bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Acceleration a Valid Proxy for Injury Risk in Minimal Damage Traffic Crashes? A Comparative Review of Volunteer, ADL and Real-World Studies
Authors: Nolet Paul S. , Nordhoff Larry , Kristman Vicki L. , Croft Arthur C. , Zeegers Maurice P. , Freeman Michael D.
Published: March 2021

Injury claims associated with minimal damage rear impact traffic crashes are often defended using a “biomechanical approach,” in which the occupant forces of the crash are compared to the forces of activities of daily living (ADLs), resulting in the conclusion that the risk of injury from the crash is the same as for ADLs. The purpose of the present investigation is to evaluate the scientific validity of the central operating premise of the biomechanical approach to injury causation; that occupant acceleration is a scientifically valid proxy for injury risk. Data were abstracted, pooled, and compared from three categories of published literature: (1) volunteer rear impact crash testing studies, (2) ADL studies, and (3) observational studies of real-world rear impacts. We compared the occupant accelerations of minimal or no damage (i.e., 3 to 11 kph speed change or “delta V”) rear impact crash tests to the accelerations described in 6 of the most commonly reported ADLs in the reviewed studies. As a final step, the injury risk observed in real world crashes was compared to the results of the pooled crash test and ADL analyses, controlling for delta V. The results of the analyses indicated that average peak linear and angular acceleration forces observed at the head during rear impact crash tests were typically at least several times greater than average forces observed during ADLs. In contrast, the injury risk of real-world minimal damage rear impact crashes was estimated to be at least 2000 times greater than for any ADL. The results of our analysis indicate that the principle underlying the biomechanical injury causation approach, that occupant acceleration is a proxy for injury risk, is scientifically invalid. The biomechanical approach to injury causation in minimal damage crashes invariably results in the vast underestimation of the actual risk of such crashes, and should be discontinued as it is a scientifically invalid practice.
Application of Fast Non-Local Means Algorithm for Noise Reduction Using Separable Color Channels in Light Microscopy Images
Authors: Kang Seong-Hyeon , Kim Ji-Youn
Published: March 2021

The purpose of this study is to evaluate the various control parameters of a modeled fast non-local means (FNLM) noise reduction algorithm which can separate color channels in light microscopy (LM) images. To achieve this objective, the tendency of image characteristics with changes in parameters, such as smoothing factors and kernel and search window sizes for the FNLM algorithm, was analyzed. To quantitatively assess image characteristics, the coefficient of variation (COV), blind/referenceless image spatial quality evaluator (BRISQUE), and natural image quality evaluator (NIQE) were employed. When high smoothing factors and large search window sizes were applied, excellent COV and unsatisfactory BRISQUE and NIQE results were obtained. In addition, all three evaluation parameters improved as the kernel size increased. However, the kernel and search window sizes of the FNLM algorithm were shown to be dependent on the image processing time (time resolution). In conclusion, this work has demonstrated that the FNLM algorithm can effectively reduce noise in LM images, and parameter optimization is important to achieve the algorithm’s appropriate application.
Analysis of the New Kuznets Relationship: Considering Emissions of Carbon, Methanol, and Nitrous Oxide Greenhouse Gases—Evidence from EU Countries
Authors: Madaleno Mara , Moutinho Victor
Published: March 2021

Decreased greenhouse gas emissions (GHG) are urgently needed in view of global health threat represented by climate change. The goal of this paper is to test the validity of the Environmental Kuznets Curve (EKC) hypothesis, considering less common measures of environmental burden. For that, four different estimations are done, one considering total GHG emissions, and three more taking into account, individually, the three main GHG gases—carbon dioxide (CO2), nitrous oxide (N2O), and methane gas (CH4)—considering the oldest and most recent economies adhering to the EU27 (the EU 15 (Old Europe) and the EU 12 (New Europe)) separately. Using panel dynamic fixed effects (DFE), dynamic ordinary least squares (DOLS), and fully modified ordinary least squares (FMOLS) techniques, we validate the existence of a U-shaped relationship for all emission proxies considered, and groups of countries in the short-run. Some evidence of this effect also exists in the long-run. However, we were only able to validate the EKC hypothesis for the short-run in EU 12 under DOLS and the short and long-run using FMOLS. Confirmed is the fact that results are sensitive to models and measures adopted. Externalization of problems globally takes a longer period for national policies to correct, turning global measures harder and local environmental proxies more suitable to deeply explore the EKC hypothesis.
The Association between Blood Pressure Trajectories and Risk of Cardiovascular Diseases among Non-Hypertensive Chinese Population: A Population-Based Cohort Study
Authors: Li Fang , Lin Qian , Li Mingshu , Chen Lizhang , Li Yingjun
Published: March 2021

Although previous studies have discussed the association between trajectories of blood pressure (BP) and risk of cardiovascular diseases (CVDs), the association among the non-hypertensive general population of youth and middle age has not been elucidated. We used the growth mixture model to explore the trajectories of BP among the non-hypertensive Chinese population and applied Cox regression to evaluate the association between trajectories of BP and the risk of stroke or myocardial infarction (MI). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were categorized into three classes, respectively. Statistically significant associations were observed between SBP trajectories and stroke (range of adjusted hazard ratios (aHR): 1.369–3.837) or MI (rang of aHR = 6.047–13.017). Association between DBP trajectories and stroke (aHR: 3.685) or MI (range of aHR = 1.312–2.821) were also observed, although they did not reach statistical significance. Trajectories of SBP were more important risk factors than that of DBP in stroke and MI in our study population. BP management is important among pre-hypertensive adults to prevent stroke and MI when they age. Well-designed research with a larger sample size is required to confirm our findings and develop efficient methods to prevent CVDs.
Linking Perceived Policy Effectiveness and Proenvironmental Behavior: The Influence of Attitude, Implementation Intention, and Knowledge
Authors: Wang Huilin , Li Jiaxuan , Mangmeechai Aweewan , Su Jiafu
Published: March 2021

Residents’ behavior is the result of the combined effect of external environment factors and internal psychological factors. Based on the theory of planned behavior (TPB) and the attitude–behavior–condition (ABC) theory, this study aims to explore the impact of policy support on residents’ psychological factors and proenvironmental behavior. This study developed an extended TPB and ABC model and replaced the behavioral intention in the TPB model with implementation intentions to enhance the ability of the variables to explain and predict proenvironmental behavior. The longitudinal research method was adopted to collect data through a two-stage questionnaire survey of 1145 Shanghai residents. Results demonstrated that perceived policy effectiveness has a significant and positive impact on attitude, implementation intention, and proenvironmental behavior. This means that proenvironmental behavior tends to appear in people with a high perception of policy effectiveness, positive attitude, and strong implementation intention. Moreover, this study points out for the first time that high waste management knowledge weakens the relationship between perceived policy effectiveness and attitude. For residents with high waste management knowledge, the effect of simple policy publicity is limited. The findings suggest that the government should increase the breadth and depth of policy support and policy publicity to cover the entire waste management process.
Influences of Ketogenic Diet on Body Fat Percentage, Respiratory Exchange Rate, and Total Cholesterol in Athletes: A Systematic Review and Meta-Analysis
Authors: Lee Hyun Suk , Lee Junga
Published: March 2021

(1) Background: The purpose of the current meta-analysis was to investigate any positive or negative effects of ketogenic diets in athletes and provide an assessment of the size of these effects. (2) Methods: Databases were used to select relevant studies up to January 2021 regarding the effects of ketogenic diets in athletes. Inclusion criteria were as follows: data before and after ketogenic diet use, being randomized controlled trials and presenting ketogenic diets and assessments of ketone status. Study subjects were required to be professional athletes. Review studies, pilot studies, and studies in which non-athletes were included were excluded from this meta-analysis. The outcome effect sizes in these selected studies were calculated by using the standardized mean difference statistic. (3) Results: Eight studies were selected for this meta-analysis. Athletes who consumed the ketogenic diet had reduced body fat percentages, respiratory exchange rates, and increased total cholesterol compared to athletes who did not consume this diet. However, body mass index, cardiorespiratory fitness, heart rate, HDL cholesterol, glucose level, and insulin level were unaffected by the diet. (4) Conclusions: Ketogenic diets had a beneficial effect by decreasing body fat percentage, but athletes with high total cholesterol level need to be monitored when instituting a ketogenic diet. Our study sample size was limited; therefore, additional studies may be needed to confirm the current findings. Further studies need to be conducted on changes in LDL cholesterol, HDL cholesterol, total cholesterol and ratio of LDL to HDL cholesterol.
A Data Augmentation-Based Evaluation System for Regional Direct Economic Losses of Storm Surge Disasters
Authors: Sun Hai , Wang Jin , Ye Wentao
Published: March 2021

The accurate prediction of storm surge disasters’ direct economic losses plays a positive role in providing critical support for disaster prevention decision-making and management. Previous researches on storm surge disaster loss assessment did not pay much attention to the overfitting phenomenon caused by the data scarcity and the excessive model complexity. To solve these problems, this paper puts forward a new evaluation system for forecasting the regional direct economic loss of storm surge disasters, consisting of three parts. First of all, a comprehensive assessment index system was established by considering the storm surge disasters’ formation mechanism and the corresponding risk management theory. Secondly, a novel data augmentation technique, k-nearest neighbor-Gaussian noise (KNN-GN), was presented to overcome data scarcity. Thirdly, an ensemble learning algorithm XGBoost as a regression model was utilized to optimize the results and produce the final forecasting results. To verify the best-combined model, KNN-GN-based XGBoost, we conducted cross-contrast experiments with several data augmentation techniques and some widely-used ensemble learning models. Meanwhile, the traditional prediction models are used as baselines to the optimized forecasting system. The experimental results show that the KNN-GN-based XGBoost model provides more precise predictions than the traditional models, with a 64.1% average improvement in the mean absolute percentage error (MAPE) measurement. It could be noted that the proposed evaluation system can be extended and applied to the geography-related field as well.
Racial and Ethnic Disparities in Years of Potential Life Lost Attributable to COVID-19 in the United States: An Analysis of 45 States and the District of Columbia
Authors: Xu Jay J. , Chen Jarvis T. , Belin Thomas R. , Brookmeyer Ronald S. , Suchard Marc A. , Ramirez Christina M.
Published: March 2021

The coronavirus disease 2019 (COVID-19) epidemic in the United States has disproportionately impacted communities of color across the country. Focusing on COVID-19-attributable mortality, we expand upon a national comparative analysis of years of potential life lost (YPLL) attributable to COVID-19 by race/ethnicity (Bassett et al., 2020), estimating percentages of total YPLL for non-Hispanic Whites, non-Hispanic Blacks, Hispanics, non-Hispanic Asians, and non-Hispanic American Indian or Alaska Natives, contrasting them with their respective percent population shares, as well as age-adjusted YPLL rate ratios—anchoring comparisons to non-Hispanic Whites—in each of 45 states and the District of Columbia using data from the National Center for Health Statistics as of 30 December 2020. Using a novel Monte Carlo simulation procedure to perform estimation, our results reveal substantial racial/ethnic disparities in COVID-19-attributable YPLL across states, with a prevailing pattern of non-Hispanic Blacks and Hispanics experiencing disproportionately high and non-Hispanic Whites experiencing disproportionately low COVID-19-attributable YPLL. Furthermore, estimated disparities are generally more pronounced when measuring mortality in terms of YPLL compared to death counts, reflecting the greater intensity of the disparities at younger ages. We also find substantial state-to-state variability in the magnitudes of the estimated racial/ethnic disparities, suggesting that they are driven in large part by social determinants of health whose degree of association with race/ethnicity varies by state.
Media Reports about Violence against Medical Care Providers in China
Authors: Tan Liheng , Yuan Shujuan , Cheng Peixia , Ning Peishan , Gao Yuyan , Xiao Wangxin , Schwebel David C. , Hu Guoqing
Published: March 2021

Improper, unprofessional, or misleading media reports about violence against medical care providers (typically doctors and nurses) may provoke copycat incidents. To examine whether media reports about violence against medical care providers in China follow professional journalism recommendations, we identified 10 influential incidents of violence against medical care providers in China through a systematic strategy and used standardized internet-based search techniques to retrieve media reports about these events from 2007–2017. Reports were evaluated independently by trained coders to assess adherence to professional journalism recommendations using a 14-item checklist. In total, 788 eligible media reports were considered. Of those, 50.5% and 47.3%, respectively, failed to mention the real and complete names of the writer and editor. Reports improperly mentioned specific details about the time, place, methods, and perpetrators of violence in 42.1%, 36.4%, 45.4%, and 54.6% of cases, respectively. Over 80% of reports excluded a suggestion to seek help from professional agencies or mediation by a third party and only 3.8% of reports mentioned the perspectives of all three key informants about an event: medical care providers, patients, and hospital administrators. Of those that mentioned medical care providers, patient, and/or hospital administrator perspectives, less than 20% indicated they had obtained the interviewee’s consent to include their perspective. We concluded that most reports about violence against medical care providers in the Chinese media failed to strictly follow reporting recommendations from authoritative media bodies. Efforts are recommended to improve adherence to professional guidelines in media reports about violence against medical care providers in China, as adherence to those guidelines is likely to reduce future violent events against medical care providers like doctors and nurses.
The Independent Role of Body Mass Index (BMI) and Severity of Depressive Symptoms on Biological Changes of Women Affected by Overweight/Obesity
Authors: Iodice Simona , Ceresa Alessandro , Esposito Cecilia , Mucci Francesco , Conti Diana , Pergoli Laura , Tarantini Letizia , Vigna Luisella , Bollati Valentina , Buoli Massimiliano , Serati Marta ,   Stand-Up Project Group
Published: March 2021

Background: Both obesity and depression are medical conditions associated with severe disability and biological abnormalities. Our aim was to study associations between Body Mass Index (BMI), depression and biological changes in women affected by overweight or obesity. Methods: Depressive symptoms were evaluated by the Beck Depression Inventory II (BDI-II) questionnaire in 200 women affected by overweight/obesity (mean age of the sample 52.7 ± 12.9 years, BMI 33.8 ± 5.5 kg/m2). A blood sample was obtained for evaluation of biochemical (oxytocin and vitamin D), inflammatory and epigenetic (methylation of clock genes) parameters. Multivariable linear regression models were used to study the association between BMI or severity of depressive symptoms (BDI-II scores) with different biomarkers. Results: BMI was found to be associated with severity of depressive symptoms (p = 0.050). Severity of obesity resulted to be associated with lower plasma levels of oxytocin (p = 0.053), vitamin D deficiency (p = 0.006) and higher plasma levels of IFN-γ (p = 0.004), IL-6 (p = 0.013), IL-7 (p = 0.013), TNF-alpha (p = 0.036) and chemokine ligand 3 (CCL3) (p = 0.013, R2 = 0.03). Severity of depression was significantly associated with more methylation of clock genes CRY1 (p = 0.034, R2 = 0.16) and CRY2 (p = 0.019, R2 = 0.47). More severe depression together with higher levels of IL-8 strongly predicted lower methylation of CLOCK gene (p = 0.009); Conclusions: Different biological abnormalities have been found to be independently associated with BMI and severity of depressive symptoms in women affected by overweight/obesity. The complex interplay between overweight, depression and biological changes will have to be better clarified by future studies.
Telerehabilitation Intervention in Patients with COVID-19 after Hospital Discharge to Improve Functional Capacity and Quality of Life. Study Protocol for a Multicenter Randomized Clinical Trial
Authors: Pastora-Bernal José-Manuel , Estebanez-Pérez María-José , Molina-Torres Guadalupe , García-López Francisco-José , Sobrino-Sánchez Raquel , Martín-Valero Rocío
Published: March 2021

COVID-19 can cause important sequels in the respiratory system and frequently presents loss of strength, dyspnea, polyneuropathies and multi-organic affectation. Physiotherapy interventions acquire a fundamental role in the recovery of the functions and the quality of life. Regarding the recovery phases after hospital discharge, the current evidence available is very preliminary. Telerehabilitation is presented as a promising complementary treatment method to standard physiotherapy. The main objective of this research is to evaluate the effectiveness of a personalized telerehabilitation intervention after discharge from hospital for the improvement of functional capacity and quality of life compared to a program of health education and/or care in a rehabilitation center. As secondary objectives, to identify the satisfaction and perception of patients with the telerehabilitation intervention and the presence of barriers to its implementation, as well as to evaluate the cost-effectiveness from the perspective of the health system. This study protocol will be carried out through a single blind multicenter randomized clinical trial in the south of Spain. We hypothesize that the implementation of a telerehabilitation program presents results not inferior to those obtained with the current standard intervention. If the hypothesis is confirmed, it would be an opportunity to define new policies and interventions to address this disease and its consequences. Trial registration NCT04742946.
Primary Care Networks and Starfield’s 4Cs: A Case for Enhanced Chronic Disease Management
Authors: Foo Chuan De , Surendran Shilpa , Jimenez Geronimo , Ansah John Pastor , Matchar David Bruce , Koh Gerald Choon Huat
Published: March 2021

The primary care network (PCN) was implemented as a healthcare delivery model which organises private general practitioners (GPs) into groups and furnished with a certain level of resources for chronic disease management. A secondary qualitative analysis was conducted with data from an earlier study exploring facilitators and barriers GPs enrolled in PCN’s face in chronic disease management. The objective of this study is to map features of PCN to Starfield’s “4Cs” framework. The “4Cs” of primary care—comprehensiveness, first contact access, coordination and continuity—offer high-quality design options for chronic disease management. Interview transcripts of GPs (n = 30) from the original study were purposefully selected. Provision of ancillary services, manpower, a chronic disease registry and extended operating hours of GP practices demonstrated PCN’s empowering features that fulfil the “4Cs”. On the contrary, operational challenges such as the lack of an integrated electronic medical record and disproportionate GP payment structures limit PCNs from maximising the “4Cs”. However, the enabling features mentioned above outweighs the shortfalls in all important aspects of delivering optimal chronic disease care. Therefore, even though PCN is in its early stage of development, it has shown to be well poised to steer GPs towards enhanced chronic disease management.
A Review of Digital Cognitive Behavioral Therapy for Insomnia (CBT-I Apps): Are They Designed for Engagement?
Authors: Erten Uyumaz Begum , Feijs Loe , Hu Jun
Published: March 2021

There are different ways to deliver Cognitive Behavioral Therapy for Insomnia (CBT-I), of which in-person (face to face) is the traditional delivery method. However, the scalability of in-person therapy is low. Digital Cognitive Behavioral Therapy for Insomnia (dCBT-I) is an alternative and there are tools on the market that are validated in clinical studies. In this paper, we provide a review of the existing evidence-based CBT-I apps and a summary of the published usability-oriented studies of these apps. The goal is to explore the range of interaction methods commonly applied in dCBT-I platforms, the potential impact for the users, and the design elements applied to achieve engagement. Six commercially available CBT-I apps tested by scientifically valid methods were accessed and reviewed. Commonalities were identified and categorized into interactive elements, CBT-I-related components, managerial features, and supportive motivational features. The dCBT-I apps were effectively assisting the users, and the type of interactions promoted engagement. The apps’ features were based on design principles from interactive product design, experience design, online social media, and serious gaming. This study contributes to the field by providing a critical summary of the existing dCBT-I apps that could guide future developers in the field to achieve a high engagement.
Association between Physical Frailty Subdomains and Oral Frailty in Community-Dwelling Older Adults
Authors: Komatsu Ryo , Nagai Koutatsu , Hasegawa Yoko , Okuda Kazuki , Okinaka Yuto , Wada Yosuke , Tsuji Shotaro , Tamaki Kayoko , Kusunoki Hiroshi , Kishimoto Hiromitsu , Shinmura Ken
Published: March 2021

This cross-sectional study aimed to demonstrate the association between physical frailty subdomains and oral frailty. This study involved community-dwelling older adults (aged ≥65 years). Physical frailty was assessed with the Japanese version of the Cardiovascular Health Study criteria. Oral frailty was defined as limitations in at least three of six domains. Logistic regression analysis was used to analyze the association between physical frailty risk and oral frailty. In addition, we examined the association between physical frailty subdomains (gait speed, grip strength, exhaustion, low physical activity, and weight loss) and oral frailty. A total of 380 participants were recruited for this study. Overall, 18% and 14% of the participants were at risk of physical frailty and had oral frailty, respectively. Physical frailty risk (odds ratio (OR) = 2.40, 95% confidence interval (CI): 1.22–4.75, p = 0.012) was associated with oral frailty in multivariate analysis. In secondary analysis, among physical frailty subdomains, gait speed (OR = 0.85, 95% CI: 0.73–0.97, p = 0.019) was associated with oral frailty. The present findings suggest that physical frailty is closely related to oral frailty. Among physical frailty subdomains, decreased gait speed in particular is an important indicator related to the development of oral frailty.
Seasonal Changes in 25(OH)D Concentration in Young Soccer Players—Implication for Bone Resorption Markers and Physical Performance
Authors: Jastrzębska Joanna , Skalska Maria , Radzimiński Łukasz , Niewiadomska Agnieszka , Myśliwiec Artur , López-Sánchez Guillermo F. , Brzeziański Michał , Rosemann Thomas , Knechtle Beat
Published: March 2021

Searching for potential relations between changes in 25(OH)D concentration and in physical fitness is an interesting scientific topic. Thus, the main purpose of this study was to investigate the changes in serum concentrations of 25(OH)D in young football players in conjunction with indicators determining bone resorption and physical fitness. A total of 35 young soccer players were tested during the autumn competition period. Biochemical analysis of blood, aerobic capacity, running speed and power tests (Wingate test, squat jump, counter movement jump) were carried out at the beginning and at the end of the competition period. Significant decrements in concentration of 25(OH)D from 33.9 ± 5.87 to 23.7 ± 5.58 ng/mL were noted after the analyzed competition period. There were no significant changes in aerobic capacity along the competition period. Significant improvements were observed in 10 m sprint, 30 m sprint (p < 0.001), maximal power (p = 0.011) and total work capacity (p = 0.024). We found that the effect of changes in the players’ physical fitness does not occur in relation to 25 OH(D) concentration but occurs when these changes are analyzed as a function of the duration of the observation period. Changes in physical fitness of soccer players are determined by other factors then 25(OH)D concentration.
Chronic Oral Selegiline Treatment Mitigates Age-Related Hearing Loss in BALB/c Mice
Authors: Szepesy Judit , Humli Viktória , Farkas János , Miklya Ildikó , Tímár Júlia , Tábi Tamás , Gáborján Anita , Polony Gábor , Szirmai Ágnes , Tamás László , Köles László , Vizi Elek Sylvester , Zelles Tibor
Published: March 2021

Age-related hearing loss (ARHL), a sensorineural hearing loss of multifactorial origin, increases its prevalence in aging societies. Besides hearing aids and cochlear implants, there is no FDA approved efficient pharmacotherapy to either cure or prevent ARHL. We hypothesized that selegiline, an antiparkinsonian drug, could be a promising candidate for the treatment due to its complex neuroprotective, antioxidant, antiapoptotic, and dopaminergic neurotransmission enhancing effects. We monitored by repeated Auditory Brainstem Response (ABR) measurements the effect of chronic per os selegiline administration on the hearing function in BALB/c and DBA/2J mice, which strains exhibit moderate and rapid progressive high frequency hearing loss, respectively. The treatments were started at 1 month of age and lasted until almost a year and 5 months of age, respectively. In BALB/c mice, 4 mg/kg selegiline significantly mitigated the progression of ARHL at higher frequencies. Used in a wide dose range (0.15–45 mg/kg), selegiline had no effect in DBA/2J mice. Our results suggest that selegiline can partially preserve the hearing in certain forms of ARHL by alleviating its development. It might also be otoprotective in other mammals or humans.
Structural and Functional Characterization of the ABCC6 Transporter in Hepatic Cells: Role on PXE, Cancer Therapy and Drug Resistance
Authors: Bisaccia Faustino , Koshal Prashant , Abruzzese Vittorio , Castiglione Morelli Maria Antonietta , Ostuni Angela
Published: March 2021

Pseudoxanthoma elasticum (PXE) is a complex autosomal recessive disease caused by mutations of ABCC6 transporter and characterized by ectopic mineralization of soft connective tissues. Compared to the other ABC transporters, very few studies are available to explain the structural components and working of a full ABCC6 transporter, which may provide some idea about its physiological role in humans. Some studies suggest that mutations of ABCC6 in the liver lead to a decrease in some circulating factor and indicate that PXE is a metabolic disease. It has been reported that ABCC6 mediates the efflux of ATP, which is hydrolyzed in PPi and AMP; in the extracellular milieu, PPi gives potent anti-mineralization effect, whereas AMP is hydrolyzed to Pi and adenosine which affects some cellular properties by modulating the purinergic pathway. Structural and functional studies have demonstrated that silencing or inhibition of ABCC6 with probenecid changed the expression of several genes and proteins such as NT5E and TNAP, as well as Lamin, and CDK1, which are involved in cell motility and cell cycle. Furthermore, a change in cytoskeleton rearrangement and decreased motility of HepG2 cells makes ABCC6 a potential target for anti-cancer therapy. Collectively, these findings suggested that ABCC6 transporter performs functions that modify both the external and internal compartments of the cells.
The Potential of Nail Mini-Organ Stem Cells in Skin, Nail and Digit Tips Regeneration
Authors: Pulawska-Czub Anna , Pieczonka Tomasz D. , Mazurek Paula , Kobielak Krzysztof
Published: March 2021

Nails are highly keratinized skin appendages that exhibit continuous growth under physiological conditions and full regeneration upon removal. These mini-organs are maintained by two autonomous populations of skin stem cells. The fast-cycling, highly proliferative stem cells of the nail matrix (nail stem cells (NSCs)) predominantly replenish the nail plate. Furthermore, the slow-cycling population of the nail proximal fold (nail proximal fold stem cells (NPFSCs)) displays bifunctional properties by contributing to the peri-nail epidermis under the normal homeostasis and the nail structure upon injury. Here, we discuss nail mini-organ stem cells’ location and their role in skin and nail homeostasis and regeneration, emphasizing their importance to orchestrate the whole digit tip regeneration. Such endogenous regeneration capabilities are observed in rodents and primates. However, they are limited to the region adjacent to the nail’s proximal area, indicating the crucial role of nail mini-organ stem cells in digit restoration. Further, we explore the molecular characteristics of nail mini-organ stem cells and the critical role of the bone morphogenetic protein (BMP) and Wnt signaling pathways in homeostatic nail growth and digit restoration. Finally, we investigate the latest accomplishments in stimulating regenerative responses in regeneration-incompetent injuries. These pioneer results might open up new opportunities to overcome amputated mammalian digits and limbs’ regenerative failures in the future.
Therapeutic Potentials of Low-Dose Tacrolimus for Aberrant Endometrial Features in Polycystic Ovary Syndrome
Authors: Albaghdadi Ahmad J. H. , Kan Frederick W. K.
Published: March 2021

Polycystic ovary syndrome (PCOS) is a major anovulatory infertility affecting a great proportion of women of childbearing age and is associated with obesity, insulin resistance and chronic inflammation. Poor endometrial receptivity and recurrent implantation failure are major hurdles to the establishment of pregnancy in women with PCOS. The accumulating body of evidence obtained from experimental and clinical studies suggests a link between inherent adaptive and innate immune irregularities and aberrant endometrial features in PCOS. The use of conventional therapeutic interventions such as lifestyle modification, metformin and ovarian stimulation has achieved limited clinical success in restoring ovulation and endometrial receptivity in women with PCOS. Unlike other immunosuppressive drugs prescribed in the clinical management of autoimmune and inflammatory disorders that may have deleterious effects on fertility and fetal development, preclinical studies in mice and in women without PCOS but with repeated implantation failure revealed potential therapeutic benefits for the use of low-dose tacrolimus in treating female infertility. Improved systemic and ovarian immune functions, endometrial progesterone receptor and coreceptor expressions and uterine vascular adaptation to pregnancy were among features of enhanced progesterone-receptor sensitivity in the low-dose tacrolimus-treated mouse model of the disease. In this review, we have compiled available experimental and clinical data in literature on endometrial progesterone resistance and current therapeutic options, as well as mechanisms of actions and reported outcomes relevant to the potential therapeutic benefits for the use of low-dose tacrolimus in treating PCOS-associated female infertility.
Characterization of Extracellular Vesicles from Preconditioned Human Adipose-Derived Stromal/Stem Cells
Authors: Geßner Alec , Koch Benjamin , Klann Kevin , Fuhrmann Dominik C. , Farmand Samira , Schubert Ralf , Münch Christian , Geiger Helmut , Baer Patrick C.
Published: March 2021

Cell-free therapy using extracellular vesicles (EVs) from adipose-derived mesenchymal stromal/stem cells (ASCs) seems to be a safe and effective therapeutic option to support tissue and organ regeneration. The application of EVs requires particles with a maximum regenerative capability and hypoxic culture conditions as an in vitro preconditioning regimen has been shown to alter the molecular composition of released EVs. Nevertheless, the EV cargo after hypoxic preconditioning has not yet been comprehensively examined. The aim of the present study was the characterization of EVs from hypoxic preconditioned ASCs. We investigated the EV proteome and their effects on renal tubular epithelial cells in vitro. While no effect of hypoxia was observed on the number of released EVs and their protein content, the cargo of the proteins was altered. Proteomic analysis showed 41 increased or decreased proteins, 11 in a statistically significant manner. Furthermore, the uptake of EVs in epithelial cells and a positive effect on oxidative stress in vitro were observed. In conclusion, culture of ASCs under hypoxic conditions was demonstrated to be a promising in vitro preconditioning regimen, which alters the protein cargo and increases the anti-oxidative potential of EVs. These properties may provide new potential therapeutic options for regenerative medicine.
Remapping of Adult-Born Neuron Activity during Fear Memory Consolidation in Mice
Authors: Vergara Pablo , Kumar Deependra , Srinivasan Sakthivel , Koyanagi Iyo , Naoi Toshie , Singh Sima , Sakaguchi Masanori
Published: March 2021

The mammalian hippocampal dentate gyrus is a unique memory circuit in which a subset of neurons is continuously generated throughout the lifespan. Previous studies have shown that the dentate gyrus neuronal population can hold fear memory traces (i.e., engrams) and that adult-born neurons (ABNs) support this process. However, it is unclear whether ABNs themselves hold fear memory traces. Therefore, we analyzed ABN activity at a population level across a fear conditioning paradigm. We found that fear learning did not recruit a distinct ABN population. In sharp contrast, a completely different ABN population was recruited during fear memory retrieval. We further provide evidence that ABN population activity remaps over time during the consolidation period. These results suggest that ABNs support the establishment of a fear memory trace in a different manner to directly holding the memory. Moreover, this activity remapping process in ABNs may support the segregation of memories formed at different times. These results provide new insight into the role of adult neurogenesis in the mammalian memory system.
Cannabinoid Receptors Overexpression in a Rat Model of Irritable Bowel Syndrome (IBS) after Treatment with a Ketogenic Diet
Authors: Gigante Isabella , Tutino Valeria , Russo Francesco , De Nunzio Valentina , Coletta Sergio , Armentano Raffaele , Crovace Alberto , Caruso Maria Gabriella , Orlando Antonella , Notarnicola Maria
Published: March 2021

The administration of a ketogenic diet (KD) has been considered therapeutic in subjects with irritable bowel syndrome (IBS). This study aimed to investigate the molecular mechanisms by which a low-carbohydrate diet, such as KD, can improve gastrointestinal symptoms and functions in an animal model of IBS by evaluating possible changes in intestinal tissue expression of endocannabinoid receptors. In rats fed a KD, we detected a significant restoration of cell damage to the intestinal crypt base, a histological feature of IBS condition, and upregulation of CB1 and CB2 receptors. The diet also affected glucose metabolism and intestinal membrane permeability, with an overexpression of the glucose transporter GLUT1 and tight junction proteins in treated rats. The present data suggest that CB receptors represent one of the molecular pathways through which the KD works and support possible cannabinoid-mediated protection at the intestinal level in the IBS rats after dietary treatment.
PACAP-38 in Acute ST-Segment Elevation Myocardial Infarction in Humans and Pigs: A Translational Study
Authors: Szabo Dora , Sarszegi Zsolt , Polgar Beata , Saghy Eva , Nemeth Adam , Reglodi Dora , Makkos Andras , Gorbe Aniko , Helyes Zsuzsanna , Ferdinandy Peter , Herczeg Robert , Gyenesei Attila , Cziraki Attila , Tamas Andrea
Published: March 2021

Acute myocardial infarction (MI) is one of the most common causes of death worldwide. Pituitary adenylate cyclase activating polypeptide (PACAP) is a cardioprotective neuropeptide expressing its receptors in the cardiovascular system. The aim of our study was to examine tissue PACAP-38 in a translational porcine MI model and plasma PACAP-38 levels in patients with ST-segment elevation myocardial infarction (STEMI). Significantly lower PACAP-38 levels were detected in the non-ischemic region of the left ventricle (LV) in MI heart compared to the ischemic region of MI-LV and also to the Sham-operated LV in porcine MI model. In STEMI patients, plasma PACAP-38 level was significantly higher before percutaneous coronary intervention (PCI) compared to controls, and decreased after PCI. Significant negative correlation was found between plasma PACAP-38 and troponin levels. Furthermore, a significant effect was revealed between plasma PACAP-38, hypertension and HbA1c levels. This was the first study showing significant changes in cardiac tissue PACAP levels in a porcine MI model and plasma PACAP levels in STEMI patients. These results suggest that PACAP, due to its cardioprotective effects, may play a regulatory role in MI and could be a potential biomarker or drug target in MI.
The Role of Rigid Residues in Modulating TEM-1 β-Lactamase Function and Thermostability
Authors: Kolbaba-Kartchner Bethany , Kazan I. Can , Mills Jeremy H. , Ozkan S. Banu
Published: March 2021

The relationship between protein motions (i.e., dynamics) and enzymatic function has begun to be explored in β-lactamases as a way to advance our understanding of these proteins. In a recent study, we analyzed the dynamic profiles of TEM-1 (a ubiquitous class A β-lactamase) and several ancestrally reconstructed homologues. A chief finding of this work was that rigid residues that were allosterically coupled to the active site appeared to have profound effects on enzyme function, even when separated from the active site by many angstroms. In the present work, our aim was to further explore the implications of protein dynamics on β-lactamase function by altering the dynamic profile of TEM-1 using computational protein design methods. The Rosetta software suite was used to mutate amino acids surrounding either rigid residues that are highly coupled to the active site or to flexible residues with no apparent communication with the active site. Experimental characterization of ten designed proteins indicated that alteration of residues surrounding rigid, highly coupled residues, substantially affected both enzymatic activity and stability; in contrast, native-like activities and stabilities were maintained when flexible, uncoupled residues, were targeted. Our results provide additional insight into the structure-function relationship present in the TEM family of β-lactamases. Furthermore, the integration of computational protein design methods with analyses of protein dynamics represents a general approach that could be used to extend our understanding of the relationship between dynamics and function in other enzyme classes.
Physical Exercise and Alzheimer’s Disease: Effects on Pathophysiological Molecular Pathways of the Disease
Authors: López-Ortiz Susana , Pinto-Fraga Jose , Valenzuela Pedro L. , Martín-Hernández Juan , Seisdedos María M. , García-López Oscar , Toschi Nicola , Di Giuliano Francesca , Garaci Francesco , Mercuri Nicola Biagio , Nisticò Robert , Emanuele Enzo , Lista Simone , Lucia Alejandro , Santos-Lozano Alejandro
Published: March 2021

Alzheimer’s disease (AD), the most common form of neurodegenerative dementia in adults worldwide, is a multifactorial and heterogeneous disorder characterized by the interaction of genetic and epigenetic factors and the dysregulation of numerous intracellular signaling and cellular/molecular pathways. The introduction of the systems biology framework is revolutionizing the study of complex diseases by allowing the identification and integration of cellular/molecular pathways and networks of interaction. Here, we reviewed the relationship between physical activity and the next pathophysiological processes involved in the risk of developing AD, based on some crucial molecular pathways and biological process dysregulated in AD: (1) Immune system and inflammation; (2) Endothelial function and cerebrovascular insufficiency; (3) Apoptosis and cell death; (4) Intercellular communication; (5) Metabolism, oxidative stress and neurotoxicity; (6) DNA damage and repair; (7) Cytoskeleton and membrane proteins; (8) Synaptic plasticity. Moreover, we highlighted the increasingly relevant role played by advanced neuroimaging technologies, including structural/functional magnetic resonance imaging, diffusion tensor imaging, and arterial spin labelling, in exploring the link between AD and physical exercise. Regular physical exercise seems to have a protective effect against AD by inhibiting different pathophysiological molecular pathways implicated in AD.
One Heat Shock Transcription Factor Confers High Thermal Tolerance in Clematis Plants
Authors: Wang Rui , Mao Chanjuan , Jiang Changhua , Zhang Long , Peng Siyuan , Zhang Yi , Feng Shucheng , Ming Feng
Published: March 2021

Clematis plants play an important role in botanical gardens. Heat stress can destroy the activity, state and conformation of plant proteins, and its regulatory pathway has been well characterized in Arabidopsis and some crop plants. However, the heat resistance response mechanism in horticultural plants including Clematis has rarely been reported. Here, we identified a heat-tolerant clematis species, Clematis vitalba. The relative water loss and electrolytic leakage were significantly lower under heat treatment in Clematis vitalba compared to Stolwijk Gold. Differential expression heat-tolerant genes (HTGs) were identified based on nonparametric transcriptome analysis. For validation, one heat shock transcription factor, CvHSF30-2, extremely induced by heat stimuli in Clematis vitalba, was identified to confer tolerance to heat stress in Escherichia coli and Saccharomyces cerevisiae. Furthermore, silencing of HSF30-2 by virus-induced gene silencing (VIGS) led to heat sensitivity in tobacco and Clematis, suggesting that the candidate heat-resistant genes identified in this RNA-seq analysis are credible and offer significant utility. We also found that CvHSF30-2 improved heat tolerance of Clematis vitalba by elevating heat shock protein (HSP) expression, which was negatively regulated by CvHSFB2a. Taken together, this study provides insights into the mechanism of Clematis heat tolerance and the findings can be potentially applied in horticultural plants to improve economic efficiency through genetic approaches.
A Molecular Interpretation of the Dynamics of Diffusive Mass Transport of Water within a Glassy Polyetherimide
Authors: Correa Andrea , De Nicola Antonio , Scherillo Giuseppe , Loianno Valerio , Mallamace Domenico , Mallamace Francesco , Ito Hiroshi , Musto Pellegrino , Mensitieri Giuseppe
Published: March 2021

The diffusion process of water molecules within a polyetherimide (PEI) glassy matrix has been analyzed by combining the experimental analysis of water sorption kinetics performed by FTIR spectroscopy with theoretical information gathered from Molecular Dynamics simulations and with the expression of water chemical potential provided by a non-equilibrium lattice fluid model able to describe the thermodynamics of glassy polymers. This approach allowed us to construct a convincing description of the diffusion mechanism of water in PEI providing molecular details of the process related to the effects of the cross- and self-hydrogen bonding established in the system on the dynamics of water mass transport.
Regulation of Juvenile Hormone on Summer Diapause of Geleruca daurica and Its Pathway Analysis
Authors: Ma Hong-Yue , Li Yan-Yan , Li Ling , Tan Yao , Pang Bao-Ping
Published: March 2021

Juvenile hormone (JH) signaling plays an important role in regulation of reproductive diapause in insects. However, we have little understanding of the effect of JH on gene expression at the transcriptome level in diapause. Galeruca daurica is a new pest in the Inner Mongolia grasslands with obligatory summer diapause in the adult stage. Topical application of a JH analog methoprene at the pre-diapause stage delayed the adults entering diapause and inhibited lipid accumulation whereas it did not during diapause. Using Illumina sequencing technology and bioinformatics tools, 54 and 138 differentially expressed genes (DEGs) were detected at 1 and 2 d after treatment, respectively. The KEGG analysis showed that the DEGs were mainly enriched in the metabolism pathways. qRT-PCR analysis indicated that methoprene promoted the expression of genes encoding vitellogenin, fork head transcription factor and Krüppel homolog 1, whereas suppressed the expression of genes encoding juvenile hormone-binding protein, juvenile hormone esterase, juvenile hormone acid methyltransferase, juvenile hormone epoxide hydrolase and fatty acid synthase 2. These results indicate that JH signaling plays an important role in regulating reproductive diapause of G. daurica.