bluuebunny/crossref_metadata_2025 huggingface dataset:
An entropy-based metric for assessing the purity of single cell populations
Authors: Liu Baolin , Li Chenwei , Li Ziyi , Wang Dongfang , Ren Xianwen , Zhang Zemin
Published: June 2020

Single-cell RNA sequencing (scRNA-seq) is a versatile tool for discovering and annotating cell types and states, but the determination and annotation of cell subtypes is often subjective and arbitrary. Often, it is not even clear whether a given cluster is uniform. Here we present an entropy-based statistic, ROGUE, to accurately quantify the purity of identified cell clusters. We demonstrate that our ROGUE metric is broadly applicable, and enables accurate, sensitive and robust assessment of cluster purity on a wide range of simulated and real datasets. Applying this metric to fibroblast, B cell and brain data, we identify additional subtypes and demonstrate the application of ROGUE-guided analyses to detect precise signals in specific subpopulations. ROGUE can be applied to all tested scRNA-seq datasets, and has important implications for evaluating the quality of putative clusters, discovering pure cell subtypes and constructing comprehensive, detailed and standardized single cell atlas.
Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours
Authors: Fernandes Neto João M. , Nadal Ernest , Bosdriesz Evert , Ooft Salo N. , Farre Lourdes , McLean Chelsea , Klarenbeek Sjoerd , Jurgens Anouk , Hagen Hannes , Wang Liqin , Felip Enriqueta , Martinez-Marti Alex , Vidal August , Voest Emile , Wessels Lodewyk F. A. , van Tellingen Olaf , Villanueva Alberto , Bernards René
Published: June 2020

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibitor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibitor therapy.
Interactome analysis reveals that lncRNA HULC promotes aerobic glycolysis through LDHA and PKM2
Authors: Wang Chunqing , Li Yongmei , Yan Shuai , Wang Hao , Shao Xianfeng , Xiao Mingming , Yang Baicai , Qin Guoxuan , Kong Ruirui , Chen Ruibing , Zhang Ning
Published: June 2020

Interacting with proteins is a crucial way for long noncoding RNAs (lncRNAs) to exert their biological responses. Here we report a high throughput strategy to characterize lncRNA interacting proteins in vivo by combining tobramycin affinity purification and mass spectrometric analysis (TOBAP-MS). Using this method, we identify 140 candidate binding proteins for lncRNA highly upregulated in liver cancer (HULC). Intriguingly, HULC directly binds to two glycolytic enzymes, lactate dehydrogenase A (LDHA) and pyruvate kinase M2 (PKM2). Mechanistic study suggests that HULC functions as an adaptor molecule that enhances the binding of LDHA and PKM2 to fibroblast growth factor receptor type 1 (FGFR1), leading to elevated phosphorylation of these two enzymes and consequently promoting glycolysis. This study provides a convenient method to study lncRNA interactome in vivo and reveals a unique mechanism by which HULC promotes Warburg effect by orchestrating the enzymatic activities of glycolytic enzymes.
Effect of Lagoon and Sea Water Depth on Gracilaria gracilis Growth and Biochemical Composition in the Northeast of Tunisia
Authors: Mensi Fethi , Nasraoui Sarra , Bouguerra Saloua , Ben Ghedifa Aziz , Chalghaf Mohamed
Published: June 2020

This study evaluated the growth and biochemical composition of farming Gracilaria gracilis (Stackhouse) M. Steentoft, L. M. Irvine & W. F. Farnham in the Bizerte Lagoon (BL) and Bizerte Bay (BB) in the North Coast of Tunisia, using lantern nets. Effects of site and depth on alga daily growth rate (DGR) and biochemical composition were investigated. The DGR was affected by culture site (1.42 ± 0.65% day−1 and 1.19 ± 0.34% day−1 for the BL and the BB respectively). Agar yield, was higher (p < 0.05) in the BB than the BL (23.31 ± 2.64% vs. 19.19 ± 2.32%) with a higher (p < 0.05) 3,6-anhydrogalactose (3,6-AG) contents (41.37 ± 3.68% vs 23.30 ± 5.40%) and a lower (p < 0.05) sulphate degree (6 ± 2.00% vs 8.80 ± 0.86%). The proteins contents were independent of the site and depth of culture (20.74 ± 7.22% and 22.02 ± 6.34% for the BL and the BB respectively). R-phycoerythrin (R-PE) contents were significantly higher (p < 0.05) in the BB (0.86 ± 0.31 mg g−1) than those obtained in the BL (0.33 ± 0.12 mg g−1). The salinity, transparency, nitrate and ammonium were monitored in both sites, and their influences were discussed. Our results suggest that G. gracilis cultured in Bizerte Bay can be used in a cascading biorefinery approach.
Aquaponics using a fish farm effluent shifts bacterial communities profile in halophytes rhizosphere and endosphere
Authors: Oliveira Vanessa , Martins Patrícia , Marques Bruna , Cleary Daniel F. R. , Lillebø Ana I. , Calado Ricardo
Published: June 2020

The intensification of marine aquaculture raises multiple sustainability issues, namely the handling of nutrient-rich effluents that can adversely impact ecosystems. As integrated multi-trophic aquaculture (IMTA) gains momentum, the use of halophyte plants to phytoremediate aquaculture effluents has received growing attention, particularly in aquaponics. It is, therefore, important to obtain a more in-depth knowledge of the microbial communities present in the root systems of these plants, both in their natural environment (sediment) and in aquaponics, in order to understand their nutrient removal potential. The present study used denaturing gradient gel electrophoresis (DGGE) and barcoded pyrosequencing to assess the bacterial community present in the endosphere and rhizosphere of three halophyte plants: Halimione portulacoides, Salicornia ramosissima and Sarcocornia perennis. Species-specific effects were recorded in the profile and diversity of the bacterial communities present in halophyte roots, with significant differences also recorded for the same halophyte species grown in contrasting environments (sediment vs. aquaponics). In aquaponics the most abundant groups belonged to the orders Rhodocyclales, Campylobacterales, Rhodobacterales and Desulfobacterales, while in the natural environment (sediment) the most abundant groups belonged to the orders Rhizobiales, Sphingomonadales and Alteromonadales. An overall enrichment in bacterial taxa involved in nutrient cycling was recorded in the roots of halophytes grown in aquaponics (such as Denitromonas, Mesorhizobium, Colwellia, Dokdonella and Arcobacter), thereby highlighting their potential to reduce the nutrient loads from aquaculture effluents.
Adaptive model selection in photonic reservoir computing by reinforcement learning
Authors: Kanno Kazutaka , Naruse Makoto , Uchida Atsushi
Published: June 2020

Photonic reservoir computing is an emergent technology toward beyond-Neumann computing. Although photonic reservoir computing provides superior performance in environments whose characteristics are coincident with the training datasets for the reservoir, the performance is significantly degraded if these characteristics deviate from the original knowledge used in the training phase. Here, we propose a scheme of adaptive model selection in photonic reservoir computing using reinforcement learning. In this scheme, a temporal waveform is generated by different dynamic source models that change over time. The system autonomously identifies the best source model for the task of time series prediction using photonic reservoir computing and reinforcement learning. We prepare two types of output weights for the source models, and the system adaptively selected the correct model using reinforcement learning, where the prediction errors are associated with rewards. We succeed in adaptive model selection when the source signal is temporally mixed, having originally been generated by two different dynamic system models, as well as when the signal is a mixture from the same model but with different parameter values. This study paves the way for autonomous behavior in photonic artificial intelligence and could lead to new applications in load forecasting and multi-objective control, where frequent environment changes are expected.
Potentiation of Antibiotics by a Novel Antimicrobial Peptide against Shiga Toxin Producing E. coli O157:H7
Authors: Puño-Sarmiento Juan , Anderson Erin M. , Park Amber J. , Khursigara Cezar M. , Barnett Foster Debora E.
Published: June 2020

Infection with Shiga toxin-producing Escherichia coli (STEC) results in hemorrhagic colitis and can lead to life-threatening sequelae including hemolytic uremic syndrome (HUS). Conventional treatment is intravenous fluid volume expansion. Antibiotic treatment is contraindicated, due in part to the elevated risk of HUS related to increased Shiga toxin (Stx) release associated with some antibiotics. Given the lack of effective strategies and the increasing number of STEC outbreaks, new treatment approaches are critically needed. In this study, we used an antimicrobial peptide wrwycr, previously shown to enhance STEC killing without increasing Stx production, in combination with antibiotic treatments. Checkerboard and time-kill assays were used to assess peptide wrwycr-antibiotic combinations for synergistic STEC killing. Cytotoxicity and real-time PCR were used to evaluate Stx production and stx expression, respectively, associated with these combinations. The synergistic combinations that showed rapid killing, no growth recovery and minimal Stx production were peptide wrwycr-kanamycin/gentamicin. Transmission electron microscopy revealed striking differences in bacterial cell morphology associated with various treatments. This study provides proof of principle for the design of an antibiotic-peptide wrwycr combination effective in killing STEC without enhancing release of Shiga toxins. It also offers a strategy for the repurposing of antibiotics for treatment of STEC infection.
Risk of sudden cardiac arrest and ventricular arrhythmia with sulfonylureas: An experience with conceptual replication in two independent populations
Authors: Dhopeshwarkar Neil , Brensinger Colleen M. , Bilker Warren B. , Soprano Samantha E. , Flory James H. , Dawwas Ghadeer K. , Gagne Joshua J. , Hennessy Sean , Leonard Charles E.
Published: June 2020

Sulfonylureas are commonly used to treat type 2 diabetes mellitus. Despite awareness of their effects on cardiac physiology, a knowledge gap exists regarding their effects on cardiovascular events in real-world populations. Prior studies reported sulfonylurea-associated cardiovascular death but not serious arrhythmogenic endpoints like sudden cardiac arrest (SCA) or ventricular arrhythmia (VA). We assessed the comparative real-world risk of SCA/VA among users of second-generation sulfonylureas: glimepiride, glyburide, and glipizide. We conducted two incident user cohort studies using five-state Medicaid claims (1999–2012) and Optum Clinformatics commercial claims (2000–2016). Outcomes were SCA/VA events precipitating hospital presentation. We used Cox proportional hazards models, adjusted for high-dimensional propensity scores, to generate adjusted hazard ratios (aHR). We identified 624,406 and 491,940 sulfonylurea users, and 714 and 385 SCA/VA events, in Medicaid and Optum, respectively. Dataset-specific associations with SCA/VA for both glimepiride and glyburide (vs. glipizide) were on opposite sides of and could not exclude the null (glimepiride: aHRMedicaid 1.17, 95% CI 0.96–1.42; aHROptum 0.84, 0.65–1.08; glyburide: aHRMedicaid 0.87, 0.74–1.03; aHROptum 1.11, 0.86–1.42). Database differences in data availability, populations, and documentation completeness may have contributed to the incongruous results. Emphasis should be placed on assessing potential causes of discrepancies between conflicting studies evaluating the same research question.
Wheat growth, applied water use efficiency and flag leaf metabolome under continuous and pulsed deficit irrigation
Authors: Stallmann Jana , Schweiger Rabea , Pons Caroline A. A. , Müller Caroline
Published: June 2020

The intensity and frequency of precipitation events are predicted to change over the coming decades. For many areas, longer periods without rainfall are expected. We investigated the importance of irrigation frequency under water deficit conditions for growth, physiology and chemistry of wheat (Triticum aestivum). Drought-stressed plants received 40% of the water provided for control plants and were either watered every other day (continuous drought, cd) or every eight days (pulsed drought, pd). Maximum quantum yield of photosystem II (Fv/Fm), aboveground biomass, applied water use efficiency (WUEapl) and the flag leaf metabolome were assessed twice during development. Fv/Fmwas not affected by irrigation. Drought-exposed plants produced less biomass, but had higher WUEaplthan control plants. More metabolic features responded to the pd compared to the cd treatment and more features were increased than decreased in pool size in flag leaves. Salicylic acid glucoside was generally decreased under drought. In pd plants, two benzoxazinoid glucosides were enhanced at the first time point and concentrations of several flavonoid glycosides were modulated. This study extends our knowledge about drought effects on wheat; it highlights that the frequency of watering determines how plant growth, physiology and metabolism are affected by drought.
The role of innate immunity in the protection conferred by a bacterial infection against cancer: study of an invertebrate model
Authors: Jacqueline Camille , Parvy Jean-Philippe , Rollin Marie-Lou , Faugère Dominique , Renaud François , Missé Dorothée , Thomas Frédéric , Roche Benjamin
Published: June 2020

All multicellular organisms are exposed to a diversity of infectious agents and to the emergence and proliferation of malignant cells. The protection conferred by some infections against cancer has been recently linked to the production of acquired immunity effectors such as antibodies. However, the evolution of innate immunity as a mechanism to prevent cancer and how it is jeopardized by infections remain poorly investigated. Here, we explored this question by performing experimental infections in two genetically modified invertebrate models (Drosophila melanogaster) that develop invasive or non-invasive neoplastic brain tumors. After quantifying tumor size and antimicrobial peptide gene expression, we found thatDrosophilalarvae infected with a naturally occurring bacterium had smaller tumors compared to controls and to fungus-infected larvae. This was associated with the upregulation of genes encoding two antimicrobial peptides—diptericin and drosomycin—that are known to be important mediators of tumor cell death. We further confirmed that tumor regression upon infection was associated with an increase in tumor cell death. Thus, our study suggests that infection could have a protective role through the production of antimicrobial peptides that increase tumor cell death. Finally, our study highlights the need to understand the role of innate immune effectors in the complex interactions between infections and cancer cell communities in order to develop innovative cancer treatment strategies.
Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors
Authors: Falk-Petersen Christina Birkedahl , Tsonkov Tsonko M. , Nielsen Malene Sofie , Harpsøe Kasper , Bundgaard Christoffer , Frølund Bente , Kristiansen Uffe , Gloriam David E. , Wellendorph Petrine
Published: June 2020

Brain GABAΑ receptors are ionotropic receptors belonging to the class of Cys-loop receptors and are important drug targets for the treatment of anxiety and sleep disorders. By screening a compound library (2,112 compounds) at recombinant human α4β1δ GABAΑ receptors heterologously expressed in a HEK cell line, we identified a scaffold of spirocyclic compounds with nanomolar antagonist activity at GABAΑ receptors. The initial screening hit 2027 (IC50 of 1.03 μM) was used for analogue search resulting in 018 (IC50 of 0.088 μM). 018 was most potent at α3,4,5-subunit containing receptors, thus showing preference for forebrain-expressed extrasynaptic receptors. Schild analysis of 018 at recombinant human α4β1δ receptors and displacement of [3H]muscimol binding in rat cortical homogenate independently confirmed a competitive profile. The antagonist profile of 018 was further validated by whole-cell patch-clamp electrophysiology, where kinetic studies revealed a slow dissociation rate and a shallow hill slope was observed. Membrane permeability studies showed that 2027 and 018 do not cross membranes, thus making the compounds less attractive for studying central GABAΑ receptors effects, but conversely more attractive as tool compounds in relation to emerging peripheral GABAΑ receptor-mediated effects of GABA e.g. in the immune system.
Author Correction: Changes in climate patterns and their association to natural hazard distribution in South Tyrol (Eastern Italian Alps)
Authors: Schlögel Romy , Kofler Christian , Gariano Stefano Luigi , Van Campenhout Jean , Plummer Stephen
Published: June 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
LTP of inhibition at PV interneuron output synapses requires developmental BMP signaling
Authors: Vickers Evan , Osypenko Denys , Clark Christopher , Okur Zeynep , Scheiffele Peter , Schneggenburger Ralf
Published: June 2020

Parvalbumin (PV)-expressing interneurons (PV-INs) mediate well-timed inhibition of cortical principal neurons, and plasticity of these interneurons is involved in map remodeling of primary sensory cortices during critical periods of development. To assess whether bone morphogenetic protein (BMP) signaling contributes to the developmental acquisition of the synapse- and plasticity properties of PV-INs, we investigated conditional/conventional double KO mice of BMP-receptor 1a (BMPR1a; targeted to PV-INs) and 1b (BMPR1a/1b (c)DKO mice). We report that spike-timing dependent LTP at the synapse between PV-INs and principal neurons of layer 4 in the auditory cortex was absent, concomitant with a decreased paired-pulse ratio (PPR). On the other hand, baseline synaptic transmission at this connection, and action potential (AP) firing rates of PV-INs were unchanged. To explore possible gene expression targets of BMP signaling, we measured the mRNA levels of the BDNF receptor TrkB and of P/Q-type Ca2+ channel α-subunits, but did not detect expression changes of the corresponding genes in PV-INs of BMPR1a/1b (c)DKO mice. Our study suggests that BMP-signaling in PV-INs during and shortly after the critical period is necessary for the expression of LTP at PV-IN output synapses, involving gene expression programs that need to be addressed in future work.
Expansion, Exploitation and Extinction: Niche Construction in Ephemeral Landscapes
Authors: Wetherington Miles T. , Keymer Juan E.
Published: June 2020

We aim to understand general consequences of niche construction on metapopulation dynamics in ephemeral landscapes. To this effect, a contact process-like stochastic spatial model is introduced where local populations colonize and go extinct on a dynamic landscape of habitable and destroyed patches. In contrast to previous models, where the extinction threshold is a consequence of available niche rendered by global rates of patch destruction/renewal, here we investigate how the metapopulation persists when they are the sole generators of their own niche. Niche construction is full-filled by localized populations through the transformation of destroyed patches in their neighborhood to viable habitat for future colonization. With this theoretical framework we are able to address the dual nature of niche construction by investigating the ephemerality of the landscape (destruction rate) and the continuum of population level strategies, where construction comes at a cost to colonization. Using mean field theory and Monte Carlo simulations of the model, we are able to quantify optimal population level strategies in a wide range of ephemeral landscapes. Interestingly, we observe qualitative differences at the extinction threshold between analytic and numeric results. Investigating this discrepancy further, we find that increasing niche construction neighborhood in the spatial model leads to two interrelated effects i) an increased rate in range expansion ii) a loss in resiliency and return of the discontinuous transition at the extinction threshold. Furthermore, in the discontinuous regime of the model, spatial clustering prior to a critical transition disappears. This is a significant finding as spatial clustering has been considered to be an early warning signal before ecosystems reach their ‘tipping point’. In addition to maintaining stability, we find local niche construction strategies have an advantage when in scramble competition with an exploiter strategy because of their ability to monopolize the constructed niche due to spatial adjacency. As the niche construction neighborhood expands this advantage disappears and the exploiter strategy out-competes the niche constructor. In some cases the exploiter pushes the niche constructor to extinction, thus a tragedy of the commons ensues leading to ‘ecological suicide’ and a collapse of the niche.
Age, Sex and Overall Health, Measured As Frailty, Modify Myofilament Proteins in Hearts From Naturally Aging Mice
Authors: Kane Alice E. , Bisset Elise S. , Keller Kaitlyn M. , Ghimire Anjali , Pyle W. Glen , Howlett Susan E.
Published: June 2020

We investigated effects of age, sex and frailty on contractions, calcium transients and myofilament proteins to determine if maladaptive changes associated with aging were sex-specific and modified by frailty. Ventricular myocytes and myofilaments were isolated from middle-aged (~12 mos) and older (~24 mos) mice. Frailty was assessed with a non-invasive frailty index. Calcium transients declined and slowed with age in both sexes, but contractions were largely unaffected. Actomyosin Mg-ATPase activity increased with age in females but not males; this could maintain contractions with smaller calcium transients in females. Phosphorylation of myosin-binding protein C (MyBP-C), desmin, tropomyosin and myosin light chain-1 (MLC-1) increased with age in males, but only MyBP-C and troponin-T increased in females. Enhanced phosphorylation of MyBP-C and MLC-1 could preserve contractions in aging. Interestingly, the age-related decline in Hill coefficients (r = −0.816; p = 0.002) and increase in phosphorylation of desmin (r = 0.735; p = 0.010), tropomyosin (r = 0.779; p = 0.005) and MLC-1 (r = 0.817; p = 0.022) were graded by the level of frailty in males but not females. In these ways, cardiac remodeling at cellular and subcellular levels is graded by overall health in aging males. Such changes may contribute to heart diseases in frail older males, whereas females may be resistant to these effects of frailty.
A 2,000–year-old specimen with intraerythrocytic Bartonella quintana
Authors: Barbieri R. , Mai B.-H.-A. , Chenal T. , Bassi M-L. , Gandia D. , Camoin-Jau L. , Lepidi H. , Aboudharam G. , Drancourt M.
Published: June 2020

Photogrammetry and cascading microscopy investigations of dental pulp specimens collected from 2,000-year-old individuals buried in a Roman necropolis in Besançon, France, revealed unprecedented preserved tissular and cellular morphology. Photogrammetry yielded 3-D images of the smallest archaeological human remains ever recovered. Optical microscopy examinations after standard haematoxylin-phloxine-saffron staining and anti-glycophorin A immunohistochemistry exposed dental pulp cells, in addition erythrocytes were visualised by electron microscopy, which indicated the ancient dental pulp trapped a blood drop. Fluorescence in situ hybridisation applied on red blood cells revealed the louse-borne pathogen Bartonella quintana, a finding confirmed by polymerase chain reaction assays. Through paleohistology and paleocytology, we demonstrate that the ancient dental pulp preserved intact blood cells at the time of the individual’s death, offering an unprecedented opportunity to engage in direct and indirect tests to diagnose pathogens in ancient buried individuals.
Association between Serum Uric Acid and Nonalcoholic Fatty Liver Disease in Nonobese Postmenopausal Women: A Cross-sectional Study
Authors: Bao Ting , Ying Zhiye , Gong Li , Du Jing , Ji Guiyi , Li Zhengzheng , Gao Wei , Jiang Xianweng , Yang Hanwei , Huang Yan , Tang Huairong
Published: June 2020

This study aimed to determine the association between serum uric acid (sUA) and nonalcoholic fatty liver disease (NAFLD) in nonobese postmenopausal women. A total of 4323 female individuals over 18 years of age participated in this cross-sectional study. The subjects were divided into four groups according to menopause status and body mass index. sUA quartiles in this female population were categorized as follows: Q1 ≤ 230 mmol/L, Q2: 231–270 mmol/L, Q3: 271–310 mmol/L and Q4: ≥ 311 mmol/L. The presence or absence of NAFLD was assessed by abdominal ultrasonography. The prevalence of NAFLD was 38.8% in the general population, and the average age was 46.5 ± 11.3 years. Among nonobese and obese subjects, the prevalence of NAFLD was lower in nonmenopausal subjects than in postmenopausal subjects (nonobese: 20.74% vs 45.26%, respectively, P < 0.0001; obese: 70.51% vs 84.35%, respectively, P < 0.0001). After adjusting for age, current smoking status, current alcohol drinking status, diabetes, hypertension disease and triglyceride, the ORs (95% CIs) for NAFLD among individuals in Q2-Q4 were 1.518 (1.062–2.169), 1.431 (1.010–2.027) and 2.054 (1.442–2.927), respectively, P value for trend <0.0001. Higher sUA levels can be used as a predictive biomarker for NAFLD in nonobese postmenopausal women.
Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy
Authors: Dominguez-Gonzalez Cristina , Badosa Carmen , Madruga-Garrido Marcos , Martí Itxaso , Paradas Carmen , Ortez Carlos , Diaz-Manera Jordi , Berardo Andres , Alonso-Pérez Jorge , Trifunov Selena , Cuadras Daniel , Kalko Susana G. , Blázquez-Bermejo Cora , Cámara Yolanda , Martí Ramon , Mavillard Fabiola , Martin Miguel A. , Montoya Julio , Ruiz-Pesini Eduardo , Villarroya Joan , Montero Raquel , Villarroya Francesc , Artuch Rafael , Hirano Michio , Nascimento Andrés , Jimenez-Mallebrera Cecilia
Published: June 2020

GDF-15 is a biomarker for mitochondrial diseases. We investigated the application of GDF-15 as biomarker of disease severity and response to deoxynucleoside treatment in patients with thymidine kinase 2 (TK2) deficiency and compared it to FGF-21. GDF-15 and FGF-21 were measured in serum from 24 patients with TK2 deficiency treated 1–49 months with oral deoxynucleosides. Patients were grouped according to age at treatment and biomarkers were analyzed at baseline and various time points after treatment initiation. GDF-15 was elevated on average 30-fold in children and 6-fold in adults before the start of treatment. There was a significant correlation between basal GDF-15 and severity based on pretreatment distance walked (6MWT) and weight (BMI). During treatment, GDF-15 significantly declined, and the decrease was accompanied by relevant clinical improvements. The decline was greater in the paediatric group, which included the most severe patients and showed the greatest clinical benefit, than in the adult patients. The decline of FGF-21 was less prominent and consistent. GDF-15 is a potential biomarker of severity and of therapeutic response for patients with TK2 deficiency. In addition, we show evidence of clinical benefit of deoxynucleoside treatment, especially when treatment is initiated at an early age.
Resilience of cactus pear genotypes in a tropical semi-arid region subject to climatic cultivation restriction
Authors: Edvan Ricardo Loiola , Mota Rute Ribeiro Marins , Dias-Silva Tairon Pannunzio , do Nascimento Romilda Rodrigues , de Sousa Sheila Vilarindo , da Silva Alex Lopes , Araújo Marcos Jácome de , Araújo Jucilene Silva
Published: June 2020

The cactus pear has demonstrated productive potential in arid and semi-arid regions due to its photosynthetic process of crassulacean acid metabolism. Thus, this study aimed to evaluate agronomic characteristics and chemical composition of three genotypes of cactus pear at different locations of a tropical semiarid region classified as non-suitable for cactus pear cultivation. A completely randomized design in a factorial arrangement (3 × 7) (three genotypes of cactus pear [Miúda, Baiana (Nopalea cochenillifera) and Orelha de Efefante Mexicana - OEM (Opuntia stricta)] and seven locations) was used. The climatic conditions characterized an environment that restricts the growth of cactus pear genotypes, mainly due to the air relative humidity values. All morphological characteristics of the cactus pear genotypes were influenced by the interaction genotype x location, with higher expression of the characteristics on the different genotypes under hot semi-arid climate and tropical wet and dry climate. An effect of the interaction genotype x location was observed (p < 0.05) on water use efficiency, water accumulation and carrying capacity, where the highest values were observed for genotype Baiana at location 1. Also, there was influence of the interaction genotype x location over the chemical composition of the cactus pear. The cultivation of cactus pear is recommended under restricted climatic conditions in semi-arid tropical regions, especially the genotype Baiana, based on growth factors, biomass production and chemical composition.
Albumin-neprilysin fusion protein: understanding stability using small angle X-ray scattering and molecular dynamic simulations
Authors: Kulakova Alina , Indrakumar Sowmya , Sønderby Tuelung Pernille , Mahapatra Sujata , Streicher Werner W. , Peters Günther H. J. , Harris Pernille
Published: June 2020

Fusion technology is widely used in protein-drug development to increase activity, stability, and bioavailability of protein therapeutics. Fusion proteins, like any other type of biopharmaceuticals, need to remain stable during production and storage. Due to the high complexity and additional intramolecular interactions, it is not possible to predict the behavior of fusion proteins based on the behavior the individual proteins. Therefore, understanding the stability of fusion proteins on the molecular level is crucial for the development of biopharmaceuticals. The current study on the albumin-neprilysin (HSA-NEP) fusion protein uses a combination of thermal and chemical unfolding with small angle X-ray scattering and molecular dynamics simulations to show a correlation between decreasing stability and increasing repulsive interactions, which is unusual for most biopharmaceuticals. It is also seen that HSA-NEP is not fully flexible: it is present in both compact and extended conformations. Additionally, the volume fraction of each conformation changes with pH. Finally, the presence of NaCl and arginine increases stability at pH 6.5, but decreases stability at pH 5.0.
Generation of intense and coherent sub-femtosecond X-ray pulses in electron storage rings
Authors: Hwang J.-G. , Schiwietz G. , Abo-Bakr M. , Atkinson T. , Ries M. , Goslawski P. , Klemz G. , Müller R. , Schälicke A. , Jankowiak A.
Published: June 2020

Temporally short X-ray pulses are an indispensable tool for the study of electron transitions close to the Fermi energy and structural changes in molecules undergoing chemical reactions which take place on a time-scale of hundreds of femtoseconds. The time resolution of experiments at 3rdgeneration light sources which produce intense synchrotron radiation is limited fundamentally by the electron-bunch length in the range of tens of picoseconds. Here we propose a new scheme for the generation of intense and coherent sub-femtoseconds soft X-ray pulses in storage rings by applying the Echo-Enabled Harmonic Generation (EEHG) method. Many issues for obtaining the EEHG structure such as two modulators and a radiator are solved by a paradigm shift in an achromatic storage ring cell. Numerical demonstration of the feasibility of the scheme for the BESSY II beam parameters is presented.
Novel EGFP reporter cell and mouse models for sensitive imaging and quantification of exon skipping
Authors: Hara Yuko , Mizobe Yoshitaka , Inoue Yukiko U. , Hashimoto Yasumasa , Motohashi Norio , Masaki Yoshiaki , Seio Kohji , Takeda Shin’ichi , Nagata Tetsuya , Wood Matthew J. A. , Inoue Takayoshi , Aoki Yoshitsugu
Published: June 2020

Duchenne muscular dystrophy (DMD) is a fatal X-linked disorder caused by nonsense or frameshift mutations in the DMD gene. Among various treatments available for DMD, antisense oligonucleotides (ASOs) mediated exon skipping is a promising therapeutic approach. For successful treatments, however, it is requisite to rigorously optimise oligonucleotide chemistries as well as chemical modifications of ASOs. To achieve this, here, we aim to develop a novel enhanced green fluorescence protein (EGFP)-based reporter assay system that allows us to perform efficient and high-throughput screenings for ASOs. We design a new expression vector with a CAG promoter to detect the EGFP fluorescence only when skipping of mdx-type exon 23 is induced by ASOs. Then, an accurate screening was successfully conducted in C57BL/6 primary myotubes using phosphorodiamidate morpholino oligomer or locked nucleic acids (LNA)/2′-OMe mixmers with different extent of LNA inclusion. We accordingly generated a novel transgenic mouse model with this EGFP expression vector (EGFP-mdx23 Tg). Finally, we confirmed that the EGFP-mdx23 Tg provided a highly sensitive platform to check the effectiveness as well as the biodistribution of ASOs for exon skipping therapy. Thus, the assay system provides a simple yet highly sensitive platform to optimise oligonucleotide chemistries as well as chemical modifications of ASOs.
Phosphorylation of the Anaphase Promoting Complex activator FZR1/CDH1 is required for Meiosis II entry in mouse male germ cell
Authors: Tanno Nobuhiro , Kuninaka Shinji , Fujimura Sayoko , Takemoto Kazumasa , Okamura Kaho , Takeda Naoki , Araki Kimi , Araki Masatake , Saya Hideyuki , Ishiguro Kei-ichiro
Published: June 2020

FZR1/CDH1 is an activator of Anaphase promoting complex/Cyclosome (APC/C), best known for its role as E3 ubiquitin ligase that drives the cell cycle. APC/C activity is regulated by CDK-mediated phosphorylation of FZR1 during mitotic cell cycle. Although the critical role of FZR1 phosphorylation has been shown mainly in yeast and in vitro cell culture studies, its biological significance in mammalian tissues in vivo remained elusive. Here, we examined the in vivo role of FZR1 phosphorylation using a mouse model, in which non-phosphorylatable substitutions were introduced in the putative CDK-phosphorylation sites of FZR1. Although ablation of FZR1 phosphorylation did not show substantial consequences in mouse somatic tissues, it led to severe testicular defects resulting in male infertility. In the absence of FZR1 phosphorylation, male juvenile germ cells entered meiosis normally but failed to enter meiosis II or form differentiated spermatids. In aged testis, male mutant germ cells were overall abolished, showing Sertoli cell-only phenotype. In contrast, female mutants showed apparently normal progression of meiosis. The present study demonstrated that phosphorylation of FZR1 is required for temporal regulation of APC/C activity at meiosis II entry, and for maintenance of spermatogonia, which raised an insight into the sexual dimorphism of FZR1-regulation in germ cells.
Difference in Presence and Number of CD83+ Dendritic Cells in Patients with Ulcerative Colitis and Crohn’s Disease
Authors: Despalatović Bruna Rošić , Babić Marija , Bratanić Andre , Tonkić Ante , Vilović Katarina
Published: June 2020

Different pathophysiological models provide insight into the important role of CD83+ dendritic cells (DCs) in the pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC). There were 154 subjects included in this study: 60 with UC, 19 with CD and 75 in the control group. Colonic biopsy was performed in all subjects. Specimens were incubated with a primary anti-CD83 antibody. Intraepithelial DCs per 100 enterocytes were counted. The results were analysed according to demographic data, type of IBD and histological inflammation pattern. The odds ratio for CD83+ DCs=0 in the UC group was 3.4 times higher than that in the control group (OR = 3.4; 95% CI: 1.63–7.14; p = 0.001), and the odds ratio for CD83+ DCs ≥1 in the CD group was 5.3 times higher than that in the UC group (OR = 5.3; 95% CI: 1.4–20.2; p = 0.014). The odds ratio for CD83+ DCs=0 in the acute inflammation group was 2.7 times higher than that in the group without inflammation (OR = 2.7; 95% CI: 1.2–5.9; p = 0.011). In the group of patients with CD and acute inflammation (n = 11), there was only one subject without CD83+ DCs (p = 0,024). These results suggest an association of CD83+ DCs with the type of IBD and the histological inflammation pattern.
The presence of dominant follicles and corpora lutea does not perturb response to controlled ovarian stimulation in random start protocols
Authors: Filippi Francesca , Somigliana Edgardo , Busnelli Andrea , Guarneri Cristina , Noli Stefania , Restelli Liliana , Vercellini Paolo
Published: June 2020

The advent of random start protocols to shorten the time needed to store oocytes in women with malignancies has represented an important improvement in the field of fertility preservation. However, Randomized Controlled Trials are difficult to implement in this area and available evidence that supports this approach remains modest. To shed more light on this issue, we compared the follicular development between the ovary carrying the dominant follicle or the corpus luteum and the contralateral resting ovary in 90 women who underwent random start controlled ovarian stimulation (COS). In fact, ovarian response did not differ between the two ovaries. Subgroup analyses according to the phase of the cycle at the initiation of COS, the type of malignancy, the use of letrozole and the magnitude of the ovarian response did not allow to identify any condition showing a difference in the follicular response between the active and the resting ovaries. In conclusion, follicular growth does not seem to be perturbed by the presence of a dominant follicle or a corpus luteum.
Traditional versus blended CPR training program: A randomized controlled non-inferiority study
Authors: Chien Cheng-Yu , Fang Shao-Yu , Tsai Li-Heng , Tsai Shang-Li , Chen Chen-Bin , Seak Chen-June , Weng Yi-Ming , Lin Chi-Chun , Chien Wei-Che , Huang Chien-Hsiung , Lin Cheng-Yu , Chaou Chung-Hsien , Liu Peng-Huei , Tseng Hsiao-Jung , Chen Jih-Chang , Peng Shu-Yuan , Cheng Tsung-Hsuan , Hsu Kuang-Hung , Ng Chip-Jin
Published: June 2020

Cardiopulmonary resuscitation (CPR) training and its quality are critical in improving the survival rate of cardiac arrest. This randomized controlled study investigated the efficacy of a newly developed CPR training program for the public in a Taiwanese setting. A total of 832 adults were randomized to either a traditional or blended (18-minute e-learning plus 30-minute hands-on) compression-only CPR training program. The primary outcome was compression depth. Secondary outcomes included CPR knowledge test, practical test, quality of CPR performance, and skill retention. The mean compression depth was 5.21 cm and 5.24 cm in the blended and traditional groups, respectively. The mean difference in compression depth between groups was −0.04 (95% confidence interval −0.13 to infinity), demonstrating that the blended CPR training program was non-inferior to the traditional CPR training program in compression depth after initial training. Secondary outcome results were comparable between groups. Although the mean compression depth and rate were guideline-compliant, only half of the compressions were delivered with adequate depth and rate in both groups. CPR knowledge and skill retained similarly in both groups at 6 and 12 months after training. The blended CPR training program was non-inferior to the traditional CPR training program. However, there is still room for improvement in optimizing initial skill performance as well as skill retention. Clinical Trial Registration: NCT03586752; www.clinicaltrial.gov
Clinicopathological analysis of T2-FLAIR mismatch sign in lower-grade gliomas
Authors: Deguchi Shoichi , Oishi Takuma , Mitsuya Koichi , Kakuda Yuko , Endo Masahiro , Sugino Takashi , Hayashi Nakamasa
Published: June 2020

T2-FLAIR mismatch sign is known as a highly specific imaging marker of IDH-mutant astrocytomas. This study was intended to clarify what the T2-FLAIR mismatch sign represents by pathological analysis of lower-grade gliomas rediagnosed in accordance with the WHO 2016 classification. We retrospectively analyzed the records of 64 patients diagnosed with WHO grade II and III diffuse gliomas between June 2009 and November 2018. T2-FLAIR mismatch sign was found in 10 (45%) out of 22 patients with IDH-mutant astrocytoma, 1 (5%) out of 20 with oligodendroglioma, and 1 (5%) out of 22 with IDH-wild-type astrocytoma. T2-FLAIR mismatch sign as a marker of IDH-mutant astrocytomas showed positive predictive value of 83%. Among 22 patients with IDH-mutant astrocytomas, microcystic change was found in eight, of which seven showed T2-FLAIR mismatch sign. Microcystic change was significantly associated with T2-FLAIR mismatch sign (P < 0.01). From multi-sampling in a patient, abundant microcysts were observed upon HE staining of specimens from the T2-FLAIR mismatched region, while microcysts were hardly observed from the T2-FLAIR matched one. All three protoplasmic astrocytomas among our IDH-mutant astrocytomas presented T2-FLAIR mismatch sign. In conclusion, T2-FLAIR mismatch sign may reflect microcyst formation in IDH-mutant astrocytomas and be common in IDH-mutant protoplasmic astrocytoma.
Author Correction: Metabolic GWAS of elite athletes reveals novel genetically-influenced metabolites associated with athletic performance
Authors: Al-Khelaifi Fatima , Diboun Ilhame , Donati Francesco , Botrè Francesco , Abraham David , Hingorani Aroon , Albagha Omar , Georgakopoulos Costas , Suhre Karsten , Yousri Noha A. , Elrayess Mohamed A.
Published: June 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Author Correction: Artificial Intelligence based Models for Screening of Hematologic Malignancies using Cell Population Data
Authors: Syed-Abdul Shabbir , Firdani Rianda-Putra , Chung Hee-Jung , Uddin Mohy , Hur Mina , Park Jae Hyeon , Kim Hyung Woo , Gradišek Anton , Dovgan Erik
Published: June 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher Correction: A systematic review of the caries prevalence among children living in Chernobyl fallout countries
Authors: Wolgin Michael , Filina Nicole , Shakavets Natalia , Dvornyk Valentyn , Lynch Edward , Kielbassa Andrej M.
Published: June 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher Correction: Occurrence and genetic diversity of CRESS DNA viruses in wild birds: a Hungarian study
Authors: Kaszab Eszter , Lengyel György , Marton Szilvia , Dán Ádám , Bányai Krisztián , Fehér Enikő
Published: June 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Gas hydrates in sustainable chemistry
Authors: Hassanpouryouzband Aliakbar , Joonaki Edris , Vasheghani Farahani Mehrdad , Takeya Satoshi , Ruppel Carolyn , Yang Jinhai , English Niall J. , Schicks Judith M. , Edlmann Katriona , Mehrabian Hadi , Aman Zachary M. , Tohidi Bahman
Published: June 2020

This review includes the current state of the art understanding and advances in technical developments about various fields of gas hydrates, which are combined with expert perspectives and analyses.
Aldol sensor-inspired fluorescent probes for measuring protein citrullination
Authors: Chen Huihong , Zhao Hailong , Xiang Lingling , Wu Haiting , Liang Yunshi , Huang Xin-An , Zhang Jing
Published: June 2020

Inspired by aldol sensors, a novel series of fluorescent probes were developed for measuring and capturing protein citrullination.
Metabolite collision cross section prediction without energy-minimized structures
Authors: Soper-Hopper M. T. , Vandegrift J. , Baker E. S. , Fernández F. M.
Published: June 2020

Matching experimental ion mobility-mass spectrometry data to computationally-generated collision cross section (CCS) values enables more confident metabolite identifications.
Gold nanoparticle-streptavidin conjugates for rapid and efficient screening of aptamer function in lateral flow sensors using novel CD4-binding aptamers identified through Crossover-SELEX
Authors: Fellows Tamika , Ho Lance , Flanagan Shane , Fogel Ronen , Ojo Dupe , Limson Janice
Published: June 2020

Adaptation of conventional lateral flow tests: demonstration of a lateral flow assay in which gold nanoparticle conjugates, when bound to aptamers, serve as a reporting system to screen novel aptamers for the ability to bind to target proteins.
Rapid and selective detection of recombinant human erythropoietin in human blood plasma by a sensitive optical sensor
Authors: Gholami Mahnaz D. , Theiss Frederick , Sonar Prashant , Ayoko Godwin A. , Izake Emad L.
Published: June 2020

Recombinant human erythropoietin (rHuEPO) is an important hormone drug that is used to treat several medical conditions.
Biosilica layer-by-layer modified with polyamines and carboxyarsenazo for REE preconcentration prior to ICP-MS determination in lignites and volcanic fumarole sediment
Authors: Buyko Olga V. , Metelitsa Sergey I. , Losev Vladimir N. , Panasenko Alexander E. , Shimanskii Aleksandr F.
Published: June 2020

Biosilica-based adsorbents prepared from rice husk, sequentially modified with polymeric polyamines and carboxyarsenazo were proposed for the preconcentration of 13 lanthanides, La, Sc, and Y. It is shown that the proposed adsorbent quantitatively extracted rare earth elements (REEs) from solutions with pH 3.5–6.5.
Nanomaterial based drug delivery systems for the treatment of neurodegenerative diseases
Authors: Masoudi Asil Shima , Ahlawat Jyoti , Guillama Barroso Gileydis , Narayan Mahesh
Published: June 2020

The recent advances in applications of nanotechnology including the use of inorganic, polymeric, magnetic and carbon nanomaterials in drug delivery for treatment of neurodegenerative diseases are reported.
Trichromatic-emission and dual-ratio semiconducting polymer dots as fluorescent probe for simultaneous quantification of Cu2+and pHin vitroandin vivo
Authors: Zhang Qiang , Sun Junyong , Zhang Rongchao , Chen Xueli , Chen Ningning , Gao Feng
Published: June 2020

Polymer dots emitting in the red, green and blue color regions, have been successfully applied as lysosome-targeting nanoprobes for the simultaneous detection and multicolor imaging of pH and Cu2+in HeLa cells and zebrafish.
Reactivity descriptors in acid catalysis: acid strength, proton affinity and host–guest interactions
Authors: Deshlahra Prashant , Iglesia Enrique
Published: June 2020

Acid strength and proton affinity, the independent properties of catalysts and molecules, are incomplete descriptors of because cations and conjugate anions reorganize their charges as they interact as bound intermediates and transition states.