bridge.
Takeover Safety Analysis with Driver Monitoring Systems and Driver–Vehicle Interfaces in Highly Automated Vehicles
Authors: Yu Dongyeon , Park Chanho , Choi Hoseung , Kim Donggyu , Hwang Sung-Ho
Published: July 2021

According to SAE J3016, autonomous driving can be divided into six levels, and partially automated driving is possible from level three up. A partially or highly automated vehicle can encounter situations involving total system failure. Here, we studied a strategy for safe takeover in such situations. A human-in-the-loop simulator, driver–vehicle interface, and driver monitoring system were developed, and takeover experiments were performed using various driving scenarios and realistic autonomous driving situations. The experiments allowed us to draw the following conclusions. The visual–auditory–haptic complex alarm effectively delivered warnings and had a clear correlation with the user’s subjective preferences. There were scenario types in which the system had to immediately enter minimum risk maneuvers or emergency maneuvers without requesting takeover. Lastly, the risk of accidents can be reduced by the driver monitoring system that prevents the driver from being completely immersed in non-driving-related tasks. We proposed a safe takeover strategy from these results, which provides meaningful guidance for the development of autonomous vehicles. Considering the subjective questionnaire evaluations of users, it is expected to improve the acceptance of autonomous vehicles and increase the adoption of autonomous vehicles.
Explainable Deep-Learning-Based Path Loss Prediction from Path Profiles in Urban Environments
Authors: Juang Rong-Terng
Published: July 2021

This paper applies a deep learning approach to model the mechanism of path loss based on the path profile in urban propagation environments for 5G cellular communication systems. The proposed method combines the log-distance path loss model for line-of-sight propagation scenarios and a deep-learning-based model for non-line-of-sight cases. Simulation results show that the proposed path loss model outperforms the conventional models when operating in the 3.5 GHz frequency band. The standard deviation of prediction error was reduced by 34% when compared to the conventional models. To explain the internal behavior of the proposed deep-learning-based model, which is a black box in nature, eight relevant features were selected to model the path loss based on a linear regression approach. Simulation results show that the accuracy of the explanatory model reached 72% when it was used to explain the proposed deep learning model. Furthermore, the proposed deep learning model was also evaluated in a non-standalone 5G New Radio network in the urban environment of Taipei City. The real-world measurements show that the standard deviation of prediction error can be reduced by 30–43% when compared to the conventional models. In addition, the transparency of the proposed deep learning model reached 63% in the realistic 5G network.
Semi-Supervised Time Series Anomaly Detection Based on Statistics and Deep Learning
Authors: Jiang Jehn-Ruey , Kao Jian-Bin , Li Yu-Lin
Published: July 2021

Thanks to the advance of novel technologies, such as sensors and Internet of Things (IoT) technologies, big amounts of data are continuously gathered over time, resulting in a variety of time series. A semi-supervised anomaly detection framework, called Tri-CAD, for univariate time series is proposed in this paper. Based on the Pearson product-moment correlation coefficient and Dickey–Fuller test, time series are first categorized into three classes: (i) periodic, (ii) stationary, and (iii) non-periodic and non-stationary time series. Afterwards, different mechanisms using statistics, wavelet transform, and deep learning autoencoder concepts are applied to different classes of time series for detecting anomalies. The performance of the proposed Tri-CAD framework is evaluated by experiments using three Numenta anomaly benchmark (NAB) datasets. The performance of Tri-CAD is compared with those of related methods, such as STL, SARIMA, LSTM, LSTM with STL, and ADSaS. The comparison results show that Tri-CAD outperforms the others in terms of the precision, recall, and F1-score.
Cybersecurity and Privacy Risk Assessment of Point-of-Care Systems in Healthcare—A Use Case Approach
Authors: Jofre Marc , Navarro-Llobet Diana , Agulló Ramon , Puig Jordi , Gonzalez-Granadillo Gustavo , Mora Zamorano Juan , Romeu Ramon
Published: July 2021

Point-of-care systems are generally used in healthcare to respond rapidly and prevent critical health conditions. Hence, POC systems often handle personal health information; and consequently, their cybersecurity and privacy requirements are of crucial importance. While, assessing these requirements is a significant task. In this work, we propose a use case approach to assess specifications of cybersecurity and privacy requirements of POC systems in a structured and self-contained form. Such an approach is appropriate since use cases are one of the most common means adopted by developers to derive requirements. As a result, we detail a use case approach in the framework of a real-based healthcare IT infrastructure that includes a health information system, integration engines, application servers, web services, medical devices, smartphone apps and medical modalities (all data simulated) together with the interaction with participants. Since our use case also sustains the analysis of cybersecurity and privacy risks in different threat scenarios, it also supports decision making and the analysis of compliance considerations.
Influential Factors and Evaluation Methods of the Performance of Grouted Semi-Flexible Pavement (GSP)—A Review
Authors: Guo Xiaogang , Hao Peiwen
Published: July 2021

Grouted Semi-flexible Pavement (GSP) is a novel pavement composed of open-graded asphalt concrete grouted with high-fluidity cement mortar. Due to its excellent load-bearing and anti-rutting performance, it has great potential as anti-rutting overlay and surface in road construction. However, the understanding of GSP performance remains limited and pertinent findings are inconsistent. This article aims to provide a systematic literature review for the articles which were published between 2000 and 2020 on GSP, explore the problems in the recent research, identify knowledge gaps, and deliver recommendations for future research. The influential factors and the relative evaluation methods of GSP performance are summarized and discussed in this article.
Microbiological Aerosol, Particulate Matter Concentrations and Antibiotic Resistant Staphylococcus spp. in the Premises of Poland’s Oldest Agricultural School
Authors: Lenart-Boroń Anna , Drab Dagmara , Chrobak Justyna
Published: July 2021

Bioaerosol, particulate matter concentration and antibiotic resistance of airborne Staphylococcus was assessed in animal and public premises (classroom, sports hall, horse stable, cowshed, newborn calf shed and outdoor background control site) of Poland’s oldest agricultural school. The concentration and size distribution of bacteria, fungi, actinomycetes and staphylococci were assessed with a six stage Andersen impactor. Particulate matter (PM10, PM4, PM2.5 and PM1) was determined using the DustTrak aerosol monitor. The Staphylococcus species were determined with MALDI-TOF mass spectrometry and antimicrobial resistance was assessed using disk diffusion. Bioaerosol concentrations differed significantly between sampling points, with the highest levels of all microorganisms occurring in the newborn calf shed. The proportion of respirable fraction exceeded 60% in all sites, indicating potential harmfulness to exposed people. Mean concentrations of particulate matter were the smallest in school rooms and the highest in the newborn calf shed. Neither particulate matter nor microbial aerosol exceeded threshold values for workplaces. Among thirty-four isolated staphylococcal strains, S. equorum (35%), S. succinus (26%) and S. xylosus (15%) were the most prevalent. Resistance to macrolides (erythromycin) and lincosamides (clindamycin) was the most frequent. One strain was methicillin-resistant. Farm animals are significant sources of bioaerosol and therefore attention should be paid with respect to maintaining appropriate sanitary conditions and hygiene of premises and animals.
Gauss–Newton–Secant Method for Solving Nonlinear Least Squares Problems under Generalized Lipschitz Conditions
Authors: Argyros Ioannis K. , Shakhno Stepan , Iakymchuk Roman , Yarmola Halyna , Argyros Michael I.
Published: July 2021

We develop a local convergence of an iterative method for solving nonlinear least squares problems with operator decomposition under the classical and generalized Lipschitz conditions. We consider the case of both zero and nonzero residuals and determine their convergence orders. We use two types of Lipschitz conditions (center and restricted region conditions) to study the convergence of the method. Moreover, we obtain a larger radius of convergence and tighter error estimates than in previous works. Hence, we extend the applicability of this method under the same computational effort.
The Role of Glucose Transporters in Oral Squamous Cell Carcinoma
Authors: Botha Heinrich , Farah Camile S. , Koo Kendrick , Cirillo Nicola , McCullough Michael , Paolini Rita , Celentano Antonio
Published: July 2021

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy associated with a poor prognosis. The Warburg effect can be observed in OSCCs, with tumours requiring a robust glucose supply. Glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) are overexpressed in multiple malignancies, and are correlated with treatment resistance, clinical factors, and poor overall survival (OS). We conducted a systematic review to evaluate the differences in GLUT/SGLT expression between OSCC and normal oral keratinocytes (NOK), as well as their role in the pathophysiology and prognosis of OSCC. A total of 85 studies were included after screening 781 papers. GLUT-1 is regularly expressed in OSCC and was found to be overexpressed in comparison to NOK, with high expression correlated to tumour stage, treatment resistance, and poor prognosis. No clear association was found between GLUT-1 and tumour grade, metastasis, and fluorodeoxyglucose (FDG) uptake. GLUT-3 was less thoroughly studied but could be detected in most samples and is generally overexpressed compared to NOK. GLUT-3 negatively correlated with overall survival (OS), but there was insufficient data for correlations with other clinical factors. Expression of GLUT-2/GLUT-4/GLUT-8/GLUT-13/SGLT-1/SGLT-2 was only evaluated in a small number of studies with no significant differences detected. GLUTs 7 and 14 have never been evaluated in OSCC. In conclusion, the data demonstrates that GLUT-1 and GLUT-3 have a role in the pathophysiology of OSCC and represent valuable biomarkers to aid OSCC diagnosis and prognostication. Other GLUTs are comparatively understudied and should be further analysed because they may hold promise to improve patient care.
MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development
Authors: Divisato Giuseppina , Piscitelli Silvia , Elia Mariantonietta , Cascone Emanuela , Parisi Silvia
Published: July 2021

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.
Polycationic Monomeric and Homodimeric Asymmetric Monomethine Cyanine Dyes with Hydroxypropyl Functionality—Strong Affinity Nucleic Acids Binders
Authors: Mikulin Ivana , Ljubić Ivana , Piantanida Ivo , Vasilev Aleksey , Mondeshki Mihail , Kandinska Meglena , Uzelac Lidija , Martin-Kleiner Irena , Kralj Marijeta , Tumir Lidija-Marija
Published: July 2021

New analogs of the commercial asymmetric monomethine cyanine dyes thiazole orange (TO) and thiazole orange homodimer (TOTO) with hydroxypropyl functionality were synthesized and their properties in the presence of different nucleic acids were studied. The novel compounds showed strong, micromolar and submicromolar affinities to all examined DNA ds-polynucleotides and poly rA–poly rU. The compounds studied showed selectivity towards GC-DNA base pairs over AT-DNA, which included both binding affinity and a strong fluorescence response. CD titrations showed aggregation along the polynucleotide with well-defined supramolecular chirality. The single dipyridinium-bridged dimer showed intercalation at low dye-DNA/RNA ratios. All new cyanine dyes showed potent micromolar antiproliferative activity against cancer cell lines, making them promising theranostic agents.
Development and Characterization of a Novel Peptide—Drug Conjugate with DM1 for Treatment of FGFR2-Positive Tumors
Authors: Wang Yayu , Li Yadan , Cao Jieqiong , Meng Qilin , Li Xiaocen , Zhang Yibo , Lam Kit S. , Hong An , Liu Ruiwu , Chen Xiaojia
Published: July 2021

A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide–drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 °C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide–drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B–DM1 can be developed into a potential PDC for tumor treatment in the future.
Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance
Authors: Babak Maria V. , Ahn Dohyun
Published: July 2021

Copper (Cu) is a vital element required for cellular growth and development; however, even slight changes in its homeostasis might lead to severe toxicity and deleterious medical conditions. Cancer patients are typically associated with higher Cu content in serum and tumor tissues, indicating increased demand of cancer cells for this micronutrient. Cu is known to readily cycle between the +1 and +2 oxidation state in biological systems. The mechanism of action of Cu complexes is typically based on their redox activity and induction of reactive oxygen species (ROS), leading to deadly oxidative stress. However, there are a number of other biomolecular mechanisms beyond ROS generation that contribute to the activity of anticancer Cu drug candidates. In this review, we discuss how interfering with intracellular Cu balance via either diet modification or addition of inorganic Cu supplements or Cu-modulating compounds affects tumor development, progression, and sensitivity to treatment modalities. We aim to provide the rationale for the use of Cu-depleting and Cu-overloading conditions to generate the best possible patient outcome with minimal toxicity. We also discuss the advantages of the use of pre-formed Cu complexes, such as Cu-(bis)thiosemicarbazones or Cu-N-heterocyclic thiosemicarbazones, in comparison with the in situ formed Cu complexes with metal-binding ligands. In this review, we summarize available clinical and mechanistic data on clinically relevant anticancer drug candidates, including Cu supplements, Cu chelators, Cu ionophores, and Cu complexes.
Post-Treatment with Amorfrutin B Evokes PPARγ-Mediated Neuroprotection against Hypoxia and Ischemia
Authors: Wnuk Agnieszka , Przepiórska Karolina , Pietrzak Bernadeta A. , Kajta Małgorzata
Published: July 2021

In this study, we demonstrate for the first time that amorfrutin B, a selective modulator of peroxisome proliferator-activated receptor gamma—PPARγ, can protect brain neurons from hypoxia- and ischemia-induced degeneration when applied at 6 h post-treatment in primary cultures. The neuroprotective effect of amorfrutin B suggests that it promotes mitochondrial integrity and is capable of inhibiting reactive oxygen species—ROS activity and ROS-mediated DNA damage. PPARγ antagonist and Pparg mRNA silencing abolished the neuroprotective effect of amorfrutin B, which points to agonistic action of the compound on the respective receptor. Interestingly, amorfrutin B stimulated the methylation of the Pparg gene, both during hypoxia and ischemia. Amorfrutin B also increased the protein level of PPARγ during hypoxia but decreased the mRNA and protein levels of PPARγ during ischemia. Under ischemic conditions, amorfrutin B-evoked hypermethylation of the Pparg gene is in line with the decrease in the mRNA and protein expression of PPARγ. However, under hypoxic conditions, amorfrutin B-dependent hypermethylation of the Pparg gene does not explain the amorfrutin B-dependent increase in receptor protein expression, which suggests other regulatory mechanisms. Other epigenetic parameters, such as HAT and/or sirtuins activities, were affected by amorfrutin B under hypoxic and ischemic conditions. These properties position the compound among the most promising anti-stroke and wide-window therapeutics.
Role of Vitamin D in the Clinical Course of Nasal Polyposis
Authors: Murdaca Giuseppe , Paladin Francesca , Gangemi Sebastiano
Published: July 2021

Vitamin D is a lipo-soluble hormone well known for its effects on calcium homeostasis and bone metabolism. Recently, there has been growing interest in the extraskeletal effects of vitamin D. In particular, recent studies have highlighted how vitamin D plays a fundamental role in immunomodulation processes in the context of both innate and adaptive immunity, with consequent anti-inflammatory and anti-oxidant effect in different immune-mediated pathologies, such as systemic sclerosis, psoriasis, atopic dermatitis and rheumatoid arthritis; as well as in various pro-inflammatory processes affecting the airways, including chronic rhinosinusitis with (CRSwNP) or without (CRSsNP) nasal polyposis. We analyze the role of vitamin D in the genesis and progression of CRSwNP/sNP and its supplementation as a safe and valid therapeutic strategy capable of improving the clinical outcome of standard therapies.
The Bladder Microbiome Is Associated with Epithelial–Mesenchymal Transition in Muscle Invasive Urothelial Bladder Carcinoma
Authors: Li Wei Tse , Iyangar Anjali S. , Reddy Rohan , Chakladar Jaideep , Bhargava Valmik , Sakamoto Kyoko , Ongkeko Weg M. , Rajasekaran Mahadevan
Published: July 2021

The intra-tumor microbiome has recently been linked to epithelial–mesenchymal transition (EMT) in a number of cancers. However, the relationship between EMT and microbes in bladder cancer has not been explored. In this study, we profiled the abundance of individual microbe species in the tumor samples of over 400 muscle invasive bladder carcinoma (MIBC) patients. We then correlated microbe abundance to the expression of EMT-associated genes and genes in the extracellular matrix (ECM), which are key players in EMT. We discovered that a variety of microbes, including E. coli, butyrate-producing bacterium SM4/1, and a species of Oscillatoria, were associated with expression of classical EMT-associated genes, including E-cadherin, vimentin, SNAI2, SNAI3, and TWIST1. We also found significant correlations between microbial abundance and the expression of genes in the ECM, specifically collagens and elastin. Lastly, we found that a large number of microbes exhibiting significant correlations to EMT are also associated with clinical prognosis and outcomes. We further determined that the microbes we profiled were likely not environmental contaminants. In conclusion, we discovered that the intra-tumoral microbiome could potentially play a significant role in the regulation of EMT in MIBC.
BRCA2 Promotes Spontaneous Homologous Recombination In Vivo
Authors: Brown Adam D. , Greenman Scott , Claybon Alison B. , Bishop Alexander J. R.
Published: July 2021

Background: BRCA2 is known to be a tumor suppressor involved in homologous recombination repair and presumed to prevent genome instability in normal tissues prior to the development of tumors. Typical assessment of BRCA2 deficiency on the genome involves cell-based models using cancer cells with mixed genetic contexts, but the role in normal tissue in vivo has not been clearly demonstrated. Methods: Using conditional deletion of Brca2 exon 11, the region containing all eight BRC repeats, in the retinal pigment epithelium and the pink-eyed unstable mouse model, we evaluate the frequency of DNA deletion events. Results: In the current study, we show that conditional loss of Brca2 exon 11 results in a decreased frequency of spontaneous homologous recombination compared to wild-type mice. Of note, we observe no apparent concomitant increase in events that indicate single-strand annealing by the pink-eyed unstable mouse model. Conclusions: Therefore, our results demonstrate that BRCA2, as expected, is required for high-fidelity homologous recombination DNA repair in normal tissues, here in a tissue undergoing normal proliferation through normal development.
Human Papillomavirus Same Genotype Persistence and Risk of Cervical Intraepithelial Neoplasia2+ Recurrence
Authors: Iacobone Anna Daniela , Radice Davide , Sandri Maria Teresa , Preti Eleonora Petra , Guerrieri Maria Elena , Vidal Urbinati Ailyn Mariela , Pino Ida , Franchi Dorella , Passerini Rita , Bottari Fabio
Published: July 2021

To evaluate the significance of HPV persistence as a predictor for the development of CIN2+ recurrence and the impact of multiple genotypes and of HPV 16/18 on recurrence risk. A prospective cohort observational study was carried out at the European Institute of Oncology, Milan, Italy, from December 2006 to December 2014. A total of 408 women surgically treated by excisional procedure for pre-neoplastic and neoplastic cervical lesions were enrolled. HPV test was performed at baseline and at first follow-up visit planned at 6 ± 3 months after treatment. Two-year cumulative incidences for relapse were estimated and compared by the Gray’s test. Overall, 96 (23.5%) patients were persistent for at least one genotype at three to nine months from baseline and 21 (5.1%) patients relapsed. The two-year cumulative relapse incidence was higher in HPV persistent patients compared to not-persistent (CIF = 27.6%, 95% CI: 16.2–40.2% versus CIF = 1.7%, 95% CI: 0.3–5.8%, p < 0.001), in women with persistent multiple infections (CIF = 27.2%, 95% CI: 7.3–52.3%, p < 0.001), and with the persistence of at least one genotype between 16 and 18, irrespective of the presence of other HR genotypes (CIF = 32.7%, 95% CI: 17.9–48.3%, p < 0.001), but not significantly different from women positive for single infections or any other HR genotype, but not for 16 and 18. The risk of CIN2+ recurrence should not be underestimated when same HPV genotype infection persists after treatment.