bluuebunny/crossref_metadata_2025 huggingface dataset:
Resolution of the paradox of the diamagnetic effect on the Kibble coil
Authors: Li Shisong , Schlamminger Stephan , Marangoni Rafael , Wang Qing , Haddad Darine , Seifert Frank , Chao Leon , Newell David , Zhao Wei
Published: January 2021

Employing very simple electro-mechanical principles known from classical physics, the Kibble balance establishes a very precise and absolute link between quantum electrical standards and macroscopic mass or force measurements. The success of the Kibble balance, in both determining fundamental constants (h,$$N_A$$NA,e) and realizing a quasi-quantum mass in the 2019 newly revised International System of Units, relies on the perfection of Maxwell’s equations and the symmetry they describe between Lorentz’s force and Faraday’s induction, a principle and a symmetry stunningly demonstrated in the weighing and velocity modes of Kibble balances to within$$1\times 10^{-8}$$1×10-8, with nothing but imperfect wires and magnets. However, recent advances in the understanding of the current effect in Kibble balances reveal a troubling paradox. A diamagnetic effect, a force that does not cancel between mass-on and mass-off measurement, is challenging balance maker’s assumptions of symmetry at levels that are almost two orders of magnitude larger than the reported uncertainties. The diamagnetic effect, if it exists, shows up in weighing mode without a readily apparent reciprocal effect in the velocity mode, begging questions about systematic errors at the very foundation of the new measurement system. The hypothetical force is caused by the coil current changing the magnetic field, producing an unaccounted force that is systematically modulated with the weighing current. Here we show that this diamagnetic force exists, but the additional force does not change the equivalence between weighing and velocity measurements. We reveal the unexpected way that symmetry is preserved and show that for typical materials and geometries the total relative effect on the measurement is$$\approx 1\times 10^{-9}$$≈1×10-9.
Age-group determination of living individuals using first molar images based on artificial intelligence
Authors: Kim Seunghyeon , Lee Yeon-Hee , Noh Yung-Kyun , Park Frank C. , Auh Q.-Schick
Published: January 2021

Dental age estimation of living individuals is difficult and challenging, and there is no consensus method in adults with permanent dentition. Thus, we aimed to provide an accurate and robust artificial intelligence (AI)-based diagnostic system for age-group estimation by incorporating a convolutional neural network (CNN) using dental X-ray image patches of the first molars extracted via panoramic radiography. The data set consisted of four first molar images from the right and left sides of the maxilla and mandible of each of 1586 individuals across all age groups, which were extracted from their panoramic radiographs. The accuracy of the tooth-wise estimation was 89.05 to 90.27%. Performance accuracy was evaluated mainly using a majority voting system and area under curve (AUC) scores. The AUC scores ranged from 0.94 to 0.98 for all age groups, which indicates outstanding capacity. The learned features of CNNs were visualized as a heatmap, and revealed that CNNs focus on differentiated anatomical parameters, including tooth pulp, alveolar bone level, or interdental space, depending on the age and location of the tooth. With this, we provided a deeper understanding of the most informative regions distinguished by age groups. The prediction accuracy and heat map analyses support that this AI-based age-group determination model is plausible and useful.
Alligator presence influences colony site selection of long-legged wading birds through large scale facilitative nest protector relationship
Authors: Gabel Wray , Frederick Peter , Zabala Jabi
Published: January 2021

Positive ecological relationships, such as facilitation, are an important force in community organization. The effects of facilitative relationships can be strong enough to cause changes in the distributions of species and in many cases have evolved as a response to predation pressure, however, very little is known about this potential trend in vertebrate facilitative relationships. Predation is an important selective pressure that may strongly influence breeding site selection by nesting birds. The American Alligator (Alligator mississippiensis) facilitates a safer nesting location for wading birds (Ciconiiformes and Pelecaniformes) by deterring mammalian nest predators from breeding sites. However, alligators do not occur throughout the breeding range of most wading birds, and it is unclear whether alligator presence affects colony site selection. We predicted that nesting wading birds change colony site preferences when alligators are not present to serve as nest protectors. Within the northern fringe of alligator distribution we compared colony characteristics in locations where alligator presence was either likely or unlikely while controlling for availability of habitat. Wading birds preferred islands that were farther from the mainland and farther from landmasses > 5 ha when alligator presence was unlikely compared to when alligators were likely. These findings indicate that wading birds are seeking nesting locations that are less accessible to mammalian predators when alligators are not present, and that this requirement is relaxed when alligators are present. This study illustrates how a landscape-scale difference between realized and fundamental niche can result from a facilitative relationship in vertebrates.
The predictive value of TIMP-2 and IGFBP7 for kidney failure and 30-day mortality after elective cardiac surgery
Authors: Esmeijer Kevin , Schoe Abraham , Ruhaak L. Renee , Hoogeveen Ellen K. , Soonawala Darius , Romijn Fred P. H. T. M. , Shirzada Maryam R. , van Dissel Jaap T. , Cobbaert Christa M. , de Fijter Johan W.
Published: January 2021

Acute kidney injury (AKI) is an important risk factor for chronic kidney disease, renal replacement therapy (RRT), and mortality. However, predicting AKI with currently available markers remains problematic. We assessed the predictive value of urinary tissue inhibitor of metalloprotease-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) regarding the need for RRT, and 30-day mortality, in elective cardiac surgery patients. In 344 elective cardiac surgery patients, we measured urinary TIMP-2 and IGFBP7 and serum creatinine at baseline and directly after surgery. Discrimination of both urinary biomarkers was assessed by the C-statistic. Model improvement for each biomarker when added to a basic model containing serum creatinine and duration of surgery was tested by the net-reclassification index (cf-NRI) and integrated discrimination index (IDI). At baseline, mean age was 66 years and 67% were men. Of all patients, 22 required RRT following surgery. IGFBP7 pre- and post-surgery and change in TIMP-2 during surgery predicted RRT with a C-statistic of about 0.80. However, a simple model including baseline serum creatinine and duration of surgery had a C-statistic of 0.92, which was improved to 0.93 upon addition of post-surgery TIMP-2 or IGFBP7, with statistically significant cf-NRIs but non-significant IDIs. Post-surgery TIMP-2 and IGFBP predicted 30-day mortality, with C-statistics of 0.74 and 0.80. In conclusion, in elective cardiac surgery patients, pre- and peri-operative clinical variables were highly discriminating about which patients required RRT after surgery. Nonetheless, in elective cardiac surgery patients, urinary TIMP-2 and IGFBP7 improved prediction of RRT and 30-day mortality post-surgery.
Pro-inflammatory cytokine polymorphisms and interactions with dietary alcohol and estrogen, risk factors for invasive breast cancer using a post genome-wide analysis for gene–gene and gene–lifestyle interaction
Authors: Jung Su Yon , Papp Jeanette C. , Sobel Eric M. , Pellegrini Matteo , Yu Herbert , Zhang Zuo-Feng
Published: January 2021

Molecular and genetic immune-related pathways connected to breast cancer and lifestyles in postmenopausal women are not fully characterized. In this study, we explored the role of pro-inflammatory cytokines such as C-reactive protein (CRP) and interleukin-6 (IL-6) in those pathways at the genome-wide level. With single-nucleotide polymorphisms (SNPs) in the biomarkers and lifestyles together, we further constructed risk profiles to improve predictability for breast cancer. Our earlier genome-wide association gene-environment interaction study used large cohort data from the Women’s Health Initiative Database for Genotypes and Phenotypes Study and identified 88 SNPs associated with CRP and IL-6. For this study, we added an additional 68 SNPs from previous GWA studies, and together with 48 selected lifestyles, evaluated for the association with breast cancer risk via a 2-stage multimodal random survival forest and generalized multifactor dimensionality reduction methods. Overall and in obesity strata (by body mass index, waist, waist-to-hip ratio, exercise, and dietary fat intake), we identified the most predictive genetic and lifestyle variables. Two SNPs (SALL1 rs10521222 and HLA-DQA1 rs9271608) and lifestyles, including alcohol intake, lifetime cumulative exposure to estrogen, and overall and visceral obesity, are the most common and strongest predictive markers for breast cancer across the analyses. The risk profile that combined those variables presented their synergistic effect on the increased breast cancer risk in a gene–lifestyle dose-dependent manner. Our study may contribute to improved predictability for breast cancer and suggest potential interventions for the women with the risk genotypes and lifestyles to reduce their breast cancer risk.
Emerging risk of Dirofilaria spp. infection in Northeastern Europe: high prevalence of Dirofilaria repens in sled dog kennels from the Baltic countries
Authors: Alsarraf Mustafa , Levytska Viktoria , Mierzejewska Ewa J. , Poliukhovych Vasyl , Rodo Anna , Alsarraf Mohammed , Kavalevich Dziyana , Dwużnik-Szarek Dorota , Behnke Jerzy M. , Bajer Anna
Published: January 2021

Dirofilariasis is a fast-spreading disease of dogs and humans in Europe. We investigated whether Dirofilaria spp. have spread northwards in Europe, invading the Baltic countries. Altogether, 424 blood samples were collected from eight countries in the period 2017–2019, including 227 samples from sled dogs and 197 samples from other dogs. PCR amplification and sequencing were conducted employing three genetic markers (mitochondrial [mt] 12S rDNA, mt cytochrome c oxidase subunit I [COI] gene and mt dehydrogenase subunit I [NAD1] gene). The SNAP test (IDEXX) for detection of D. immitis infections was also implemented. The DNA of D. repens was detected in 59 of 424 dogs (prevalence 13.9%). D. repens was found in sled dogs from Lithuania, Latvia, Poland and Belarus. Only one dog from Estonia was infected, apparently an imported case. The highest prevalence was recorded in Lithuania (38%). Among pet dogs from the Ukraine, six dogs tested positive (3.8%). Our study has revealed a high prevalence of D. repens infections in Lithuania and Latvia, but no evidence for spread of the heartworm D. immitis. We conclude that sled dog kennels constitute hot spots for D. repens transmission.
Evaluation of Acanthamoeba keratitis cases in a tertiary medical care centre over 21 years
Authors: List Wolfgang , Glatz Wilfried , Riedl Regina , Mossboeck Georg , Steinwender Gernot , Wedrich Andreas
Published: January 2021

To report on Acanthamoeba keratitis cases in a tertiary university eye-hospital in Graz, Austria, over a 21-year period. Retrospective study. Parameters included demographics, diagnostics, clinical courses, medical therapies, surgical interventions, secondary complications, and best spectacle-corrected visual acuity (BSCVA). Patient records for 44 eyes of 42 patients were analysed; 2 bilateral infections. Mean age at presentation was 31 ± 13 (16–65) years; contact lenses were used in 41 of 44 eyes (93.2%). Symptoms at initial presentation were mainly pain (41/43, 95.3%) and photophobia (16/43, 37.2%). Most frequent morphological findings were stromal infiltrates (30/44, 68.2%). Diagnosis was mainly confirmed by smears (40/42, 95.2%) and polymerase chain reaction (8/42, 19%). Antiamoebic treatment comprised biguanides and diamidines. Penetrating keratoplasty was performed in 10/44 (22.7%) eyes. Median time from symptom onset to initial visit was 2 (0–26) weeks; median follow-up was 30 (2–1008) weeks. BSCVA improved in 23/36 (63.9%) eyes, remained unchanged in 6/36 (16.7%) eyes and deteriorated in 7/36 (19.4%) eyes. Acanthamoeba keratitis predominantly occurs in young contact lens wearers. Diagnosis should be considered in patients with pain and stromal infiltrates. In the majority of cases, BSCVA can be improved. Early diagnosis and adequate treatment should be implemented to prevent complications.
NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization
Authors: Šašinková Markéta , Heřman Petr , Holoubek Aleš , Strachotová Dita , Otevřelová Petra , Grebeňová Dana , Kuželová Kateřina , Brodská Barbora
Published: January 2021

Nucleophosmin (NPM) mutations causing its export from the nucleoli to the cytoplasm are frequent in acute myeloid leukemia (AML). Due to heterooligomerization of wild type NPM with the AML-related mutant, the wild-type becomes misplaced from the nucleoli and its functions are significantly altered. Dissociation of NPM heterooligomers may thus restore the proper localization and function of wild-type NPM. NSC348884 is supposed to act as a potent inhibitor of NPM oligomerization. The effect of NSC348884 on the NPM oligomerization was thoroughly examined by fluorescence lifetime imaging with utilization of FRET and by a set of immunoprecipitation and electrophoretic methods. Leukemia-derived cell lines and primary AML cells as well as cells transfected with fluorescently labeled NPM forms were investigated. Our results clearly demonstrate that NSC348884 does not inhibit formation of NPM oligomers neither in vivo nor in vitro. Instead, we document that NSC348884 cytotoxicity is rather associated with modified cell adhesion signaling. The cytotoxic mechanism of NSC348884 has therefore to be reconsidered.
Kernel-based formulation of intervening opportunities for spatial interaction modelling
Authors: Kotsubo Masaki , Nakaya Tomoki
Published: January 2021

Understanding spatial interactions such as human mobility has been one of the main analytical themes in geography, spatial economics, and traffic engineering for a long time. The intervening opportunities models, including the radiation model, provide a framework to elucidate spatial interactions generated by an individual’s distance-ordered decision-making process. However, such classical definitions of intervening opportunities have often failed to predict realistic flow volumes, particularly for short-distance flows. To overcome this problem, we have proposed a new formulation of intervening opportunities with a kernel function to introduce a fuzziness in spatial search behaviours of destinations, to develop a new variant of the radiation model. The mobility patterns resulting from the modified radiation model that included kernel-based intervening opportunities outperformed the original radiation model when fitted to four datasets of inter-regional flows.
Impact of long-term antiretroviral therapy on gut and oral microbiotas in HIV-1-infected patients
Authors: Imahashi Mayumi , Ode Hirotaka , Kobayashi Ayumi , Nemoto Michiko , Matsuda Masakazu , Hashiba Chieko , Hamano Akiko , Nakata Yoshihiro , Mori Mikiko , Seko Kento , Nakahata Masashi , Kogure Ayumi , Tanaka Yasuhito , Sugiura Wataru , Yokomaku Yoshiyuki , Iwatani Yasumasa
Published: January 2021

In HIV-1-infected patients, antiretroviral therapy (ART) is a key factor that may impact commensal microbiota and cause the emergence of side effects. However, it is not fully understood how long-term ART regimens have diverse impacts on the microbial compositions over time. Here, we performed 16S ribosomal RNA gene sequencing of the fecal and salivary microbiomes in patients under different long-term ART. We found that ART, especially conventional nucleotide/nucleoside reverse transcriptase inhibitor (NRTI)-based ART, has remarkable impacts on fecal microbial diversity: decreased α-diversity and increased ß-diversity over time. In contrast, dynamic diversity changes in the salivary microbiome were not observed. Comparative analysis of bacterial genus compositions showed a propensity for Prevotella-enriched and Bacteroides-poor gut microbiotas in patients with ART over time. In addition, we observed a gradual reduction in Bacteroides but drastic increases in Succinivibrio and/or Megasphaera under conventional ART. These results suggest that ART, especially NRTI-based ART, has more suppressive impacts on microbiota composition and diversity in the gut than in the mouth, which potentially causes intestinal dysbiosis in patients. Therefore, NRTI-sparing ART, especially integrase strand transfer inhibitor (INSTI)- and/or non-nucleotide reverse transcriptase inhibitor (NNRTI)-containing regimens, might alleviate the burden of intestinal dysbiosis in HIV-1-infected patients under long-term ART.
Comparative transcriptomic analysis for identification of candidate sex-related genes and pathways in Crimson seabream (Parargyrops edita)
Authors: Shan Binbin , Liu Yan , Yang Changping , Zhao Yu , Sun Dianrong
Published: January 2021

Teleost fishes display the largest array of sex-determining systems among animals, resulting in various reproductive strategies. Research on sex-related genes in teleosts will broaden our understanding of the process, and provide important insight into the plasticity of the sex determination process in vertebrates in general. Crimson seabream (Parargyrops edita Tanaka, 1916) is one of the most valuable and abundant fish resources throughout Asia. However, little genomic information on P. edita is available. In the present study, the transcriptomes of male and female P. edita were sequenced with RNA-seq technology. A total of 388,683,472 reads were generated from the libraries. After filtering and assembling, a total of 79,775 non redundant unigenes were obtained with an N50 of 2,921 bp. The unigenes were annotated with multiple public databases, including NT (53,556, 67.13%), NR (54,092, 67.81%), Swiss-Prot (45,265, 56.74%), KOG (41,274, 51.74%), KEGG (46,302, 58.04%), and GO (11,056, 13.86%) databases. Comparison of the unigenes of different sexes of P. edita revealed that 11,676 unigenes (9,335 in females, 2,341 in males) were differentially expressed between males and females. Of these, 5,463 were specifically expressed in females, and 1,134 were specifically expressed in males. In addition, the expression levels of ten unigenes were confirmed to validate the transcriptomic data by qRT-PCR. Moreover, 34,473 simple sequence repeats (SSRs) were identified in SSR-containing sequences, and 50 loci were randomly selected for primer development. Of these, 36 loci were successfully amplified, and 19 loci were polymorphic. Finally, our comparative analysis identified many sex-related genes (zps, amh, gsdf, sox4, cyp19a, etc.) and pathways (MAPK signaling pathway, p53 signaling pathway, etc.) of P. edita. This informative transcriptomic analysis provides valuable data to increase genomic resources of P. edita. The results will be useful for clarifying the molecular mechanism of sex determination and for future functional analyses of sex-associated genes.
A randomized clinical trial on the effect of a lidocaine patch on shoulder pain relief in laparoscopic cholecystectomy
Authors: Kim Ha Yeon , Choi Jong Bum , Min Sang Kee , Chang Min Ying , Lim Gang Mee , Kim Ji Eun
Published: January 2021

The incidence of laparoscopy-related shoulder pain reaches 90% in women. We evaluated the effect of lidocaine patch 5% on the shoulder pain after laparoscopic cholecystectomy (LC) in female patients. Total 63 female patients were randomly allocated to patch group (n = 31) and control group (n = 32). Patch group received lidocaine patch 5% and dressing retention tape on both shoulder, and control group received only dressing retention tape. Abdominal and shoulder pains were evaluated with rating on numeric rating scale (0 = no pain and 10 = the worst pain) at baseline and at 30 min, 6 h, 24 h, and 48 h after surgery. There were no significant differences in patient characteristics and operation details. The overall incidence of shoulder pain was significantly lower in patch group than in control group (42% vs. 78%, P = 0.005). The severity of shoulder pain also was significantly reduced in patch group compared to control group at 24 h and 48 h after surgery (P = 0.01 and P = 0.015, respectively). Complications related to lidocaine patch were not found except nausea. Lidocaine patch 5% reduced the incidence and severity of postoperative shoulder pain in female patients undergoing LC without complications.
Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide
Authors: Santamaria Salvatore , Cuffaro Doretta , Nuti Elisa , Ciccone Lidia , Tuccinardi Tiziano , Liva Francesca , D’Andrea Felicia , de Groot Rens , Rossello Armando , Ahnström Josefin
Published: January 2021

ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors.
De novo transcriptomic analysis and identification of EST-SSR markers in Stephanandra incisa
Authors: Zhang Cuiping , Wu Zhonglan , Jiang Xinqiang , Li Wei , Lu Yizeng , Wang Kuiling
Published: January 2021

Stephanandra incisa is a wild-type shrub with beautiful leaves and white flowers and is commonly used as a garden decoration accessory. However, the limited availability of genomic data of S. incisa has restricted its breeding process. Here, we identified EST-SSR markers using de novo transcriptome sequencing. In this study, a transcriptome database containing 35,251 unigenes, having an average length of 985 bp, was obtained from S. incisa. From these unigene sequences, we identified 5,555 EST-SSRs, with a distribution density of one SSR per 1.60 kb. Dinucleotides (52.96%) were the most detected SSRs, followed by trinucleotides (34.64%). From the EST-SSR loci, we randomly selected 100 sites for designing primer and used the DNA of 60 samples to verify the polymorphism. The average value of the effective number of alleles (Ne), Shannon’s information index (I), and expective heterozygosity (He) was 1.969, 0.728, and 0.434, respectively. The polymorphism information content (PIC) value was in the range of 0.108 to 0.669, averaging 0.406, which represented a middle polymorphism level. Cluster analysis of S. incisa were also performed based on the obtained EST-SSR data in our work. As shown by structure analysis, 60 individuals could be classified into two groups. Thus, the identification of these novel EST-SSR markers provided valuable sequence information for analyzing the population structure, genetic diversity, and genetic resource assessment of S. incisa and other related species.
Multi-critical topological transition at quantum criticality
Authors: Kumar Ranjith R. , Kartik Y. R. , Rahul S. , Sarkar Sujit
Published: January 2021

The investigation and characterization of topological quantum phase transition between gapless phases is one of the recent interest of research in topological states of matter. We consider transverse field Ising model with three spin interaction in one dimension and observe a topological transition between gapless phases on one of the critical lines of this model. We study the distinct nature of these gapless phases and show that they belong to different universality classes. The topological invariant number (winding number) characterize different topological phases for the different regime of parameter space. We observe the evidence of two multi-critical points, one is topologically trivial and the other one is topologically active. Topological quantum phase transition between the gapless phases on the critical line occurs through the non-trivial multi-critical point in the Lifshitz universality class. We calculate and analyze the behavior of Wannier state correlation function close to the multi-critical point and confirm the topological transition between gapless phases. We show the breakdown of Lorentz invariance at this multi-critical point through the energy dispersion analysis. We also show that the scaling theories and curvature function renormalization group can also be effectively used to understand the topological quantum phase transitions between gapless phases. The model Hamiltonian which we study is more applicable for the system with gapless excitations, where the conventional concept of topological quantum phase transition fails.
Regulation of trehalase activity by multi-site phosphorylation and 14-3-3 interaction
Authors: Dengler Lisa , Örd Mihkel , Schwab Lucca M. , Loog Mart , Ewald Jennifer C.
Published: January 2021

Protein phosphorylation enables a rapid adjustment of cellular activities to diverse intracellular and environmental stimuli. Many phosphoproteins are targeted on more than one site, which allows the integration of multiple signals and the implementation of complex responses. However, the hierarchy and interplay between multiple phospho-sites are often unknown. Here, we study multi‐site phosphorylation using the yeast trehalase Nth1 and its activator, the 14-3-3 protein Bmh1, as a model. Nth1 is known to be phosphorylated by the metabolic kinase PKA on four serine residues and by the cell cycle kinase CDK on one residue. However, how these five phospho-sites adjust Nth1 activity remains unclear. Using a novel reporter construct, we investigated the contribution of the individual sites for the regulation of the trehalase and its 14-3-3 interactor. In contrast to the constitutively phosphorylated S20 and S83, the weaker sites S21 and S60 are only phosphorylated by increased PKA activity. For binding Bmh1, S83 functions as the high‐affinity “gatekeeper” site, but successful binding of the Bmh1 dimer and thus Nth1 activation requires S60 as a secondary site. Under nutrient-poor conditions with low PKA activity, S60 is not efficiently phosphorylated and the cell cycle dependent phosphorylation of S66 by Cdk1 contributes to Nth1 activity, likely by providing an alternative Bmh1 binding site. Additionally, the PKA sites S20 and S21 modulate the dephosphorylation of Nth1 on downstream Bmh1 sites. In summary, our results expand our molecular understanding of Nth1 regulation and provide a new aspect of the interaction of 14-3-3 proteins with their targets.
The mammalian efferent vestibular system utilizes cholinergic mechanisms to excite primary vestibular afferents
Authors: Schneider Glenn T. , Lee Choongheon , Sinha Anjali K. , Jordan Paivi M. , Holt Joseph C.
Published: January 2021

Electrical stimulation of the mammalian efferent vestibular system (EVS) predominantly excites primary vestibular afferents along two distinct time scales. Although roles for acetylcholine (ACh) have been demonstrated in other vertebrates, synaptic mechanisms underlying mammalian EVS actions are not well-characterized. To determine if activation of ACh receptors account for efferent-mediated afferent excitation in mammals, we recorded afferent activity from the superior vestibular nerve of anesthetized C57BL/6 mice while stimulating EVS neurons in the brainstem, before and after administration of cholinergic antagonists. Using a normalized coefficient of variation (CV*), we broadly classified vestibular afferents as regularly- (CV* < 0.1) or irregularly-discharging (CV* > 0.1) and characterized their responses to midline or ipsilateral EVS stimulation. Afferent responses to efferent stimulation were predominantly excitatory, grew in amplitude with increasing CV*, and consisted of fast and slow components that could be identified by differences in rise time and post-stimulus duration. Both efferent-mediated excitatory components were larger in irregular afferents with ipsilateral EVS stimulation. Our pharmacological data show, for the first time in mammals, that muscarinic AChR antagonists block efferent-mediated slow excitation whereas the nicotinic AChR antagonist DHβE selectively blocks efferent-mediated fast excitation, while leaving the efferent-mediated slow component intact. These data confirm that mammalian EVS actions are predominantly cholinergic.
Transcriptional analysis reveals key insights into seasonal induced anthocyanin degradation and leaf color transition in purple tea (Camellia sinensis (L.) O. Kuntze)
Authors: Maritim Tony Kipkoech , Masand Mamta , Seth Romit , Sharma Ram Kumar
Published: January 2021

Purple-tea, an anthocyanin rich cultivar has recently gained popularity due to its health benefits and captivating leaf appearance. However, the sustainability of purple pigmentation and anthocyanin content during production period is hampered by seasonal variation. To understand seasonal dependent anthocyanin pigmentation in purple tea, global transcriptional and anthocyanin profiling was carried out in tea shoots with two leaves and a bud harvested during in early (reddish purple: S1_RP), main (dark gray purple: S2_GP) and backend flush (moderately olive green: S3_G) seasons. Of the three seasons, maximum accumulation of total anthocyanin content was recorded in S2_GP, while least amount was recorded during S3_G. Reference based transcriptome assembly of 412 million quality reads resulted into 71,349 non-redundant transcripts with 6081 significant differentially expressed genes. Interestingly, key DEGs involved in anthocyanin biosynthesis [PAL, 4CL, F3H, DFR and UGT/UFGT], vacuolar trafficking [ABC, MATE and GST] transcriptional regulation [MYB, NAC, bHLH, WRKY and HMG] and Abscisic acid signaling pathway [PYL and PP2C] were significantly upregulated in S2_GP. Conversely, DEGs associated with anthocyanin degradation [Prx and lac], repressor TFs and key components of auxin and ethylene signaling pathways [ARF, AUX/IAA/SAUR, ETR, ERF, EBF1/2] exhibited significant upregulation in S3_G, correlating positively with reduced anthocyanin content and purple coloration. The present study for the first-time elucidated genome-wide transcriptional insights and hypothesized the involvement of anthocyanin biosynthesis activators/repressor and anthocyanin degrading genes via peroxidases and laccases during seasonal induced leaf color transition in purple tea. Futuristically, key candidate gene(s) identified here can be used for genetic engineering and molecular breeding of seasonal independent anthocyanin-rich tea cultivars.
Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine
Authors: Saravanan Pasupathy , Dusthackeer V. N. Azger , Rajmani R. S. , Mahizhaveni B. , Nirmal Christy R. , Rajadas Sam Ebenezer , Bhardwaj Neerupma , Ponnuraja C. , Bhaskar Adhin , Hemanthkumar A. K. , Ramachandran Geetha , Tripathy Srikanth P.
Published: January 2021

Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). The present work reports the design and synthesis of a hybrid of the precursors of rifampicin and clofazimine, which led to the discovery of a novel Rifaphenazine (RPZ) molecule with potent anti-TB activity. In addition, the efficacy of RPZ was evaluated in-vitro using the reference strain Mtb H37Rv. Herein, 2,3 diamino phenazine, a precursor of an anti-TB drug clofazimine, was tethered to the rifampicin core. This 2,3 diamino phenazine did not have an inherent anti-TB activity even at a concentration of up to 2 µg/mL, while rifampicin did not exhibit any activity against Mtb at a concentration of 0.1 µg/mL. However, the synthesized novel Rifaphenzine (RPZ) inhibited 78% of the Mtb colonies at a drug concentration of 0.1 µg/mL, while 93% of the bacterial colonies were killed at 0.5 µg/mL of the drug. Furthermore, the Minimum Inhibitory Concentration (MIC) value for RPZ was 1 µg/mL. Time-kill studies revealed that all bacterial colonies were killed within a period of 24 h. The synthesized novel molecule was characterized using high-resolution mass spectroscopy and NMR spectroscopy. Cytotoxicity studies (IC50) were performed on human monocytic cell line THP-1, and the determined IC50 value was 96 µg/mL, which is non-cytotoxic.
Performance simulation of polymer-based nanoparticle and void dispersed photonic structures for radiative cooling
Authors: Bijarniya Jay Prakash , Sarkar Jahar , Maiti Pralay
Published: January 2021

Passive radiative cooling is an emerging field and needs further development of material. Hence, the computational approach needs to establish for effective metamaterial design before fabrication. The finite difference time domain (FDTD) method is a promising numerical strategy to study electromagnetic interaction with the material. Here, we simulate using the FDTD method and report the behavior of various nanoparticles (SiO2, TiO2, Si3N4) and void dispersed polymers for the solar and thermal infrared spectrums. We propose the algorithm to simulate the surface emissive properties of various material nanostructures in both solar and thermal infrared spectrums, followed by cooling performance estimation. It is indeed found out that staggered and randomly distributed nanoparticle reflects efficiently in the solar radiation spectrum, become highly reflective for thin slab and emits efficiently in the atmospheric window (8–13 µm) over the parallel arrangement with slight variation. Higher slab thickness and concentration yield better reflectivity in the solar spectrum. SiO2-nanopores in a polymer, Si3N4 and TiO2 with/without voids in polymer efficiently achieve above 97% reflection in the solar spectrum and exhibits substrate independent radiative cooling properties. SiO2 and polymer combination alone is unable to reflect as desired in the solar spectrum and need a highly reflective substrate like silver.
Drug related problems in clinical practice: a cross-sectional study on their prevalence, risk factors and associated pharmaceutical interventions
Authors: Garin Noe , Sole Nuria , Lucas Beatriz , Matas Laia , Moras Desiree , Rodrigo-Troyano Ana , Gras-Martin Laura , Fonts Nuria
Published: January 2021

Drug-related problems (DRP) cause preventable negative health outcomes, especially during hospital admissions. The aim of our study was to examine the prevalence and characteristics of DRP in regular clinical pharmacy, as well as to determine those factors associated with a higher risk of DRP in the hospital setting. We analyzed data from a standardized registry database of regular pharmacy practice (2015- 2016). DRP were classified according to the Pharmaceutical Care Network Europe v6.2 classification. Cross-sectional data were obtained from 1602 adults admitted to medical wards. Crude and adjusted binary logistic regressions were performed to identify associations between potential risk factors and DRP. Overall DRP prevalence was high across medical specialties (45,1%), in a population characterized by advanced age, polypharmacy and multimorbidity. Problems leading to DRP were mainly classified into two domains (effectiveness and adverse reactions), being drug and dose selection the most frequent causes. Interventions were accepted and DRP were totally or partially solved in 74.1% and 4.81% of cases, respectively. In the adjusted model polypharmacy, allergies, BMI > 25 kg/m2 and clearance < 30 mL/min were associated with a higher risk of DRP. The participation of clinical pharmacists into multidisciplinary teams promotes the detection and solution of DRP. Polypharmacy, obesity, renal impairment and allergy are associated with a higher risk of DRP during admission.
Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery
Authors: Chang Lyra , Campbell James , Raji Idris O. , Guduru Shiva K. R. , Kandel Prasanna , Nguyen Michelle , Liu Steven , Tran Kevin , Venugopal Navneet K. , Taylor Bethany C. , Holt Matthew V. , Young Nicolas L. , Samuel Errol L. G. , Jain Prashi , Santini Conrad , Sankaran Banumathi , MacKenzie Kevin R. , Young Damian W.
Published: January 2021

Despite the established roles of the epigenetic factor UHRF1 in oncogenesis, no UHRF1-targeting therapeutics have been reported to date. In this study, we use fragment-based ligand discovery to identify novel scaffolds for targeting the isolated UHRF1 tandem Tudor domain (TTD), which recognizes the heterochromatin-associated histone mark H3K9me3 and supports intramolecular contacts with other regions of UHRF1. Using both binding-based and function-based screens of a ~ 2300-fragment library in parallel, we identified 2,4-lutidine as a hit for follow-up NMR and X-ray crystallography studies. Unlike previous reported ligands, 2,4-lutidine binds to two binding pockets that are in close proximity on TTD and so has the potential to be evolved into more potent inhibitors using a fragment-linking strategy. Our study provides a useful starting point for developing potent chemical probes against UHRF1.
Investigating real-life emotions in romantic couples: a mobile EEG study
Authors: Packheiser Julian , Berretz Gesa , Rook Noemi , Bahr Celine , Schockenhoff Lynn , Güntürkün Onur , Ocklenburg Sebastian
Published: January 2021

The neural basis of emotional processing has been largely investigated in constrained spatial environments such as stationary EEGs or fMRI scanners using highly artificial stimuli like standardized pictures depicting emotional scenes. Typically, such standardized experiments have low ecological validity and it remains unclear whether their results reflect neuronal processing in real-life affective situations at all. Critically, emotional situations do not only encompass the perception of emotions, but also behavioral components associated with them. In this study, we aimed to investigate real-life emotions by recording couples in their homes using mobile EEG technology during embracing, kissing and emotional speech. We focused on asymmetries in affective processing as emotions have been demonstrated to be strongly lateralized in the brain. We found higher alpha and beta power asymmetry during kissing and embracing on frontal electrodes during emotional kisses and speech compared to a neutral control condition indicative of stronger left-hemispheric activation. In contrast, we found lower alpha power asymmetry at parieto-occipital electrode sites in the emotional compared to the neutral condition indicative of stronger right-hemispheric activation. Our findings for alpha power asymmetries are in line with models of emotional lateralization that postulate a valence-specific processing over frontal cortices and right-hemispheric dominance in emotional processing in parieto-occipital regions. In contrast, beta power asymmetries pointed more towards valence-specific processing indicating that, while alpha and beta frequencies seem to be functionally associated, they are not reflecting identical cognitive processing.
Treatment pathways and disease journeys differ before and after introduction of novel agents in newly diagnosed multiple myeloma in Taiwan
Authors: Liu Yanfang , Tang Chao-Hsiun , Qiu Hong , Siggins Sarah , Hou Hsin-An
Published: January 2021

Limited real-world data are available regarding treatment practices and outcomes of multiple myeloma (MM) in Asia. We conducted a retrospective cohort study using the Taiwan National Healthcare Insurance Research database and Taiwan Death Registry and used a Markov model to describe disease progression and outcomes in 4092 patients newly diagnosed with MM from 01-Jan-2007 to 31-Dec-2015. We observed marked differences in the characteristics, length and outcome of the clinical journey between patients who did/did not receive autologous stem cell transplant, and between patients initiated on novel agents versus other treatment regimens. In transplant recipients, initiation with combined thalidomide + bortezomib increased over time (12.2–77.5%). Progression-free survival after first-line treatment improved and a lower percentage of patients died. Lenalidomide in second and third-line regimens increased (15.5–31.5%). In non-transplanted patients, initiation with novel agents increased (17.5–54.6%), but death rates remained high (60.3%). The treatment landscape of MM in Taiwan has evolved, with increased use of combined bortezomib + thalidomide for first-line and lenalidomide for second/third-line but many patients die before receiving second-line treatment. Novel agents with different modes of action should be used as early as possible to maximize their benefits. Improved MM treatments remains a critical medical need.
LEDs driven by AC without transformers or rectifiers
Authors: Hughes Robin W. , Warner Mark
Published: January 2021

We explore the driving of LEDs by untransformed AC. An extreme case is driving 1.9 V threshold (red) LEDs with UK mains, peak voltage 325 V. Commonly, driving is by transformed, rectified (DC) supply with a series resistor (where a significant fraction of the power is wasted) to limit current in the LED. With AC, one can instead reactively limit to a maximum current safe for an LED by employing a series capacitive impedance. Cheaper and simpler supplies can thus be employed in some cases. We analyse such non-linear circuits, and also explore questions of duty cycle and power experimentally.
Alterations in B cell subsets correlate with body composition parameters in female adolescents with anorexia nervosa
Authors: Freff Jana , Schwarte Kathrin , Bröker Lisa , Bühlmeier Judith , Kraft Isabelle , Öztürk Dana , Hinney Anke , Arolt Volker , Dannlowski Udo , Romer Georg , Baune Bernhard T. , Hebebrand Johannes , Föcker Manuel , Alferink Judith
Published: January 2021

Anorexia nervosa (AN) is a severe eating disorder and often associated with altered humoral immune responses. However, distinct B cell maturation stages in peripheral blood in adolescents with AN have not been characterized. Treatment effects and the relationship between clinical and B cell parameters are also not fully understood. Here we investigated the phenotype of circulating B cell subsets and the relationship with body composition in adolescents with AN before (T0, n = 24) and after 6 weeks (T1, n = 20) of treatment. Using multi-parameter flow cytometry, we found increased percentages of antigen-experienced B cells and plasmablasts in patients with AN compared to healthy controls (n = 20). In contrast, percentages of CD1d+CD5+ B cells and transitional B cells with immunoregulatory roles were reduced at T0 and T1. These B cell frequencies correlated positively with fat mass, fat mass index (FMI), free fat mass index, and body mass index standard deviation score. In addition, scavenger-like receptor CD5 expression levels were downregulated on transitional B cells and correlated with fat mass and FMI in AN. Our findings that regulatory B cell subgroups were reduced in AN and their strong relationship with body composition parameters point toward an impact of immunoregulatory B cells in the pathogenesis of AN.
MicroRNA-494-3p inhibits formation of fast oxidative muscle fibres by targeting E1A-binding protein p300 in human-induced pluripotent stem cells
Authors: Iwasaki Hirotaka , Ichihara Yoshinori , Morino Katsutaro , Lemecha Mengistu , Sugawara Lucia , Sawano Tatsuya , Miake Junichiro , Sakurai Hidetoshi , Nishi Eiichiro , Maegawa Hiroshi , Imamura Takeshi
Published: January 2021

MYOD-induced microRNA-494-3p expression inhibits fast oxidative myotube formation by downregulating myosin heavy chain 2 (MYH2) in human induced pluripotent stem cells (hiPSCs) during skeletal myogenesis. However, the molecular mechanisms regulating MYH2 expression via miR-494-3p remain unknown. Here, using bioinformatic analyses, we show that miR-494-3p potentially targets the transcript of the E1A-binding protein p300 at its 3′-untranslated region (UTR). Myogenesis in hiPSCs with the Tet/ON-myogenic differentiation 1 (MYOD1) gene (MyoD-hiPSCs) was induced by culturing them in doxycycline-supplemented differentiation medium for 7 days. p300 protein expression decreased after transient induction of miR-494-3p during myogenesis. miR-494-3p mimics decreased the levels of p300 and its downstream targets MYOD and MYH2 and myotube formation efficiency. p300 knockdown decreased myotube formation efficiency, MYH2 expression, and basal oxygen consumption rate. The binding of miR-494-3p to the wild type p300 3′-UTR, but not the mutated site, was confirmed using luciferase assay. Overexpression of p300 rescued the miR-494-3p mimic-induced phenotype in MyoD-hiPSCs. Moreover, miR-494-3p mimic reduced the levels of p300, MYOD, and MYH2 in skeletal muscles in mice. Thus, miR-494-3p might modulate MYH2 expression and fast oxidative myotube formation by directly regulating p300 levels during skeletal myogenesis in MyoD-hiPSCs and murine skeletal muscle tissues.
Cone-beam CT image quality improvement using Cycle-Deblur consistent adversarial networks (Cycle-Deblur GAN) for chest CT imaging in breast cancer patients
Authors: Tien Hui-Ju , Yang Hsin-Chih , Shueng Pei-Wei , Chen Jyh-Cheng
Published: January 2021

Cone-beam computed tomography (CBCT) integrated with a linear accelerator is widely used to increase the accuracy of radiotherapy and plays an important role in image-guided radiotherapy (IGRT). For comparison with fan-beam computed tomography (FBCT), the image quality of CBCT is indistinct due to X-ray scattering, noise, and artefacts. We proposed a deep learning model, “Cycle-Deblur GAN”, combined with CycleGAN and Deblur-GAN models to improve the image quality of chest CBCT images. The 8706 CBCT and FBCT image pairs were used for training, and 1150 image pairs were used for testing in deep learning. The generated CBCT images from the Cycle-Deblur GAN model demonstrated closer CT values to FBCT in the lung, breast, mediastinum, and sternum compared to the CycleGAN and RED-CNN models. The quantitative evaluations of MAE, PSNR, and SSIM for CBCT generated from the Cycle-Deblur GAN model demonstrated better results than the CycleGAN and RED-CNN models. The Cycle-Deblur GAN model improved image quality and CT-value accuracy and preserved structural details for chest CBCT images.