bluuebunny/crossref_metadata_2025 huggingface dataset:
Large for Gestational Age and Risk for Academic Delays and Learning Disabilities: Assessing Modification by Maternal Obesity and Diabetes
Authors: Duffany Kathleen O’Connor , McVeigh Katharine H. , Lipkind Heather S. , Kershaw Trace S. , Ickovics Jeannette R.
Published: July 2020

The objective of this study was to examine academic delays for children born large for gestational age (LGA) and assess effect modification by maternal obesity and diabetes and then to characterize risks for LGA for those with a mediating condition. Cohort data were obtained from the New York City Longitudinal Study of Early Development, linking birth and educational records (n = 125,542). Logistic regression was used to compare children born LGA (>90th percentile) to those born appropriate weight (5–89th percentile) for risk of not meeting proficiency on assessments in the third grade and being referred to special education. Among children of women with gestational diabetes, children born LGA had an increased risk of underperforming in mathematics (ARR: 1.18 (95% CI: 1.07–1.31)) and for being referred for special education (ARR: 1.18 (95% CI: 1.02–1.37)). Children born LGA but of women who did not have gestational diabetes had a slightly decreased risk of academic underperformance (mathematics-ARR: 0.94 (95% CI: 0.90–0.97); Language arts-ARR: 0.96 (95% CI: 0.94–0.99)). Children born to women with gestational diabetes with an inadequate number of prenatal care visits were at increased risk of being born LGA, compared to those receiving extensive care (ARR: 1.67 (95% CI: 1.20–2.33)). Children born LGA of women with diabetes were at increased risk of delays; greater utilization of prenatal care among these diabetic women may decrease the incidence of LGA births.
The Relationship between Masculinity and Internalized Homophobia amongst Australian Gay Men
Authors: Thepsourinthone Jack , Dune Tinashe , Liamputtong Pranee , Arora Amit
Published: July 2020

Due to the heterosexist ideals associated with gender norms, gay men often experience negative attitudes towards their own sexuality—internalized homophobia. As a result, gay men often feel compelled to compensate for their perceived lack of masculinity. The study aimed to investigate the relationship and predictive power of masculinity on gay men’s experiences of internalized homophobia. A sample of 489 self-identified Australian gay men 18–72 years old participated in an online survey on masculinity and homosexuality. Descriptive statistics, bivariate correlations, and sequential multiple regressions were used to test the study’s aims. Sequential multiple regressions revealed that conformity to masculine norms and threats to masculinity contingency were stronger predictors of internalized homophobia over and above demographic and other factors. Given the already known psychological risks associated with social isolation, internalized homophobia, and the poor mental health outcomes associated with sexual minority groups, it is suggested that gay men who are experiencing high degrees of internalized homophobia should not be distancing themselves from other gay men but, conversely, seek a strong relationship with the LGBTI community.
Correlation between COVID-19 Morbidity and Mortality Rates in Japan and Local Population Density, Temperature, and Absolute Humidity
Authors: Kodera Sachiko , Rashed Essam A. , Hirata Akimasa
Published: July 2020

This study analyzed the morbidity and mortality rates of the coronavirus disease (COVID-19) pandemic in different prefectures of Japan. Under the constraint that daily maximum confirmed deaths and daily maximum cases should exceed 4 and 10, respectively, 14 prefectures were included, and cofactors affecting the morbidity and mortality rates were evaluated. In particular, the number of confirmed deaths was assessed, excluding cases of nosocomial infections and nursing home patients. The correlations between the morbidity and mortality rates and population density were statistically significant (p-value < 0.05). In addition, the percentage of elderly population was also found to be non-negligible. Among weather parameters, the maximum temperature and absolute humidity averaged over the duration were found to be in modest correlation with the morbidity and mortality rates. Lower morbidity and mortality rates were observed for higher temperature and absolute humidity. Multivariate linear regression considering these factors showed that the adjusted determination coefficient for the confirmed cases was 0.693 in terms of population density, elderly percentage, and maximum absolute humidity (p-value < 0.01). These findings could be useful for intervention planning during future pandemics, including a potential second COVID-19 outbreak.
Introducing the Extended Safety Fractal: Reusing the Concept of Safety Management Systems to Organize Resilient Organizations
Authors: Accou Bart , Reniers Genserik
Published: July 2020

Although mandatory in most high-risk industries, the safety management system (SMS) is often criticized as burdensome and complex. Through its requirement to formalize all main activities, the SMS is perceived as bureaucratic and a vehicle for pure compliance and Safety I (one). Furthermore, the SMS is often detached from an organization’s core activities, goes against local practice and does not deliver the safe performance that was hoped for. By comparing the model behind SMS with specific requirements for process capability, this paper identifies a safety fractal that reflects the basic requirements that are needed to control safety related activities at all levels within an organization. It is further argued that the constituent elements of this safety fractal are particularly suitable to organize resilient performance, provided that resilience is explicitly identified as the safety strategy to follow and, as such, consequently implemented. This approach is then positioned against common safety management concepts as management system maturity, leadership and safety culture, leading to a systematic and a more comprehensive view on how to measure safety performance and resilience.
Effects of Prehospital Factors on Survival of Out-Of-Hospital Cardiac Arrest Patients: Age-Dependent Patterns
Authors: Rhee Bo Yoon , Kim Boram , Lee Yo Han
Published: July 2020

Many prehospital factors that are known to influence survival rates after out-of-hospital cardiac arrest (OHCA) have been rarely studied as to how their influence varies depending on the age. In this study, we tried to find out what prehospital factors affect the survival rate after OHCA by age groups and how large the effect size of those factors is in each age group. We used the South Korean OHCA registry, which includes information on various prehospital factors relating OHCA and final survival status. The association between prehospital factors and survival was explored through logistic regression analyses for each age group. The effects of prehospital factors vary depending on the patient’s age. Being witnessed was relatively more influential in younger patients and the presence of first responders became more important as patients became older. While bystander cardiopulmonary resuscitation (CPR) did not appear to significantly affect survival in younger people, use of an automated external defibrillator (AED) showed the largest effect size on the survival in all age groups. Since the pathophysiology and etiologies of OHCA vary according to age, more detailed information on life support by age is needed for the development and application of more specialized protocols for each age.
Obstructions and the Recognition of Cancer Inpatient Physical Activity Based on Exercise Experience
Authors: Sangwan Jeon , Eunsurk Yi , Jiyoun Kim
Published: July 2020

The purpose of this study was to analyze and understand the mechanisms of physical activity obstructions in hospitalized cancer patients by investigating their physical activity levels, previous exercise experience levels, and exercise recognition. A survey was conducted for 194 hospitalized cancer patients using a questionnaire. In addition, we performed exploratory factor analysis, frequency analysis, reliability analysis, and hierarchical multiple regression analysis, using SPSS Statistics for Windows, Ver. 23.0. The results were as follows: (1) The physical activity level of the previous exercise participation experience (EPE) group had a greater effect on physical activity obstructions compared with the non-experience (NE) group. (2) The results for the effects of exercise recognition on the physical activity level and physical activity obstructions indicated that exercise recognition in the two groups increased the relative effects on physical activity obstructions in all variables except for the physical obstructions of the EPE group. Consequently, the physical activity level, exercise experience level, and exercise recognition in those patients were confirmed to be the major factors affecting their physical activity obstruction. Therefore, in this study, we provided quantitative data required for establishing healing environments based on motion.
Challenging Aggressive Behaviors Experienced by Personal Support Workers in Comparison to Home Care Workers: Relationships between Caregiver Experiences and Psychological Health
Authors: Womack Kelsey N. , Alvord Teala W. , Trullinger-Dwyer Caitlyn F. , Rice Sean P. M. , Olson Ryan
Published: July 2020

Personal support workers (PSW) are caregivers for children and adults with intellectual and developmental disabilities (IDDs) or adults experiencing mental illness or other behavioral health conditions. The work can be very meaningful, but many PSWs must prepare for, monitor, and manage challenging behaviors, including aggression. This study was designed to estimate the prevalence of aggression experienced by PSWs in Oregon, and compare it to a previous sample of Oregon home care workers (HCWs). This comparison included an analysis of relationships between exposures to aggression and psychological health factors. PSWs in Oregon (N = 240) were surveyed electronically at a single time point. PSWs generally reported higher rates of exposure to aggression compared to HCWs. Experiences with aggression were positively associated with fatigue and weakly associated with depression, but not stress. PSWs’ self-reported lost work time injury rate was elevated compared to the US average, but it was comparable to previous self-reported injury rates from HCWs. Physical demands of work were the most prevalent reported primary safety concern, followed by challenging behaviors (including aggression). Developing tailored training to help PSWs understand, plan for, minimize, and manage challenging behaviors is a social priority.
Perinatal Mental Illness in the Middle East and North Africa Region—A Systematic Overview
Authors: Doraiswamy Sathyanarayanan , Jithesh Anupama , Chaabane Sonia , Abraham Amit , Chaabna Karima , Cheema Sohaila
Published: July 2020

Aims: Perinatal mental illness (PMI) is associated with a high risk of maternal and infant morbidity. Recently, several systematic reviews and primary studies have explored the prevalence and risk factors of PMI in the Middle East and North Africa (MENA) region. To our knowledge, there has been no critical analysis of the existing systematic reviews (SRs) on this topic in the MENA region. Our systematic overview primarily aimed to synthesize evidence from the published SRs on PMI in the MENA countries focusing on a) the prevalence of PMI and b) the risk factors associated with PMI. Methods: We conducted a systematic overview of the epidemiology of PMI in the Middle East and North Africa region by searching the PubMed, Embase, and PsycInfo databases for relevant publications between January 2008 and July 2019. In addition to searching the reference lists of the identified SRs for other relevant SRs and additional primary studies of relevance (those which primarily discussed the prevalence of PMI and/or risk and protective factors), between August and October 2019, we also searched Google Scholar for relevant studies. Results: After applying our inclusion and exclusion criteria, 15 systematic reviews (SRs) and 79 primary studies were included in our overview. Studies utilizing validated diagnostic tools report a PMI prevalence range from 5.6% in Morocco to 28% in Pakistan. On the other hand, studies utilizing screening tools to detect PMI report a prevalence range of 9.2% in Sudan to 85.6% in the United Arab Emirates. Wide variations were observed in studies reporting PMI risk factors. We regrouped the risk factors applying an evidence-based categorization scheme. Our study indicates that risk factors in the relational, psychological, and sociodemographic categories are the most studied in the region. Conversely, lifestyle-related risk factors were less studied. Conclusions: Our systematic overview identifies perinatal mental illness as an important public health issue in the region. Standardizing approaches for estimating, preventing, screening, and treating perinatal mental illness would be a step in the right direction for the region.
Designing Effective Warnings about Addiction on the Patient Information Leaflet of Over-the-Counter Codeine Sold in England to University Students
Authors: Zhao Jianan , Chen Yun , Han Ting , Westland Stephen
Published: July 2020

(1) Background: The harm of misusing over-the-counter (OTC) codeine-containing medicines among university students in England is being increasingly recognized. Based on English university students, this paper aims to study the importance of information design on information communication, explore methods for effective warning design, and investigate university students’ perception of OTC codeine. (2) Methods: The effective warning design is addressed through case studies, answering correctness by the heat map generated from the eye-tracking experiment (ETE), and the total time spent on the tasks. User perceptions are made though online surveys. (3) Results: Information design significantly affects the way user processes information. Therefore, two emphasized warnings displayed in the headline, and the “possible side effect (PSE)” sections and warning signs of addiction presented under the PSE are suggested as effective ways to display warnings. For students’ perception of OTC codeine, 80% of university students are unfamiliar with the substance. After reading the patient information leaflets (PILs), 47% recommended tight regulation on codeine. (4) Conclusions: The misuse of OTC codeine could be a potential problem among English university students. The design of the PIL significantly influences the chance of unintentional medicine misuse. The display of warnings on the PILs of OTC codeine should be redesigned for better understanding.
Trends in Work Conditions and Associations with Workers’ Health in Recent 15 Years: The Role of Job Automation Probability
Authors: Cheng Wan-Ju , Pien Li-Chung , Kubo Tomohide , Cheng Yawen
Published: July 2020

Job automation and associated psychosocial hazards are emerging workplace challenges. This study examined the trends in work conditions and associations with workers’ health over time in jobs with different automation probabilities. We utilized data from six waves of national questionnaire surveys of randomly selected 95,762 employees between 2001 and 2016. The Job Content Questionnaire, the Copenhagen Burnout Inventory, and the Self-Rated Health Scale were applied, and working time was self-reported. Automation probability was derived for 38 occupations and then categorized into three groups. Trends in work conditions and the associations between automation probability, work conditions and health were examined. We observed a 7% decrease in high automation probability jobs, an overall increase in job demands for and prevalence of shift work, and a decrease in job control. Workers with high automation probability jobs had low job demands, low job control and high job insecurity. Low automation probability was associated with burnout in logistic regression models. The odds ratio of job insecurity, long working hours, and shift work relating to health was higher in the later years of the surveys. In conclusion, there has been a decrease in high automation probability jobs. Workers employed in jobs with different levels of automation probability encountered different work condition challenges.
Expression of Nectin-4 and PD-L1 in Upper Tract Urothelial Carcinoma
Authors: Tomiyama Eisuke , Fujita Kazutoshi , Rodriguez Pena Maria Del Carmen , Taheri Diana , Banno Eri , Kato Taigo , Hatano Koji , Kawashima Atsunari , Ujike Takeshi , Uemura Motohide , Takao Tetsuya , Yamaguchi Seiji , Fushimi Hiroaki , Yoshimura Kazuhiro , Uemura Hirotsugu , Netto George J. , Nonomura Norio
Published: July 2020

Enfortumab vedotin is a novel antibody–drug conjugate targeting Nectin-4, which is highly expressed in urothelial carcinoma. However, the expression status of Nectin-4 in upper tract urothelial carcinoma (UTUC) remains unclear. The relationship between Nectin-4 and Programmed Death Ligand 1 (PD-L1) in UTUC is also ambiguous. We performed immunohistochemical analysis of 99 UTUC tissue microarray to assess the expression of Nectin-4 and PD-L1 in UTUC. Nectin-4-positivity was detected in 65 (65.7%) samples, and PD-L1 was detected in 24 (24.2%) samples. There was no correlation between the expression of Nectin-4 and PD-L1. Patients with strong Nectin-4-expressing tumors had a significantly higher risk of progression (p = 0.031) and cancer-specific mortality (p = 0.036). Strong Nectin-4 expression was also an independent predictor of disease progression in the high-risk group (pT3 ≤ or presence of lymphovascular invasion or lymph node metastasis) (Hazard ratio, 3.32 [95% confidence interval, 1.20–7.98; p = 0.027]). In conclusion, we demonstrated that Nectin-4 expression rate in UTUC was 65.7% and independent of PD-L1 expression. Strong Nectin-4 expression was associated with worse progression-free survival in high-risk UTUC. These findings suggested that enfortumab vedotin may be effective in a broad range of patients with UTUC, regardless of PD-L1 expression.
Characterization of the Proteins Involved in the DNA Repair Mechanism in M. smegmatis
Authors: Di Somma Angela , Canè Carolina , Moretta Antonio , Cirillo Arianna , Cemič Franz , Duilio Angela
Published: July 2020

Several alkylating agents that either occur in the environment or are self-produced can cause DNA-damaging injuries in bacterial cells. Therefore, all microorganisms have developed repair systems that are able to counteract DNA alkylation damage. The adaptive response to alkylation stress in Escherichia coli consists of the Ada operon, which has been widely described; however, the homologous system in Mycobacterium tuberculosis (MTB) has been shown to have a different genetic organization but it is still largely unknown. In order to describe the defense system of MTB, we first investigated the proteins involved in the repair mechanism in the homologous non-pathogenic mycobacterium M. smegmatis. Ogt, Ada-AlkA and FadE8 proteins were recombinantly produced, purified and characterized. The biological role of Ogt was examined using proteomic experiments to identify its protein partners in vivo under stress conditions. Our results suggested the formation of a functional complex between Ogt and Ada-AlkA, which was confirmed both in silico by docking calculations and by gel filtration chromatography. We propose that this stable association allows the complex to fulfill the biological roles exerted by Ada in the homologous E. coli system. Finally, FadE8 was demonstrated to be structurally and functionally related to its E. coli homologous, AidB.
Immunoglobulins with Non-Canonical Functions in Inflammatory and Autoimmune Disease States
Authors: Ermakov Evgeny A. , Nevinsky Georgy A. , Buneva Valentina N.
Published: July 2020

Immunoglobulins are known to combine various effector mechanisms of the adaptive and the innate immune system. Classical immunoglobulin functions are associated with antigen recognition and the initiation of innate immune responses. However, in addition to classical functions, antibodies exhibit a variety of non-canonical functions related to the destruction of various pathogens due to catalytic activity and cofactor effects, the action of antibodies as agonists/antagonists of various receptors, the control of bacterial diversity of the intestine, etc. Canonical and non-canonical functions reflect the extreme human antibody repertoire and the variety of antibody types generated in the organism: antigen-specific, natural, polyreactive, broadly neutralizing, homophilic, bispecific and catalytic. The therapeutic effects of intravenous immunoglobulins (IVIg) are associated with both the canonical and non-canonical functions of antibodies. In this review, catalytic antibodies will be considered in more detail, since their formation is associated with inflammatory and autoimmune diseases. We will systematically summarize the diversity of catalytic antibodies in normal and pathological conditions. Translational perspectives of knowledge about natural antibodies for IVIg therapy will be also discussed.
Differences in the Formation Mechanism of Giant Colonies in Two Phaeocystis globosa Strains
Authors: Liang Dayong , Wang Xiaodong , Huo Yiping , Wang Yan , Li Shaoshan
Published: July 2020

Phaeocystis globosa has become one of the primary causes of harmful algal bloom in coastal areas of southern China in recent years, and it poses a serious threat to the marine environment and other activities depending upon on it (e.g., aquaculture, cooling system of power plants), especially in the Beibu Gulf. We found colonies of P. globosa collected form Guangxi (China) were much larger than those obtained from Shantou cultured in lab. To better understand the causes of giant colonies formation, colonial cells collected from P. globosa GX strain (GX-C) and ST strain (ST-C) were separated by filtration. Morphological observations, phylogenetic analyses, rapid light-response curves, fatty acid profiling and transcriptome analyses of two type cells were performed in the laboratory. Although no differences in morphology and 18S rRNA sequences of these cells were observed, the colonies of GX strain (4.7 mm) are 30 times larger than those produced by the ST strain (300 μm). The rapid light-response curve of GX-C was greater than that of ST-C, consistent with the upregulated photosynthetic system, while the fatty acid content of GX-C was lower than that of ST-C, also consistent with the downregulated synthesis of fatty acids and the upregulated degradation of fatty acids. In summary, the increased energy generated by GX-C is allocated to promote the secretion of extracellular polysaccharides for colony formation. We performed a physiological and molecular assessment of the differences between the GX-C and ST-C strains, providing insights into the mechanisms of giant colonies formation in P. globosa.
Polymorphisms in the Angiogenesis-Related Genes EFNB2, MMP2 and JAG1 Are Associated with Survival of Colorectal Cancer Patients
Authors: Scherer Dominique , Deutelmoser Heike , Balavarca Yesilda , Toth Reka , Habermann Nina , Buck Katharina , Kap Elisabeth Johanna , Botma Akke , Seibold Petra , Jansen Lina , Lorenzo Bermejo Justo , Weigl Korbinian , Benner Axel , Hoffmeister Michael , Ulrich Alexis , Brenner Hermann , Burwinkel Barbara , Chang-Claude Jenny , Ulrich Cornelia M.
Published: July 2020

An individual’s inherited genetic variation may contribute to the ‘angiogenic switch’, which is essential for blood supply and tumor growth of microscopic and macroscopic tumors. Polymorphisms in angiogenesis-related genes potentially predispose to colorectal cancer (CRC) or affect the survival of CRC patients. We investigated the association of 392 single nucleotide polymorphisms (SNPs) in 33 angiogenesis-related genes with CRC risk and survival of CRC patients in 1754 CRC cases and 1781 healthy controls within DACHS (Darmkrebs: Chancen der Verhütung durch Screening), a German population-based case-control study. Odds ratios and 95% confidence intervals (CI) were estimated from unconditional logistic regression to test for genetic associations with CRC risk. The Cox proportional hazard model was used to estimate hazard ratios (HR) and 95% CIs for survival. Multiple testing was adjusted for by a false discovery rate. No variant was associated with CRC risk. Variants in EFNB2, MMP2 and JAG1 were significantly associated with overall survival. The association of the EFNB2 tagging SNP rs9520090 (p < 0.0001) was confirmed in two validation datasets (p-values: 0.01 and 0.05). The associations of the tagging SNPs rs6040062 in JAG1 (p-value 0.0003) and rs2241145 in MMP2 (p-value 0.0005) showed the same direction of association with overall survival in the first and second validation sets, respectively, although they did not reach significance (p-values: 0.09 and 0.25, respectively). EFNB2, MMP2 and JAG1 are known for their functional role in angiogenesis and the present study points to novel evidence for the impact of angiogenesis-related genetic variants on the CRC outcome.
Few Layered Oxidized h-BN as Nanofiller of Cellulose-Based Paper with Superior Antibacterial Response and Enhanced Mechanical/Thermal Performance
Authors: Onyszko M. , Markowska-Szczupak A. , Rakoczy R. , Paszkiewicz O. , Janusz J. , Gorgon-Kuza A. , Wenelska K. , Mijowska E.
Published: July 2020

In this study, hexagonal boron nitride nanosheets enriched with hydroxyl groups (h-BN-OH) were successfully grafted on the surface of cellulose fibers after the simple and effective exfoliation and oxidation of bulk h-BN. OH groups of h-BN-OH and the ones presented on the surface of cellulose fibers interacted via hydrogen bonding. Both spectroscopic (FT-IR, XRD) and microscopic (TEM, SEM, and atomic force microscopy (AFM)) methods results proved the successful functionalization of the cellulose fibers with the nanomaterial. Modified cellulose fibers were used to prepare paper sheets samples with different concentrations of the nanomaterial (1 wt %, 2 wt %, and 3 wt %). All the samples were tested for the antibacterial properties via the colony forming unit method and exhibited good performance against both Gram-negative (E. coli) and Gram-positive (S. epidermidis) model bacteria. Additionally, the influence of the volume of working bacterial suspension on the antibacterial efficiency of the obtained materials was examined. The results showed significantly better antibacterial performance when the volume of bacterial suspension was reduced. Mechanical properties of the paper samples with and without nanofiller were also characterized. Tensile strength, tearing strength, and bursting strength of the paper samples containing only 2 wt % of the nanofiller were improved by 60%, 61%, and 118% in comparison to the control paper samples, respectively. Furthermore, the nanofiller improved the thermal properties of the composite paper—the heat release rate decreased by up to 11.6%. Therefore, the composite paper can be further explored in a wide range of antibacterial materials, such as packaging or paper coatings
RhoA/ROCK Pathway Activation is Regulated by AT1 Receptor and Participates in Smooth Muscle Migration and Dedifferentiation via Promoting Actin Cytoskeleton Polymerization
Authors: Qi Yan , Liang Xiuying , Dai Fan , Guan Haijing , Sun Jingwen , Yao Wenjuan
Published: July 2020

Background: In this study, we investigated the mechanism of Rho GTPases signaling on Ang II-mediated cell migration and dedifferentiation in human aortic vascular smooth muscle cells (HA-VSMCs) and an Ang II-infusion mouse model. Methods: Cells were pretreated with different inhibitors or Ang II. Cell migration was detected by Wound healing and Transwell assay. Mice were treated with Ad-RhoA-shRNA virus or Irbesartan or fasudil and then infused with Ang II. Results: Ang II treatment induced HA-VSMCs migration in a dose- and time-dependent manner and reduced the expression of VSMC contractile proteins. These effects were significantly suppressed by the inhibition of Ang II type 1 receptor (AT1 receptor), RhoA, and Rho-associated kinase (ROCK). Furthermore, Ang II treatment promoted the activation of RhoA and ROCK, which was reduced by AT1 receptor inhibition. Meanwhile, Ang II treatment induced F-actin polymerization, which was inhibited after ROCK inhibition. In mice, Ang II infusion increased VSMC migration into the neointima and reduced VSMC differentiation proteins levels, and these effects were shown to be dependent on AT1 receptor and RhoA/ROCK pathway. Conclusion: This study reveals a novel mechanism by which Ang II regulates RhoA/ROCK signaling and actin polymerization via AT1 receptor and then affects VSMC dedifferentiation.
Investigating the Product Profiles and Structural Relationships of New Levansucrases with Conventional and Non-Conventional Substrates
Authors: Hill Andrea , Karboune Salwa , Narwani Tarun J. , de Brevern Alexandre G.
Published: July 2020

The synthesis of complex oligosaccharides is desired for their potential as prebiotics, and their role in the pharmaceutical and food industry. Levansucrase (LS, EC 2.4.1.10), a fructosyl-transferase, can catalyze the synthesis of these compounds. LS acquires a fructosyl residue from a donor molecule and performs a non-Lenoir transfer to an acceptor molecule, via β-(2→6)-glycosidic linkages. Genome mining was used to uncover new LS enzymes with increased transfructosylating activity and wider acceptor promiscuity, with an initial screening revealing five LS enzymes. The product profiles and activities of these enzymes were examined after their incubation with sucrose. Alternate acceptor molecules were also incubated with the enzymes to study their consumption. LSs from Gluconobacter oxydans and Novosphingobium aromaticivorans synthesized fructooligosaccharides (FOSs) with up to 13 units in length. Alignment of their amino acid sequences and substrate docking with homology models identified structural elements causing differences in their product spectra. Raffinose, over sucrose, was the preferred donor molecule for the LS from Vibrio natriegens, N. aromaticivorans, and Paraburkolderia graminis. The LSs examined were found to have wide acceptor promiscuity, utilizing monosaccharides, disaccharides, and two alcohols to a high degree.
TRPM8 Channel Activation Reduces the Spontaneous Contractions in Human Distal Colon
Authors: Amato Antonella , Terzo Simona , Lentini Laura , Marchesa Pierenrico , Mulè Flavia
Published: July 2020

The transient receptor potential-melastatin 8 (TRPM8) is a non-selective Ca2+-permeable channel, activated by cold, membrane depolarization, and different cooling compounds. TRPM8 expression has been found in gut mucosal, submucosal, and muscular nerve endings. Although TRPM8 plays a role in pathological conditions, being involved in visceral pain and inflammation, the physiological functions in the digestive system remain unclear as yet. The aims of the present study were: (i) to verify the TRPM8 expression in human distal colon; (ii) to examine the effects of TRPM8 activation on colonic contractility; (iii) to characterize the mechanism of action. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting were used to analyze TRPM8 expression. The responses of human colon circular strips to different TRPM8 agonists [1-[Dialkyl-phosphinoyl]-alkane (DAPA) 2–5, 1-[Diisopropyl-phosphinoyl]-alkane (DIPA) 1–7, DIPA 1–8, DIPA 1–9, DIPA 1–10, and DIPA 1–12) were recorded using a vertical organ bath. The biomolecular analysis revealed gene and protein expression of TRPM8 in both mucosal and smooth muscle layers. All the agonists tested, except-DIPA 1–12, produced a concentration-dependent decrease in spontaneous contraction amplitude. The effect was significantly antagonized by 5-benzyloxytryptamine, a TRPM8 antagonist. The DIPA 1–8 agonist resulted in the most efficacious and potent activation among the tested molecules. The DIPA 1–8 effects were not affected by tetrodotoxin, a neural blocker, but they were significantly reduced by tetraethylammonium chloride, a non-selective blocker of K+ channels. Moreover, iberiotoxin, a blocker of the large-conductance Ca2+-dependent K+-channels, but not apamin, a blocker of small-conductance Ca2+-dependent K+ channels, significantly reduced the inhibitory DIPA 1–8 actions. The results of the present study demonstrated that TRPM8 receptors are also expressed in human distal colon in healthy conditions and that ligand-dependent TRPM8 activation is able to reduce the colonic spontaneous motility, probably by the opening of the large-conductance Ca2+-dependent K+-channels.
Functional Imaging for Therapeutic Assessment and Minimal Residual Disease Detection in Multiple Myeloma
Authors: Jamet Bastien , Zamagni Elena , Nanni Cristina , Bailly Clément , Carlier Thomas , Touzeau Cyrille , Michaud Anne-Victoire , Moreau Philippe , Bodet-Milin Caroline , Kraeber-Bodere Françoise
Published: July 2020

Serum markers and bone marrow examination are commonly used for monitoring therapy response in multiple myeloma (MM), but this fails to identify minimal residual disease (MRD), which frequently persists after therapy even in complete response patients, and extra-medullary disease escape. Positron emission tomography with computed tomography using 18F-deoxyglucose (FDG-PET/CT) is the reference imaging technique for therapeutic assessment and MRD detection in MM. To date, all large prospective cohort studies of transplant-eligible newly diagnosed MM patients have shown a strong and independent pejorative prognostic impact of not obtaining complete metabolic response by FDG-PET/CT after therapy, especially before maintenance. The FDG-PET/CT and MRD (evaluated by flow cytometry or next-generation sequencing at 10−5 and 10−6 levels, respectively) results are complementary for MRD detection outside and inside the bone marrow. For patients with at least a complete response, to reach double negativity (FDG-PET/CT and MRD) is a predictive surrogate for patient outcome. Homogenization of FDG-PET/CT interpretation after therapy, especially clarification of complete metabolic response definition, is currently underway. FDG-PET/CT does not allow MRD to be evaluated when it is negative at initial workup of symptomatic MM. New PET tracers such as CXCR4 ligands have shown high diagnostic value and could replace FDG in this setting. New sensitive functional magnetic resonance imaging (MRI) techniques such as diffusion-weighted MRI appear to be complementary to FDG-PET/CT for imaging MRD detection. The goal of this review is to examine the feasibility of functional imaging, especially FDG-PET/CT, for therapeutic assessment and MRD detection in MM.
Paternal Exposure to Bisphenol-A Transgenerationally Impairs Testis Morphology, Germ Cell Associations, and Stemness Properties of Mouse Spermatogonial Stem Cells
Authors: Karmakar Polash Chandra , Ahn Jin Seop , Kim Yong-Hee , Jung Sang-Eun , Kim Bang-Jin , Lee Hee-Seok , Kim Sun-Uk , Rahman Md Saidur , Pang Myung-Geol , Ryu Buom-Yong
Published: July 2020

Bisphenol-A (BPA) exposure in an adult male can affect the reproductive system, which may also adversely affect the next generation. However, there is a lack of comprehensive data on the BPA-induced disruption of the association and functional characteristics of the testicular germ cells, which the present study sought to investigate. Adult male mice were administered BPA doses by gavage for six consecutive weeks and allowed to breed, producing generations F1–F4. Testis samples from each generation were evaluated for several parameters, including abnormal structure, alterations in germ cell proportions, apoptosis, and loss of functional properties of spermatogonial stem cells (SSCs). We observed that at the lowest-observed-adverse-effect level (LOAEL) dose, the testicular abnormalities and alterations in seminiferous epithelium staging persisted in F0–F2 generations, although a reduced total spermatogonia count was found only in F0. However, abnormalities in the proportions of germ cells were observed until F2. Exposure of the male mice (F0) to BPA alters the morphology of the testis along with the association of germ cells and stemness properties of SSCs, with the effects persisting up to F2. Therefore, we conclude that BPA induces physiological and functional disruption in male germ cells, which may lead to reproductive health issues in the next generation.
The Effects of Cannabidiol and Prognostic Role of TRPV2 in Human Endometrial Cancer
Authors: Marinelli Oliviero , Morelli Maria Beatrice , Annibali Daniela , Aguzzi Cristina , Zeppa Laura , Tuyaerts Sandra , Amantini Consuelo , Amant Frédéric , Ferretti Benedetta , Maggi Federica , Santoni Giorgio , Nabissi Massimo
Published: July 2020

Several studies support, both in vitro and in vivo, the anti-cancer effects of cannabidiol (CBD), a transient receptor potential vanilloid 2 (TRPV2) ligand. TRPV2, often dysregulated in tumors, is associated with altered cell proliferation and aggressiveness. Endometrial cancer (EC) is historically divided in type I endometrioid EC and type II non-endometrioid EC, associated with poor prognosis. Treatment options with chemotherapy and combinations with radiation showed only limited efficacy. Since no data are reported concerning TRPV2 expression as well as CBD potential effects in EC, the aim of this study was to evaluate the expression of TRPV2 in biopsies and cell lines as well as the effects of CBD in in vitro models. Overall survival (OS), progression-free survival (PFS), cell viability, migration, and chemo-resistance have been evaluated. Results show that TRPV2 expression increased with the malignancy of the cancer tissue and correlated with shorter PFS (p = 0.0224). Moreover, in vitro TRPV2 over-expression in Ishikawa cell line increased migratory ability and response to cisplatin. CBD reduced cell viability, activating predominantly apoptosis in type I cells and autophagy in mixed type EC cells. The CBD improved chemotherapeutic drugs cytotoxic effects, enhanced by TRPV2 over-expression. Hence, TRPV2 could be considered as a marker for optimizing the therapy and CBD might be a useful therapeutic option as adjuvant therapy.
Ectodomain Pulling Combines with Fusion Peptide Inserting to Provide Cooperative Fusion for Influenza Virus and HIV
Authors: Akimov Sergey A. , Kondrashov Oleg V. , Zimmerberg Joshua , Batishchev Oleg V.
Published: July 2020

Enveloped viruses include the most dangerous human and animal pathogens, in particular coronavirus, influenza virus, and human immunodeficiency virus (HIV). For these viruses, receptor binding and entry are accomplished by a single viral envelope protein (termed the fusion protein), the structural changes of which trigger the remodeling and merger of the viral and target cellular membranes. The number of fusion proteins required for fusion activity is still under debate, and several studies report this value to range from 1 to 9 for type I fusion proteins. Here, we consider the earliest stage of viral fusion based on the continuum theory of membrane elasticity. We demonstrate that membrane deformations induced by the oblique insertion of amphipathic fusion peptides mediate the lateral interaction of these peptides and drive them to form into a symmetric fusion rosette. The pulling force produced by the structural rearrangements of the fusion protein ectodomains gives additional torque, which deforms the membrane and additionally stabilizes the symmetric fusion rosette, thus allowing a reduction in the number of fusion peptides needed for fusion. These findings can resolve the large range of published cooperativity indices for HIV, influenza, and other type I fusion proteins.
Apocynin Treatment Prevents Cardiac Connexin 43 Hemichannels Hyperactivity by Reducing Nitroso-Redox Stress in Mdx Mice
Authors: Vielma Alejandra Z. , Boric Mauricio P. , Gonzalez Daniel R.
Published: July 2020

Duchenne muscular dystrophy (DMD) is a fatal disease that causes cardiomyopathy and is associated with oxidative stress. In the heart, oxidative stress interferes with the location of connexin 43 (Cx43) to the intercalated discs causing its lateralization to the plasma membrane where Cx43 forms hemichannels. We tested the hypothesis that in DMD cardiomyopathy, increased oxidative stress is associated with the formation and activation of Cx43 hemichannels. For this, we used mdx mice as a DMD model and evaluated cardiac function, nitroso-redox changes and Cx43 hemichannels permeability. Mdx hearts presented increased NADPH oxidase-derived oxidative stress and increased Cx43 S-nitrosylation compared to controls. These redox changes were associated with increased Cx43 lateralization, decreased cardiac contractility and increased arrhythmic events. Pharmacological inhibition of NADPH oxidase using apocynin (one month) reduced systemic oxidative stress and reversed the aforementioned changes towards normal, except Cx43 lateralization. Opening of Cx43 hemichannels was blocked by apocynin treatment and by acute hemichannel blockade with carbenoxolone. NADPH oxidase inhibition also prevented the occurrence of apoptosis in mdx hearts and reversed the ventricular remodeling. These results show that NADPH oxidase activity in DMD is associated with S-nitrosylation and opening of Cx43 hemichannels. These changes lead to apoptosis and cardiac dysfunction and were prevented by NADPH oxidase inhibition.
Network Neuromodulation of Opioid and GABAergic Receptors Following a Combination of “Juvenile” and “Adult Stress” in Rats
Authors: Horovitz Omer , Ardi Ziv , Ashkenazi Shiri Karni , Ritov Gilad , Anunu Rachel , Richter-Levin Gal
Published: July 2020

Early life stress is suggested to alter behavioral responses during stressful challenges in adulthood and to exacerbate pathological symptoms that reminisce posttraumatic stress disorder (PTSD). These effects are often associated with changes in γ-Aminobutyric acid type A (GABAA) and κ opioid receptor expression and neuromodulation of the limbic system. Anxiety-like and stress coping behaviors were assessed in rats exposed to stress in adulthood on the background of previous exposure to stress in juvenility. Two weeks following behavioral assessment in adulthood, GABAAR α1 and α2 subunits and κ opioid receptor expression levels were measured in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, and periaqueductal gray (PAG). To illustrate changes at the network level, an integrated expression profile was constructed. We found that exposure to juvenile stress affected rats’ behavior during adult stress. The combination of juvenile and adult stress significantly affected rats’ long term anxious-like behavior. Probabilities predicting model integrating the expression of GABAA α1-α2 and κ opioid receptors in different brain regions yielded highly successful classification rates. This study emphasizes the ability of exposure to stress in juvenility to exacerbate the impact of coping with stress in adulthood. Moreover, the use of integrated receptor expression network profiling was found to effectively characterize the discussed affective styles and their behavioral manifestations.
Resveratrol Favors Adhesion and Biofilm Formation of Lacticaseibacillus paracasei subsp. paracasei Strain ATCC334
Authors: Al Azzaz Jana , Al Tarraf Alissar , Heumann Arnaud , Da Silva Barreira David , Laurent Julie , Assifaoui Ali , Rieu Aurélie , Guzzo Jean , Lapaquette Pierre
Published: July 2020

Bacterial strains of the Lactobacillaceae family are widely used as probiotics for their multifaceted potential beneficial properties. However, no official recommendations for their clinical use exist since, in many cases, oral administrations of these bacteria displayed limited beneficial effects in human. Additional research is thus needed to improve the efficiency of existing strains with strong potential. In this context, we assess in vitro the effects of nine polyphenols to stimulate biofilm formation by lactobacilli, a feature enhancing their functionalities. Among these polyphenols, we identify trans-Resveratrol (referred to hereafter as Resveratrol) as a potent inducer of biofilm formation by Lacticaseibacillus paracasei (formerly designated as Lactobacillus paracasei) ATCC334 strain. This effect is strain-dependent and relies on the enhancement of L. paracasei adhesion to abiotic and biotic surfaces, including intestinal epithelial cells. Mechanistically, Resveratrol modify physico-chemical properties of the bacterial surface and thereby enhances L. paracasei aggregation, subsequently facilitating adhesion and biofilm development. Together, our in vitro data demonstrate that Resveratrol might be used to modulate the behavior of Lactobacilli with probiotic properties. Combination of probiotics and polyphenols could be considered to enhance the probiotic functionalities in further in vivo studies.
Epigenetic Silencing of LMX1A Contributes to Cancer Progression in Lung Cancer Cells
Authors: Wu Ti-Hui , Chang Shan-Yueh , Shih Yu-Lueng , Chian Chih-Feng , Chang Hung , Lin Ya-Wen
Published: July 2020

Epigenetic modification is considered a major mechanism of the inactivation of tumor suppressor genes that finally contributes to carcinogenesis. LIM homeobox transcription factor 1α (LMX1A) is one of the LIM-homeobox-containing genes that is a critical regulator of growth and differentiation. Recently, LMX1A was shown to be hypermethylated and functioned as a tumor suppressor in cervical cancer, ovarian cancer, and gastric cancer. However, its role in lung cancer has not yet been clarified. In this study, we used public databases, methylation-specific PCR (MSP), reverse transcription PCR (RT-PCR), and bisulfite genomic sequencing to show that LMX1A was downregulated or silenced due to promoter hypermethylation in lung cancers. Treatment of lung cancer cells with the demethylating agent 5-aza-2’-deoxycytidine restored LMX1A expression. In the lung cancer cell lines H23 and H1299, overexpression of LMX1A did not affect cell proliferation but suppressed colony formation and invasion. These suppressive effects were reversed after inhibition of LMX1A expression in an inducible expression system in H23 cells. The quantitative RT-PCR (qRT-PCR) data showed that LMX1A could modulate epithelial mesenchymal transition (EMT) through E-cadherin (CDH1) and fibronectin (FN1). NanoString gene expression analysis revealed that all aberrantly expressed genes were associated with processes related to cancer progression, including angiogenesis, extracellular matrix (ECM) remodeling, EMT, cancer metastasis, and hypoxia-related gene expression. Taken together, these data demonstrated that LMX1A is inactivated through promoter hypermethylation and functions as a tumor suppressor. Furthermore, LMX1A inhibits non-small cell lung cancer (NSCLC) cell invasion partly through modulation of EMT, angiogenesis, and ECM remodeling.