bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trimethylamine modulates dauer formation, neurodegeneration, and lifespan through tyra‐3/daf‐11 signaling in Caenorhabditis elegans
Authors: Khanna Amit , Sellegounder Durai , Kumar Jitendra , Chamoli Manish , Vargas Miguel , Chinta Shankar J. , Rane Anand , Nelson Christopher , Peiris T. Harshani , Brem Rachel , Andersen Julie , Lithgow Gordon , Kapahi Pankaj 
Published: April 2021

AbstractIn the nematode Caenorhabditis elegans, signals derived from bacteria in the diet, the animal's major nutrient source, can modulate both behavior and healthspan. Here we describe a dual role for trimethylamine (TMA), a human gut flora metabolite, which acts as a nutrient signal and a neurotoxin. TMA and its associated metabolites are produced by the human gut microbiome and have been suggested to serve as risk biomarkers for diabetes and cardiovascular diseases. We demonstrate that the tyramine receptor TYRA‐3, a conserved G protein‐coupled receptor (GPCR), is required to sense TMA and mediate its responses. TMA activates guanylyl cyclase DAF‐11 signaling through TYRA‐3 in amphid neurons (ASK) and ciliated neurons (BAG) to mediate food‐sensing behavior. Bacterial mutants deficient in TMA production enhance dauer formation, extend lifespan, and are less preferred as a food source. Increased levels of TMA lead to neural damage in models of Parkinson's disease and shorten lifespan. Our results reveal conserved signaling pathways modulated by TMA in C. elegans that are likely to be relevant for its effects in mammalian systems.
Five‐year follow‐up after cervical cytology and histology discordance: A retrospective cohort study
Authors: Scheck Simon M. , Liddle Catherine , Wood Zoë , Lockett Bruce , Sircar Sikhar 
Published: April 2021

BackgroundCervical smear cytology and colposcopic biopsy histology are prone to error at both collection and interpretation stages, leading to a large number of discordant cases.AimsInvestigation of five‐year outcomes for women who have cervical cytology that is discordant and higher grade than histology results.Materials and MethodsA retrospective cohort study was carried out for 111 women with cervical cytology discordant and higher grade than histology, after cytopathological review, over a three‐year period. Five‐year follow‐up data were reviewed to identify the highest level of pathology seen within five years from the discordance.ResultsWomen with atypical squamous cells with possible high‐grade change (ASC‐H) cytology and negative biopsy (n = 28) had a 46% chance of high‐grade histological disease within 5 years; with cervical intraepithelial neoplasia grade 1 (CIN1) histology (n = 20), this was reduced to 30%. With high‐grade cytology and negative histology (n = 23), 48% had high‐grade disease within five years, including one case of invasive disease; with CIN1 histology 50% had high‐grade disease within five years.ConclusionsThis study demonstrates a 30–50% chance of high‐grade disease within five years, in the setting of ASC‐H or high‐grade cytology with a negative or low‐grade colposcopic biopsy. This highlights that in the setting of cytology and histology discordance, at least one of the tests indicating high‐grade pathology warrants the need for treatment or close ongoing surveillance.
Impact of chronic vitamin A excess on sperm morphogenesis in mice
Authors: Yokota Satoshi , Sekine Nao , Wakayama Tomohiko , Oshio Shigeru 
Published: April 2021

AbstractBackgroundThe increasing availability of fortified foods and supplements has caused an overconsumption of vitamin A (VA), above the recommended level. To date, the effects of chronic VA excess (VAE) on spermatogenesis remain unclear.ObjectiveThis study aims to investigate the long‐term excessive intake of VA effects on spermatogenesis in mice.Materials and methodsDams were initially fed a control diet (4 IU/g) or a VAE diet (250 IU/g), 4 weeks prior to mating and during pregnancy. Dams and their male pups continued this diet regimen until the offspring reached 12 weeks of age. At 12 weeks of age, epididymis caudal spermatozoa and testes were collected. For histological analysis, sections were stained with periodic acid‐Schiff‐hematoxylin, and quantitative PCR was used to detect changes in gene expression in the testes of the VAE mice. Sperm motility and morphology were evaluated to detect the endpoint of VAE toxicity.ResultsBody weights were not significantly different between the control and VAE groups. Testicular cross‐sections from the control and VAE mice contained a normal array of germ cells, and the daily sperm production was similar between the two groups. However, the percentage of seminiferous tubules in stages VII and VIII was significantly lower in the VAE mice than in the control. In addition, significant changes in the expression of genes involved in retinoid metabolism, spermatogenesis, and spermiogenesis were detected in the testes of the VAE mice. Consistently, sperm motility and head morphology were significantly impaired in the VAE mice.Discussion and ConclusionOur findings suggest that long‐term dietary intake of VAE was able to influence both pre‐ and post‐meiotic spermatogenesis. As a result of testicular toxicity, we demonstrated, to the best of our knowledge, for the first time that long‐term VAE caused sperm‐head abnormalities.
No functional TRPA1 in cardiomyocytes
Authors: Hoebart Clara , Rojas‐Galvan Natalia S. , Ciotu Cosmin I. , Aykac Ibrahim , Reissig Lukas F. , Weninger Wolfgang J. , Kiss Attila , Podesser Bruno K. , Fischer Michael J. M. , Heber Stefan 
Published: April 2021

AbstractAimThere is mounting evidence that TRPA1 has a role in cardiac physiology and pathophysiology. We aim to clarify the site of TRPA1 expression in the heart and in particular whether the channel is expressed in cardiomyocytes.MethodsDue to the high calcium conductance of TRPA1, and marginal calcium changes being detectable, microfluorimetry in primary mouse cardiomyocytes, and in the cardiomyocyte cell lines H9c2 and HL‐1, was applied. TRPA1 mRNA in mouse and human hearts, primary cardiomyocytes, and the cardiac cell lines were quantified. Dorsal root ganglia served as control for both methods.ResultsIn addition to AITC, the more potent and specific TRPA1 agonists JT010 and PF‐4840154 failed to elicit a TRPA1‐mediated response in native and electrically paced primary cardiomyocytes, and the cardiomyocyte cell lines H9c2 and HL‐1. There were only marginal levels of TRPA1 mRNA in cardiomyocytes and cardiac cell lines, also in conditions of cell differentiation or inflammation, which might occur in pathophysiological conditions. Similarly, TRPV1 agonist capsaicin did not activate primary mouse cardiomyocytes, did not alter electrically paced activity in these, and did not activate H9c2 cells or alter spontaneous activity of HL‐1 cells. Human pluripotent stem cells differentiated to cardiomyocytes had no relevant TRPA1 mRNA levels. Also in human post‐mortem heart samples, TRPA1 mRNA levels were substantially lower compared with the respective dorsal root ganglion.ConclusionThe results do not question a role of TRPA1 in the heart but exclude a direct effect in cardiomyocytes.
The non‐consensus 1992 consensus
Authors: Wang Austin Horng‐En , Yeh Yao‐Yuan , Wu Charles K. S. , Chen Fang‐Yu 
Published: April 2021

AbstractThe 1992 Consensus is perhaps the most crucial political term for cross‐strait relations. Surveys show that the public consistently supports it in Taiwan. Despite the alleged broad support, there has not been an academic study examining if Taiwanese people understand the content of the 1992 Consensus. Such an inquiry is important as the administration in Taiwan has yet accepted the Consensus in its interactions with Beijing. A nearly representative online survey was conducted in July 2018, and 1001 Taiwanese respondents were recruited to choose among different “definitions” of the 1992 Consensus. Results show that only one‐third of the respondents chose the version that Kuomintang agreed on, while another one‐third misperceived the 1992 Consensus as a country‐to‐country agreement. Taiwanese people might have supported the Consensus for content that it is not. We then discuss the policy implications of our study for both China and Taiwan and provide future research orientations.
Influence of N‐acetyltransferase 2 gene polymorphisms on the in vitro metabolism of the epidermal growth factor receptor inhibitor rociletinib
Authors: Ramirez Jacqueline , House Larry K. , Ratain Mark J. 
Published: April 2021

AimsRociletinib showed activity in T790M‐positive non‐small cell lung cancer patients. It undergoes amide hydrolysis to form M502, followed by N‐acetylation to M544 or amide hydrolysis to M460. We identified the enzymes responsible for rociletinib metabolism, and investigated the relationship between M544 formation and N‐acetyltransferase 2 (NAT2) polymorphisms.MethodsRociletinib and metabolites were incubated with carboxylesterase (CES)1b, CES1c, CES2, NAT1, NAT2, arylacetamide deacetylase, inhibitors, pooled human liver microsomes (HLM) and cytosols (HLC). Cytosols (n = 107) were genotyped for NAT2 polymorphisms (rs1041983 and rs1801280) and incubated with M502. Human hepatocytes from intermediate (NAT2*6/*12A) and slow (NAT2*5B/*5B) acetylators were incubated with 10 μM rociletinib and metabolites for 24 hours. Metabolites were measured by high‐performance liquid chromatography.ResultsM502 was formed from rociletinib and M544 by CES2 and HLM; M544 and N‐acetyl‐M460 were formed by NAT2 and HLC; M460 was not formed by CES or arylacetamide deacetylase. M502 formation by HLM was inhibited by bis‐(4‐nitrophenyl)phosphate and eserine (10 μM). M544 formation in HLC was inhibited by 100 μM quercetin and was associated with NAT2 genotype (P < .0001). M460 formation in HLM was inhibited by eserine, and M460 was N‐acetylated in HLC. Hepatocytes formed M502, M544 and M460. The intermediate acetylator showed higher production (range: 3.4–5.1‐fold) of N‐acetylated metabolites than the slow acetylator.ConclusionsResults indicate that NAT2 and CES2 are involved in rociletinib metabolism, and polymorphic NAT2 could alter drug exposure in patients. Slow NAT2 acetylators would have higher exposure to M502 and M460 and consequently, be at increased risk of experiencing hyperglycaemia and QTc prolongation.
The oxysterome and its receptors as pharmacological targets in inflammatory diseases
Authors: Guillemot‐Legris Owein , Muccioli Giulio G. 
Published: April 2021

Oxysterols have gained attention over the last decades and are now considered as fully fledged bioactive lipids. The study of their levels in several conditions, including atherosclerosis, obesity and neurodegenerative diseases, led to a better understanding of their involvement in (patho)physiological processes such as inflammation and immunity. For instance, the characterization of the cholesterol‐7α,25‐dihydroxycholesterol/GPR183 axis and its implication in immunity represents an important step in the oxysterome study. Besides this axis, others were identified as important in several inflammatory pathologies (such as colitis, lung inflammation and atherosclerosis). However, the oxysterome is a complex system notably due to a redundancy of metabolic enzymes and a wide range of receptors. Indeed, deciphering oxysterol roles and identifying the potential receptor(s) involved in a given pathology remain challenging. Oxysterol properties are very diverse, but most of them could be connected by a common component: inflammation. Here, we review the implication of oxysterol receptors in inflammatory diseases.LINKED ARTICLESThis article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc
Identification of a critical binding site for local anaesthetics in the side pockets of Kv1 channels
Authors: Kiper Aytug K. , Bedoya Mauricio , Stalke Sarah , Marzian Stefanie , Ramírez David , de la Cruz Alicia , Peraza Diego A. , Vera‐Zambrano Alba , Márquez Montesinos José C. E. , Arévalo Ramos Bárbara A. , Rinné Susanne , Gonzalez Teresa , Valenzuela Carmen , Gonzalez Wendy , Decher Niels 
Published: April 2021

Background and PurposeLocal anaesthetics block sodium and a variety of potassium channels. Although previous studies identified a residue in the pore signature sequence together with three residues in the S6 segment as a putative binding site, the precise molecular basis of inhibition of Kv channels by local anaesthetics remained unknown. Crystal structures of Kv channels predict that some of these residues point away from the central cavity and face into a drug binding site called side pockets. Thus, the question arises whether the binding site of local anaesthetics is exclusively located in the central cavity or also involves the side pockets.Experimental ApproachA systematic functional alanine mutagenesis approach, scanning 58 mutants, together with in silico docking experiments and molecular dynamics simulations was utilized to elucidate the binding site of bupivacaine and ropivacaine.Key ResultsInhibition of Kv1.5 channels by local anaesthetics requires binding to the central cavity and the side pockets, and the latter requires interactions with residues of the S5 and the back of the S6 segments. Mutations in the side pockets remove stereoselectivity of inhibition of Kv1.5 channels by bupivacaine. Although binding to the side pockets is conserved for different local anaesthetics, the binding mode in the central cavity and the side pockets shows considerable variations.Conclusion and ImplicationsLocal anaesthetics bind to the central cavity and the side pockets, which provide a crucial key to the molecular understanding of their Kv channel affinity and stereoselectivity, as well as their spectrum of side effects.
Investigation of implant internal screw loosening under hyperbaric conditions: An in vitro study
Authors: Özyurt Anıl 
Published: April 2021

AbstractBackground and purposeThe internal screw has an essential role in carrying abutment and prosthesis loading. Some dental implant patients such as scuba divers, mineworkers, and hyperbaric oxygen patients are exposed to hyperbaric atmospheres. The aim of this study was to investigate internal screw loosening under hyperbaric conditions.Materials and methodsForty‐two dental implants were placed into plexiglass blocks. Abutments were fixed with internal screws by 25 Ncm torque force. Groups were set as control, 2.8‐bar air pressure, and 4‐bar air pressure groups. Hyperbaric groups were subdivided and exposed to either one or six cycles. Removal torque values were measured with a digital torque meter. Data were analyzed statistically using analysis of variance and Tamhane's T2 tests, considering p < 0.05 as the level of statistical significance. Internal screw threads were qualitatively observed under magnification.ResultsFour‐bar groups showed the lowest removal torque values among all groups (p < 0.001). 2.8‐Bar groups did not show significant differences compared with control groups. There was no statistically significant difference between the one and six pressure cycle subgroups in each group. All internal screw threads had various deformations.ConclusionFour‐bar air pressure had a significant effect on internal screw loosening. Internal screw tightening protocols should be reconsidered for patients exposed to advanced hyperbaric conditions.
Study on the effect of different dyeing systems on the interaction of multi‐component reactive dyes by Raman spectroscopy
Authors: Dai Yamin , Xu Hong , Zhong Yi , Zhang Linping , Sui Xiaofeng , Feng Xueling , Wang Bijia , Mao Zhiping 
Published: April 2021

AbstractThe interaction of dye molecules in different adsorption systems is diverse, which affects the adsorption process. In this work, the real‐time adsorption process of CI Reactive Red 195 (RR195), CI Reactive Yellow 145 (RY145), and CI Reactive Blue 194 (RB194) in the actual dyeing process have been studied on cotton fabric by Raman spectroscopy. Three single, three binary, and one ternary system have been investigated at different temperatures (40, 50, 60, and 80°C). The equilibrium dye‐uptake of RR195 and RY145 on cotton fabric decreased with the addition of other components, while that of RB194 remained unchanged. The temperature has little effect on the dyeing of cotton fabric with the RR195/RY145 system. The RR195/RB194 system is more suitable for high‐temperature dyeing. RY145 is less affected by temperature below 60°C while dyeing at 80°C is greatly affected by temperature in the four systems. RB194 with a higher substantivity to the cotton fibre is less affected by temperature in the four systems. The batch adsorption rate data for the seven systems have been analysed based on pseudo‐second‐order kinetics. The results showed that the increase in temperature can accelerate the dyeing rate and time for dye adsorption to reach equilibrium. Activation parameters revealed the potential barrier that dyes need to overcome when dyeing cotton fabrics in different systems. In the actual combination dyeing process, the analysis of each component process can optimise the dye formulation and improve the dye utilisation.
Fire and landscape context shape plant and butterfly diversity in a South African shrubland
Authors: Topp Emmeline N. , Tscharntke Teja , Loos Jacqueline 
Published: April 2021

AbstractAimTo understand effects of fire history and landscape composition on butterfly diversity in a fragmented agricultural landscape.LocationWe studied critically endangered renosterveld remnants within the fynbos biome in the Swartland municipality, Western Cape, South Africa, a global biodiversity hotspot.MethodWe selected survey sites on renosterveld fragments in the agricultural landscape along a gradient of fire history to test the response of biodiversity patterns to fire and landscape composition. We surveyed butterfly species richness, abundance and community composition as well as vegetation structure in five survey rounds on 58 sites between August 2018 and April 2019. We analysed data through linear modelling and multidimensional scaling.ResultsFire was associated with reduced shrub and understorey plant cover and with increased plant species richness. Butterfly species richness was three to four times higher when natural habitat increased in the surrounding landscape (within a 2 km radius), while butterfly abundance was negatively associated with increasing time since fire, with approximately 50% fewer individuals after 9 years. Fire was indirectly associated with increased butterfly species richness and abundance through the alteration of vegetation structure, particularly through removal of shrubs and enhanced plant diversity. Low‐mobility butterfly species were more positively associated with less vegetation cover than were high‐mobility species, which were more associated with sites characterized by long absence of fire.Main conclusionsOur findings suggest that species respond differently to fire, so a diversity of fire frequencies is recommended. Partially burning areas approximately every 10 years may benefit particularly low‐mobility butterfly species through gap creation and fostering plant diversity. Hence, including fire into management activities can benefit butterfly and plant populations alike in critically endangered renosterveld.
Insect predation reduces the abundance of a nidicolous ectoparasite
Authors: Salido Angela , Veiga Jesús , Reyes‐López Joaquín L. , Nieves‐Aldrey Jose L. , Valera Francisco 
Published: April 2021

1. Parasites are one of the main actors in host–parasite interactions. Still, their role as a prey and the related consequences for such interactions and in other respects, such as food webs, are frequently overlooked.2. This paper analyses predation pressure on a ubiquitous avian ectoparasitic fly,Carnus hemapterus, identifies their main natural enemies and quantifies their relative effect on the abundance of the parasite. Also, the effect of nest‐site type on their main enemies' predation pressure was analysed.3. Several ant species were found in the nest boxes of the host species, the European roller (Coracias garrulus), during the breeding season and preyed upon adult and larval stages ofCarnus.4. Ants were also the putative predators of carnid pupae after the breeding season, when significant reduction (on average, by half) in the abundance of carnid pupae occurred in 75% of nest boxes within few months.5. Carnid pupae are also reported here, for the first time, to be parasitised by the parasitoid waspChartocerus conjugalis, whose prevalence was around 21%.6. Nest‐site type had no clear effect on the predation rate of carnid pupae after the breeding season.7. It was concluded that predation is an important factor regulating the abundance of ectoparasites, and thus, it may influence the outcome of host–parasite relationships.
Brain circuit dysfunction in specific symptoms of depression
Authors: Lv Qun Y. , Chen Ming M. , Li Yu , Yu Yang , Liao Hong 
Published: April 2021

AbstractSince the depressive disorder manifests complex and diverse symptoms clinically, its pathological mechanism and therapeutic options are difficult to determine. In recent years, the advent of optogenetics, chemogenetics and viral tracing techniques, along with the well‐established rodent model of depression, has led to a shift in the focus of depression research from single molecules to neural circuits. In virtue of the powerful tools above, psychiatric disorder such as depression could be well related to the disfunction of brain's connection. Moreover, compelling studies also support that the diversity of depressive behaviour could be involved with the discrete changes in a distinct circuit of the brain. Therefore, summarising the differential changes of the neural circuits in mice with depression‐like behaviour may provide a better understanding of the causal relationships between neural circuit and depressive behaviour. Here, we focus on the changes in the neural circuitry underlying various depression‐like phenotypes, including motivation, despair, social avoidance and comorbid sequelae, which may provide an explanation to circuit‐specific discrepancy in depression‐like behaviour.